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The Future Outlook of Antimalarial Drugs and Recent Work on the Treatment of Malaria
Archives of Medical Research 33 (2002) 416–421
BRIEF REPORT
The Future Outlook of Antimalarial Drugs and Recent Work on the Treatment of Malaria Polrat Wilairatana, Srivicha Krudsood, Sombat Treeprasertsuk, Kobsiri Chalermrut and Sornchai Looareesuwan Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Received for publication December 6, 2001; accepted December 6, 2001 (01/218).
Background. With the emergence of multidrug-resistant falciparum malaria, new drugs and drugs in combination are urgently needed. Methods. New antimalarial drugs investigated at the Hospital for Tropical Diseases of the Faculty of Tropical Medicine at Mahidol University in Bangkok, Thailand in recent years for treatment of uncomplicated and severe falciparum malaria are as follows: atovaquone, and artemisinin derivatives (artesunate, artemether, arteether, and dihydroartemisinin) combined with other antimalarials. Results. Malarone®, artemisinin derivatives combined with lumefantrine or doxycycline, and mefloquine combined with tetracycline or doxycycline have been evaluated with improvement of the cure rate in uncomplicated malaria. Artemisinin derivatives intravenously or intrarectally combined with mefloquine may be alternatives to intravenous quinine for treatment of severe malaria. Conclusions. In Thailand, drug treatment for uncomplicated malaria consists of the combinations or artesunate plus mefloquine or artemether plus lumefantrine or quinine plus tetracycline. In treatment of severe malaria, antimalarial drugs of choice are intravenous quinine or artemisinin derivatives. © 2002 IMSS. Published by Elsevier Science Inc. Key Words: Future, Outlook, Antimalarials, Thailand.
Drug Resistance Antimalarial drug resistance emerges when malaria parasites with amplifications or mutations conferring reduced drug susceptibility are selected by antimalarial drug concentrations that provide differential inhibition to distinct genetic parasite types, i.e., the parasite population encounters drug concentrations sufficient to reduce or eradicate the susceptible parasite population but that inhibit or do not inhibit multiplication of the mutants (1). Antimalarial drug resistance usually ensues from either changes in drug accumulation or efflux (chloroquine, amodiaquine, quinine, mefloquine, halofantrine resistance), which leads to reduced
Address reprint requests to: Polrat Wilairatana, Ph.D., Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, 420/ 6 Rajvithi Road, Rajthevi, Bangkok, 10400, Thailand. Tel.: (66) (2) 2483183; FAXES: (66) (2) 245-7288 and 247-1957; E-mail: dirctm@ mucc.mahidol.ac.th
intraparasitic concentrations of the drug, or reduced affinity of the drug target for the particular drug resulting from point mutations in the respective genes encoding the target (pyrimethamine, cycloguanil, sulfonamide, atovaqone resistance) (2,3). Other mechanisms of drug resistance found in bacteria such as transferable resistance genes, production of drug-destroying enzymes, or activation of accessory metabolic pathways do not appear involved in antimalarial resistance. To overcome this problem, the use of drug combinations has been suggested (4). Preventing Antimalarial Drug Resistance Resistance can be prevented or at least delayed. Malaria must be treated adequately and selective pressures minimized. Currently recommended methodology for assessing drug resistance in high transmission areas ignores lowgrade resistance, yet this is the stage at which preventive measures are most effective. Experimentally, drug resistance
0188-4409/02 $–see front matter. Copyright © 2002 IMSS. Published by Elsevier Science Inc. PII S0188-4409(02)00 3 7 1 - 5
Future Outlook, Recent Work, Antimalarial Drugs
can be induced most efficiently by reducing parasite load in vivo or in vitro repeatedly by an antimalarial drug treatment insufficient to eradicate it. This is what occurs in vivo with inadequately treated malaria either as a result of inappropriate prescribing, poor compliance, or occasionally unusual pharmacokinetic properties of the drug. Factors contributing to treatment failures depend upon three major elements (Table 1). Complete treatment courses with adequate antimalarial doses must be given. For example, short-acting drugs such as artemisinin and its derivatives or quinine need to be present at therapeutic concentrations for at least four asexual cycles (a 7-day treatment course) to ensure eradication of all parasites. Drugs that persist for weeks or months at subtherapeutic levels in the blood unfortunately cannot be completely protective no matter how well prescribed (5). In management of malaria, early diagnosis and early treatment with potent antimalarials are fundamental components of strategy. Patients who deteriorate should be referred to a hospital (Table 2). Correct use of an effective antimalarial drug will not only shorten the duration of malaria illness but also will reduce the incidence of complications and risk of death. Antimalarial drug resistance has spread and intensified over the past 40 years (Table 3), leading to dramatic decline in the efficacy of the most affordable antimalarial drugs. However, new drug development is not keeping pace, and the problems related to distribution and use of these drugs has confounded the situation. The future outlook for antimalarials by drug discovery (Table 4) could be either through inhibition of MSP 1-processing protease, third-generation antifolate malaria drug combinations, Plasmodium falciparum fatty acid biosynthesis, inhibition of malaria lactate dehydrogenase, inhibition of phospholipid metabolism, or P. falciparum protein farnesyl (transferase inhibitors) (6,7). However, it may take over 5 years to discover a truly new antimalarial drug (Table 5). In contrast, new developments using existing antimalarial drugs might involve a shorter period (3–5 years). This includes the following: development of intravenous artemisinin (artelinate) derivative for severe malaria; development of an artesunate/dihydroartemisinin suppository; developTable 1. Elements Parasite intrinsic resistance Drug dose
Host immunity (age, pregnancy)
Factors Load Variations in absorption (e.g., halofantrine, atovaquone increased absorption by fatty food) Intrinsic pharmacokinetic properties Synergistic/antagonistic effect Insufficient absorption (e.g., vomiting, diarrhea) Alterations in drug metabolism or disposition (genetic polymorphisms) Other diseases
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Table 2. Clinical criteria for referral to a higher level of health care Alteration in level of consciousness Jaundice Severe anemia Acidotic breathing (deep, labored breathing) Convulsions Bleeding Black urine
ment of an artesunate-sulfadoxine/pyrimethamine, artesunateamodiaquine, an artesunate-chlorproguanil-dapsone combination; development of a synthetic endoperoxide; development of isoquine (4-aminoquinoline), and development of artesunate-pyronaridine in combination and artesunate/dihydroartemisinin-piperaquine. Combination Therapy Many endemic countries are beginning to face a situation in which there are no affordable, effective antimalarial drugs available. Combination therapy offers hope for preserving the efficacy of antimalarial drugs and prolongs their useful therapeutic employment, although it may not be necessary to provide better treatment of consumers. Development of artemisinin, the most rapidly acting of all the current antimalarial drugs, and its derivatives and recognition of their potential role as a component of combination therapy have led to several large trials aimed at assessing different combinations of existing drugs and to specific development of new combination drugs. In addition, several countries have felt the need to evaluate, as potential first-line treatments, drug combinations not including artemisinin. These changes have provided a move for updating and rationalizing antimalarial treatment policies. The potential value of drug combinations, notably those including an artemisinin derivative, to improve efficacy, delay development, and selection of drug-resistant parasites thus prolonging the useful therapeutic life of existing antimalarial drugs, is widely adopted. Combination therapy is standard therapeutic practice in other diseases, such as tuberculosis, most HIV, and cancer, because resistance is due to mutations in genes controlling the structure/activity of the therapeutic target. The chance that a mutant will emerge that is simultaneously resistant to two drugs with different mechanisms of action is the product of mutation rates to respective drugs multiplied by number of cells exposed to drugs. Combining two antimalarial drugs with different modes of action often increases efficacy and protects against the emergence of resistance. Combinations not conTable 3. First report of drug resistance Pyrimethamine Chloroquine Mefloquine Atovaquone
1953 1960 1990 1996
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Wilairatana et al./ Archives of Medical Research 33 (2002) 416–421 Table 6. Benefits of combination of an artemisinin derivative with any long-acting antimalarial drug
Table 4. Approaches to antimalarial drug discovery Develop analogs of existing agents alone or in combination Optimize therapy with existing agent alone or in combination Compounds active against other diseases Natural products and their derivatives Drug-resistance reversers Compounds active against new targets
taining an artemisinin derivative could be a preferred option for reasons of cost and accessibility in some countries. However, the combination of an artemisinin derivative with a long-acting antimalarial is preferred because artemisinin will act on the first part and residual parasites will be cleared by long-acting drugs (Table 6). Standard doses of both drugs are used. Although this also increases the potential for toxicity, it has not proved to be a problem in practice. However, combination therapy could be a viable option for countries that already have widespread resistance of P. falciparum to chloroquine, amodiaquine, and sulfadoxine-pyrimethamine, provided issues of cost and complexity of implementation can be addressed. Further data on factors affecting access to treatment including health-seeking behaviors in endemic countries should be explored. There is a need for a continuing monitoring system for antimalarial sensitivity patterns in Southeast Asia, where stronger information bases and intercountry exchanges are required. Efforts should be made to intensify support for resistance monitoring and to develop improved easy-to-use tools, kits, and methodologies to facilitate this activity. New Antimalarial Drug Trials in Thailand New antimalarial drugs investigated at the Hospital for Tropical Diseases of the Faculty of Tropical Medicine at Mahidol University in Bangkok, Thailand, in recent years (8,9) are as follows: atovaquone, a naphthoquinone, was evaluated, and it was found that atovaquone alone proved safe and effective. All patients treated experienced a clinical cure; nonetheless, one third of patients had late recrudescence (RI). When atovaquone was combined with proguanil, the cure rate increased to 100% (10,11). This combination has now been developed into a fixed drug named Malarone®. Artemisinin derivatives such as artesunate, artemether, arteether, and Table 5. Antimalarial drugs exploited since 1930 Old drugs Cinchona alkaloids, pamaquine Mepacrine, chloroquine Proguanil, amodiaquine Pyrimethamine, primaquine Pyrimethamine-sulfa combinations
New drugs Artemisinin Artesunate, artemether, arteether Pyronaridine Mefloquine, halofantrine Atovaquone-proguanil Artemether-lumefantrine Tafenoquine
Accelerate therapeutic response Reduce transmission Prevent dangerous early treatment failures in case of high-grade resistance Reduce parasite load Reduce chances of survival of a resistant mutant Long-acting antimalarial will protect artemisinin derivative
dihydroartemisinin are also being tested. Artesunate and artemether alone at a total dose of 600–750 mg administered over 5–7 days produced cure rates of 80–95%. However, when they were combined with mefloquine (1,250 mg total dose), cure rates increased to 95–100% (12–15). Artesunate and dihydroartemisinin suppositories have proved successful for treatment of severe malaria (16–19). Artemisinin derivatives (600–750 mg) when used in combination with mefloquine (1,250 mg) over 3 days in adults improved cure rates up to 95–100%. Dihydroartemisinin alone with a total dose of 480 mg administered over 5 days gave a cure rate of 90% (20,21). Arteether, a World Health Organization/Special Program for Research and Training in Tropical Diseases (WHO/TDR) supported drug, has been evaluated and has now been registered for use in severe malaria under the name Artemotil® (22). Other combinations (artemisinin derivatives combined with lumefantrine or doxycycline, and mefloquine combined with tetracycline or doxycycline) have also been evaluated with improvement in cure rates (23,24). Recently, a fixed drug (artemether plus lumefantrine) named Coartem® (six doses administered over 72 h) proved a safe and effective drug for treatment of P. falciparum malaria and has been registered for use in many Western countries (25,26). At present, studies with combinations of artemisinin derivatives plus mefloquine (in various doses and durations of treatment) are being conducted. In general, artemisinin derivatives (12 mg/kg administered over 2–3 days) combined with mefloquine (25 mg/kg total dose) have been a standard regimen for treatment of multidrug-resistant P. falciparum malaria in Thailand. Until proven otherwise, drug combinations are still recommended for patients suffering from acute uncomplicated falciparum malaria contracted in multidrug-resistant areas. Severe Malaria Hospital-based data indicate that death from severe P. falciparum malaria varies from 10 to 40% depending on the time lag between initial symptoms and effective treatment and hospital facilities for management of complications. The disease can progress so rapidly that survival of a patient rapidly evolving from uncomplicated malaria and who can no longer take oral drugs normally available at the periphery depends upon speedy access to facilities where treatment can be given via parenteral route. Clinical criteria for referral to a higher level of health care are shown in Table 2.
Future Outlook, Recent Work, Antimalarial Drugs
Symptoms associated with malaria in which a patient no longer can take drugs by mouth include repeated vomiting, prostration, obtundation, changes in mental status (unable to localize pain, recognize family members), deep breathing, severe anemia, generalized convulsions, and coma. Unfortunately, facilities for providing parenteral treatment safely and effectively usually are not quickly accessible to patients. In severe malaria, choice of antimalarial chemotherapy depends on clinical severity, drug sensitivity of parasites, and availability and preparation of the drug. It is important to educate medical staff concerning the clinical features and rapid evaluation of severe disease in febrile patients possibly exposed to P. falciparum infection. In rural areas of the tropics, where the majority of the estimated 1–2 million deaths per year from malaria occur, high-risk communities should be made aware of the key symptoms of malaria. Management of severe malaria is listed in Table 7. Early, appropriate antimalarial chemotherapy may prevent the development of severe disease. At the most peripheral level of health service, oral treatment with tablets or capsules and in those who are vomiting, use of suppository formulations might be useful to health personnel or community health workers. It is accepted that discrimination between malaria and acute lower respiratory tract infection is not possible under these circumstances. Normally, patients in whom severe malaria is suspected should be transferred to the highest level of medical care available (Table 2); however, on many occasions factors such as seasonal flooding, lack of vehicles for transportation, or patient condition may render this impossible. Early treatment with a preferably parenterally administered potent antimalarial drug is of utmost importance. The earlier that treatment is started, the better the prognosis. Dose should be calculated by body weight and response monitored clinically and parasitologically. Patients should be observed for known side effects of antimalarial drugs, such as the hypoglycemic and cardiovascular effects of cinchona alkaloids. Quinine-induced hypoglycemia may develop during recovery, i.e., several days after the initiation of treatment and is particularly common in children and pregnant women. In patients with algid malaria, the possibility of a complicating secondary Gram-negative septicemia should be considered and appropriate broad-spectrum antibiotics given. In the reTable 7. Management of severe malaria Pre-hospital
Village level
Hospital
Awareness Preventive chemotherapy Any effective antimalarial by any route is better than no treatment at all Rectal formulations of artemisinin are single and potentially life-saving treatments Early diagnosis, early treatment with a potent antimalarial Treatment of complications Keep fluid and electrolyte balance Avoid harmful adjuvant treatments Supportive treatment (Follow WHO 2000 Guidelines)
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covery phase, antimalarial drugs should be administered by oral route as soon as possible. Chloroquine remains the drug of choice for combating chloroquine-sensitive parasites occurring in some areas in Africa. Quinine and quinidine are the only widely available drugs effective against chloroquine-resistant strains. Two new synthetic antimalarial drugs, mefloquine and halofantrine, are also effective against chloroquine-resistant strains but have no parenteral formulation, and cases of resistance to these drugs have already been reported. Qinghaosu (artemisinin: an ancient Chinese herbal medicine) and its derivatives have been used successfully in treating both uncomplicated and severe P. falciparum malaria. Their effectiveness in eliminating parasites has been extensively documented; nevertheless, the recrudescence rate (RR) is rather high (10–30%). Recrudescence rate depends upon the dose, duration of artemisinin derivatives used, and severity of disease: the more severe the disease, the greater the chance of recrudescence. Intravenous (i.v.)/intramuscular (i.m.) artesunate (2.4 mg/kg i.v. or i.m., followed by 1.2 mg/kg injection at (12) 24 h, then daily 5 days) is effective but not generally available in some countries. Intramuscular artemether (3.2 mg/kg i.m. injection followed by 1.6 mg/kg at (12) 24 h, then daily 5 days) is also effective and the drug is easily available in most countries. Recently, i.m. artemether (Artemotil®), developed by Artecef BV (Maarssen, The Netherlands) and supported by WHO/TDR has proved safe and is effective for treatment of severe malaria. It is useful in remote areas where intravenous facilities are unavailable. WHO/TDR has also concentrated efforts on the potential of artesunate in suppository form to cure parasites rapidly and significantly, thus reducing the mortality of severe P. falciparum malaria. The advantage of life-saving suppository is considerable in two ways: first, because its formulation offers the prospect of providing a safe and effective treatment for severe malaria in areas of rural tropics where parenteral drugs cannot be given. Therefore, the life-saving suppository can be administered at an earlier point in evolution toward severe disease than normally would be the case. Additionally, children and infants who are most at risk for early death are the main beneficiaries. Potential Future Drugs Ideal antimalarial drugs would be cheap, well-tolerated, oral drugs also efficacious in short courses for uncomplicated P. falciparum malaria. For severe malaria, a potent antimalarial drug, either i.v., i.m., or suppository, is needed. Effective adjunct therapy should also be investigated. Most antimalarial activity of artemisinin derivatives (but not artemisinin itself) is due to the metabolite dihydroartemisinin. Oral dihydroartemisinin treatment produces cure rates and parasite-clearance times equivalent to historical controls treated with oral artesunate. Dihydroartemisinin can be manufactured more cheaply, but its pharmacokinetic
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and pharmacodynamic properties vary greatly. Artelinic acid, currently under development, is a water-soluble artemisinin derivative more stable in solution than artesunate. Trioxanes, simplified analogs of artemisinin retaining the crucial endoperoxide bridge, are being developed but have not yet entered into clinical trials. Pyronaridine, a Mannich base synthesized by Chinese scientists, is effective in chloroquine-resistant P. falciparum. In Thailand, 28-day follow-up after a 5-day pyronaridine course demonstrated a 12% RR (27), suggesting its use preferably in combination with an artemisinin derivative. Formulation and dose-optimization studies are in progress. Two new potent 8-aminoquinolones, tafenoquine and CDRI 80/53, are undergoing clinical trials (28,29). Other potential approaches being developed include phosphatidylcholine and orotic acid analogs and inhibitors of aspartate and cysteine proteases.
Conclusions Output of new antimalarials may never keep pace with loss of drugs due to resistance. Resistance is the prime determinant of a drug’s life span (30). Protecting the effective use of a drug must rank as a number-one priority for research and control programs. Rational deployment when a drug is first introduced for use and sensible prescription are effective measures for protecting drug efficacy. Analogous with other diseases, more benefits may be obtained from available compounds by utilizing drug combinations (4) and rotating the use of antimalarials. In Thailand, drug treatment for uncomplicated malaria is aimed at radical cure using the combination of artesunate (4 mg/kg/day) plus mefloquine (8 mg/kg/day) for 3 days or a fixed dose of artemether and lumefantrine named Coartem® (six doses in 3 days) or quinine 10 mg/kg 8-hourly plus tetracycline 250 mg 6-hourly for 7 days in patients aged 8 years and over. In treating severe malaria, early diagnosis and early treatment with a potent antimalarial drug are recommended to save a patient’s life. The antimalarial drugs of choice are i.v. quinine or artemisinin derivatives. Early recognition of complications and adequate treatment also play an important role as complications (hypoglycemia, pulmonary edema, acute renal failure, metabolic acidosis, convulsions) that often increase mortality rate. Other symptomatic and supportive treatments include careful monitoring of fluid input and urine output and good nursing care. Despite these efforts, mortality from severe malaria is still high.
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5. 6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
References 1. Peters W. The prevention of antimalarial drug resistance. Pharmacol Ther 1990;47:499–508. 2. Foote SJ, Cowman AF. The mode of action and the mechanism of action of antimalarial drugs. Acta Trop 1994;56:157–171. 3. Wards SA, Bray PG, Mungthin M, Hawley SR. Current views on the
20.
mechanisms of resistance to quinoline-containing drugs in Plasmodium falciparum. Ann Trop Med Parasitol 1995;89:121–124. Looareesuwan S, Viravan C. Drug combinations for the treatment of falciparum malaria in Thailand. J Infect Dis Antimicrob Agents 1995;12:41–46. White NJ. Delaying antimalarial drug resistance with combination chemotherapy. Parasitologia 1999;41:301–308. Rosenthal PJ, Miller LH. The need for new approaches to antimalarial chemotherapy. In: Rosenthal PJ, editor. Antimalarial chemotherapy. Totowa, NJ, USA: Humana Press;2001. pp. 1–13. Olliaro PL, Milhours WK. The antimalarial drug portfolio and research pipeline. Antimalarial chemotherapy. In: Rosenthal PJ, editor. Antimalarial chemotherapy. Totowa, NJ, USA: Humana Press;2001. pp. 219–232. Looareesuwan S, Olliaro P, White NJ, Chongsuphajaisiddhi T, Subcharoen A, Thimasarn K, Nosten F, Singhasivanon P, Supavej S, Khusmith S, Wyling S, Kanyok T, Walsh D, Leggat PA, Doberstyn EB. Consensus recommendation on the treatment of malaria in Southeast Asia. Southeast Asian J Trop Med Public Health 1998;29:355–360. Looareesuwan S, Wilairatana P, Chokejindachai W, Viriyavejakul P, Krudsood S, Singhasivanon P. Research on new antimalarial drugs and the use of drugs in combination at the Bangkok Hospital for Tropical Diseases. Southeast Asian J Trop Med Public Health 1998;29:344–354. Looareesuwan S, Wilairatana P, Chalermrut K, Rattanapong Y, Canfield C, Hutchinson DBA. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999;60:526–532. Looareesuwan S, Wilairatana P, Glanarongran R, Indravijit KA, Supeeranontha L, Chinnapha S, Scott TR, Chulay JD. Atovaquone and proguanil hydrochloride followed by primaquine for treatment of Plasmodium vivax malaria in Thailand. Trans R Soc Trop Med Hyg 1999;93:637–640. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, Arnold K, Kyle D, Canfield C, Webster K. Randomised trials of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet 1992;339:821–824. Bunnag D, Karbwang J, Harinasuta T. Artemether in the treatment of multiple drug resistant falciparum malaria. Southeast Asian J Trop Med Public Health 1992;23:762–768. Looareesuwan S, Wilairatana P, Viravan C, Vanijanonta S, Pitisuttithum P, Kyle DE. Open randomized trial of oral artemether alone and sequential combination with mefloquine for acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1997;56:613–617. Looareesuwan S, Wilairatana P, Vanijanonta S, Pitisuttithum P, Rattanapong Y, Andrial M. Monotherapy with artesunate for uncomplicated falciparum malaria: a comparison of 5-day and 7-day regimens. Acta Trop 1997;67:197–205. Looareesuwan S, Wilairatana P, Molunto W, Chalermrut K, Olliaro P, Andrial M. A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand. Am J Trop Med Hyg 1997;57:348–353. Looareesuwan S, Wilairatana P, Vanijanonta S, Viravan C, Andrial M. Efficacy and tolerability of a sequential, artesunate suppository plus mefloquine, treatment of severe falciparum malaria. Ann Trop Med Parasitol 1995;89:469–475. Wilairatana P, Viriyavejakul P, Looareesuwan S, Chongsuphajaisiddhi T. Artesunate suppositories: an effective treatment for severe falciparum malaria in rural areas. Ann Trop Med Parasitol 1997;91:891–896. Wilairatana P, Krudsood S, Silachamroon U, Singhasivanon P, Vannaphan S, Faithong S, Klabprasit M, Na-Bangchang S, Olliaro P, Looareesuwan S. Clinical trial of sequential treatments of moderately severe and severe malaria with dihydroartemisinin suppository followed by mefloquine in Thailand. Am J Trop Med Hyg 2000;63:290– 294. Looareesuwan S, Wilairatana P, Vanijanonta S, Pitisuttithum P, Viravan C, Kraisintu K. Treatment of acute uncomplicated falciparum ma-
Future Outlook, Recent Work, Antimalarial Drugs
21.
22.
23.
24.
25.
laria with oral dihydroartemisinin. Ann Trop Med Parasitol 1996;90: 21–28. Wilairatana P, Chantavanich P, Singhasivanon P, Treeprasertsuk S, Krudsood S, Chalermrut K, Phisalaphong C, Kraisintu K, Loareesuwan S. A clinical trial of dihydroartemisinin for the treatment of acute uncomplicated falciparum malaria in Thailand: a comparison of three different formulations. Int J Parasitol 1998;28:1213–1218. Looareesuwan S, Schilizzi BM, Oosterhuis B, Sollie FAE, Wilairatana P, Krudsood S, Lugt C, Peeters PAM, Peggins JO. Dose-finding and efficacy study for i.m. artemotil (beta-artemether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria. Br J Clin Pharmacol 2002;53:492–500. Looareesuwan S, Vanijanonta S, Viravan C, Wilairatana P, Charoenlarp P, Lasserre R, Canfield C, Kyle DE, Webster HK. Randomised trial of mefloquine-tetracycline, and quinine-tetracycline for acute uncomplicated falciparum malaria. Acta Trop 1994;57:47–53. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Charoenlarp P, Canfield CJ, Kyle DE. Randomized trial of mefloquine-doxycycline, and artesunate-doxycycline for treatment of acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1994;50:784–789. Looareesuwan S, Wilairatana P, Chokejindachai W, Chalermrut K, Werndorfer W, Gemperli B, Gathmann I, Royce C. A randomized, double-blind, comparative trial of a new oral combination of arte-
26.
27.
28. 29.
30.
421
mether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999;60:238–243. Van Vugt M, Wilairatana P, Gemperli B, Gathmann I, Phaipun L, Brockman A, Luxemburger C, White NJ, Nosten F, Looareesuwan S. Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 1999;60:936–942. Looareesuwan S, Kyle DE, Viravan C, Vanijanonta S, Wilairatana P, Wernsdorfer WH. Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand. Am J Trop Med Hyg 1996;54:205–209. Newton P, White NJ. Malaria: new developments in treatment and prevention. Annu Rev Med 1999;50:179–192. Walsh DS, Looareesuwan S, Wilairatana P, Heppner DG, Tang D, Brewer TG, Chokejindachai W, Viriyavejakul P, Kyle DE, Milhous WK, Schuster BG, Horton J, Braitman DJ, Brueckner RP. Randomized dose-ranging study of the safety and efficacy of WR 238605 (tafenoquine) in the prevention of relapse of Plasmodium vivax malaria in Thailand. J Infect Dis 1999;180:1282–1287. Looareesuwan S, Harinasuta T, Chongsuphajaisiddhi T. Drug resistant malaria with special reference to Thailand. Southeast Asian J Trop Med Public Health 1992;23:621–634.
BRIEF REPORT
The Future Outlook of Antimalarial Drugs and Recent Work on the Treatment of Malaria Polrat Wilairatana, Srivicha Krudsood, Sombat Treeprasertsuk, Kobsiri Chalermrut and Sornchai Looareesuwan Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Received for publication December 6, 2001; accepted December 6, 2001 (01/218).
Background. With the emergence of multidrug-resistant falciparum malaria, new drugs and drugs in combination are urgently needed. Methods. New antimalarial drugs investigated at the Hospital for Tropical Diseases of the Faculty of Tropical Medicine at Mahidol University in Bangkok, Thailand in recent years for treatment of uncomplicated and severe falciparum malaria are as follows: atovaquone, and artemisinin derivatives (artesunate, artemether, arteether, and dihydroartemisinin) combined with other antimalarials. Results. Malarone®, artemisinin derivatives combined with lumefantrine or doxycycline, and mefloquine combined with tetracycline or doxycycline have been evaluated with improvement of the cure rate in uncomplicated malaria. Artemisinin derivatives intravenously or intrarectally combined with mefloquine may be alternatives to intravenous quinine for treatment of severe malaria. Conclusions. In Thailand, drug treatment for uncomplicated malaria consists of the combinations or artesunate plus mefloquine or artemether plus lumefantrine or quinine plus tetracycline. In treatment of severe malaria, antimalarial drugs of choice are intravenous quinine or artemisinin derivatives. © 2002 IMSS. Published by Elsevier Science Inc. Key Words: Future, Outlook, Antimalarials, Thailand.
Drug Resistance Antimalarial drug resistance emerges when malaria parasites with amplifications or mutations conferring reduced drug susceptibility are selected by antimalarial drug concentrations that provide differential inhibition to distinct genetic parasite types, i.e., the parasite population encounters drug concentrations sufficient to reduce or eradicate the susceptible parasite population but that inhibit or do not inhibit multiplication of the mutants (1). Antimalarial drug resistance usually ensues from either changes in drug accumulation or efflux (chloroquine, amodiaquine, quinine, mefloquine, halofantrine resistance), which leads to reduced
Address reprint requests to: Polrat Wilairatana, Ph.D., Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, 420/ 6 Rajvithi Road, Rajthevi, Bangkok, 10400, Thailand. Tel.: (66) (2) 2483183; FAXES: (66) (2) 245-7288 and 247-1957; E-mail: dirctm@ mucc.mahidol.ac.th
intraparasitic concentrations of the drug, or reduced affinity of the drug target for the particular drug resulting from point mutations in the respective genes encoding the target (pyrimethamine, cycloguanil, sulfonamide, atovaqone resistance) (2,3). Other mechanisms of drug resistance found in bacteria such as transferable resistance genes, production of drug-destroying enzymes, or activation of accessory metabolic pathways do not appear involved in antimalarial resistance. To overcome this problem, the use of drug combinations has been suggested (4). Preventing Antimalarial Drug Resistance Resistance can be prevented or at least delayed. Malaria must be treated adequately and selective pressures minimized. Currently recommended methodology for assessing drug resistance in high transmission areas ignores lowgrade resistance, yet this is the stage at which preventive measures are most effective. Experimentally, drug resistance
0188-4409/02 $–see front matter. Copyright © 2002 IMSS. Published by Elsevier Science Inc. PII S0188-4409(02)00 3 7 1 - 5
Future Outlook, Recent Work, Antimalarial Drugs
can be induced most efficiently by reducing parasite load in vivo or in vitro repeatedly by an antimalarial drug treatment insufficient to eradicate it. This is what occurs in vivo with inadequately treated malaria either as a result of inappropriate prescribing, poor compliance, or occasionally unusual pharmacokinetic properties of the drug. Factors contributing to treatment failures depend upon three major elements (Table 1). Complete treatment courses with adequate antimalarial doses must be given. For example, short-acting drugs such as artemisinin and its derivatives or quinine need to be present at therapeutic concentrations for at least four asexual cycles (a 7-day treatment course) to ensure eradication of all parasites. Drugs that persist for weeks or months at subtherapeutic levels in the blood unfortunately cannot be completely protective no matter how well prescribed (5). In management of malaria, early diagnosis and early treatment with potent antimalarials are fundamental components of strategy. Patients who deteriorate should be referred to a hospital (Table 2). Correct use of an effective antimalarial drug will not only shorten the duration of malaria illness but also will reduce the incidence of complications and risk of death. Antimalarial drug resistance has spread and intensified over the past 40 years (Table 3), leading to dramatic decline in the efficacy of the most affordable antimalarial drugs. However, new drug development is not keeping pace, and the problems related to distribution and use of these drugs has confounded the situation. The future outlook for antimalarials by drug discovery (Table 4) could be either through inhibition of MSP 1-processing protease, third-generation antifolate malaria drug combinations, Plasmodium falciparum fatty acid biosynthesis, inhibition of malaria lactate dehydrogenase, inhibition of phospholipid metabolism, or P. falciparum protein farnesyl (transferase inhibitors) (6,7). However, it may take over 5 years to discover a truly new antimalarial drug (Table 5). In contrast, new developments using existing antimalarial drugs might involve a shorter period (3–5 years). This includes the following: development of intravenous artemisinin (artelinate) derivative for severe malaria; development of an artesunate/dihydroartemisinin suppository; developTable 1. Elements Parasite intrinsic resistance Drug dose
Host immunity (age, pregnancy)
Factors Load Variations in absorption (e.g., halofantrine, atovaquone increased absorption by fatty food) Intrinsic pharmacokinetic properties Synergistic/antagonistic effect Insufficient absorption (e.g., vomiting, diarrhea) Alterations in drug metabolism or disposition (genetic polymorphisms) Other diseases
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Table 2. Clinical criteria for referral to a higher level of health care Alteration in level of consciousness Jaundice Severe anemia Acidotic breathing (deep, labored breathing) Convulsions Bleeding Black urine
ment of an artesunate-sulfadoxine/pyrimethamine, artesunateamodiaquine, an artesunate-chlorproguanil-dapsone combination; development of a synthetic endoperoxide; development of isoquine (4-aminoquinoline), and development of artesunate-pyronaridine in combination and artesunate/dihydroartemisinin-piperaquine. Combination Therapy Many endemic countries are beginning to face a situation in which there are no affordable, effective antimalarial drugs available. Combination therapy offers hope for preserving the efficacy of antimalarial drugs and prolongs their useful therapeutic employment, although it may not be necessary to provide better treatment of consumers. Development of artemisinin, the most rapidly acting of all the current antimalarial drugs, and its derivatives and recognition of their potential role as a component of combination therapy have led to several large trials aimed at assessing different combinations of existing drugs and to specific development of new combination drugs. In addition, several countries have felt the need to evaluate, as potential first-line treatments, drug combinations not including artemisinin. These changes have provided a move for updating and rationalizing antimalarial treatment policies. The potential value of drug combinations, notably those including an artemisinin derivative, to improve efficacy, delay development, and selection of drug-resistant parasites thus prolonging the useful therapeutic life of existing antimalarial drugs, is widely adopted. Combination therapy is standard therapeutic practice in other diseases, such as tuberculosis, most HIV, and cancer, because resistance is due to mutations in genes controlling the structure/activity of the therapeutic target. The chance that a mutant will emerge that is simultaneously resistant to two drugs with different mechanisms of action is the product of mutation rates to respective drugs multiplied by number of cells exposed to drugs. Combining two antimalarial drugs with different modes of action often increases efficacy and protects against the emergence of resistance. Combinations not conTable 3. First report of drug resistance Pyrimethamine Chloroquine Mefloquine Atovaquone
1953 1960 1990 1996
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Wilairatana et al./ Archives of Medical Research 33 (2002) 416–421 Table 6. Benefits of combination of an artemisinin derivative with any long-acting antimalarial drug
Table 4. Approaches to antimalarial drug discovery Develop analogs of existing agents alone or in combination Optimize therapy with existing agent alone or in combination Compounds active against other diseases Natural products and their derivatives Drug-resistance reversers Compounds active against new targets
taining an artemisinin derivative could be a preferred option for reasons of cost and accessibility in some countries. However, the combination of an artemisinin derivative with a long-acting antimalarial is preferred because artemisinin will act on the first part and residual parasites will be cleared by long-acting drugs (Table 6). Standard doses of both drugs are used. Although this also increases the potential for toxicity, it has not proved to be a problem in practice. However, combination therapy could be a viable option for countries that already have widespread resistance of P. falciparum to chloroquine, amodiaquine, and sulfadoxine-pyrimethamine, provided issues of cost and complexity of implementation can be addressed. Further data on factors affecting access to treatment including health-seeking behaviors in endemic countries should be explored. There is a need for a continuing monitoring system for antimalarial sensitivity patterns in Southeast Asia, where stronger information bases and intercountry exchanges are required. Efforts should be made to intensify support for resistance monitoring and to develop improved easy-to-use tools, kits, and methodologies to facilitate this activity. New Antimalarial Drug Trials in Thailand New antimalarial drugs investigated at the Hospital for Tropical Diseases of the Faculty of Tropical Medicine at Mahidol University in Bangkok, Thailand, in recent years (8,9) are as follows: atovaquone, a naphthoquinone, was evaluated, and it was found that atovaquone alone proved safe and effective. All patients treated experienced a clinical cure; nonetheless, one third of patients had late recrudescence (RI). When atovaquone was combined with proguanil, the cure rate increased to 100% (10,11). This combination has now been developed into a fixed drug named Malarone®. Artemisinin derivatives such as artesunate, artemether, arteether, and Table 5. Antimalarial drugs exploited since 1930 Old drugs Cinchona alkaloids, pamaquine Mepacrine, chloroquine Proguanil, amodiaquine Pyrimethamine, primaquine Pyrimethamine-sulfa combinations
New drugs Artemisinin Artesunate, artemether, arteether Pyronaridine Mefloquine, halofantrine Atovaquone-proguanil Artemether-lumefantrine Tafenoquine
Accelerate therapeutic response Reduce transmission Prevent dangerous early treatment failures in case of high-grade resistance Reduce parasite load Reduce chances of survival of a resistant mutant Long-acting antimalarial will protect artemisinin derivative
dihydroartemisinin are also being tested. Artesunate and artemether alone at a total dose of 600–750 mg administered over 5–7 days produced cure rates of 80–95%. However, when they were combined with mefloquine (1,250 mg total dose), cure rates increased to 95–100% (12–15). Artesunate and dihydroartemisinin suppositories have proved successful for treatment of severe malaria (16–19). Artemisinin derivatives (600–750 mg) when used in combination with mefloquine (1,250 mg) over 3 days in adults improved cure rates up to 95–100%. Dihydroartemisinin alone with a total dose of 480 mg administered over 5 days gave a cure rate of 90% (20,21). Arteether, a World Health Organization/Special Program for Research and Training in Tropical Diseases (WHO/TDR) supported drug, has been evaluated and has now been registered for use in severe malaria under the name Artemotil® (22). Other combinations (artemisinin derivatives combined with lumefantrine or doxycycline, and mefloquine combined with tetracycline or doxycycline) have also been evaluated with improvement in cure rates (23,24). Recently, a fixed drug (artemether plus lumefantrine) named Coartem® (six doses administered over 72 h) proved a safe and effective drug for treatment of P. falciparum malaria and has been registered for use in many Western countries (25,26). At present, studies with combinations of artemisinin derivatives plus mefloquine (in various doses and durations of treatment) are being conducted. In general, artemisinin derivatives (12 mg/kg administered over 2–3 days) combined with mefloquine (25 mg/kg total dose) have been a standard regimen for treatment of multidrug-resistant P. falciparum malaria in Thailand. Until proven otherwise, drug combinations are still recommended for patients suffering from acute uncomplicated falciparum malaria contracted in multidrug-resistant areas. Severe Malaria Hospital-based data indicate that death from severe P. falciparum malaria varies from 10 to 40% depending on the time lag between initial symptoms and effective treatment and hospital facilities for management of complications. The disease can progress so rapidly that survival of a patient rapidly evolving from uncomplicated malaria and who can no longer take oral drugs normally available at the periphery depends upon speedy access to facilities where treatment can be given via parenteral route. Clinical criteria for referral to a higher level of health care are shown in Table 2.
Future Outlook, Recent Work, Antimalarial Drugs
Symptoms associated with malaria in which a patient no longer can take drugs by mouth include repeated vomiting, prostration, obtundation, changes in mental status (unable to localize pain, recognize family members), deep breathing, severe anemia, generalized convulsions, and coma. Unfortunately, facilities for providing parenteral treatment safely and effectively usually are not quickly accessible to patients. In severe malaria, choice of antimalarial chemotherapy depends on clinical severity, drug sensitivity of parasites, and availability and preparation of the drug. It is important to educate medical staff concerning the clinical features and rapid evaluation of severe disease in febrile patients possibly exposed to P. falciparum infection. In rural areas of the tropics, where the majority of the estimated 1–2 million deaths per year from malaria occur, high-risk communities should be made aware of the key symptoms of malaria. Management of severe malaria is listed in Table 7. Early, appropriate antimalarial chemotherapy may prevent the development of severe disease. At the most peripheral level of health service, oral treatment with tablets or capsules and in those who are vomiting, use of suppository formulations might be useful to health personnel or community health workers. It is accepted that discrimination between malaria and acute lower respiratory tract infection is not possible under these circumstances. Normally, patients in whom severe malaria is suspected should be transferred to the highest level of medical care available (Table 2); however, on many occasions factors such as seasonal flooding, lack of vehicles for transportation, or patient condition may render this impossible. Early treatment with a preferably parenterally administered potent antimalarial drug is of utmost importance. The earlier that treatment is started, the better the prognosis. Dose should be calculated by body weight and response monitored clinically and parasitologically. Patients should be observed for known side effects of antimalarial drugs, such as the hypoglycemic and cardiovascular effects of cinchona alkaloids. Quinine-induced hypoglycemia may develop during recovery, i.e., several days after the initiation of treatment and is particularly common in children and pregnant women. In patients with algid malaria, the possibility of a complicating secondary Gram-negative septicemia should be considered and appropriate broad-spectrum antibiotics given. In the reTable 7. Management of severe malaria Pre-hospital
Village level
Hospital
Awareness Preventive chemotherapy Any effective antimalarial by any route is better than no treatment at all Rectal formulations of artemisinin are single and potentially life-saving treatments Early diagnosis, early treatment with a potent antimalarial Treatment of complications Keep fluid and electrolyte balance Avoid harmful adjuvant treatments Supportive treatment (Follow WHO 2000 Guidelines)
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covery phase, antimalarial drugs should be administered by oral route as soon as possible. Chloroquine remains the drug of choice for combating chloroquine-sensitive parasites occurring in some areas in Africa. Quinine and quinidine are the only widely available drugs effective against chloroquine-resistant strains. Two new synthetic antimalarial drugs, mefloquine and halofantrine, are also effective against chloroquine-resistant strains but have no parenteral formulation, and cases of resistance to these drugs have already been reported. Qinghaosu (artemisinin: an ancient Chinese herbal medicine) and its derivatives have been used successfully in treating both uncomplicated and severe P. falciparum malaria. Their effectiveness in eliminating parasites has been extensively documented; nevertheless, the recrudescence rate (RR) is rather high (10–30%). Recrudescence rate depends upon the dose, duration of artemisinin derivatives used, and severity of disease: the more severe the disease, the greater the chance of recrudescence. Intravenous (i.v.)/intramuscular (i.m.) artesunate (2.4 mg/kg i.v. or i.m., followed by 1.2 mg/kg injection at (12) 24 h, then daily 5 days) is effective but not generally available in some countries. Intramuscular artemether (3.2 mg/kg i.m. injection followed by 1.6 mg/kg at (12) 24 h, then daily 5 days) is also effective and the drug is easily available in most countries. Recently, i.m. artemether (Artemotil®), developed by Artecef BV (Maarssen, The Netherlands) and supported by WHO/TDR has proved safe and is effective for treatment of severe malaria. It is useful in remote areas where intravenous facilities are unavailable. WHO/TDR has also concentrated efforts on the potential of artesunate in suppository form to cure parasites rapidly and significantly, thus reducing the mortality of severe P. falciparum malaria. The advantage of life-saving suppository is considerable in two ways: first, because its formulation offers the prospect of providing a safe and effective treatment for severe malaria in areas of rural tropics where parenteral drugs cannot be given. Therefore, the life-saving suppository can be administered at an earlier point in evolution toward severe disease than normally would be the case. Additionally, children and infants who are most at risk for early death are the main beneficiaries. Potential Future Drugs Ideal antimalarial drugs would be cheap, well-tolerated, oral drugs also efficacious in short courses for uncomplicated P. falciparum malaria. For severe malaria, a potent antimalarial drug, either i.v., i.m., or suppository, is needed. Effective adjunct therapy should also be investigated. Most antimalarial activity of artemisinin derivatives (but not artemisinin itself) is due to the metabolite dihydroartemisinin. Oral dihydroartemisinin treatment produces cure rates and parasite-clearance times equivalent to historical controls treated with oral artesunate. Dihydroartemisinin can be manufactured more cheaply, but its pharmacokinetic
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and pharmacodynamic properties vary greatly. Artelinic acid, currently under development, is a water-soluble artemisinin derivative more stable in solution than artesunate. Trioxanes, simplified analogs of artemisinin retaining the crucial endoperoxide bridge, are being developed but have not yet entered into clinical trials. Pyronaridine, a Mannich base synthesized by Chinese scientists, is effective in chloroquine-resistant P. falciparum. In Thailand, 28-day follow-up after a 5-day pyronaridine course demonstrated a 12% RR (27), suggesting its use preferably in combination with an artemisinin derivative. Formulation and dose-optimization studies are in progress. Two new potent 8-aminoquinolones, tafenoquine and CDRI 80/53, are undergoing clinical trials (28,29). Other potential approaches being developed include phosphatidylcholine and orotic acid analogs and inhibitors of aspartate and cysteine proteases.
Conclusions Output of new antimalarials may never keep pace with loss of drugs due to resistance. Resistance is the prime determinant of a drug’s life span (30). Protecting the effective use of a drug must rank as a number-one priority for research and control programs. Rational deployment when a drug is first introduced for use and sensible prescription are effective measures for protecting drug efficacy. Analogous with other diseases, more benefits may be obtained from available compounds by utilizing drug combinations (4) and rotating the use of antimalarials. In Thailand, drug treatment for uncomplicated malaria is aimed at radical cure using the combination of artesunate (4 mg/kg/day) plus mefloquine (8 mg/kg/day) for 3 days or a fixed dose of artemether and lumefantrine named Coartem® (six doses in 3 days) or quinine 10 mg/kg 8-hourly plus tetracycline 250 mg 6-hourly for 7 days in patients aged 8 years and over. In treating severe malaria, early diagnosis and early treatment with a potent antimalarial drug are recommended to save a patient’s life. The antimalarial drugs of choice are i.v. quinine or artemisinin derivatives. Early recognition of complications and adequate treatment also play an important role as complications (hypoglycemia, pulmonary edema, acute renal failure, metabolic acidosis, convulsions) that often increase mortality rate. Other symptomatic and supportive treatments include careful monitoring of fluid input and urine output and good nursing care. Despite these efforts, mortality from severe malaria is still high.
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References 1. Peters W. The prevention of antimalarial drug resistance. Pharmacol Ther 1990;47:499–508. 2. Foote SJ, Cowman AF. The mode of action and the mechanism of action of antimalarial drugs. Acta Trop 1994;56:157–171. 3. Wards SA, Bray PG, Mungthin M, Hawley SR. Current views on the
20.
mechanisms of resistance to quinoline-containing drugs in Plasmodium falciparum. Ann Trop Med Parasitol 1995;89:121–124. Looareesuwan S, Viravan C. Drug combinations for the treatment of falciparum malaria in Thailand. J Infect Dis Antimicrob Agents 1995;12:41–46. White NJ. Delaying antimalarial drug resistance with combination chemotherapy. Parasitologia 1999;41:301–308. Rosenthal PJ, Miller LH. The need for new approaches to antimalarial chemotherapy. In: Rosenthal PJ, editor. Antimalarial chemotherapy. Totowa, NJ, USA: Humana Press;2001. pp. 1–13. Olliaro PL, Milhours WK. The antimalarial drug portfolio and research pipeline. Antimalarial chemotherapy. In: Rosenthal PJ, editor. Antimalarial chemotherapy. Totowa, NJ, USA: Humana Press;2001. pp. 219–232. Looareesuwan S, Olliaro P, White NJ, Chongsuphajaisiddhi T, Subcharoen A, Thimasarn K, Nosten F, Singhasivanon P, Supavej S, Khusmith S, Wyling S, Kanyok T, Walsh D, Leggat PA, Doberstyn EB. Consensus recommendation on the treatment of malaria in Southeast Asia. Southeast Asian J Trop Med Public Health 1998;29:355–360. Looareesuwan S, Wilairatana P, Chokejindachai W, Viriyavejakul P, Krudsood S, Singhasivanon P. Research on new antimalarial drugs and the use of drugs in combination at the Bangkok Hospital for Tropical Diseases. Southeast Asian J Trop Med Public Health 1998;29:344–354. Looareesuwan S, Wilairatana P, Chalermrut K, Rattanapong Y, Canfield C, Hutchinson DBA. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999;60:526–532. Looareesuwan S, Wilairatana P, Glanarongran R, Indravijit KA, Supeeranontha L, Chinnapha S, Scott TR, Chulay JD. Atovaquone and proguanil hydrochloride followed by primaquine for treatment of Plasmodium vivax malaria in Thailand. Trans R Soc Trop Med Hyg 1999;93:637–640. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Suntharasamai P, Charoenlarp P, Arnold K, Kyle D, Canfield C, Webster K. Randomised trials of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet 1992;339:821–824. Bunnag D, Karbwang J, Harinasuta T. Artemether in the treatment of multiple drug resistant falciparum malaria. Southeast Asian J Trop Med Public Health 1992;23:762–768. Looareesuwan S, Wilairatana P, Viravan C, Vanijanonta S, Pitisuttithum P, Kyle DE. Open randomized trial of oral artemether alone and sequential combination with mefloquine for acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1997;56:613–617. Looareesuwan S, Wilairatana P, Vanijanonta S, Pitisuttithum P, Rattanapong Y, Andrial M. Monotherapy with artesunate for uncomplicated falciparum malaria: a comparison of 5-day and 7-day regimens. Acta Trop 1997;67:197–205. Looareesuwan S, Wilairatana P, Molunto W, Chalermrut K, Olliaro P, Andrial M. A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand. Am J Trop Med Hyg 1997;57:348–353. Looareesuwan S, Wilairatana P, Vanijanonta S, Viravan C, Andrial M. Efficacy and tolerability of a sequential, artesunate suppository plus mefloquine, treatment of severe falciparum malaria. Ann Trop Med Parasitol 1995;89:469–475. Wilairatana P, Viriyavejakul P, Looareesuwan S, Chongsuphajaisiddhi T. Artesunate suppositories: an effective treatment for severe falciparum malaria in rural areas. Ann Trop Med Parasitol 1997;91:891–896. Wilairatana P, Krudsood S, Silachamroon U, Singhasivanon P, Vannaphan S, Faithong S, Klabprasit M, Na-Bangchang S, Olliaro P, Looareesuwan S. Clinical trial of sequential treatments of moderately severe and severe malaria with dihydroartemisinin suppository followed by mefloquine in Thailand. Am J Trop Med Hyg 2000;63:290– 294. Looareesuwan S, Wilairatana P, Vanijanonta S, Pitisuttithum P, Viravan C, Kraisintu K. Treatment of acute uncomplicated falciparum ma-
Future Outlook, Recent Work, Antimalarial Drugs
21.
22.
23.
24.
25.
laria with oral dihydroartemisinin. Ann Trop Med Parasitol 1996;90: 21–28. Wilairatana P, Chantavanich P, Singhasivanon P, Treeprasertsuk S, Krudsood S, Chalermrut K, Phisalaphong C, Kraisintu K, Loareesuwan S. A clinical trial of dihydroartemisinin for the treatment of acute uncomplicated falciparum malaria in Thailand: a comparison of three different formulations. Int J Parasitol 1998;28:1213–1218. Looareesuwan S, Schilizzi BM, Oosterhuis B, Sollie FAE, Wilairatana P, Krudsood S, Lugt C, Peeters PAM, Peggins JO. Dose-finding and efficacy study for i.m. artemotil (beta-artemether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria. Br J Clin Pharmacol 2002;53:492–500. Looareesuwan S, Vanijanonta S, Viravan C, Wilairatana P, Charoenlarp P, Lasserre R, Canfield C, Kyle DE, Webster HK. Randomised trial of mefloquine-tetracycline, and quinine-tetracycline for acute uncomplicated falciparum malaria. Acta Trop 1994;57:47–53. Looareesuwan S, Viravan C, Vanijanonta S, Wilairatana P, Charoenlarp P, Canfield CJ, Kyle DE. Randomized trial of mefloquine-doxycycline, and artesunate-doxycycline for treatment of acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1994;50:784–789. Looareesuwan S, Wilairatana P, Chokejindachai W, Chalermrut K, Werndorfer W, Gemperli B, Gathmann I, Royce C. A randomized, double-blind, comparative trial of a new oral combination of arte-
26.
27.
28. 29.
30.
421
mether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999;60:238–243. Van Vugt M, Wilairatana P, Gemperli B, Gathmann I, Phaipun L, Brockman A, Luxemburger C, White NJ, Nosten F, Looareesuwan S. Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 1999;60:936–942. Looareesuwan S, Kyle DE, Viravan C, Vanijanonta S, Wilairatana P, Wernsdorfer WH. Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand. Am J Trop Med Hyg 1996;54:205–209. Newton P, White NJ. Malaria: new developments in treatment and prevention. Annu Rev Med 1999;50:179–192. Walsh DS, Looareesuwan S, Wilairatana P, Heppner DG, Tang D, Brewer TG, Chokejindachai W, Viriyavejakul P, Kyle DE, Milhous WK, Schuster BG, Horton J, Braitman DJ, Brueckner RP. Randomized dose-ranging study of the safety and efficacy of WR 238605 (tafenoquine) in the prevention of relapse of Plasmodium vivax malaria in Thailand. J Infect Dis 1999;180:1282–1287. Looareesuwan S, Harinasuta T, Chongsuphajaisiddhi T. Drug resistant malaria with special reference to Thailand. Southeast Asian J Trop Med Public Health 1992;23:621–634.