Current Views on Malaria Prophylaxis

A Review Article

Dr Arlene Goldman MB.BCh. MRCP(UK) MACP

The development of resistance to familiar anti-malarials has created confusion both for Doctors and travellers as to what is the best and most effective anti-malarial to take and which areas of the World require special precautions. Further difficulties are created by the serious side-effects encountered on using the newer drugs. This review will endeavour to elucidate current areas of resistance and recommendations for prophylaxis and treatment. Great stress is given to the warning that no prophylaxis is foolproof and failures arise most commonly from not taking the drugs as prescribed. In particular they must be started 1 week before departure and continued for 4-6 weeks after leaving the malaria area. Any fever up to 12-18months after leaving a malaria area should arouse suspicion of malaria and be investigated accordingly. Appropriate advice must be sought prior to departure from a reputable travel advice centre.

 

Antimalarial drugs

Newer drugs

Areas of Drug Resistant Plasmodium falciparum and Plasmodium vivax malaria.

Further discussion on use of Mefloquine

Concomitant conditions eg epilepsy

Malaria and Pregnancy

 

Malaria and children

Protective measures

Malaria Vaccines

Update on Vaccines

Malaria for the Layman

Summary

References

 

Antimalarial drugs

An update from the University of Oxford in Drug Safety 8(4) 1993 stated that a careful risk-benefit analysis is required to balance the risk of acquiring potentially serious malaria against the risk of harm from the prophylactic agent. Chloroquine and Proguanil) have an excellent safety record in the recommended dosages. Recent publicity has been given to side effects of Mefloquine which is used extensively in areas of resistance to Chloroquine and Proguanil.(Luzzi.GA Peto TE), Chloroquine-150mgs(base)-2 tablets/week.

Most common side effect - dyspepsia. Pruritis and exacerbations of psoriasis may occur.In standard doses Retinopathy does not appear to be a complication when used short term.1

Proguanil-hydrochloride(paludrine)-200mgs/day alone or with weekly

Chloroquine.Used with Chloroquine in pregnant women,children and others who cannot take mefloquine or doxycycline.1

Mefloquine 250mgs(salt) once per week.Not recommended for patients taking betablocker drugs or quinidine,for pilots and others who need fine motor skills,known neurologic or psychiatric disorders,pregnant women in first trimester,or children less than 15kgs.1 Mefloquine may provoke severe neuropsychiatric reactions with a frequency of 1 in 15000-20,000 users at the prophylactic dosage.

Pyrimethamine-sulfadoxine (Fansidar) 25mgs of Pyrimethamine and 500mgs of Sulfadoxine/tablet. has been associated with a relatively high incidence of potentially fatal reactions and is no longer recommended for prophylaxis..May be used for standby treatment. Should not be taken by pregnant women or if sensitive to sulphonamides.Serious adverse reactions include Stevens Johnson syndrome,toxic epidermal necrolysis,agranulocytosis,hypersensitivity pneumonitis and hepatitis.

Pyrimethamine-Dapsone (Maloprim) 1 tablet/week 12.5mgs of Pyrimethamine and 100mgs of Dapsone. Used with Chloroquine. Not on sale in the USA. Pyrimethamine-dapsone has been associated with agranulocytosis and should be reserved as a second line drug for travellers to high risk areas.

Doxycycline Used if unable to take Chloroquine or Mefloquine in high risk areas and areas of mefloquine resistance in South East Asia.Unsuitable for children and during pregnancy and lactation. Must be taken after meals standing up and with a lot of fluid. Use for more than 3 months to be avoided.2

Halofantrine 250mgs/tablet. 2 tablets in one dose,then 2 tabs after 6 hours and 2 more 6 hours after that one.Course repeated 7 days later.Halofantrine-is well tolerated and has a rapid antimalarial activity.It is more expensive than other antimalarials and the existence of cross resistance links its usefulness to the demise of mefloquine.The discovery of a potentially lethal cardiotoxicity associated with Halofantrine limits its use. Halofantrine lengthens the QT interval especially in those taking Mefloquine.Sudden deaths have occurred. Was used as standby treatment not prophylaxis. No longer recommended for standby treatment.2

Quinine Standby treatment not prophylaxis. 300mgs/tablet. 2tabs 3 times per day for 7 days. Note that it is not a suitable standby if mefloquine is used as a prophylactic.2

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Newer drugs

Artemisinin or Qinghaosu - Artemesia annua (sweet wormwood) is found in many parts of the world. In the early 1970's Chinese scientists recognised its potential for treating malaria and isolated the active principle,artemesinin or qinghaosu.3

Qinghaosu can be produced from natural sources and has been well studied.(artemisinin,arteannuin A).A novel ring system present in Yinghaosu was synthesised and a series of analogues were tested in mice against Plasmodium berghei.The optimised analogues possessed activity comparable to Qinghaosu.One of the best compounds Ro(arteflene)was selected for detailed preclinical evaluation. It had low acute toxicity after oral or subcut administration.4

To combat increasing problems with drug resistance to Plasmodium falciparum Viet Nam has turned increasingly to the artemisinin derivatives. Oral and suppository formulations are produced from locally grown plants. These compounds have been rapidly effective in a large number of studies.5

Arteflene- A synthetic derivative of Yinghaosu was evaluated extensively against various drug-sensitive and drug-resistant Plasmodium falciparum in vitro and Plasmodium berghei in mice.The potential therapeutic and prophylactic activities were studied comparatively with chloroquine, mefloquine, quinine as well as Qinghaosu and the derivatives artemether and artesunic acid. Experimentally arteflene proved to be a highly effective antimalarial drug.The suppressive and prophylactic properties were comparable to chloroquine and superior to Qinghaosu artemether and artesunic acid.It was consistently rather more active against drug-resistant than against drug sensitive strains of Plasmodium falciparum. Drug interactions in vitro and in vivo with Chloroquine,Mefloquine and Quinine revealed an additive to synergistic effect with arteflene.6

Artemether- The use of drug combinations may be necessary in areas where drug resistant parasites exist. In eastern Thailand a study was done using artemether 300mgs single dose followed by mefloquine 750mgs at 24hrs and 500mgs at 30hrs,or oral artemether 300mgs on day 1,followed by Mefloquine 750mgs at 24hrs and placebo at 30hrs.No serious adverse effect was seen in either group;mild and transient nausea and vomiting and loss of appetite were noted.The results suggested that a single oral dose of artemether(300mgs)can markedly improve the cure rate of mefloquine in multiple drug resistant malaria.7

Artesunate - Artesunate has been shown to be effective against Plasmodium falciparum but is associated with a high recrudescence rate.A study done in Bangkok Hospital for Tropical Diseases compared quinine plus tetracycline with oral artesunate in patients with acute uncomplicated Plasmodium falciparum malaria.Oral artesunate had faster parasite and fever clearance times than the combination but the cure rate was not significantly different.Nausea and dizziness were common with artesunate. They drew the conclusion that oral artesunate can be considered as an alternative drug for multiple drug resistant Plasmodium falciparum malaria but adverse effects especially neurotoxicity must be closely monitored before its widespread use can be recommended. 8

Pyronaridine a hydroxyanilino-benzonaphthyridine derivative synthesised in 1970 has been in use in China for more than 10 years(date of article 1992). The drug is highly effective against Plasmodium falciparum and Plasmodium vivax.It is efficacious against Chloroquine resistant Plasmodium falciparum in vitro and in vivo. It has been given orally,IM or by I-V drip and has low toxicity.9

Pyronaridine was synthesised from either 2-aminopyridine or pyridine.A series of studies revealed it was a promising drug against the erythrocytic stage of malaria parasites.It showed low toxicity and had no cross-resistance to chloroquine. A combination of Pyronaridine/Sulfadoxine/Pyrimethamine was used in the treatment of Chloroquine resistant Plasmodium falciparum in Hainan Province in order to retard the development of resistance to pyronaridine.A further in vivo test in the Diaoluo area using the combined formula was used for 5 years(1986-1990).

Drug resistance wad not demonstrated in this study.10 6 Azithromycin-A study was done to determine whether azithromycin 250mgs/day could be an effective prophylactic agent for Plasmodium falciparum malaria. The study was a controlled phase 2 trial with two cohorts entered sequentially.The data suggested that azithromycin has potential to be a well tolerated and effective clinical prophylactic agent for malaria.Compared with Mefloquine and Doxycycline it has less teratogenicity(class B) in lab animals but well controlled clinical studies have not been done. A liquid formulation for young children is being developed.11

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Areas of Drug Resistant Plasmodium falciparum and Plasmodium vivax malaria.

Thailand

The Thai-Cambodian border harbours the world's most severe multi- drug resistant Plasmodium falciparum.12 Plasmodium falciparum in Thailand is highly resistant to chloroquine and sulfdoxine/pyrimethamine(Fansidar) and there is increasing resistance to the alternative anti-malarials, quinine and mefloquine.7 The situation is most serious in the Thai/Cambodia and Thai/Myanmar border areas where multi-resistance necessitated the shift to the last line drugs-artemisinin derivatives.13

South America and Indochina subcontinent

In the late 1950's Chloroquine resistance to Plasmodium falciparum occurred in S America and the Indochina Subcontinent. Since then it has conquered most of the areas where the parasite species is endemic. In wide areas of South-east Asia,western Oceania and South America Sulfadoxine/Pyrimethamine combinations have lost adequate efficacy.13

Indonesia

Chloroquine resistance in Plasmodium vivax has recently been recognised in Indonesia14

China

Pyronaridine is highly effective against Plasmodium falciparum and Plasmodium vivax .It is efficacious against chloroquine-resistant strain of Plasmodium falciparum in vitro and in vivo.9 Pyronaridine/Fansidar was used in the treatment of chloroquine-resistant Plasmodium falciparum malaria in Hainan Province.10

Oceania

-in Papua New Guinea, Solomon Islands and Vanuatu Chloroquine resistance is intense for Plasmodium falciparum and some reports of resistant Plasmodium vivax. Mefloquine now the recommended regimen with Maloprim plus Chloroquine as an alternative.2

West Africa

Chloroquine-resistant Plasmodium falciparum malaria is an emerging problem in the West African subregion.15 Gabon(Lambarene) A substantial increase to Chloroquine resistance in contrast to reports from neighbouring countries.16 Burkina Faso (Africa) risk very high.2 Cameroon Two opposite situations were encountered. In Northern Cameroon where mefloquine resistance is prevalent a close correlation was found between the responses of Plasmodium falciparum to Mefloquine and to Quinine but not between Mefloquine and Chloroquine.In the South where Chloroquine resistance is highly prevalent no correlation was found between the responses to Quinine and Chloroquine or Chloroquine and Mefloquine.The responses to Chloroquine and Quinine appear partly correlated.17

East Africa

Kenya Chloroquine resistance widespread. Deaths in British travellers usually from malaria contracted in Africa especially Kenya. Some highland areas of Kenya and Namibia are malaria free as is central Nairobi but the surroundings have malaria.2

South Africa

North east, low altitude areas of north and eastern Transvaal,and eastern Natal down to 100kms north of Durban have some Chloroquine resistance. Botswana only in northern half of the country,Nov-J une. Swaziland high risk area Chloroquine resistance widespread. Namibia northern third only,Nov-June.

Zimbabwe

Areas below 1200m,Nov-June; all year in Zambesi valley. Mauritius low risk except rural areas where Chloroquine prophylaxis is appropriate.2
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Further discussion on use of Mefloquine

Mefloquine-is an orally administered schizonticide.Studies between 1977 and 1989 demonstrated efficacy of Mefloquine against multidrug resistant Plasmodium falciparum.It was also effective against Plasmodium vivax. Data about P ovale and P malariae infections were limited.Treatment failures were noted combining Mefloquine with Sulfadoxine/Pyrimethamine.The WHO no longer recommends this combination for malaria prophylaxis.. Mefloquine resistance is established in certain areas of Thailand and becoming a problem in other regions of the World.Future options may be the combination of Mefloquine with other agents such as Qinghaosu derivatives.18 Mefloquine- Preferred antimalarial for those at high risk of highly Chloroquine resistant Plasmodium falciparum who are not in the first trimester of pregnancy,not liable to become pregnant within three months of stopping Mefloquine, and not lactating.It gives greater protection than other regimens in sub-saharan Africa.One 250mg tablet/week is required.It may be used for up to a year. Pregnancy is best avoided for 3 months after stopping prophylactic Mefloquine but pregnancy in these circumstances need not be terminated.

The main problems have been neuropsychiatric side effects The symptoms vary and may include anxiety, depression,sleep disturbances, nightmares,hallucinations and occasionally overt psychoses or convulsions.Symptoms usually occur early on in the use of the drug,70% from the first 3 doses.It should not be given to those with a history of convulsions,epilepsy in first degree relatives,or serious psychiatric disorder. 2

A letter was published in the BMJ 24/6/95 expressing concern about the recommended wider use of mefloquine for British travellers as recommended in above paragraph.I.C. Perry states that of 250 mining engineers and their families based in west Africa more than 162 developed problems which include malaise,lethargy,headache and dizziness.Dehydration increases the frequency of side effects.Advice from the UK CAA restricts the use of mefloquine in pilots.

G.C.Cook also reacted against the recommendation to prescribe mefloquine and wrote to the BMJ 15/7/95. He states that Chloroquine plus Proguanil remains moderately effective in most countries under consideration. He states that the Hospital for Tropical Diseases receives constant reports of side effects of mefloquine prophylaxis-many of them severe.Cross resistance exists between Mefloquine and Quinine and the likelihood of resistance to Quinine developing is a problem. Mefloquine should be reserved for chemotherapy of infection with Plasmodium falciparum that is resistant to Quinine.

Five successive surveys were performed on French travellers attitudes to prophylaxis principally in sub-saharan Africa.Chloroquine has largely been replaced by mefloquine and by mefloquine-proguanil combination.96% of them knew the risk of malaria and the measures of prevention19

In eastern Thailand a study was done using artemether 300mgs single dose followed by mefloquine 750mgs at 24hrs and 500mgs at 30hrs,or oral artemether 300mgs on day 1,followed by Mefloquine 750mgs at 24hrs and placebo at 30hrs.No serious adverse effect was seen in either group;mild and transient nausea and vomiting and loss of appetite were noted.The results suggested that a single oral dose of artemether(300mgs)can markedly improve the cure rate of mefloquine in multiple drug resistant malaria.7

Mefloquine-Has the advantage of a single day regimen.Serious adverse reactions although rare do occur and the drug cannot be used in severe malaria. The discovery of a potentially lethal cardiotoxicity associated with Halofantrine limits its use. The artemisinin derivatives represent an exciting breakthrough.They seem remarkably free from adverse effects although the neurotoxicity seen in animal studies with the liposoluble derivatives gives cause for concern.The lack of pharmokinetic and toxicity data preclude their approval by Western drug regulation authorities.20 The sensitivity of Plasmodium falciparum to Chloroquine, mefloquine, quinine, halofantrine, and sulfadoxine/pyrimethamine was investigated at Lambarene in the Gabon.The highest degree of resistance to Chloroquine ever reported from Central Africa was found in 43 isolates which were all resistant.A significant positive correlation was found between responses to Quinine and Mefloquine.16
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Concomitant Illnesses

Epilepsy-Both mefloquine and chloroquine are unsuitable.In malaria areas with no Chloroquine resistance Proguanil 200mgs daily is recommended. For sub-saharan Africa doxycycline should be considered in spite of its side effects. Phenytoin,carbamazepine and barbiturates shorten the half-life of doxycycline.Maloprim is an alternative.2 Renal failure Chloroquine and Proguanil are excreted by the kidney.Mefloquine and doxycycline are largely metabolised and excreted by the liver. 2 Splenectomy Avoid unnecessary visits to malaria areas.2 Psoriasis-Chloroquine may cause exacerbation and is not recommended.

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Malaria and pregnancy

Plasmodium falciparum malaria infection during pregnancy contributes to low birth weight(LBW) -one of the greatest risks for neonatal mortality.In areas hyperendemic for Chloroquine resistant Plasmodium falciparum a two dose Sulfadoxine/Pyrimethamine is a cost effective way to reduce LBW incidence and should be part of the antenatal care package21 Routine chemoprophylaxis appears to have an effect on antenatal morbid episodes and packed cell volume.There is a trend towards higher birthweight in chemoprophylaxis groups.22 Pregnant women are at particular risk of severe malaria and should avoid visiting endemic areas if feasible. Chloroquine and Proguanil have a long history of safe use during pregnancy and mefloquine can also be used in the 2nd and 3rd trimesters.2


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Malaria and children

Children are unable to tolerate certain antimalarials due to toxicities unique for them. some of the safest and most palatable antimalarials for children are not available in the USA.23 Most of the fatalities occur in infants and children under the age of 5 years.In the past 5 years sporadic cases of drug resistant Plasmodium vivax malaria in Indonesia,IrianJaya and Papua New Guinea have been reported especially in children.Plasmodium ovale and Plasmodium malariae remain susceptible to most antimalarial agents. Prophylaxis in children as in adults is to use nonpharmacologic protective strategies. Because of rare reports of toxic encephalopathy and seizures,repellents containing DEET should be used judiciously in children. They should be applied to exposed clothing but not to mucous membranes,open wounds or hands.Repellents should be washed off when children come indoors to protected areas. Doxycycline is contraindicated in children under the age of 12 years and the safety of mefloquine has not been established in children weighing less than 15kgs14. Chloroquine remains the prophylactic of choice in areas of no Chloroquine resistance such as the Middle East, Central America and the Caribbean.For young children unable to take pills pulverised powder may be mixed with food.Chloroquine is quite bitter and more palatable alternatives eg Chloroquine suspension(Nivaquine)may be substituted.Chloroquine suspension is not available in the USA.Prophylaxis commences 1-2weeks prior to departure and must continue for 4 weeks after returning home.14
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Protective Measures

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Malaria Vaccines

In March 1988 a letter in Nature from a Columbian scientist claimed he had a malaria vaccine. A chemical vaccine SPF66 was tested and appeared to reduce clinical malaria by 30%. A trial in Tanzania in children also reported a 30% reduction. A second trial in Gambia on infants 6mths-1 year showed only an 8% reduction. Dr Emanuel Pataroya the developer of the vaccine in Columbia felt the criticism of his vaccine based on this trial was invalid as such young babies have not yet developed their immune system fully and the greatest incidence is in children 1-5years and up to 10years. A few more small scale trials have been recommended.

Update on malaria vaccines

January 1997

The NEJM of January 9th 1997 reported that a malaria vaccine based on fusion of a circumsporozoite protein and HBsAg plus a potent adjuvant could protect against experimental challenge with P.Falciparum malaria. The circumsporozoite protein is the principal antigen on the surface of the sporozoites.Sporozoites are injected into the host by a bite from an infected mosquito. They rapidly invade hepatocytes and multiply-the asymptomatic,pre-erythrocytic phase of malaria. After release from the hepatocyte they invade erythrocytes- the asexual erythrocytic phase responsible for the symptoms of the disease, Some of the intraerythrocytic parasites transform into gametocytes -a sexual stage from which the the differentiated sporozoites migrate to the salivary glands of the mosquitos. The SPF66 vaccine has been aimed at the erythrocytic phase but recent trials in endemic areas have not confirmed the efficacy of the vaccine as was reported in my last update. 46 subjects aged 18-45 who had not previously been exposed to malaria were immunised in the recent study reported in the NEJM.3 formulations of the vaccine were used. The vaccine was considered efficacious if there was no parasitologic evidence of P.Falciparum infection after a sporozoite challenge that caused infection in 100% of unimmunised subjects. 22 subjects who received 3 doses of vaccine agreed to a challenge with P Falciparum sporozoites. 8 were given vaccine 1.Seven were given vaccine 2 and seven were given vaccine3.Malaria developed in seven out of 8 subjects given vaccine 1. Five out of 7 subjects given vaccine 2 became infected. Only one of the seven given vaccine 3 became infected. Summary of Review Although the results are encouraging work must continue as the numbers reported on are very small and there are still many unanswered questions as regards mechanism of action. This summary is based on the RTS,S Malaria Vaccine Evaluation Group NEJM Jan 9,1997 Pages 86-91. Editorial Ruth S Nussenzweig MD., Ph.D and Fidel Zavala,MD New York University Medical Centre.

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Summary of Malaria Review

Increasing areas of chloroquine resistant Plasmodium falciparum have been reported. The use of chloroquine and/or proguanil is under extensive review and alternative regimens using mefloquine or doxycycline have been discussed. The newer Artemisinin derivatives show promise and are being tested particularly in Thailand. Azithromycin has been shown in animals to be promising

Protective measures have become of increasing importance due to serious side effects of newer drugs in particular Mefloquine. A balanced decision must be taken based on the risk of getting Plasmodium falciparum malaria with a high mortality and approximately 7 deaths/year in the UK weighed against serious side effects. Approximately 200,000,000 cases occur Worldwide annually and 1 or 2 million die. The greatest number of deaths occur in small children in Sub-saharan Africa.

Malaria vaccines are not yet in use by the WHO but trials are still being considered. The recommendations for prophylaxis vary greatly from country to country and there is no generally accepted regime in areas of chloroquine resistance. Protective measures plus Chloroquine and Proguanil still represent the most generally recommended regimes together with standby drugs in areas of chloroquine resistance. Sub-saharan Africa is a tremendous problem and in spite of potential side effects many authorities recommend Mefloquine for this part of the World


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References

1 Wyler David J, "Malaria Chemoprophylaxis for the Traveler," Drug Therapy 329 No1 (July 19,1993): 31-37.

2 Bradley DJ Warhurst DC Comm Malaria Ref Lab, "Malaria prophylaxis:guidelines for travellers from Britain ," BMJ 310 (Mar 18,1995): 709-14.

3 Trevett A Lalloo D, "A new look at an old drug:artemesinin and qinghaosu," Papua New Guinea Medical Journal 35(4) (Dec 1992): 264-9

4 Hofheinz W Burgin H Gocke E Jaquet C Masciadri R Schmid G Stohler H Urwyler H, "Ro 42-1611(arteflene),a new effective antimalarial:chemical structure and biological activity," Tropical Medicine and Parasitology 45(3) (Sep 1994): 261-5.

5 Hien TT, "An overview of the clinical use of artemesinin and its derivatives in the treatment of falciparum malaria in Viet Nam," Transactions of the Royal Society of Tropical Medicine and Hygiene Suppl 1 (Jun 1994): S7-8

6 Jaquet C Stohler HR Chollett J Peters W, "Antimalarial activity of the bicyclic peroxide Ro 42-1611 in experimental models," Tropical Medicine and Parasitology 45(3) (Sep 1994): 266-71.

7 Bunnag D Kanda T Karbwang J Thimasarn K Pungpak S Harinasutu T, "Artemether-mefloquine combination in multidrug resistant falciparum malaria," Transactions of the Royal Society of Tropical Medicine and Hygiene 89(20 (Mar-April 1995): 213-5.

8 Karbwang J Na-Bangchang K Thanavibul A Bunnag D Chongsuphajaisiddhi T Harinasutu T, "Comparison of oral artesunate and quinine plus tetracycline in acute uncomplicated falciparum malaria," Bulletin of the World Health Organisation 72(20 (1994): 233-8.

9 Chang C Lin-Hua T Jantanavivat C, "Studies on a new antimalarial compound:pyronaridine," Transactions of the Royal Society of Tropical Medicine and Hygiene 86(1) (Jan-Feb 1992): 7-10.

10 Chen C Zheng x, "Development of the new antimalarial compound:pyronaridine," Biomedical and Environmental Sciences 5(2) (Jun 1992): 149-60.

11 Anderson SL Berman J Kuschner R Wesche D Magill A Wellde B Schneider I Dunne M Schuster B, "Prophylaxis of Plasmodium falciparum Malaria with Azithromycin Administered to Volunteers," Annals of Internal Medicine 123 (Nov 15 1995): 771-3.

12 Looareesuwan S Harinasutu T Chongsuphajaisiddhi T, "Drug Resistant Malaria,with special reference to Thailand ," Southeast Asian Journal of Trop Med and Pub health 23(4) (Dec 1992): 621-34.

13 Wernsdorfer WH, "Epidemiology of drug resistance in malaria," Acta Tropica 56(2-3) (Mar 1994): 143-56.

14 Longworth DL, "Drug resistant malaria in children and in travelers," Pediatric Clinics of North America 42(3) (Jun 1995): 649-64.

15 Adubofour KO, "Drug resistance in malaria:a review of the West African situation.," Journal of the National Medical Association 84(12) (Dec 1992): 1025-9.

16 Winkler S Brandts C Wersdorfer WH Graninger W Bienzle U Kremsner BG, "Drug sensitivity of Plasmodium falciparum in Gabon.Activity correlations between various antimalarials," Tropical Medicine and Parasitology 45(3) (Sep 1994): 214-8.

17 Brasseur P Kouamouo J Moyou RS Druilhe P, "Mefloquine resistant malaria in Cameroon and correlation with resistance to Quinine.," Memorias do Instituto Oswaldo Cruz 87 Suppl 3 (1992): 271-3.

18 Palmer KJ Holliday SM Brogden RN, "Mefloquine. A review of its antimalarial activity,pharmokinetic properties and therapeutic efficacy.," Drugs 45(3) (Mar 1993): 430-75.

19 Armengaud M Picot T Piccoli S, "Development and trends from 1986-1993 of the attitude of intercontinental travellers on departure from France,with respect to malaria prophylaxis ," Bulletin de Sociiti de Pathologie Exotique 86(5 Pt 2 ) (1993): 421-3.+

20 Nosten N Price RN, "New antimalarials.A risk- benefit analysis.," Drug Safety 12(4) (Apr 1995): 264-73.

21 Schultz LJ Steketee RW Chitsulo L Wirima JJ, "Antimalarials during pregnancy:a cost-effective analysis," Bulletin of the World Health Organisation 73(2) (1995): 207-14.

22 Garner P Brabin B, "A review of randomized controlled trials of routine antimalarial drug prophylaxis during pregnancy in endemic malarious areas," Bulletin of the World Health Organization 72(10 (1994): 89-99.

23 Bia FJ, "Malaria prophylaxis:taking aim at constantly moving targets," Yale Journal of Biology and Medicine 65(4) (Jul-Aug 1992): 3236.

 

 

 

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