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PubMed2002

[A collective malarial infestation during a humanitarian mission in west Africa].

Four truck drivers involved in a humanitarian mission across the Sahara towards Mali fell ill 15 days after their return. Plasmodium falciparum malaria (thankfully, non pernicious) was diagnosed with 3 to 4 days delay. The four drivers had been treated with chloroquine and proguanil but the dosage may have been insufficient with regard to their body weight (average weight = 110 kg). These 4 travelers had all slept outside (in Tintane, near Kiffa in Mauritania), without any anti-vectorial protection, whereas their other 8 companions (none of whom caught malaria) had slept in their vehicles. The evolution of the 4 cases was favourable despite the difficulties involved in urgently obtaining sufficient amounts of quinine for treatment. How can these cases be explained in relation to prophylactic treatment of associated chloroquine and proguanil? One explanation might be resistance of the P. falciparum strain. We were unable to study this possibility. The high incidence and similitude of cases points towards a hypothesis of resistance both to proguanil and chloroquine. Resistance to chloroquine, as has been formally ascertained in Mauritania, reinforces such a conviction. And yet prophylaxis does not prevent pernicious malaria. This clinical form of the disease, with P. falciparum primo-invasion occurring under rigorous chemoprophylaxis is characteristic of a partially resistant strain. The most reasonable explanation besides "chance" is that we are dealing here with a partially resistant strain of Plasmodium falciparum which is thus also partially sensitive to--in this case highly effective--therapeutic treatment. Indeed, chloroquino-resistant strains are more sensitive to mefloquine and halofantrine. Another explanation might be under-dosage of Savarine with relation to the body weight of these 4 patients. We should be aware of adapting more rigorously the posology of prescribed prophylaxis. But above all, this outbreak should remind us that we should recommend to travelers and drivers planning a trip to Sub-Saharan Africa to take with them anti-vectorial protective gear. Finally, the observation of these cases indicates once more the difficulty in France of establishing a proper diagnosis in face of malaria. Health personnel must systematically call to mind malaria in face of thrombopenia or fever following a sojourn in an endemic area even when chemoprophylaxis has been correctly followed.

Adult↗
PubMed2003

[Adverse drug reactions (ADRs) to antimalarial drugs. Analysis of spontaneous report from the French pharmacovigilance database (1996-2000)].

OBJECTIVE: Although the benefit/risk ratio of older antimalarial drugs (quinine, chloroquine) is well established less is known concerning the data about newer drugs. This article assesses and analyses the antimalarial-induced ADRs reported to the French pharmacovigilance system. METHODS: All cases of ADR(s) reported to the French pharmacovigilance database over a period of 5 years, from January 1, 1996 to December 31, 2000. Our study included the antimalarials (excluding doxycycline) used in France for the cure and prophylaxis of malaria. For each notification we noted the data relative to the patient (gender, age), the antimalarial drug (prevention or cure), the associated drugs and the adverse events (imputability, delay before onset, severity and evolution). RESULTS: Between 1996 and 2000, a total of 508 reports were collected, representing 0.6% of the notifications reported to the French pharmacovigilance database over the same period. For chemoprophylaxis, the chloroquine-proguanil combination predominated (n=230, i.e. 54%), followed by mefloquine (n=163, i.e. 38%) and chloroquine (n=36, i.e. 8%). Women predominated (53%). The mean age of the patients was of 40.6+/-16.1 years (range: 0-77 years). The majority of cases (67%) were aged 26 to 60 years (n=337). For curative treatment, halofantrine was the first line drug (n=30, i.e. 38%), followed by mefloquine (n=20, i.e. 26%), quinine (n=18, i.e. 24%) and chloroquine (n=9, i.e. 12%). Whatever the indication, the chloroquine-proguanil combination (n=230) and mefloquine (n=183) represented 81% of the reports (45 and 36% respectively). We noted 1 040 adverse events corresponding to 508 observations. The adverse events were classified as severe in 41.4% of cases. However, the percentage was highest for the curative (64%) than for the prophylactic treatments (37.5%) (p<0.01). For halofantrine and quinine, the adverse events were classified as severe in respectively 76 and 67% of cases. We studied the profile of adverse events of each antimalarial drug. CONCLUSION: Our study underlined several elements: the considerable number of psychiatric problems related to the use of chloroquine-proguanil and the hepatic disorders due to halofantrine, the profile of the adverse events of each drug and the unexpected adverse events which should not be neglected in some cases.

Adolescent↗
PubMed1997

[Adverse effects associated with antimalarial chemoprophylaxis].

BACKGROUND: To evaluate the frequency and type of adverse drug reactions associated to the antimalarial chemoprophylaxis advised to travellers visiting endemic areas. SUBJECTS AND METHODS: We included the travellers who from july 1992 to june 1994 came to the Travellers Advise Department and made short-term travels to areas with malarial infection risk. The adverse drug reactions were reported by the travellers through a questionnaire handed at the consulting room. The pharmacological regimens advised were: a) chloroquine base 5 mg/kg/week. b) chloroquine base 5 mg/kg/week + proguanil 100 mg/day if weight less than 55 kg and 200 mg/day if weight more than 55 kg. c) mefloquine 250 mg/week. RESULTS: We evaluated 1,054 questionnaires for the study. The 18.4% of the travellers reported adverse drug reactions. The 12.4% of the travellers who were on chloroquine, the 17.2% of those who were on chloroquine + proguanil and the 20.3% from mefloquine group presented adverse drug reactions (differences without significance). Comparing the regimens studied, we observed that neuropsychiatric reactions were more frequent in the mefloquine group (p < 0.01), the gastrointestinal reactions were less common in the chloroquine group (p = 0.04) and the transitory eye disorders were more frequent in the chloroquine + proguanil group (p = 0.01). In the mefloquine group the travellers with adverse drug reactions had a significantly lower weight than those who did not present them (p < 0.01). CONCLUSIONS: The adverse drug reactions reported agree with the toxicologic profile described in the literature about these drugs. Mefloquine presents an outstanding neuropsychiatric toxicity and is worse tolerated in low weight patients.

Adolescent↗
PubMed1997

Poor efficacy of antimalarial biguanide-dapsone combinations in the treatment of acute, uncomplicated, falciparum malaria in Thailand.

Combinations of dapsone with proguanil or chlorproguanil have proved effective in the treatment of chloroquine-resistant falciparum malaria in Africa and for prophylaxis in Asia. These combinations have not been used for treatment in areas with multi-drug-resistant parasites such as in Thailand. Combinations of dapsone (approximately 4 mg/kg) plus ether proguanil (approximately 8 mg/kg; DP regimen; N = 10) or chlorproguanil (approximately 1.4 mg/kg; DC regimen; N = 16) were given once a day for 3 days to adult Thai patients with acute, uncomplicated, falciparum malaria. The two regimens were well tolerated and had no side-effects, but the cure rates, assessed at 28-day follow-up, were only 10% for DP (60% with RI response and 30% with RII) and 14% for DC (29% with RI response and 57% with RII). The mean (S.D.) fever-clearance times in those patients who were cured (S) or whose infections recrudesced (RI response) were 103 (56) h for those given DP and 90 (42) h for 6 those given DC. The corresponding parasite-clearance times were 83 (46) for DP and 53 (21) h for DC. In-vitro susceptibility testing of isolates obtained both before treatment and at recrudescence demonstrated marked resistance to cycloguanil, dapsone, chloroquine and mefloquine. The results demonstrate that short-course treatment with dapsone plus either proguanil or chlorproguanil is ineffective for the treatment of falciparum malaria in Thailand.

Adolescent↗
PubMed2001

Recent Advances in the Prophylaxis and Treatment of Malaria.

Increases in international travel and escalating drug resistance are putting put a growing number of travelers at risk of contracting malaria. Resistance to chloroquine and proguanil and real and perceived intolerance to standard agents, such as mefloquine, has highlighted the need for new antimalarials to prevent and treat malaria. Promising new agents to prevent malaria include the combination of atovaquone and proguanil, primaquine, and a related 8-aminoquinoline, tafenoquine. These agents are active against the liver stage of the malaria parasite, and therefore can be discontinued shortly after the traveler leaves the malaria-endemic area; this offers a clear advantage, in terms of adherence to a treatment regimen. For treatment of multidrug-resistant Plasmodium falciparum malaria, the combination of artemisinin derivatives plus mefloquine, or atovaquone plus proguanil, are the most active drug regimens.

Journal Article↗
PubMed1958

Some observations on cardiac automatism in certain animals.

Certain aspects of the acetylcholine hypothesis of cardiac automaticity have been tested in vitro with spontaneously beating cardiac tissue from rabbits, rats, dams, and hagfish. The beat of atria from rabbits and rats may be depressed or excited by acetylcholine, depending upon the state of the tissue. Proguanil and cocaine inhibition of the beat in the rat may be antagonized by acetylcholine so that reversal of the depression occurs. The action of acetylcholine on the hearts of clams was found to be strictly inhibitory. Proguanil and cocaine, in contrast to their action on mammalian atria, exert a stimulatory effect on the heart of the molluscs studied. In fact, cocaine stimulated these hearts when they were inhibited by acetylcholine. Studies on the non-innervated hagfish heart revealed that this tissue is completely insensitive to the action of acetylcholine. Extracts prepared from beating hearts of this species will accelerate hypodynamic hearts of the hagfish as well as of the mussel. An extract of the neurogenic lobster heart was without effect on the hagfish heart. Proguanil was likewise ineffective in concentrations which produced inhibition and excitation in rat and clam hearts respectively. It was concluded that acetylcholine does not play a role in the myogenic automatism of all species, and that another mechanism is responsible is suggested on the basis of results obtained in the hagfish hearts.

Acetylcholine↗
PubMed1997

Safety and immunogenicity of live oral cholera and typhoid vaccines administered alone or in combination with antimalarial drugs, oral polio vaccine, or yellow fever vaccine.

The effects of concomitant administration of antimalarial drugs, oral polio vaccine, or yellow fever vaccine on the immune response elicited by the Vibrio cholerae CVD103-HgR and Salmonella typhi Ty21a live oral vaccines were investigated. Healthy adults were immunized with CVD103-HgR alone or combined with Ty21a. Subjects were randomized to simultaneously receive mefloquine, chloroquine or proguanil, or oral polio or yellow fever vaccine. The vibriocidal antibody seroconversion rate was significantly reduced (P = .008) only in the group that received chloroquine with the CVD103-HgR. The geometric mean vibriocidal antibody titer was significantly decreased in the groups that received chloroquine (P = .001) or mefloquine (P = .02) compared with titers in groups that received CVD103-HgR alone. However, similar immunosuppressive effects were not observed in the groups immunized with Ty21a and CVD103-HgR. Only the concomitant administration of proguanil effected a significant (P = .013) decline in the anti-S. typhi lipopolysaccharide antibody response. These results indicate that chloroquine and proguanil should not be simultaneously administered with the CVD103-HgR and Ty21a vaccine strains, respectively.

Administration, Oral↗
PubMed1990

Risk of malaria in British residents returning from malarious areas.

OBJECTIVES: To identify which British residents travelling abroad are at greatest risk of malaria infection, and to determine the efficacy of malaria chemoprophylaxis for preventing P falciparum infections in tropical Africa. DESIGN: Prospective cohort study (case-base linkage) with routine national surveillance systems. Denominators (base population) were obtained from monitoring a random sample of returning British travellers with the international passenger survey. Numerators (cases) were obtained from reports of malaria infections in British residents, through the Malaria Reference Laboratory network. SETTING: International passenger survey conducted at passport control of international airports in Britain. Malaria reports received nationally were collated centrally in London. SUBJECTS: 2948 British residents (0.2%) returning to Britain in 1987 randomly selected and questioned and 1052 British residents with microscopically confirmed malaria infections in 1987, whose case reports were reviewed and on whom additional data were collected by postal survey. MAIN OUTCOME MEASURES: Annual incidence subdivided by categories of risk. Chemoprophylactic efficacy for east and west Africa by principal regimens and compliance. RESULTS: Annual rates of reported infection per 100,000 travellers to Oceania were 4100; to west and east Africa were 375 and 172 respectively; to Latin America, the Far East, and the Middle East were 12, 2, and 1 respectively. Immigrants visiting friends and relatives in Ghana and Nigeria were at greatest risk (1303 and 952 per 100,000 respectively) in west Africa. Business travellers to Kenya experienced the highest attack rates in east Africa (465 per 100,000). Age-sex specific attack rates varied by region. No prophylaxis was reported to have been used by 23% of British visitors to west Africa, 17% to east Africa, 46% to central or southern Africa, and 58% visiting south Asia. The efficacy of chloroquine plus proguanil against P falciparum infection was 73% and 54% in west and east Africa respectively. Lower values were obtained for chloroquine alone and proguanil alone. The efficacy of Maloprim (pyrimethamine-dapsone) was 61% in west Africa, but only 9% in east Africa. Visitors to west Africa who did not comply with their chemoprophylactic regimen were at a 2.5-fold higher risk of infection than fully compliant users. Non-compliant visitors to east Africa had similar rates of infection as non-drug users. CONCLUSIONS: In 1987 chloroquine plus proguanil was the preferred chemoprophylactic regimen for P falciparum infection in Africa; antimalarial drugs must be taken regularly to be effective.

Adolescent↗
PubMed1974

Treatment of drug-resistant malaria in man.

The progressive spread in Asia and South America of falciparum malaria resistant to 4-aminoquinolines, and the focal occurrence in all malarious regions of infections resistant to dihydrofolate dehydrogenase inhibitors such as pyrimethamine and proguanil, make it everywhere necessary to be alert to the failure of accepted curative, prophylactic, or sporontocidal chemotherapeutic agents. Resistance to 4-aminoquinolines may be met curatively with courses of treatment lasting 1-14 days, or more, the longer courses relying on quinine, often with a sulfonamide, or on tetracyclines, and the shorter courses on associations of sulfonamides or sulfones with pyrimethamine or trimethoprim. Suppressive prophylaxis of these infections is obtained by the injection at 3-month intervals of a repository mixture of acedapsone and cycloguanil, or by the weekly ingestion of sulfadoxine, sulfalene, or diformyl-dapsone associated with pyrimethamine, or the daily ingestion of dapsone with proguanil. Primaquine, although continuing to be an efficient sporontocide of P. falciparum when pyrimethamine and proguanil no longer suffice, is becoming less effective in preventing relapses of P. vivax in countries around New Guinea.

Africa↗
PubMed2002

[Value of malarone in therapy of malaria tropica].

BACKGROUND: A widespread resistance of falciparum malaria to common antimalaria drugs is observed during the last years. Long-distance travel to high-risk destinations of falciparum malaria will contribute to increased exposition of travelers to highly resistant parasites. PHARMACOLOGY: Malarone (GlaxoSmithKline) is a fixed combination of atovaquone and proguanil licensed for prophylaxis and treatment of falciparum malaria. Both atovaquone and proguanil demonstrate synergistic activity against liver and blood schizonts. Malarone is well tolerated with a low rate of side effects. Malarone has an excellent efficacy profile in nonimmune subjects. CONCLUSIONS: Malarone appears to be a valuable alternative malaria prophylaxis in case of intolerance of other antimalaria drugs. Atovaquone/proguanil is effective in treating acute uncomplicated malaria caused by multiresistant strains of Plasmodium falciparum.

Animals↗
PubMed1994

Malaria and pregnancy: epidemiology, pathophysiology and control options.

Extensive research on the epidemiology, pathophysiology, and control of malaria during pregnancy has led to new developments and some controversies. Meanwhile, malaria remains a major environmental factor causing serious pregnancy complications, whose incidence and severity depend on gestational age, parity, and the level of malaria endemicity. There is no cohesive explanation for pregnancy-related immunosuppression, though several pathophysiological hypotheses have been proposed. Furthermore, the emergence and rapid spread of chloroquine resistance has complicated the epidemiology, and the policy on alternative chemoprophylaxis. Chemoprophylaxis is probably the only available option for the control of malaria during pregnancy in Africa. However, the best delivery strategy still has to be established. Daily proguanil is the best chemoprophylactic drug at hand. Its deployment should include constant monitoring for the emergence of proguanil resistance, as well as controlled supervision of the distribution of the drug. New control options, such as the use of insecticide-impregnated bed nets, and intermittent targeted mass chemotherapy, require more operational research before they can be broadly recommended.

Africa↗
PubMed1984

Concomitant resistance to pyrimethamine and cycloguanil of chloroquine-resistant falciparum malaria from East Africa: an in vitro study of 12 isolates.

The susceptibility of 12 isolates of Plasmodium falciparum to chloroquine, pyrimethamine and cycloguanil was studied in vitro after adaptation of the isolates to continuous culture by a 48-hour single-step multiplication inhibition assay. All of seven isolates imported from Tanzania since 1981 proved chloroquine resistant and six of these had an IC50 above 0.64 X 10(-6)M suggesting RII-RIII resistance. All chloroquine-resistant isolates were concomitantly resistant to pyrimethamine (IC50 above 10(-6)M). All chloroquine and pyrimethamine-resistant strains had IC50 values for cycloguanil of at least 0.6 X 10(-6)M which is higher than the Malayan (Camp.) strain studied in vitro and known to be proguanil/cycloguanil-resistant in vivo. Cycloguanil is the active metabolite of proguanil, and this result makes it doubtful whether proguanil would be a more effective prophylactic than chloroquine in East Africa, and whether any advantage over chloroquine alone would be derived from a combination of the two.

Africa, Eastern↗
PubMedDate not supplied

Activity of dihydrofolate reductase inhibitors on the hepatic stages of Plasmodium yoelii yoelii in vitro.

The effects of the dihydrofolate reductase inhibitors proguanil and chlorproguanil, their active metabolites cycloguanil and chlorcycloguanil, and pyrimethamine, against the hepatic stages of Plasmodium yoelii yoellii were investigated in cultured BALB/c mouse hepatocytes. Proguanil was inactive at concentrations of 10(-8) M, whereas the other compounds were fully active at this and lower concentrations. Chlorcycloguanil was the most active compound and almost completely inhibited schizont development in concentrations as low as 10(-12) M.

Animals↗
PubMed1991

Use of immunoglobulin gene rearrangements to show clonal lymphoproliferation in hyper-reactive malarial splenomegaly.

In Africa, hyper-reactive malarial splenomegaly (HMS), which is also known as tropical splenomegaly syndrome, can be associated with a prominent lymphocytosis in blood and bone marrow that is difficult to distinguish clinically from chronic lymphocytic leukaemia (CLL). The observation that some patients with HMS become resistant to treatment with anti-malarial drugs has led to the suggestion that HMS may evolve into a malignant lymphoproliferative disorder. To test this hypothesis, 22 Ghanaian patients with HMS and/or lymphocytosis were categorised by degree of response to proguanil according to standard clinical criteria, and DNA was extracted from peripheral blood cells and screened for rearrangements of the Jh region of the immunoglobulin gene with a DNA probe. Clonal rearrangements of the Jh region were found in all 3 patients with no response, in none of 13 patients with sustained response, and in 2 of 6 patients with moderate response or relapse on proguanil therapy. The detection of such rearrangements, and hence clonal lymphoproliferation in individuals with clinical features intermediate between HMS and CLL, supports the hypothesis that HMS may evolve into a malignant lymphoproliferative disorder.

Adolescent↗
PubMed1993

Long-term malaria prophylaxis with weekly mefloquine.

The spread of chloroquine-resistant Plasmodium falciparum malaria has led to increased use of mefloquine prophylaxis by US Peace Corps volunteers in sub-Saharan Africa. We compared long-term mefloquine with other drug regimens for effectiveness and tolerance. The incidence of Plasmodium falciparum infections and of adverse reactions was compared in Peace Corps volunteers who took chloroquine weekly, mefloquine weekly, mefloquine every other week, or weekly chloroquine plus daily proguanil. Weekly mefloquine was 94% more effective than chloroquine (95% CI 86% to 97%), 86% more effective than chloroquine plus proguanil (95% CI 67% to 94%), and 82% more effective than prophylaxis with mefloquine when taken every other week (95% CI 68% to 90%). No serious adverse reactions were observed. Mild adverse events were equally frequent in mefloquine users and chloroquine users, and the frequency of these events declined with increasing duration of prophylaxis. Mefloquine is an effective and well-tolerated drug for prophylaxis of malaria by short-term and long-term travellers.

Africa, Western↗
PubMed2005

Efficacy of antimalarial chemoprophylaxis among French residents travelling to Africa.

Controversy exists about which antimalarial chemoprophylaxis regimen should be used among travellers to Africa: the WHO and other experts recommend the use of mefloquine throughout sub-Saharan Africa, whereas French experts still support the combination of chloroquine and proguanil in most of West Africa (the so-called zone 2 countries). In this case-control study based at a travel clinic, we examined the compliance with antimalarial chemoprophylaxis and its efficacy among travellers to tropical areas. Cases were patients with Plasmodium falciparum malaria (n = 131). Controls were patients who had a negative malaria film (n = 158). Of all controls, only 36 (22.8%) were adequately protected (i.e. compliant with an adapted regimen of chemoprophylaxis). In zone 2 countries, the efficacy of the combined chloroquine and proguanil was 58% (95% CI 22-78%) for all users, but increased to 100% (95% CI 89-100%) for compliant users. In zone 3 countries, the efficacy of mefloquine was 90% (95% CI 51-98%) and 100% (95% CI 58-100%) for all users and compliant users, respectively.

Adult↗
PubMed1987

Neutropenia associated with dual antimalarial chemoprophylaxis--use of bone-marrow culture as an aid in further drug management.

Bone-marrow culture in soft agar was used to determine the cause of neutropenia in a visitor to Tanzania who had been taking both amodiaquine and proguanil for antimalarial prophylaxis. Desethyl-amodiaquine, a major metabolite of amodiaquine (but not amodiaquine itself, proguanil, cycloguanil or chloroquine) was implicated. Supplementary studies using amodiaquine binding techniques supported the notion that the parent compound, amodiaquine, was not the cause of the neutropenia. The bone-marrow culture technique proved useful in deciding further anti-malarial prophylaxis and in formulating the choice of curative antimalarial therapy, should this have proved necessary. The procedure may help in the managing other such patients with presumed drug-induced blood dyscrasias when the choice of appropriate and effective antimalarial drugs is limited.

Adult↗
PubMed1998

Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutations expressed in yeast.

Two new dihydrofolate reductase (DHFR) mutations were recently discovered in Plasmodium falciparum samples from an area of Bolivia with high rates of in vivo resistance to pyrimethamine-sulfadoxine: a Cys-->Arg point mutation in codon 50 and a five amino acid insertion after codon 30, termed the Bolivia repeat. We used a yeast expression system to screen these new DHFR mutants, as well as all of the other known DHFR mutant genotypes, against four antifolates: pyrimethamine, cycloguanil, chlorcycloguanil, and WR99210. The prodrug proguanil was also evaluated. The primary 108-Asn mutation, the known secondary mutations 51-Ile, 59-Arg and 164-Leu, as well as the 50-Arg mutation, all progressively enhanced pyrimethamine resistance in naturally observed combinations with one another, with the presence of 164-Leu most significantly increasing resistance. Cycloguanil and chlorcycloguanil resistance were most impacted by 164-Leu and the paired 16-Val/108-Thr. Proguanil had no effect on malaria DHFR. All DHFRs analyzed were sensitive to WR99210. The Bolivia repeat did not markedly affect drug sensitivity. We conclude that malaria DHFR can be reliably, rapidly and inexpensively analyzed in yeast for activity against a broad spectrum of antifolates. This system may be useful for initially characterizing newly discovered genotypes before proceeding to P. falciparum transfection; for large-scale geographic surveys of drug resistance; and for screening new antifolates or new antifolate combinations for their effectiveness against a large panel of DHFR mutants.

Animals↗