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PubMed2005

[Molecular epidemiological surveillance of markers for antimalarial drugs in Plasmodium falciparum isolates imported to Barcelona, Spain].

BACKGROUND AND OBJECTIVE: There have been described compelling correlations between mutations in some Plasmodium falciparum genes and resistance to antimalarial drugs. To apply molecular techniques in the mechanisms of epidemiological surveillance in the Hospital Clínic of Barcelona and to map potential levels of resistance, we investigated the presence of mutations in the relevant codons of genes associated with resistance in P. falciparum isolates imported by travellers. PATIENTS AND METHOD: The genes pfctr, pfmdr1, dhfr, dhps and cytochrome b were analyzed by PCR and enzymatic restriction in P. falciparum isolates from 53 persons attending the Tropical Medicine Department after a trip to a malaria endemic area. RESULTS: 63% of patients were infected with a P. falciparum isolate with the K76T mutation in pfctr. Tyr86 in pfmdr1 was found in 54% of the isolates. Mutations in codons 51, 59 and 108 in dhfr were found in 33%, 49% and 44% of the isolates, respectively. Mutations in codons 436, 437 and 540 in dhps were found in 35%, 35% and 8.5% of the isolates. 30% of travellers were infected by parasites displaying 3 or more mutations in any of the codons of dhps and dhfr. None of the patients had a mutation in the Tyr268 codon of the cytochrome B gene. CONCLUSIONS: The high prevalence of mutations in the imported isolates suggests a fast development and expansion of resistance against most of the antimalarial drugs commonly used. The concurrence of more than one mutation in different loci suggests the expansion of multiple resistances.

Animals↗
PubMed1975

Antimalarials: screening of (orally administered) silver solfonamides against Plasmodium berghei.

Orally administered silver sulfadiazine is effective against Plasmodium berghei. Attempts to synthesize an active analogue with antimalarial activity failed. Although several of the analogues were chemically stable (like silver sulfadiazine) in sodium chloride, none of the analogues were biologically active. This suggests that the antimalarial activity of silver sulfadiazine is stereo-specific.

Administration, Oral↗
PubMed1980

In vitro synergism between tetracyclines and antimalarials.

The in vitro activity of various tetracyclines and antimalarials alone and in combinations against 20 clinical isolates of Escherichia coli was investigated. The minimum inhibition concentration of the tetracyclines ranged from 1.2 to 160 micrograms/ml. Demeclocycline was the highest in activity. The antimalarials were ineffective. Variable percentage of strains responded to the synergistic effect of the various antibiotics-drugs combinations. Strains which are relatively insensitive to the tetracyclines did not respond to the synergistic effect of the combinations. The bactericidal effect of the combinations was shown by the enhanced rate of killing that occurred at 6 h. Synergism was reversed by divalent cations.

Animals↗
PubMed1987

Multiple-dose pharmacokinetics of the antimalarial drug Fansimef (pyrimethamine + sulfadoxine + mefloquine) in healthy subjects.

Fansimef is a new antimalarial combination containing pyrimethamine, sulfadoxine and mefloquine in the weight proportions 1 + 20 + 10. It has been designed to fight plasmodia resistant to the presently used antimalarial drugs and to counter the development of new resistant forms of the parasites. In the present study tablets containing 25 mg pyrimethamine, 500 mg sulfadoxine and 250 mg mefloquine were used. Six Brazilian volunteers received a loading dose of 2 tablets followed by 20 maintenance doses of 1 tablet at a dosage interval of 7 days. The pharmacokinetic evaluation of each of the three components was based on the assumption of an open linear two-compartment model. After the last maintenance dose the following kinetic parameters were determined for pyrimethamine, sulfadoxine and mefloquine, respectively: elimination half-life = 123, 179 and 550 h; volume of distribution in the postdistributive phase = 2.5, 0.15 and 18.6 1 X kg-1, and total systemic clearance = 14.0, 0.64 and 24.0 ml X h-1 X kg-1. All these values agree fairly well with those measured in previous single-dose kinetic studies. At steady state, Cmin values of each of the three components generally showed small variations. No unexpected accumulation of any of the three components was observed, indicating that induction or inhibition of metabolic enzymes did not occur during the trial.

Adult↗
PubMed2004

Antimalarial drug resistance.

Malaria, the most prevalent and most pernicious parasitic disease of humans, is estimated to kill between one and two million people, mainly children, each year. Resistance has emerged to all classes of antimalarial drugs except the artemisinins and is responsible for a recent increase in malaria-related mortality, particularly in Africa. The de novo emergence of resistance can be prevented by the use of antimalarial drug combinations. Artemisinin-derivative combinations are particularly effective, since they act rapidly and are well tolerated and highly effective. Widespread use of these drugs could roll back malaria.

Antimalarials↗
PubMed2006

Antimalarial drug therapy: the role of parasite biology and drug resistance.

Malaria continues to affect public health and economic growth in many regions of the world. The number of infections continues to rise and is associated with increased mortality, despite basic science and public health efforts. Drug therapy remains the mainstay of treatment and prevention of this disease. Plasmodium has a complex life cycle involving an arthropod vector and distinct stages within the human host. Each parasite stage plays a unique role in transmission, disease, and latency. These different stages may vary in their response to the various antimalarial compounds. This article will review antimalarial therapies and drug resistance in the context of the parasites' biology.

Animals↗
PubMed2002

Development of a plasmepsin II fluorescence polarization assay suitable for high throughput antimalarial drug discovery.

Despite decades of research, malaria remains the world's most deadly parasitic disease. New treatments with novel mechanisms of action are urgently needed. Plasmepsin II is an aspartyl protease that has been validated as an antimalarial therapeutic target enzyme. Although natural products form the basis of most modern antimalarial drugs, no systematic high-throughput screening has been reported against this target. We have designed an effective strategy for carrying out high-throughput screening of an extensive library of natural products that uses a fluorescence resonance energy transfer primary screening assay in tandem with a fluorescence polarization assay. This strategy allows rapid screening of the library coupled with effective discrimination and elimination of false-positive samples and selection of true hits for chemical isolation of inhibitors of plasmepsin II.

Animals↗
PubMed2003

In-vivo antimalarial activity of some oxygenated xanthones.

A series of oxygenated xanthones was prepared so that the antimalarial activity of each compound could be evaluated in vivo, using 4-day suppressive assays against Plasmodium berghei ANKA in BALB/c mice. When given in a dose of 20 mg/kg.day for 4 days, most of the compounds produced significant chemosuppression of parasitaemia. The most active compound was 1,3,6,8-tetrahydroxyxanthone, which reduced the percentage of erythrocytes infected by 70.5%, followed by norlichexanthone (44.3%) and its isomer, 1,3,8-trihydroxy-6-methylxanthone (37.0%). Whereas di-C-allyl-dihydroxyxanthone showed lower but still notable activity (33.4%), 1,3-dihydroxyxanthone was much less active (15.1%). This appears to be the first demonstration of the antimalarial activity of some hydroxyxanthones in vivo.

Animals↗
PubMed2003

Glutathione is involved in the antimalarial action of chloroquine and its modulation affects drug sensitivity of human and murine species of Plasmodium.

Ferriprotoporphyrin IX (FP) is released inside the food vacuole of the malaria parasite during the digestion of host cell hemoglobin. FP is detoxified by its biomineralization to hemozoin. This process is effectively inhibited by chloroquine (CQ) and amodiaquine (AQ). Undegraded FP accumulates in the membrane fraction and inhibits enzymes of infected cells in parallel with parasite killing. FP is demonstrably degraded by reduced glutathione (GSH) in a radical-mediated mechanism. This degradation is inhibited by CQ and AQ in a competitive manner, thus explaining the ability of increased GSH levels in Plasmodium falciparum-infected cells to increase resistance to CQ and vice versa, and to render Plasmodium berghei that were selected for CQ resistance in vivo sensitive to the CQ when glutathione synthesis is inhibited. Some over-the-counter drugs that are known to reduce GSH in body tissues when used in excess were found to enhance the antimalarial action of CQ and AQ in mice infected either with P. berghei or Plasmodium vinckei. In contrast, N-acetyl-cysteine which is expected to increase the cellular levels of GSH, antagonized the action of CQ. These results suggest that some over-the-counter drugs can be used in combination with some antimalarials to which the parasite has become resistant.

Acetylcysteine↗
PubMed2003

Mechanisms of in situ activation for peroxidic antimalarials.

This review describes mechanisms of action of artemisinin-related antimalarials, emphasizing the site and target of activation, pathways of generating reactive species, and possible targets of free radicals with implications for antimalarial peroxide drug design. It also presents a useful link between the mode of action of artemisinin and that of chloroquine, and highlights redox cycles involved in the interaction between the drug and vital biomolecules.

Animals↗
PubMed2006

Fractions of an antimalarial neem-leaf extract have activities superior to chloroquine, and are gametocytocidal.

The antimalarial activities of two fractions (IRDN-A and IRDN-B) of an extract from the leaves of the neem tree (Azadirachta indica) were compared with those of chloroquine, in in-vitro assays against Plasmodium falciparum. The asexual stages of a chloroquine-sensitive clone (ITG2F6) and a chloroquine-resistant isolate (W2) and the gametocytes of the NF 54 (BD-7) isolate of P. falciparum were used as the drug targets. Activity against the asexual stages was generally evaluated as the concentrations inhibiting the parasitaemias recorded in the control cultures, after an incubation of 48-72 h, by 50% (IC50) or 100% (IC100). For the ITG2F6 strain, the IC50 and IC100 (in microg/ml) were, respectively, 10(-5) and 10(-4) for IRDN-A, 10(-3) and 10(-2) for IRDN-B, and 10(-2) and 1.0 for chloroquine. The corresponding values for the W2 strain were 10(-5) and 1.0 for IRDN-A, and 10.0 and >100 for chloroquine (even at 100 microg/ml, chloroquine only inhibited the parasitaemia by 85%). Each of the two neem-leaf fractions lysed 50% and 100% of developing gametocytes, at 10(-3) and 1.0 microg/ml, respectively; and 50% and 100% of mature gametocytes at 10(-3) and 10(2) microg/ml, respectively. If they are found safe and effective in vivo, the neem-leaf fractions may form the basis of new antimalarial drugs that not only cure chloroquine-sensitive and chloroquine-resistant malaria but also markedly reduce transmission.

Animals↗
PubMed2006

Adherence of community caretakers of children to pre-packaged antimalarial medicines (HOMAPAK) among internally displaced people in Gulu district, Uganda.

BACKGROUND: In 2002, home-based management of fever (HBMF) was introduced in Uganda, to improve access to prompt, effective antimalarial treatment of all fevers in children under 5 years. Implementation is through community drug distributors (CDDs) who distribute pre-packaged chloroquine plus sulfadoxine-pyrimethamine (HOMAPAK) free of charge to caretakers of febrile children. Adherence of caretakers to this regimen has not been studied. METHODS: A questionnaire-based survey combined with inspection of blister packaging was conducted to investigate caretakers' adherence to HOMAPAK. The population surveyed consisted of internally displaced people (IDPs) from eight camps. RESULTS: A total of 241 caretakers were interviewed. 95.0% (CI: 93.3% - 98.4%) of their children had received the correct dose for their age and 52.3% of caretakers had retained the blister pack. Assuming correct self-reporting, the overall adherence was 96.3% (CI: 93.9% - 98.7%). The nine caretakers who had not adhered had done so because the child had improved, had vomited, did not like the taste of the tablets, or because they forgot to administer the treatment. For 85.5% of cases treatment had been sought within 24 hours. Blister packaging was considered useful by virtually all respondents, mainly because it kept the drugs clean and dry. Information provided on, and inside, the package was of limited use, because most respondents were illiterate. However, CDDs had often told caretakers how to administer the treatment. For 39.4% of respondents consultation with the CDD was their reported first action when their child has fever and 52.7% stated that they consult her/him if the child does not get better. CONCLUSION: In IDP camps, the HBMF strategy forms an important component of medical care for young children. In case of febrile illness, most caretakers obtain prompt and adequate antimalarial treatment, and adhere to it. A large proportion of malaria episodes are thus likely to be treated before complications can arise. Implementation in the IDP camps now needs to focus on improving monitoring, supervision and general support to CDDs, as well as on targeting them and caretakers with educational messages. The national treatment policy for uncomplicated malaria has recently been changed to artemether-lumefantrine. Discussions on a suitable replacement combination for HBMF are well advanced, and have raised new questions about adherence.

Adult↗
PubMed2001

Antimalarial therapy: a panacea for mild lupus?

Antimalarial therapy has a long and successful track record in the management of patients with mild SLE. Medium to long term use of hydroxychloroquine, alone or in combination with mepacrine, ameliorates lupus and may reduce the relapse rate. Recent guidelines for monitoring hydroxychloroquine have reduced the need for frequent visual checks. Antimalarials have other beneficial effects on lipid and glucose metabolism as well as having weak anticoagulant activity. They should be considered for most patients with mild lupus.

Antimalarials↗
PubMed1998

4-Aminoquinoline antimalarials enhance UV-B induced c-jun transcriptional activation.

Previous work has documented that the earliest observable response in mammalian cells following ultraviolet (UV) irradiation is the activation of plasma membrane-associated Src tyrosine kinases. These molecules then trigger a signalling cascade that results in activation of the transcription factor AP-1 which subsequently transactivates the early immediate genes including c-jun. This pathway has been postulated to play a protective role against UV damage. As aminoquinoline antimalarials such as chloroquine are known to downregulate several photoinduced cutaneous disorders including LE-specific skin disease, we asked whether chloroquine might be capable of modulating this early limb of the UV light response. A431 cells (a human epidermal keratinocyte cell line) that had been transfected with a c-jun luciferase reporter gene construct were then treated with physiologically relevant concentrations of chloroquine followed by exposure to 0-125 J/m2 of UV-B from a bank of unfiltered FS20 lamps. Chloroquine pretreatment resulted in a dose-dependent increase in luciferase activity in permanently transfected A431 cells (luciferase activity was increased by 45% at 2.5 x 10(-5) M chloroquine and 125 J/m2 of UV-B). Hydroxychloroquine pretreatment also resulted in an increase in luciferase activity. Primaquine, an 8-aminoquinoline, did not influence the UV-B induced c-jun activity. Furthermore, chloroquine did not have a similar impact on HSP-70 gene activity during heat shock. These studies suggest that the beneficial effect of the 4-aminoquinoline antimalarials in various photodermatoses including cutaneous LE might result in part from the capacity of these drugs to enhance the protective early limb of the UV response.

Aminoquinolines↗
PubMed2001

Synthesis of new arylaminoquinoxalines and their antimalarial activity in mice.

2-Arylaminoquinoxalines were prepared by the condensation of 2-chloroquinoxaline with the appropriate Mannich bases in the presence of HCl. To synthesize the Mannich bases, 4-acetamidophenol was reacted with formaldehyde and dialkylamine to yield 3-[(dialkylamino) methyl]-4-hydroxyacetanilide, followed by hydrolysis. Antimalarial activities of the new arylaminoquinoxalines were evaluated against the rodent malaria parasite Plasmodium yoelii at a dose of 75 mg kg(-1). Three compounds synthesized (2-[3-[(diethylamino) methyl]-4-hydroxyanilino]-quinoxaline dihydrochloride (2b), 2-[3-[(pyrrolidinyl) methyl]-4-hydroxyanilino]-quinoxaline dihydrochloride (2f), and 2-[3-[(piperidinyl) methyl]-4-hydroxyanilino]-quinoxaline dihydrochloride (2g)) showed moderate antimalarial activity.

Animals↗
PubMed1999

Discovery of new antimalarial compounds by use of molecular connectivity techniques.

Molecular connectivity has been applied to the search for new compounds with antimalarial activity. Linear discriminant analysis and connectivity functions were used to select several potentially suitable drugs which were tested for antimalarial properties by use of an in-vitro micro test which estimates parasite growth by measurement of incorporation of [3H]hypoxanthine. Hexetidine stands out among the compounds selected. Activity assays were performed with Plasmodium falciparum passou and 3CD7 strains, for which the IC50 values (doses resulting in 50% inhibition) were 320 and 400 ng mL(-1), respectively. These results are comparable with those obtained for quinine chlorhydrate (IC50 = 60 and 107.8 ng mL(-1)) and chloroquine sulphate (IC50 = 231 and 415 ng mL(-1)), the drugs used for reference. These results demonstrate the usefulness of our topological approach for the selection and design of new lead drugs active against Plasmodium falciparum.

Animals↗
PubMed2003

Antimalarial drug discovery: old and new approaches.

New drugs against malaria are greatly needed. Many approaches to antimalarial drug discovery are available. These approaches must take into account specific concerns, in particular the requirement for very inexpensive and simple to use new therapies and the need to limit the cost of drug discovery. Among important efforts that are currently ongoing are the optimization of therapy with available drugs, including the use of combination therapy, the development of analogs of existing agents, the discovery of natural products, the use of compounds that were originally developed against other diseases, the evaluation of drug resistance reversers, and the consideration of new chemotherapeutic targets. The last category benefits from recent advances in malaria research technologies and genomics and is most likely to identify new classes of drugs. A number of new antimalarial therapies will likely be needed over the coming years, so it is important to pursue multiple strategies for drug discovery.

Animals↗
PubMed2003

Trends in antimalarial drug deployment in sub-Saharan Africa.

Antimalarial drug resistance is forcing newly developed pharmaceuticals into widespread use at an accelerating pace. To have the greatest public health impact, new pharmaceuticals will need to be deployed effectively in sub-Saharan Africa. Achieving effective antimalarial drug deployment over the short- to medium-term will require an appreciation of how drugs are currently used in Africa and the development of innovative approaches to optimize that use. Over the long-term, fundamental changes in the way that drugs are deployed will probably be required. There are many new strategies and initiatives that, to a greater or lesser degree, will influence how drugs are used. These influences may have a positive or negative effect on reducing malaria morbidity and mortality. The concept of analyzing and monitoring programmatic effectiveness allows for a more holistic understanding of these influences and allows for more unbiased, evidence-based decision making related to drug policy and deployment.

Africa South of the Sahara↗