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PubMed1981

Antimalarial activity of cyclosporin A.

Cyclosporin A has been shown to possess antimalarial activity in mice infected with Plasmodium berghei NK 65 or Plasmodium chabaudi. Significant antimalarial effects were obtained with five daily oral doses of 25 mg/kg. Cyclosporin A treatment started concurrently with the inoculation of parasites was less effective than treatment started when parasitaemia was already established. Evidence so far suggests that the antimalarial action results from a direct toxic effect on the parasite. Combined treatment with Cyclosporin A and Pyrimethamine indicated that the two compounds may act synergistically.

Animals↗
PubMed1997

Adverse effects and compliance with mefloquine or proguanil antimalarial chemoprophylaxis.

OBJECTIVE: We had the impression that adverse reactions to standard antimalarial prophylaxis were reported much more often than stated by the package insert and medical drug references; and that side effects adversely affected compliance. Therefore, we evaluated adverse effects and compliance of the two standard malaria prophylactic regimens (mefloquine 250 mg per week and proguanil 100 mg twice per day) among short-term travellers. We expected that travellers who had experienced possible adverse effects on previous journeys might avoid antimalarial drugs on subsequent journeys (self-selection) and we therefore looked at adverse effects dependent on prior use. METHODS: The presence of neuropsychological and gastrointestinal symptoms were assessed by telephone interviewing of 300 travellers who had visited the travel vaccination service of our regional public health institute. Symptoms, prior use and non-compliance of 104 mefloquine users and 103 proguanil users were compared with 93 non-users in order to control for travel-related symptoms. RESULTS: Mefloquine showed the following adverse effects: depression [excess risk (ER) 7.2 per 100 users], dizziness (ER 9.3) and itching (ER 12.3). Adverse effects of proguanil were dizziness (ER 7.5) and nausea (ER 12.7). Adverse effects were mostly mild to moderate and occurred mainly during the time abroad. These results did not change when adjusting for age, sex, or destination. For almost every symptom, we found a remarkable difference between the relationship of symptoms and antimalarial drugs in first-time users and that in prior users: in the first-time users the relationship was positive, while in prior users it was absent or negative. This could be due to self-selection or adaptation to adverse effects. 22% of mefloquine users were non-compliant, whereas 35% of proguanil users were non-compliant. Adverse effects (experienced or expected) were the most often reported reason for mefloquine users to stop or even not to start taking the drug (42%). For proguanil, most of the non-compliant participants saw no point in starting or continuing its use (perceived uselessness 54%). CONCLUSION: We can confirm the reports by users that adverse effects of mefloquine and proguanil are common and, although mostly mild, adversely affect compliance. We suggest that a longer run-in period for mefloquine as well as counselling travellers about possible adverse effects might improve compliance.

Adult↗
PubMed2002

Synergistic in vitro antimalarial activity of plant extracts used as traditional herbal remedies in Mali.

In Mali, where malaria is endemic, plants are extensively used for treating periodic fevers and malaria. According to the advice of traditional medicine, plants are often mixed during the preparation of febrifugal decoctions. In previous studies, we demonstrated the potent in vitro antimalarial activity of extracts isolated from four plants commonly used in traditional remedies: Mitragyna inermis (Willd.) O. Kuntze, Rubiaceae, Nauclea latifolia (Sm.), Rubiaceae, Guiera senegalensis (Gmel.), Combretaceae, and Feretia apodanthera (Del.), Rubiaceae. In the present work, we evaluate the potent in vitro synergistic antimalarial interaction between these extracts, using standard isobologram analysis. Then, we evaluate their cytotoxicity on human monocytes and their mutagenic activity on an in vitro system of two beta-carboline alkaloids isolated from Guiera senegalensis (harman and tetrahydroharman). Three combinations demonstrate a strong, synergistic, inhibitory effect on in vitro plasmodial development and are devoid of cytotoxicity towards human cells. These results justify their use in association in traditional medicine. Moreover, tetrahydroharman, isolated from G. senegalensis, presents interesting antimalarial activity, no cytotoxicity and is not genotoxic in the Salmonella Ames test with and without metabolic activation.

Animals↗
PubMed1983

Antimalarial drugs for rheumatoid arthritis.

Chloroquine and hydroxychloroquine effectively suppress rheumatoid arthritis with a superior benefit to risk ratio. Controlled studies demonstrate moderate efficacy in about 70 percent of patients. High-grade suppression is seen in 15 percent and partial suppression in 55 percent. The dropout rate for poor efficacy is 30 percent and for side effects 3 to 7 percent. Most studies show antimalarials to be almost equivalent to chrysotherapy in potency. Antimalarials are indicated for active rheumatoid arthritis not optimally controlled with nonsteroidal anti-inflammatory drugs and for all cases of progressive disease. Therapy is continued indefinitely. Safe use of these drugs depends on daily dosage. With the single exception of late stage retinopathy, other adverse effects are fully reversible. Strict adherence to three tested safety rules virtually eliminates retinopathy and prevents loss of vision: (1) limit the daily dosage: chloroquine 3.5 to 4.0 mg/kg per day or hydroxychloroquine 6.0 to 6.5 mg/kg per day based on lean body weight; (2) subject the patient to an annual ocular examination to age 65, twice annually thereafter; (3) adjust treatment for pharmacokinetic variables. The lower risk and nearly comparable efficacy make antimalarials first choice among remittive drugs.

Amodiaquine↗
PubMed1988

Antimalarial drugs and pregnancy.

The use of chloroquine and hydroxychloroquine during pregnancy is controversial. These 4-aminoquinoline drugs cross the placenta and have been reported to cause fetal abnormalities, including loss of vision, ototoxicity, and cochleovestibular dysfunction. However, other reports suggest that 4-aminoquinoline drugs can be taken safely during pregnancy, even in dosages used to control systemic connective tissue diseases. We retrospectively studied eight patients who took antimalarial drugs continuously throughout pregnancy. There was a total of 14 pregnancies in women receiving these drugs; three occurred during periods of disease activity and all of these resulted in failure to complete pregnancy successfully. Of the remaining 11 pregnancies exposed to antimalarial drugs, one resulted in stillbirth; four resulted in spontaneous abortion; and six had normal full-term standard deliveries. None of the live births demonstrated any congenital abnormalities. Hence, it is possible for women to produce normal live babies despite taking large doses of these drugs. If patients with systemic lupus erythematosus are already taking antimalarial drugs when they become pregnant, it is believed that the risk of disease flare and loss of pregnancy from discontinuing therapy outweighs any risks to fetuses from continuing the medication.

Antimalarials↗
PubMed1988

Antimalarial agents compared with or in combination with other disease-modifying antirheumatic drugs.

Available published comparisons of antimalarial drugs with other disease-modifying antirheumatic drugs (DMARDs) are reviewed, as well as reports of combinations of DMARDs, in the treatment of rheumatoid arthritis and juvenile rheumatoid arthritis. These reports suggest that antimalarial drug toxicity is less than that of parenteral gold, D-penicillamine, auranofin, or dapsone. Its efficacy appears to be equal to or slightly less than that of most comparison DMARDs. Combinations of DMARDs with antimalarials are probably used by a substantial proportion of rheumatologists, but the few prospective, double-blind studies with a balanced design show little or no advantage to combination DMARD therapy. Open, nonrandomized studies and preliminary reports suggest that combination therapy may be useful, usually when another DMARD is added to one or more DMARDs to which the patients did not have a satisfactory response. A few large, prospective, double-blind, randomized studies comparing hydroxychloroquine with several other DMARDs and placebo are needed to establish more confidence in the relative efficacy and utility of hydroxychloroquine. Although the rationale for combination DMARD therapy is attractive, additional preliminary studies of the various possible combinations and doses are needed before definitive trials of promising combinations can be justified.

Anti-Inflammatory Agents↗
PubMed1988

Effects of quinoline-containing antimalarials on the erythrocyte membrane and their significance to drug action on Plasmodium falciparum.

Quinoline-containing antimalarials are cationic amphiphiles which accumulate to high levels in lysosomes and are known to interact with membrane phospholipids. It was therefore hypothesized that they could exert their antimalarial effect by compromising the integrity of the parasite's acidic organelles. To test this hypothesis, the effects of chloroquine (CQ), quinine (Q) and mefloquine (MQ) on the osmotic stability of human red blood cells exposed to hypotonic solutions have been investigated. With CQ and Q stabilization was observed at pH 7.8 and destabilization at pH 5, indicating that destabilization is caused by the protonated forms of the drugs. With MQ the pH dependence was reversed, i.e. it destabilized at pH 7.8 and stabilized at pH 5, suggesting that destabilization is caused by the unprotonated drug. MQ caused cell lysis at the tenth millimolar range by a detergent effect. The possible destabilizing effect of drugs on the membranes of Plasmodium falciparum acidic organelles was investigated in metabolically-labelled parasites. We expected an increase in degradation of parasite proteins if drugs did indeed cause the release of acid hydrolases from destabilized organelles to the cytoplasm. No effect of drugs on parasite protein degradation could be observed, but protein synthesis was inhibited at therapeutic drug concentrations. These results imply that quinoline-containing antimalarials do not compromise the integrity of parasite acidic organelles, and that inhibition of protein synthesis results from a limited supply of essential amino acid(s) due to the demonstrable drug-mediated suppression of parasite digestion of host cell cytosol.

Animals↗
PubMed1989

Alkalinization of the food vacuole of malaria parasites by quinoline drugs and alkylamines is not correlated with their antimalarial activity.

Quinoline-containing antimalarial drugs accumulate inside the acid food vacuole of the parasite where they inhibit the digestion of ingested host cell cytosol, and consequently, parasite growth. In order to verify whether this inhibition is caused by drug-induced alkalinization of the food vacuole, we investigated the accumulation of acridine orange (AO) as a vacuolar pH probe in intact Plasmodium falciparum-infected human erythrocytes as affected by the drugs chloroquine (CQ), 7H-quinoleine (7HQ), quinine (Q) and mefloquine (MQ). It was established by various criteria that AO accumulates primarily in the acid compartment(s) of the parasite as a function of the pH difference between it and the extracellular medium. This pH gradient was dissipated by the drugs in the rank order MQ greater than CQ greater than Q greater than 7HQ. The kinetics of vacuolar alkalinization and the concentration ranges at which it was observed imply that the monoprotic drugs MQ and Q exerted their effect mostly by translocating protons across the vacuolar membrane, i.e. they could cross the membrane as a protonated species, while the diprotic drugs CQ and 7HQ raised the vacuolar pH mostly by proton trapping. Similarly, hydrophobic alkylamines raised the vacuolar pH by proton translocation, while their relatively more polar congeners and ammonia did so by proton titration. However, the alkalinizing effect of each drug was observed at a concentration which was 1-2 orders of magnitude larger than the IC50 of its antimalarial effect. These results mean that vacuolar alkalinization is not the primary effect of antiparasitic action of quinoline antimalarials.

Acridine Orange↗
PubMed1987

Effect of artemisinin (qinghaosu) and chloroquine on drug-sensitive and drug-resistant strains of Plasmodium falciparum malaria: use of [2,8-3H]adenosine as an alternative to [G-3H]hypoxanthine in the assessment of in vitro antimalarial activity.

Using [G-3H]hypoxanthine uptake as a radioactive indicator for the growth of malarial parasites, we measured the antimalarial activity of artemisinin (Qinghaosu, QHS) against FCMSU1/Sudan strain (chloroquine-sensitive strain) and FCB K+ strain (chloroquine-resistant strain) of Plasmodium falciparum in continuous culture in vitro. The 50% inhibitory concentrations (IC50) for QHS against FCMSU1/Sudan strain and FCB K+ strain were 2.8 X 10(-8) and 3.0 X 10(-8) M, respectively. On the contrary, the response of the two strains to chloroquine was quite different. The IC50 for chloroquine against FCMSU1/Sudan strain was 5.6 ng/ml, whereas that for the FCB K+ strain was 65.6 ng/ml. Therefore, QHS did not appear to exhibit any cross-resistance with chloroquine. If [2,8-3H]adenosine was used as a radioactive precursor instead of [G-3H]hypoxanthine for the determination of antimalarial activity, virtually identical results were obtained. Therefore, [2,8-3H]adenosine can be used as an alternative to [G-3H]hypoxanthine for the assessment of antimalarial action.

Adenosine↗
PubMed1994

Comparison of in vivo and in vitro antimalarial activity of artemisinin, dihydroartemisinin and sodium artesunate in the Plasmodium berghei-rodent model.

The in vitro and in vivo antimalarial activity of artemisinin, artesunate and dihydroartemisinin has been compared using the Plasmodium berghei-rodent model. Drugs were added to synchronized short-term in vitro cultures of the erythrocytic stages and inhibition of parasite development was determined by measuring DNA synthesis by flow cytometry. Dihydroartemisinin was the most effective drug. IC50 values of artemisinin, artesunate and dihydroartemisinin were 1.9, 1.1 and 0.3 x 10(-8) M, respectively, when drugs were present during the complete 24 h developmental cycle. IC50 values increased significantly when drugs were added to old trophozoites, indicating that the older stages are less sensitive. To determine the in vivo antimalarial activity, mice with a parasitaemia between 1% and 3% were injected intramuscularly on 3 consecutive days with a single dose of the drugs dissolved in Miglyol 812. Again dihydroartemisinin was the most effective drug in vivo, showing a cure rate of 47% at 10 mg/kg bodyweight, while with both other drugs the recrudescence rate was 100% at the same dosage. This study showed that the P. berghei-rodent model is a useful tool for accurate comparisons of the in vivo and in vitro antimalarial activity of drugs.

Animals↗
PubMed1987

Synergistic antimalarial activity of dapsone/dihydrofolate reductase inhibitors and the interaction of antifol, antipyrimidine and antipurine combinations against Plasmodium falciparum in vitro.

Using low folate, low p-aminobenzoic acid medium, 2 isolates of Plasmodium falciparum were tested in vitro against a wide range of antimetabolite compounds with known or potential antimalarial activity. ID50 values (the concentration of compound causing 50% inhibition of [3H]hypoxanthine incorporation) were determined for each compound against both isolates. The compounds tested may affect folate, pyrimidine or purine metabolism in malaria parasites and various combinations of compounds were examined for further synergistic antimalarial effects. The combination of any of the dihydrofolate reductase inhibitors cycloguanil, pyrimethamine or WR 99210 with the sulphone drug dapsone demonstrated strongly synergistic antimalarial activity. Combinations of dihydrofolate reductase inhibitors with the antipyrimidine compounds pyrazofurin or menoctone, or with the antipurine compounds tubercidin, bredinin or hadacidin, or with primaquine, failed to demonstrate synergistic activity. Most combinations of an antipurine with an antipyrimidine compound also failed to show any synergistic effect. However, weak synergism was consistently seen in the tubercidin/pyrazofurin and tubercidin/menoctone combinations. Over the 48 h intraerythrocytic cycle using tightly synchronized parasites, tubercidin demonstrated both a cytotoxic and a cytostatic effect.

Animals↗
PubMed1994

Economic prospects for a new antimalarial drug.

The market for antimalarial drugs consists of the 2.8 billion (2.8 x 10(9) people living in malaria endemic areas and about 20-30 million people, mainly Europeans and North Americans, who travel or live in malarious areas, and the wealthy elite of malarious developing countries. Some of the largest markets include China, India, and Indonesia with a total of 1.9 billion people exposed; Latin America, with 119 million; and sub-Saharan Africa with 400 million. An estimated 200 million clinical cases occur each year, with around 2 million deaths annually, primarily in African children. Antimalarial drugs are distributed through several different networks and are purchased by governments and private individuals. At present the world market is dominated by chloroquine by virtue of its safety, wide availability and low price. Approximately 20% of the total production of chloroquine was distributed through national control programmes and 80% through other channels; chloroquine is probably the second or third most widely consumed drug in the world. The global market for antimalarial drugs is likely to be of the order of US$100-120 million, with chloroquine making up about US$64-80 m, sulfadoxine/pyrimethamine about US$20 m, and other drugs making up US$10-20 m. Chloroquine is rapidly losing its effectiveness against the malaria parasite, and a safe, effective, cheap replacement is urgently needed. Another product which was found to be safe and effective against malaria, with a price per treatment held at or near the present price of chloroquine, could quickly replace chloroquine as the first-line treatment against malaria.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimalarials↗
PubMed1986

Potential antimalarial candidates from African plants: and in vitro approach using Plasmodium falciparum.

Twenty-one compounds isolated from nine medicinal plants used in traditional medicine in the Sudan and other African countries were examined in vitro for antimalarial activity against Plasmodium falciparum, the major human malaria parasite. Compounds tested include alkaloids, lignans, triterpenes, coumarins, limonoids and flavonoids. Most were relatively inactive; one limonoid, gedunin, had an IC50 value of about 1 microM after 48 h exposure (0.3 microM after 96 h), roughly equivalent to quinine. In this protocol, the flavonoid quercetin purified from Diosma pilosa was found to have the same activity as a commercially obtained preparation. Simple radiometric assays for antimalarial activity can thus be used to rapidly screen purified plant material or secondary plant metabolites. The high potency and efficacy of quinine and the Chinese herbal antimalarial quinghaosu (artemisinine) illustrate the merit of this approach.

Africa↗
PubMed1991

Can ethnopharmacology contribute to the development of antimalarial agents?

The resistance of Plasmodium falciparum, the cause of tertian malaria, to synthetic antimalarials, together with the resistance of the vector mosquitoes to insecticides, has resulted in a resurgence in the use of quinine and a search for new antimalarial agents. In recent years, artemisinin, isolated from Artemisia annua which is used in Chinese traditional medicine for the treatment of malaria, has proved to be effective in the treatment of cerebral malaria due to chloroquine-resistant strains of P. falciparum. The development of in vitro tests utilising P. falciparum obtained from malaria patients means that it is possible to use bioassay guided fractionation of active extracts in order to isolate active principles. A number of laboratories throughout the world are currently investigating plants used in traditional medicine for their active constituents. Some of their results will be described and in particular two aspects of our investigations with species of Simaroubaceae and Menispermaceae will be discussed. There is every possibility that such approaches which use leads from Ethnopharmacology will result in the development of new antimalarial agents. It is vitally important to those populations relying on traditional medicines for the treatment of malaria that the safety and efficacy of such medicines be established, their active principles determined and that reproducible dosage forms be prepared and made available for use.

Animals↗
PubMed2005

Inhibition assay of beta-hematin formation initiated by lecithin for screening new antimalarial drugs.

Measurement of heme crystallization provides a tool for screening new antimalarial drugs. Current assays for heme crystallization have employed initiators such as thermo, histidine-rich proteins, and lipids extracted from parasites and infected plasma. These initiators are unnatural or require laborious steps to prepare. In this study, we used a commercially available lipid, lecithin, a kind of phospholipid containing about 50% unsaturated fatty acids, as an initiator for heme crystal (beta-hematin) formation. We demonstrated that the inhibition of lecithin-based beta-hematin formation by antimalarial drugs is highly correlated with the preformed beta-hematin-based method. In addition, the lecithin-based assay is sensitive and convenient for large-scale screening of new novel antimalarials. We also indicated that dimethyl sulfoxide is an ideal solvent for preparation of heme stock solution, which is stable and can be used for 1 month.

Antimalarials↗
PubMed2004

Development of artemisinin and its structurally simplified trioxane derivatives as antimalarial drugs.

Artemisinin and simplified trioxane analogs constitute a promising class of antimalarial chemotherapeutic agents. Their development since the early 1970s into clinical trials and clinical use has drawn much attention from medical scientists worldwide although the crude extract containing artemisinin has been used in China for treatment of fever for many centuries. Many research groups have independently and collaboratively conducted various studies on the artemisinin system both in search for the new compounds more antimalarially active than the parent artemisinin and in an attempt to understand its molecular mechanism(s) of action. Ongoing studies have provided a better understanding of the putative intermediates essential for the antimalarial activity and have led to designer trioxanes whose chemical structures have been simplified and modified to increase efficacy while lowering toxicity. Other desirable features beneficial to clinical uses such as bioavailability, drug stability and water solubility have been considered, and portions of the trioxane skeleton have been added or modified to accommodate these parameters accordingly.

Anti-Infective Agents↗
PubMed2005

Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana.

The emergence and spread of Plasmodium falciparum resistance to commonly used antimalarials such as chloroquine and sulphadoxine/pyrimethamine poses major challenges to malaria control in sub-Saharan Africa. We undertook a study on the efficacy of some antimalarial drugs in 2003 with the view of supporting the National Malaria Control Programme in the review of the antimalarial drug treatment policy in Ghana. Children aged 6-59 months with signs/symptoms of uncomplicated malaria including axillary temperature > or =37.5 degrees C; mono infection with P. falciparum; and parent's willingness to give consent, were randomized into four treatment groups and followed up for a maximum of 28 days. The treatment groups were chloroquine (CHQ), sulphadoxine/pyrimethamine (SP), amodiaquine+artesunate (ADQ+ART) combination, and artemether+lumefantrine (Coartem) combination. Clinical evaluation of 168 children studied showed that cumulative pcr-corrected cure rates on day 28 were 100% for ADQ+ART; 97.5% for coartem, 60% for SP and 25% for CHQ. The artemisinin-based combinations effected rapid fever and parasite clearance. Prevalence of gametocytaemia was highest in the SP group whilst the CHQ group did not show any significant changes in haemoglobin levels during the follow-up period. The findings are in agreement with current recommendations for using artemisinin-based combinations for treating uncomplicated malaria in areas of high CHQ failure such as Ghana.

Amodiaquine↗
PubMed2004

8-Quinolinamines conjugated with amino acids are exhibiting potent blood-schizontocidal antimalarial activities.

Alanine, lysine, ornithine and valine conjugated to primaquine and other 8-quinolinamine antimalarials were prepared for blood-schizontocidal antimalarial activity evaluation. The analogues were examined in vivo against Plasmodium berghei (drug-sensitive strain) and Plasmodium yoelii nigeriensis (highly virulent multi-drug-resistant strain) infected mice models. N(1)-[4-(5-Butoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyl]-(2S)-2,6-diaminohexanamide (20) which showed curative activity at 5mg/kg in the P. berghei test emerged as the most effective compound. N(1)-[4-(4-Ethyl-5-hexoxy-6-methoxy-8-quinolylamino)pentyl]-(2S)-2,6-diaminohexanamide (22) exhibited curative activity at 50mg/kg against P. yoelii nigeriensis in mice and emerged as the most potent analogue against multi-drug resistant strain. The results of this study represent development of highly potent 8-quinolinamines for antimalarial drug development.

Amino Acids↗