Azadirachta indica extract–artesunic acid combination produces an increased cure rate of Plasmodium berghei-infected mice

Context: Available artemisinin-combination therapies (ACTs) are expensive. Various traditional herbal remedies for malaria involve plants, proven scientifically to have antiplasmodial effects, e.g., Azadirachta indica A. Juss. (Meliaceae).

Objective: Combination of an artemisinin-based compound and a medicinal herb extract will provide an indigenous alternative/herb-based ACT.

Materials and methods: The in vivo schizontocidal activity of the crude aqueous extract of 100, 500, and 1000?mg/kg of A. indica fresh leaves (NCE) and 6, 15, and 20?mg/kg of artesunic acid were determined, alone and in combination, while keeping the dose of artesunic acid constant at 15?mg/kg, using the Peter’s 4-day suppressive test and Swiss albino mice. The ED₅₀ was calculated from the dose-response relationships. Percentage survival and cure were also determined.

Results: The average yield of two extractions of NCE was 8.33?±?1.67%. Combination of 1000?mg/kg of NCE and 15?mg/kg of artesunic acid, produced a significant reduction of parasitemia (96.87%), compared to 20?mg/kg of artesunic acid alone (68.14%). The combination had an ED₅₀ of 0.58?mg/kg while that of artesunic acid alone was 8.814?mg/kg. The combinations of NCE with artesunic acid produced a cure, although the artesunic acid did not produce a cure in 30?d.

Discussion: NCE increased the activity of artesunic acid in terms of reduction in parasitemia, and increased survival time and cure rate.

Conclusion: The combination of an artemisinin and aqueous extract of neem leaf is possible, providing a potentiated reduction of parasitemia, and increased cure rate.     

Reversal activity of the naturally occurring chemosensitizer malagashanine in Plasmodium malaria

Malagashanine (MG) is the parent compound of a new type of indole alkaloids, the N(b)C(21)-secocuran, isolated so far from the Malagasy Strychnos species traditionally used as chloroquine adjuvants in the treatment of chronic malaria. Previously, it was shown to have weak in vitro intrinsic antiplasmodial activity (IC(50) = 146.5 +/- 0.2 microM), but did display marked in vitro chloroquine-potentiating action against the FcM29 chloroquine-resistant strain of Plasmodium falciparum. The purpose of the present study was to further investigate its reversal activity. Thus, the previous in vitro results were tested in vivo. The interaction of MG with several antimalarials against various strains of P. falciparum was also assessed. As expected, MG enhanced the effect of chloroquine against the resistant strain W2, but had no action on the susceptible strain 3D7 and two sensitive isolates. Interestingly, MG was found to exhibit significant chloroquine-potentiating action against the FcB1 strain formerly described as a resistant strain but one which has since lost its resistance for unknown reasons. One other relevant result that arose from our study was the observation of the selective enhancing action of MG on quinolines (chloroquine, quinine, and mefloquine), aminoacridines (quinacrine and pyronaridine), and a structurally unrelated drug (halofantrine), all of which are believed to exert their antimalarial effect by binding with haematin. MG was finally found to specifically act with chloroquine on the old trophozoite stage of the P. falciparum cycle. Similarities and differences between verapamil and MG reversal activity are briefly presented.     

Antimalarial efficacy of arteether against multiple drug resistant strain of Plasmodium yoelii nigeriensis

New quick-acting blood schizontocides are needed to contain the spread of multiple drug resistant strains of P. falciparum and for the treatment of the cerebral malaria cases. A multiple drug resistant strain of P. yoelii nigeriensis resistant to mefloquine (128 mg/kg x 6 days), quinine (300 mg/kg x 7 days) and chloroquine (64 mg/kg x 8 days) was found to be completely susceptible to arteether (a 30:70 mixture of alpha and beta enantiomers) and a dose of 5 mg/kg x 3 days by i.m. route was curative in Swiss mice. Artemisinin at 50 mg/kg x 7 days had only suppressive action against this strain.     

In vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline against Plasmodium falciparum.

The in vitro activity of the enantiomers of mefloquine, halofantrine and enpiroline was compared against chloroquine-resistant and -susceptible strains of Plasmodium falciparum using a semi-micro drug susceptibility test. For each strain, the corresponding enantiomers exhibited similar activities. The enantiomers of halofantrine were the most active against both susceptible and resistant strains, followed by the enantiomers of mefloquine and enpiroline.     

Haem polymerase as a novel target of antimalarial action of cyproheptadine

An antihistaminic drug, cyproheptadine (20-25mg/kg x 4 days), showed significant schizontocidal activity in the blood against a lethal multidrug-resistant (MDR) strain of Plasmodium yoelii nigeriensis (highly resistant to chloroquine, mefloquine, and quinine); the protection of mice ranged between 75 and 100%. A combination of cyproheptadine (15 mg/kg) and chloroquine improved antimalarial activity compared to treatment with either drug alone, whereas a combination of cyproheptadine with quinine or mefloquine did not improve its antimalarial activity. Chloroquine and cyproheptadine inhibited haem polymerization activity in cell-free extracts and in in vivo experiments with MDR P. yoelii, but the combination did not cause a more significant inhibition than found with either drug alone. Cyproheptadine has been shown to produce dose-dependent inhibition of haem polymerization activity both in vitro and in vivo. The mechanism of the antimalarial action of cyproheptadine and its enhanced antimalarial activity with chloroquine could be due, in part, to their inhibitory effect on haem polymerization.     

Impact of residual and therapeutic doses of ciprofloxacin in the human-flora-associated mice model

A study was conducted to evaluate the effects of therapeutic and residual doses of ciprofloxacin on the human intestinal flora implanted into germ-free mice. Ciprofloxacin was administered daily via drinking water at concentrations to provide doses of 0, 0.125, 1.25, and 12.5mg/kg b.w. Changes in the intestinal flora composition, alteration in bacterial enzyme activities, fecal short chain fatty acid concentration and bacterial cellular fatty acid profiles, overgrowth of resistant bacteria, and disruption of the colonization barrier were the endpoints evaluated in the feces of human-flora-associated (HFA) mice. Ciprofloxacin at all tested doses decreased significantly the aerobic populations and particularly the population of Enterobacteriaceae. Selection of resistant Bacteroides fragilis group was noticed in HFA mice receiving 12.5mg/kg b.w. In mice challenged with a Salmonella strain, exogenous Salmonella persisted in the feces of all treated mice indicating that the flora responsible for the colonization barrier effect was disturbed by the antibiotic treatment. None of the studied metabolic parameters of the flora were affected by ciprofloxacin at any dose level. Under the experimental conditions of the study, the no-observed-effect level of ciprofloxacin was found to be less than 0.125 mg/kg b.w.     

Quinoline antimalarials as investigational drugs for HIV‐1/AIDS: in vitro effects on HIV‐1 replication,HIV‐1 response to antiretroviral drugs,and intracellular antiretroviral drug concentrations

In this study, the effects of the quinoline antimalarials, chloroquine and mefloquine, were tested on: (1) HIV‐1 replication; (2) virus response to existing antiretrovirals; (3) functional activity of drug efflux pumps; and (4) intracellular accumulation of antiretrovirals. Antiretroviral activity was evaluated using cells acutely infected with drug‐sensitive/resistant HIV‐1 isolates or retroviral vectors, chronically infected cell lines, and syncytium assays. Drug interactions were assessed isobolographically. Activity of efflux pumps was tested using specific fluorochromes. Antitretroviral concentrations were quantitated by HPLC. Results indicated that: (1) the antimalarials (mefloquine > chloroquine) inhibited the replication of drug‐sensitive and drug‐resistant HIV‐1 at therapeutically achievable concentrations and specifically impaired the formation of fusion‐competent viral glycoproteins; (2) anti‐HIV‐1 effects were additive to those of zidovudine and nevirapine, and synergistic to those of lopinavir; (3) the antimalarials (mefloquine > chloroquine) inhibited the P‐glycoprotein, multidrug‐resistance‐associated proteins, and breast‐cancer resistance‐associated protein; (4) Chloroquine, but not mefloquine, increased lopinavir concentrations in peripheral blood mononuclear cells (PBMCs) by approximately 5 (five)‐fold. Thus quinoline antimalarials inhibited HIV‐1 replication by a novel mechanism, resulting in additive or synergistic effects in combination with known antiretrovirals. These drugs may also have an impact on the cellular pharmacokinetics of antiretrovirals. Drug Dev. Res. 67:806–817, 2006. © 2007 Wiley‐Liss, Inc.     

Effect of artemisinins and amino alcohol partner antimalarials on mammalian sarcoendoplasmic reticulum calcium adenosine triphosphatase activity

The aim of this study was to assess the ability of currently deployed antimalarials to inhibit mammalian sarcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA). Artemisinins exert their antiplasmodial action by inhibiting parasite PfATP6, a SERCA enzyme, and possess neurotoxic potential; mefloquine is neurotoxic and inhibits mammalian SERCA, an orthologue of PfATP6. SERCA in rabbit muscle was tested in vitro for inhibition by artemisinin and amino alcohol antimalarials. Significant inhibition of mammalian SERCA, as mean difference from uninhibited, control values was seen with both enantiomers of mefloquine: (+)-mefloquine (10 microM: -35.83, 95% CI -59.63 to -12.03; 50 microM: -54.06, 95% CI -77.86 to -30.26); (-)-mefloquine (10 microM: -24.35, 95% CI -41.56 to -7.15; 50 microM: -58.42, 95% CI -75.62 to -41.22); lumefantrine (1 microM: -25.46, 95% CI -45.82 to -5.10; 5 microM -34.83, 95% CI -60.08 to -9.58; 10 microM: -25.80, 95% CI -51.05 to -0.55); desbutyl-lumefantrine (5 microM: -50.16, 95% CI -84.24 to -16.08); dihydroartemisinin (1 microM: -39.25, 95% CI -63.74 to -14.76; 5 microM: -39.30, 95% CI -64.88 to -13.72). Dihydroartemisinin in higher concentrations (10 microM) stimulated SERCA activity: (+40.90, 95% CI 11.37 to 70.44). No statistically significant inhibition was seen with artemether at 1, 5 and 10 microM. Equimolar combinations of artemether and lumefantrine or of dihydroartemisinin and lumefantrine, when studied at concentrations that inhibit SERCA individually, failed to show any inhibition. Dihydroartemisinin, mefloquine, lumefantrine and desbutyl lumefantrine inhibit mammalian SERCA at periphysiological concentrations, although the neurotoxicity of mefloquine is not wholly attributable to this property. Candidate antimalarials should be screened pre-clinically for SERCA inhibition.     

Biopharmaceutics: Submicron Oil-in-water Emulsion Formulations for Mefloquine and Halofantrine: Effect of Electric-charge Inducers on Antimalarial Activity in Mice

Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non-ionic submicron emulsions containing halofantrine and mefloquine. The in-vivo antimalarial activity of drug-loaded emulsions, evaluated in mice, was affected by the nature of the additives used. In particular, the electric-charge inducers markedly affected the pharmacological activity of mefloquine, but not of halofantrine. After subcutaneous administration ED50 values (the doses affording 50% protection) were 3 and 15 mg kg^?1, respectively, for halofantrine and mefloquine emulsions without charge inducers. The mefloquine-loaded emulsions with charge inducers were active at 10 mg kg^?1 for dicetylphosphate, 17 mg kg^?1 for phosphatidylserine, 23 mg kg^?1 for oleic acid and 27 mg kg^?1 for stearylamine, again after subcutaneous administration. This work has enabled the formulation of stable emulsions, incorporating drugs with high antimalarial activity, which are proposed for parenteral delivery of these fairly soluble drugs.     

Reversal of chloroquine and mefloquine resistance in Plasmodium falciparum by the two monoindole alkaloids, icajine and isoretuline

Eight naturally occurring monoindole alkaloids were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance of a chloroquine-resistant strain of Plasmodium falciparum. None of these indole alkaloids has significant intrinsic antiplasmodial activity (IC(50) > 10 microM or 5 microg/ml). Nevertheless, three alkaloids (icajine, isoretuline and strychnobrasiline) did reverse chloroquine resistance at concentrations between 2.5 and 25 microg/ml (IF of 12.82 for isoretuline on W2 strain). The Interaction Factor (IF) equals 2, < 2, or > 2 for additive, antagonistic or synergistic effects of alkaloids on chloroquine inhibition, respectively. Icajine and isoretuline were also assessed in vitro for their mefloquine potentiating activity on a mefloquine-resistant strain of Plasmodium falciparum. Only icajine proved to be synergistic with mefloquine (IF = 15.38).     

Pharmacokinetic and pharmacodynamic interactions of mefloquine and quinine

This study was carried out to investigate the pharmacokinetic and pharmacodynamic interactions between two antimalarial drugs, mefloquine and quinine. A randomized, comparative, three-way crossover study was performed in seven healthy male Thais after the administration of three drug regimens on three occasions i.e., a single oral dose of quinine sulfate (600 mg), mefloquine (750 mg) alone, or the combination of mefloquine (750 mg) and quinine (600 mg given 24 h after mefloquine). QTc interval was significantly prolonged in subjects following the combination regimen (at 2.5, 3, 4, 6, 8, 12, 18, 24 h after the quinine dose) but no abnormal clinical signs or symptoms were found. There were no significant changes in vital signs or routine laboratory values in any of the subjects. The pharmacokinetics of mefloquine and quinine were influenced by the presence of the other drug. Greater blood schizonticidal activities were collected from the sera of subjects on the combination regimen than from the sera of subjects the quinine or mefloquine regimens. The minimum inhibitory concentrations (MICs) of the equivalent concentrations (Eqs) of quinine or mefloquine, which completely inhibited the growth of the K1 strain of Plasmodium falciparum in vitro (MICs of quinine Eq and mefloquine Eq) were significantly lower in the sera of subjects on the combination regimens, than in the sera of subjects on mefloquine or quinine alone [MICs of quinine Eq: 41.2 (21.25-73.5) vs. 135 (118-150) ng/ml; MICs of mefloquine Eq: 18.2 (17-19.2) vs. 25.2 (24.4-26.8) ng/ml].     

Study of potential in vitro and in vivo genotoxicity in hepatocytes of quinolone antibiotics

The genotoxicity of quinolone antibiotics has been evaluated in hepatocytes following in vitro and in vivo exposure. Unscheduled DNA synthesis (UDS) was induced in vitro in rat hepatocytes by norfloxacin, ofloxacin, pefloxacin, and ciprofloxacin but not by nalidixic acid. In vivo UDS was not observed in hepatocytes isolated 4 to 24 hr after exposure of adult male F344 rats to either a single dose (30 to 190 mg/kg) or repeated doses (40 mg/kg) of ciprofloxacin. Using the 32P-postlabeling technique, no modified bases were detected in hepatocytes exposed in vitro to ciprofloxacin. In summary, UDS was induced in hepatocytes by in vitro exposure to high concentrations of norfloxacin, ofloxacin, pefloxacin, or ciprofloxacin. There was no evidence of in vitro DNA adduct formation by ciprofloxacin or in vivo DNA damage under the conditions tested. These findings suggest that ciprofloxacin is not DNA reactive, but it induces in vitro UDS as a consequence of some indirect action.     

Status of hepatic oxidative stress and antioxidant defense systems during chloroquine treatment of Plasmodium yoelii nigeriensis infected mice

BACKGROUND: Plasmodium yoelii nigeriensis (P. y. nigeriensis) produces lethal malaria infection in Swiss albino mice. Reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide have been implicated in the pathogenesis of malaria. OBJECTIVE: Study the effect of the chloroquine treatment on hepatic oxidative stress and antioxidant defense indices in multiple drug resistant (MDR) P. y. nigeriensis infected mice. METHODS: Mice were divided into four groups. Normal group, chloroquine treated normal group, P. y. nigeriensis infected group, and P. y. nigeriensis infected mice treated with chloroquine group (10 mg/kg body weight, i.p.). RESULTS: P. y. nigeriensis infection resulted in a significant decrease in the hepatic protein levels and caused a significant increase in the hepatic oxidative stress indices such as xanthine oxidase and lipid peroxidation and also an increase in the antioxidant defense indices viz, reduced glutathione (GSH), and glutathione reductase, but a significant decrease in superoxide dismutase (SOD) and catalase. The chloroquine treatment of P. y. nigeriensis (MDR strain) infected mice did not completely cure blood parasitemia, but resulted in a decrease of blood parasitemia. This was accompanied by decrease in hepatic oxidative stress indices and an associated change in the antioxidant defense indices towards normalization. CONCLUSION: Chloroquine therapy alone is not sufficient to treat the malaria infection caused by multiple drug resistant strain of P. y. nigeriensis. Therefore, there is a need to develop newer antimalarials which could act alone or in combination with traditional antimalarials to be effective against drug resistant malarial parasites.     

Population pharmacokinetic and pharmacodynamic modelling of artemisinin and mefloquine enantiomers in patients with falciparum malaria

OBJECTIVES: The aims of this study were to investigate whether artemisinin influences the pharmacokinetics of mefloquine enantiomers or vice versa and to model the antiparasitic effect of these drugs alone and in combination in Plasmodium falciparum malaria patients. METHODS: Forty-two male and female patients were randomised to treatment with either oral artemisinin 500 mg daily for 3 days followed by oral mefloquine 750 mg on day 4, oral artemisinin 500 mg daily for 3 days plus oral mefloquine 750 mg on day 1 or a single 750-mg oral dose of mefloquine. The data was modelled using NONMEM. RESULTS: All patients were successfully treated regardless of treatment. The fastest parasite clearance rates were observed in patients receiving artemisinin together with mefloquine on the first day of treatment. A pharmacodynamic model based on the life cycle of P. falciparum successfully described the efficacy of artemisinin, mefloquine and the combination. The time artemisinin concentration stays above a minimum inhibitory concentration was estimated to 2.97 h (relative standard error 4.7 h). The two mefloquine enantiomers exhibited different pharmacokinetics, with an oral clearance of 3.51 (7.9) l/h and 0.602 (6.9) l/h for RS-mefloquine and SR-mefloquine, respectively. In patients receiving only artemisinin the first 3 days, artemisinin oral clearance was 6.9-fold higher the last day of treatment compared with the first day. There was no difference in the pharmacokinetics of mefloquine enantiomers when mefloquine was given alone, in combination with artemisinin or after a 3-day regimen of artemisinin. There was a tendency towards, although non-significant, higher artemisinin concentrations when artemisinin was given together with mefloquine compared with when given alone. CONCLUSIONS: No significant pharmacokinetic interactions were observed after co-administration of artemisinin and mefloquine. The P. falciparum malaria pharmacodynamic model successfully described the antimalarial effect of artemisinin, mefloquine and a combination of the two drugs.     

Pharmacodynamic analysis of antimalarials used in Plasmodium falciparum imported malaria in northern Italy

BACKGROUND: Conventional treatment of imported malaria in Italy consists of quinine or mefloquine. Since beta-arthemeter is now available, an open-label pharmacodynamic analysis was performed in 73 adults with uncomplicated Plasmodium falciparum malaria. In vitro susceptibility to mefloquine and quinine was evaluated at admission. METHODS: According to clinical status, baseline parasitemia (P(0)), and premunition, the patients received intravenous quinine, oral mefloquine, or beta-arthemeter. The following parameters were measured: parasitemia at 0, 6, 12, and 24 hours and then every 24 hours until negative; time to 50%, 90%, and 100% reduction in parasite density (PC(50), PC(90), and PCT); parasite reduction ratio at 24 and 48 hours (PRR(24) and PRR(48)); percentage of patients with undetectable parasitemia at 48 hours (PPUP(48)); time required to eradication; in vitro susceptibility to mefloquine and quinine by World Health Organization Microtest Mark III. RESULTS: Of the study patients, 54.8% were immigrants from malaria-endemic countries. All the infections were acquired in Africa. All the patients were treated successfully. According to the pharmacodynamic parameters measured, no significant differences were recorded among patients with or without prior exposure to malaria. Pharmacodynamic comparison was performed between quinine and beta-arthemeter. Significantly higher clearance times were recorded for beta-arthemeter vs quinine (PC(50), PC(90), and PCT: 16.8, 42.6, and 72 h for quinine vs 7.9, 12.2, and 48 h for beta-arthemeter; p values: .02, < .0001, and .008, respectively). The number of patients who obtained a PPUP(48) with beta-arthemeter was higher than with quinine (66.7 vs 9.1%, p < .003), and PRR(24) was significantly higher in beta-arthemeter-treated patients (617 vs 3.15, p = .0001). PRR(48) and time to eradication were not measurable in the beta-arthemeter group (negative P at 48 h in most cases). Two recrudescences occurred after 5 and 7 days of beta-arthemeter monotherapy. All strains were fully susceptible to quinine and mefloquine. CONCLUSIONS: Pharmacodynamic properties of mefloquine and quinine are in the range reported in literature. The better PCT and pharmacodynamics of beta-arthemeter suggest that it could be used as a first-line agent, coadministered with mefloquine.     

Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action

A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. The IC(50) values of several compounds (11a, 11k-m, 11o, 13) against Plasmodium falciparum (strain K1) were <0.1 muM, 5-10-fold lower than that of 1 but their cytotoxicities were only 2-4 times greater than that of 1. Compounds with a halogen in the quinoline ring and a halogen or a nitro group in the indole ring have enhanced antiplasmodial activity. In mice infected with P. berghei, the 7-bromo-2-chloro (11k) and 2-bromo-7-nitro (13) derivatives of 1 suppressed parasitemia by >90% at doses of 25 mg kg(-1) day(-1) with no apparent toxicity to the mice. 2,7-Dibromocryptolepine (15) was evaluated at several dose levels, and a dose-dependent suppression of parasitemia was seen (ED(90) = 21.6 mg kg(-1) day(-1)). The antimalarial mode of action of 1 appears to be similar to that of chloroquine and involves the inhibition of hemozoin formation. A number of analogues were assessed for their effects on the inhibition of beta-hematin (hemozoin) formation, and the results were compared with their antiplasmodial activities having taken account of their predicted accumulation into the acidic parasite food vacuole. No correlation was seen (r(2) = 0.0781) suggesting that the potent antimalarial activity of compounds such as 15 involves other mechanisms in addition to the inhibition of hemozoin formation.     

Antimalarial activity of new water-soluble dihydroartemisinin derivatives

The usefulness of sodium artesunate (3), a water-soluble derivative of artemisinin (1), is impaired by its poor stability in aqueous solution. To overcome the ease of hydrolysis of the ester group in 3, a new series of derivatives of dihydroartemisinin (2) was prepared in which the solubilizing moiety, which contains a carboxylate group, is joined to dihydroartemisinin by an ether rather than an ester linkage. The new derivatives were prepared in good yield by treatment of dihydroartemisinin with an appropriate alcohol under boron trifluoride etherate catalysis at room temperature. All major condensation products are the beta isomer. Hydrolysis of the esters with 2.5% KOH/MeOH gave the corresponding potassium salts, which were converted to free acids (8b-d) by acidification. The derivatives were tested in vitro against two clones of human malaria, Plasmodium falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone). No cross-resistance to the antimalarial agents mefloquine, chloroquine, pyrimethamine, sulfadoxine, and quinine was observed. In general, the new compounds are more effective against the W-2 than the D-6 strain. Esters (5a-d) possess activity comparable to that of the parent compounds 1 and 2; however, conversion of the esters to their corresponding carboxylates (7a-d) or acids (8b-d), with the exception of artelinic acid (8d), drastically decreases the antimalarial activities in both cell lines. Artelinic acid, which is both soluble and stable in 2.5% K2CO3 solution, possesses superior in vivo activity against Plasmodium berghei than artemisinin or artesunic acid.     

Pharmacological evaluation of garenoxacin,a novel des-F(6)-quinolone antimicrobial agent: effects on the central nervous system

The effects of garenoxacin (formerly T-3811 or BMS-284756) on the central nervous system (CNS) were compared with various quinolones. Garenoxacin injected intracerebroventricularly into mice caused clonic convulsion at a higher dose (50 micrograms/body) than norfloxacin, ciprofloxacin, sitafloxacin and trovafloxacin. Additionally the convulsant activity of garenoxacin was not potentiated by biphenylacetic acid (BPAA). Garenoxacin did not induce any convulsions at intravenous doses up to 60 mg/kg in combination with 200 mg/kg oral administration of fenbufen in mice, and its convulsant activity was weaker than those of enoxacin, norfloxacin, ciprofloxacin, alatrofloxacin and ofloxacin. In addition, convulsions were not induced by combination administration of garenoxacin (60 mg/kg, i.v.) and any of 9 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) or BPAA. In a rotarod test, which was performed in order to evaluate the drug-induced dizziness, coordinated locomotor activity of mice was suppressed by alatrofloxacin at an intravenous dose of 60 mg/kg, but not by garenoxacin, ciprofloxacin and norfloxacin at up to 60 mg/kg. In an in vitro study using rat brain synaptic membrane, garenoxacin had no inhibitory effect on GABA binding in the presence or absence of NSAIDs. In conclusion, the effects of garenoxacin on CNS were weaker than those of other quinolones in experimental animals, so it might possess a low potential for CNS adverse reactions such as convulsion and dizziness in clinical use.     

Compliance with a 2 day course of artemether-mefloquine in an area of highly multi-drug resistant Plasmodium falciparum malaria

Aims Multi-drug resistant Plasmodium falciparum malaria is a rapidly increasing problem in the world, particularly Thailand. Practical antimalarial regimens which are highly effective against multi-drug resistant parasites with short-term course of administration are needed. In this study, we assessed the patient compliance of a short course regimen using artemether-mefloquine.
Methods Clinical effectiveness (efficacy, tolerability and patient compliance) of a 2-day regimen of artemether-mefloquine was evaluated in 126 patients with acute uncomplicated falciparum malaria who were attending the two malaria clinics in an area of highly multi-drug resistant P. falciparum malaria (Thai-Myanmar border). Patients were treated with a single oral dose of 300  mg artemether on the day of attendance. Two additional doses of mefloquine were given for home treatment on the following day (750 and 500  mg after breakfast and lunch, respectively).
Results The combination regimen was effective, with a cure rate of 92.6%. Based upon the concentrations of whole blood mefloquine on day-2, compliance for this 2 day regimen of artemether-mefloquine was 98.1% (full compliance 86.8%, partial compliance 11.3%, non-compliance 1.9%).
Conclusions We conclude that the 2 day regimen of artemether-mefloquine is, at present, a good alternative regimen for the treatment of uncomplicated multi-drug resistant falciparum malaria.