Influence of MAMA decoction, an Herbal Antimalarial, on the Pharmacokinetics of Amodiaquine in Mice.

BACKGROUND AND OBJECTIVE: MAMA decoction (MD) is an antimalarial product prepared from the leaves of Mangifera indica L. (Anacardiaceae), Alstonia boonei De Wild (Apocynaceae), Morinda lucida Benth (Rubiaceae) and Azadirachta indica A. Juss (Meliaceae). A previous report showed that MD enhanced the efficacy of amodiaquine (AQ) in malaria-infected mice, thus suggesting a herb-drug interaction. The present study hence evaluated the effect of MD on the disposition of AQ in mice with a view to investigating a possible pharmacokinetic interaction. METHODS: In a 3-period study design, three groups of mice (n = 72) were administered oral doses of AQ (10 mg/kg/day) alone, concurrently with MD (120 mg/kg/day), and in the 3rd period, mice were given AQ after a 3-day pre-treatment with MD. Blood samples were collected between 0 and 96 h for quantification of AQ and its major metabolite, desethylamodiaquine, by a validated high-performance liquid chromatography method. RESULTS: Maximum concentrations of AQ increased by 12% with the concurrent dosing of MD and by 85% in the group of mice pre-treated with MD. The exposure and half-life of desethylamodiaquine increased by approximately 11% and 21%, respectively, with concurrent administration. Corresponding increases of approximately 20% and 33% of desethylamodiaquine were also observed in mice pre-treated with MD. CONCLUSION: MD influenced the pharmacokinetics of AQ and desethylamodiaquine, its major metabolite. The increase in the half-life and systemic exposure of AQ following its co-administration with MD may provide a basis for the enhanced pharmacological effect of the combination in an earlier study in Plasmodium-infected mice.

Toxicokinetics of hydroxychloroquine following a massive overdose.

BACKGROUND: We report a patient with a massive hydroxychloroquine overdose manifested by profound hypokalemia and ventricular dysrhythmias and describe hydroxychloroquine toxicokinetics. CASE REPORT: A 20-year-old woman (60 kg) presented 1 h after ingesting 36 g of hydroxychloroquine. Vital signs were: BP, 66 mmHg/palpation; heart rate, 115/min; respirations 18/min; oxygen saturation, 100% on room air. She was immediately given intravenous fluids and intubated. Infusions of diazepam and epinephrine were started. Activated charcoal was administered. Her initial serum potassium of 5.3 mEq/L decreased to 2.1 mEq/L 1 h later. The presenting electrocardiogram (ECG) showed sinus tachycardia at 119 beats/min with a QRS duration of 146 ms, and a QT interval of 400 ms (Bazett's QTc 563 ms). She had four episodes of ventricular tachydysrhythmias requiring cardioversion, electrolyte repletion, and lidocaine infusion. Her blood hydroxychloroquine concentration peaked at 28,000 ng/mL (therapeutic range 500-2000 ng/mL). Serial concentrations demonstrated apparent first-order elimination with a half-life of 11.6 h. She was extubated on hospital day three and had a full recovery. CONCLUSION: We present a massive hydroxychloroquine overdose treated with early intubation, activated charcoal, epinephrine, high dose diazepam, aggressive electrolyte repletion, and lidocaine. The apparent 11.6 hour half-life of hydroxychloroquine was shorter than previously described.

Liquid chromatography-tandem mass spectrometry assay for the simultaneous determination of three major flavonoids and their glucuronidated metabolites in rats after oral administration of Artemisia annua L. extract at a therapeutic ultra-low dose.

The traditional antimalarial herb Artemisia annua L., from which artemisinin is isolated, is widely used in endemic regions. It has been suggested that artemisinin activity can be enhanced by flavonoids in A. annua; however, how fast and how long the flavonoids are present in the body remains unknown. In the present study, a rapid and sensitive liquid chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of three major flavonoids components, i.e. chrysosplenol D, chrysoplenetin, and artemetin and their glucuronidated metabolites in rats after oral administrations of A. annua extracts at a therapeutic ultra-low dose. The concentration of the intact form was determined directly, and the concentration of the glucuronidated form was assayed in the form of flavonoids aglycones, after treatment with ß-glucuronidase/sulfatase. The method was linear in the range of 0.5-300.0 ng/mL for chrysoplenetin and artemetin, and 2-600 ng/mL for chrysosplenol D. All the validation data conformed to the acceptance requirements. The study revealed a significantly higher exposure of the flavonoid constituents in conjugated forms in rats, with only trace intact from. Multiple oral doses of A. annua extracts led to a decreased plasma concentration levels for three flavonoids.

Optimization and validation of extraction and quantification methods of antimalarial triterpenic esters in Keetia leucantha plant and plasma.

The aim of this study is to develop validated methods for the extraction and quantification of antimalarial triterpene esters from Keetia leucantha and from plasma samples. These compounds, showing in vitro and in vivo antiplasmodial activities, were optimally extracted from Keetia leucantha twigs using ultrasounds with dichloromethane and from plasma using protein precipitation with acetonitrile. We then developed and validated HPLC-UV quantification methods, which proved to be selective, accurate, linear, true and precise, both in plant and plasma samples for the eight triterpenic esters in mixture. Based on the total error concept as decision criteria, the validated dosage ranges of the triterpene esters mixture were set between 14.68 and 73.37 µg/mL in plants and 15.90 and 106.01 µg/mL in plasma injected solutions, corresponding to 7.95 and 53.01 µg/mL in plasma. These reliable methods were used to determine effectively triterpene esters content in collected samples, that seems highly variable in plant extracts, and will be helpful to further investigate pharmacokinetics parameters of these interesting bioactive compounds.

Development and validation of a bioanalytical method by LC-MS/MS for the quantification of the LAFIS 10 - an antimalarial candidate - and its pharmacokinetics first evaluation.

A rapid and highly sensitive method by LC-MS/MS was developed and validated for the quantification of an antimalarial candidate (LAFIS10) in rat plasma using dexamethasone as internal standard (IS). The chromatographic separation was performed with a Poroshell 120 EC-C18 column. The mobile phase consisted of water (A) and acetonitrile (B), both containing 10 m m of ammonium formate and 0.1% formic acid, delivered in the form of elution gradient. The LAFIS10 was monitored using an electrospray ionization interface operating in the positive mode in multiple reaction monitoring mode, monitoring the transitions 681.47 → 538.2 for LAFIS10 and 393.20 → 355.30 for the IS. The flow rate was 500 µL/min. The column temperature was kept at 40 °C and the injection volume was 2 µL. The lower limit of quantification was of 10 ng/mL and linearity between 10 and 1000 ng/mL was observed, with an R(2) > 0.99. The accuracy of the method was >90%. The relative standard deviations intra- and interday were <8.80 and <6.37%, respectively. The method showed sensitivity, linearity, precision, accuracy and selectivity required to quantify LAFIS 10 in preclinical pharmacokinetic studies according to criteria established by the US Food and Drug Administration and European Medicines Agency.

Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves in healthy vs. Plasmodium chabaudi-infected mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese have used Artemisia annua as a tea infusion to treat fever for >2000 years. The active component is artemisinin. Previously we showed that when compared to mice fed an equal amount of pure artemisinin, a single oral dose of dried leaves of Artemisia annua (pACT) delivered to Plasmodium chabaudi-infected mice reduced parasitemia at least fivefold. Dried leaves also delivered >40 times more artemisinin in the blood with no toxicity. The pharmacokinetics (PK) of artemisinin delivered from dried plant material has not been adequately studied. MATERIALS AND METHODS: Healthy and Plasmodium chabaudi-infected mice were oral gavaged with pACT to deliver a 100 mg kg(-1) body weight dose of artemisinin. Concentrations of serum artemisinin and one of its liver metabolites, deoxyartemisinin, were measured over two hours by GCMS. RESULTS: The first order elimination rate constant for artemisinin in pACT-treated healthy mice was estimated to be 0.80 h(-1) with an elimination half-life (T½) of 51.6 min. The first order absorption rate constant was estimated at 1.39 h(-1). Cmax and Tmax were 4.33 mg L(-1) and 60 min, respectively. The area under the curve (AUC) was 299.5 mg min L(-1). In contrast, the AUC for pACT-treated infected mice was significantly greater at 435.6 mg min L(-1). Metabolism of artemisinin to deoxyartemisinin was suppressed in infected mice over the period of observation. Serum levels of artemisinin in the infected mice continued to rise over the 120 min of the study period, and as a result, the T½ was not determined; the Cmax and Tmax were estimated at ≥6.64 mgL(-1) and ≥120 min, respectively. Groups of healthy mice were also fed either artemisinin or artemisinin mixed in mouse chow. When compared at 60 min, artemisinin was undetectable in the serum of mice fed 100 mg AN kg(-1) body weight. When plant material was present either as mouse chow or Artemisia annua pACT, artemisinin levels in the serum rose to 2.44 and 4.32 mg L(-1), respectively, indicating that the presence of the plant matrix, even that of mouse chow, had a positive impact on the appearance of artemisinin in the blood. CONCLUSIONS: These results showed that artemisinin and one of its drug metabolites were processed differently in healthy and infected mice. The results have implications for possible therapeutic use of pACT in treating malaria and other artemisinin-susceptible diseases.

Understanding the pharmacokinetics of Coartem.

Artemether and lumefantrine (AL), the active constituents of Coartem exhibit complementary pharmacokinetic profiles. Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA) occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Lumefantrine is absorbed and cleared more slowly (terminal elimination half-life 3-4 days in malaria patients), and accumulates with successive doses, acting to prevent recrudescence by destroying any residual parasites that remain after artemether and DHA have been cleared from the body. Food intake significantly enhances the bioavailability of both artemether and lumefantrine, an effect which is more apparent for the highly lipophilic lumefantrine. However, a meal with only a small amount of fat (1.6 g) is considered sufficient to achieve adequate exposure to lumefantrine. The pharmacokinetics of artemether or lumefantrine are similar in children, when dosed according to their body weight, compared with adults. No randomized study has compared the pharmacokinetics of either agent in pregnant versus non-pregnant women. Studies in healthy volunteers and in children with malaria have confirmed that the pharmacokinetic characteristics of crushed standard AL tablets and the newly-developed Coartem Dispersible tablet formulation are similar. Studies to date in healthy volunteers have not identified any clinically relevant drug-drug interactions; data relating to concomitant administration of HIV therapies are limited. While dose-response analyses are difficult to undertake because of the low rate of treatment failures under AL, it appears that artemether and DHA exposure impact on parasite clearance time while lumefantrine exposure is associated with cure rate, consistent with their respective modes of action. In conclusion, knowledge of the pharmacokinetic profiles of artemether and lumefantrine is increasing within a range of settings, including infants and children. However, additional data would be warranted to better characterize artemether and lumefantrine pharmacokinetics in patients with hepatic impairment, in pregnant women, and in patients undergoing HIV/AIDS chemotherapy.

Rapid resolution liquid chromatography-mass spectrometry determination of SAR97276 in monkey matrices. Pharmacokinetics in rhesus monkey infected by Plasmodium cynomolgi.

Since several years, we developed a new class of antimalarial drugs targeting the phospholipid metabolism of the Plasmodium falciparum malaria parasite. The bis-thiazolium compound, SAR97276, is the lead compound and is now in clinical development. In this paper, we applied the fast rapid resolution liquid chromatography-mass spectrometry technique to the analysis of SAR97276 in monkey matrices. The sample pre-treatment procedure involved an acidic precipitation of proteins followed by solid-phase extraction. The monocationic compound, T2, was used as internal standard. A good separation was achieved on a Zorbax eclipse XDB C8 column (1.8 microm, 50 mm x 4.6mm) with a mobile phase consisting of acetonitrile-trimethylamine-formate buffer (pH 3) gradient elution. The total run time was 8 min. Inter-assay precisions were <10% in plasma, and 85% in plasma, and >75% in blood. The lower limits of quantitation were 3.3 microg/l in plasma and 3.3 microg/kg in blood. No matrix effect was observed. This newly developed method is sensitive, selective, reproducible, and stability indicating. It was used to analyse samples taken during a pharmacokinetic/pharmacodynamic study carried out in infected Rhesus monkey by Plasmodium cynomolgi as part of the ongoing development of SAR97276.

Comparative preclinical drug metabolism and pharmacokinetic evaluation of novel 4-aminoquinoline anti-malarials.

The disposition of three 4-aminoquinoline leads, namely isoquine (ISO), des-ethyl isoquine (DEI) and N-tert-butyl isoquine (NTBI), were studied in a range of in vivo and in vitro assays to assist in selecting an appropriate candidate for further development. Analogous to amodiaquine (ADQ), ISO undergoes oxidative N-dealkylation to form DEI in vivo. Blood clearance of DEI was as much as 10-fold lower than that of ISO in animals and after oral administration, metabolite exposure exceeded that of parent by as much as 14-fold. Replacement of the N-ethyl with an N-tert-butyl substituent substantially reduced N-dealkylation as blood clearance of NTBI was approximately 2 to 3-fold lower than DEI in mouse, rat, dog and monkey. Mean NTBI oral bioavailability was generally higher than the other leads (>/=68%). Blood cell association was substantial for NTBI, particularly in dog and monkey, where blood to plasma concentration ratios >4 were observed. Human plasma protein binding was similar for NTBI, DEI, and des-ethyl amodiaquine (DEA). Allometric scaling predicted human blood clearance (CL) for NTBI to be low ( approximately 12% liver blood flow). All the 4-aminoquinolines inhibited recombinant human cytochrome P450 2D6 with similar potency; DEI also inhibited 1A2. On balance, NTBI appeared the most promising lead to progress towards full development.

Simplified antimalarial therapeutic monitoring: using the day-7 drug level?

The blood concentration profiles of most antimalarial drugs vary considerably between patients. The interpretation of antimalarial drug trials evaluating efficacy and effectiveness would be improved considerably if the exposure of the infecting parasite population to the antimalarial drug treatment could be measured. Artemisinin combination treatments are now recommended as first-line drugs for the treatment of falciparum malaria. Measurement of the blood, serum or plasma concentration of the slowly eliminated partner antimalarial drug on day 7 of follow-up is simpler and might be a better determinant of therapeutic response than the area under the concentration-time curve. Measurement of the day-7 drug level should be considered as a routine part of antimalarial drug trials.

Comparative study of the effectiveness and pharmacokinetics of two rectal artesunate/oral mefloquine combination regimens for the treatment of uncomplicated childhood falciparum malaria.

BACKGROUND: Rectal artesunate has been shown to be an effective treatment for falciparum malaria and is useful in patients who cannot take medicine orally or when parenteral medication is inconvenient. A combination with mefloquine can decrease the duration of treatment, increase compliance and delay development of resistance. There are no clear data on whether a higher dosage of rectal artesunate results in a better clinical response. AIM: To assess two rectal artesunate/oral mefloquine regimens for treating uncomplicated multi-drug-resistant childhood falciparum malaria. METHODS: Seventy children aged 1-14 years with uncomplicated falciparum malaria were randomly assigned to receive either 10 (range 8-12) or 20 (range 16-24) mg/kg/day rectal artesunate for 3 days followed by 25 mg/kg oral mefloquine. The study endpoints were fever clearance time, parasite clearance time and proportion of patients with recrudescence. Serum levels of artesunate and dihydro-artemisinin were measured after the first dose of rectal artesunate in 16 subjects. RESULTS: Both regimens were safe and effective. The cure rate was 100% in the 53 patients who completed 28-day follow-up. All of the study endpoints were comparable between both treatment groups. CONCLUSION: A regimen of rectal artesunate 10 mg/kg/day for 3 days followed by mefloquine 25 mg/kg is optimal for the treatment of uncomplicated falciparum malaria. There was no definite benefit from increasing the dosage of rectal artesunate from 10 to 20 mg/kg/day.

Efficacy of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Cambodia.

OBJECTIVE: To determine the efficacy of artemether-lumefantrine malaria treatment, as an alternative to artesunate + mefloquine, which is becoming ineffective in some areas of the Thai-Cambodian border. METHODS: Two studies were conducted to monitor the efficacy of artemether-lumefantrine in Sampov Lun referral hospital, Battambang Province, in 2002 and 2003, and one study was conducted to assess the efficacy of mefloquine + artesunate in 2003 for comparison. The studies were performed according to the WHO standardized protocol with a follow-up of 28 days. The therapeutic efficacy tests were complemented with in vitro tests and in 2003, with the measurement of lumefantrine plasma concentration at day 7 for the patients treated with artemether-lumefantrine. RESULTS: A total of 190 patients were included: 55 were treated with artemether-lumefantrine in 2002 (AL2002), 80 with artemether-lumefantrine and food supplementation in 2003 (AL2003) and 55 with artesunate + mefloquine in 2003 (AM2003). With the per-protocol analysis, the cure rate was 71.1% in study AL2002, 86.5% in study AL2003 and 92.4% in study AM2003. All the data were PCR corrected. The artemether-lumefantrine cure rate was unexpectedly low in 2002, but it increased with food supplementation in 2003. There was a significant difference (P = 0.02) in lumefantrine plasma concentrations between adequate clinical and parasitological responses and treatment failure cases. In vitro susceptibility to lumefantrine was reduced for isolates sampled from patients presenting with treatment failure, but the difference was not statistically different from isolates sampled from patients who were successfully treated. CONCLUSION: Treatment failure cases of artemether-lumefantrine are most probably because of low levels of lumefantrine blood concentration. Further investigations are necessary to determine whether resistance of Plasmodium falciparum isolates to lumefantrine is present in the region.

Preclinical drug metabolism and pharmacokinetic evaluation of GW844520, a novel anti-malarial mitochondrial electron transport inhibitor.

GW844520 is a potent and selective inhibitor of the cytochrome bc1 complex of mitochondrial electron transport in P. falciparum, the parasite primarily responsible for the mortality associated with malaria worldwide. GW844520 is fully active against the parasite including resistance isolates, showing no cross resistance with agents in use. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-malarial. GW844520 had low blood clearance of about 0.5-4% of hepatic blood flow and a steady-state volume of distribution of 2-4 times total body water in mouse, rat, dog, and monkey. Oral bioavailability was high (51-100%). Consistent with the in vivo data, GW844520 had low intrinsic clearance in liver microsomes and hepatocytes of animal and human origin, high passive cellular permeability and was not a P-glycoprotein substrate. GW844520 did not associate appreciably with blood cells but was highly bound to plasma proteins (>99%) in all species. GW844520 was a substrate and inhibitor of human CYP2D6 but not of CYP1A2, 2C9, 2C19, and 3A4. This conjunctive analysis supports continued evaluation of this compound in definitive pre-IND studies and exemplifies our strategy supporting the discovery of novel agents to treat diseases of the developing world.

Fatty food does not alter blood mefloquine concentrations in the treatment of falciparum malaria.

Food has been reported to increase the bioavailability of mefloquine in healthy volunteers, but its role in increasing blood mefloquine concentrations in malaria patients treated with mefloquine is unclear. In this study, we compared blood mefloquine concentrations after the administration of artesunate (8 mg/kg) and mefloquine (15 mg/kg) over 12h with either a low-fat (approximately 3g of fat) or high-fat (approximately 30 g of fat) meal for the treatment of Plasmodium falciparum malaria in 12 Vietnamese patients. No statistical differences were detected in the following kinetic parameters between the low-fat (n=6) and high-fat (n=6) groups, respectively: maximum blood mefloquine concentrations (2838+/-531 ng/ml and 2556+/-657 ng/ml, 95% CI -486 to 1050 ng/ml, P=0.43) and the area under the blood mefloquine concentration versus time curves (246.8+/-58.3 microg.h/ml and 238.3+/-28.4 microg.h/ml, 95% CI -50.5 to 67.5 microg.h/ml, P=0.75). A fatty meal does not appear to increase the bioavailability of mefloquine in malaria patients and should not affect the response of malaria infections to treatment.

Pretreatment blood concentrations of chloroquine in patients with malaria infection: relation to response to treatment.

Resistance of Plasmodium falciparum to chloroquine has been reported in many areas in Ghana. Most of these reports, which are from hospital-based studies, indicate RI and RII rather than RIII type of resistance. Since high pretreatment levels of chloroquine have also been measured in patients with malaria infection in Ghana, we hypothesized that the 'added effect' of the pretreatment ingested drug to the full dose given at the hospital may be responsible for the low proportion of RIII type of resistance observed. To ascertain this, pretreatment blood levels of chloroquine were correlated with treatment outcomes in 231 paediatric malaria patients, referred to a major hospital in Ghana. The rate of parasite clearance and prevalence of recrudescence, 14 days post-treatment, were determined for each patient. Results from this study showed no correlation between pretreatment chloroquine levels and day 0 parasitaemia. Two hundred and seven patients (89.6 per cent) had parasites that were sensitive to chloroquine whilst 24 (10.4 per cent) had resistant parasites. Of the latter group 17, six, and one patients had P. falciparum parasites, which were resistant at RI, RII and RIII levels, respectively. Seventy-five per cent of the patients without any detectable pretreatment blood chloroquine had parasites that were sensitive to chloroquine whilst 89.8 per cent, 98 per cent, and 100 per cent with pretreatment blood chloroquine concentration ranges of 0.5--100.5 ng/ml, 100.5--200 ng/ml, and >200 ng/ml, respectively, had chloroquine-sensitive parasites. An inverse relationship was thus observed between pretreatment blood chloroquine concentration and the degree of resistance in this study. We conclude that pre-hospital treatment ingested chloroquine contributes significantly to the resolution of malaria in children in Ghana, in the presence of chloroquine resistance.

Adherence to a six-dose regimen of artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Uganda.

Measuring baseline levels of adherence and identifying risk factors for non-adherence are important steps before the introduction of new antimalarials. In Mbarara in southwestern Uganda, we assessed adherence to artemether-lumefantrine (Coartem) in its latest World Health Organization blister formulation. Patients with uncomplicated Plasmodium falciparum malaria were prescribed artemether-lumefantrine and received an explanation of how to take the following five doses at home. A tablet count was made and a questionnaire was completed during a home visit. Among 210 analyzable patients, 21 (10.0%) were definitely or probably non-adherent, whereas 189 (90.0%) were probably adherent. Age group was not associated with adherence. Lack of formal education was the only factor associated with non-adherence after controlling for confounders (odds ratio = 3.1, 95% confidence interval [CI] = 1.1-9.7). Mean lumefantrine blood levels were lower among non-adherent (n = 16) (2.76 microg/mL, 95% CI = 1.06-4.45) than among adherent (n = 171) (3.19 microg/mL, 95% CI = 2.84-3.54) patients, but this difference was not statistically significant. The high adherence to artemether-lumefantrine found in our study suggest that this drug is likely to be very effective in Mbarara provided that patients receive clear dosage explanations.

Transdermal delivery of chloroquine by amidated pectin hydrogel matrix patch in the rat.

The aim of the present study was to investigate the suitability of amidated pectin matrix patch for transdermal chloroquine delivery in an effort to mask the bitter taste when orally administered. Chloroquine has easily measurable outputs that are linked to increased renal Na+ excretion. We thus monitored urinary Na+ output in separate groups intravenously administered chloroquine or topically applied pectin hydrogel chloroquine matrix patch. Male groups of anesthetized Sprague-Dawley rats were placed on a continuous jugular infusion of 0.077 M NaCl at 150 microL min(-1). After 3 h equilibration period, consecutive 20 min urine collections were made over the subsequent 4 h of 1 h control, 1 h 20 min treatment, and 1 h 40 min recovery periods for measurements of urine flow and Na+ and K+ excretion rates. The effects of intravenous chloroquine infusion or topical application of pectin hydrogel chloroquine matrix patch were examined in rats in which the drug was added to the infusate or patch applied onto the shaved area during the 1 h 20 min treatment period. The animals were switched back to the infusate alone for the final 1 h 40 min recovery period. Vehicle infused animals acted as controls. Trunk blood was collected after the treatment period from parallel groups for chloroquine measurements. The plasma chloroquine concentrations following iv chloroquine or application of pectin chloroquine hydrogel matrix patch were 9.3 +/- 0.8 mg L(-1) and 7.3 +/- 1.1 mg L(-1) respectively (n = 7 in both groups). Chloroquine infusion and pectin chloroquine patch significantly (p < 0.01) increased Na+ excretion to peak values of 14.1 +/- 0.9 micromol min(-1). and 20.35 +/- 1.0 micromol min(-1), respectively by comparison with controls (9.1 +/- 0.9 micromol min(-1)), at the corresponding period. The results suggest that the pectin chloroquine patch matrix preparation has potential applications for transdermal delivery of chloroquine and perhaps in the management of malaria.

Chloroquine-resistant Plasmodium malariae in south Sumatra, Indonesia.

Oral chloroquine is the treatment of choice for uncomplicated Plasmodium malariae infections worldwide. We did a prospective 28-day in-vivo assessment of the efficacy of chloroquine for treatment of P malariae on Legundi Island in Lampung Bay, Sumatra, Indonesia. Of 28 patients, one had recurrent parasitaemia on day 28, and two had persistent parasitaemia to day 8. Whole-blood chloroquine and desethylchloroquine concentrations were at ordinarily effective levels (> or = 100 microg/L) on day 8 in both cases of persistent parasitaemia. These findings suggest that clinical resistance to chloroquine by P malariae occurs in the Indonesian archipelago of southeast Asia.

Efficacy of scopadulcic acid A against Plasmodium falciparum in vitro.

Scoparia dulcis is a perennial herb widely distributed in many tropical countries. It is used as an herbal remedy for gastrointestinal and many other ailments, and in Nicaragua extracts are used to treat malaria. Phytochemical screening has shown that scopadulcic acid A (SDA), scopadulcic acid B (SDB), and semisynthetic analogues are pharmacologically active compounds from S. dulcis. SDB has antiviral activity against Herpes simplex virus type 1, antitumor activity in various human cell lines, and direct inhibitory activity against porcine gastric H(+), K(+)-ATPase. A methyl ester of scopadulcic acid B showed the most potent inhibitory activity against gastric proton pumps of 30 compounds tested in one study. Compounds with antiviral, antifungal, and antitumor activity often show activity against Plasmodium falciparum. In P. falciparum, the plasma membrane and food vacuole have H(+)-ATPases and the acidocalcisome has an H(+)-Ppase. These proton pumps are potential targets for antimalarial therapy and may have their function disrupted by compounds known to inhibit gastric proton pumps. We tested pure SDA and found in vitro activity against P. falciparum with an IC(50) of 27 and 19 microM against the D6 and W2 clones, respectively. The IC(50) against the multidrug-resistant isolate, TM91C235, was 23 microM.

Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria.

The single-dose pharmacokinetics of 100 mg of orally administered artesunate (AS) were studied in 6 patient volunteers with uncomplicated falciparum malaria and in 6 healthy volunteers. Plasma concentrations of both the parent drug, AS, and its major metabolite, dihydroartemisinin (DHA), were measured simultaneously by high-performance liquid chromatography (HPLC) with electrochemical detection (ECD). The antimalarial activity of each plasma sample measured by an in vitro bioassay (BA) was used to derive activity concentrations. Artesunate was absorbed rapidly and then almost completely hydrolyzed to DHA in patients, whereas hydrolysis was incomplete in healthy volunteers. The mean +/- standard deviation (SD) maximum concentration (Cmax) of AS was 296+/-110 nmol/L, the time to peak blood level (tmax was 0.71+/-0.66 hr, the half-life (t1/2,z) was 0.41+/-0.34 hr, and the bioavailability over 12 hr (area under the curve [AUC](0-12)) was 253+/-185 nmol hr/L. Measured by HPLC, the Cmax and AUC(0-12) values of DHA in patients with malaria were significantly greater than in volunteers (1,948+/-772 and 1,192+/-315 nmol/L; 4,024+/-1,585 and 1,763+/-607 nmol hr/L, respectively; P < or = 0.05). These differences were even greater when measured by BA. The Cmax for patients with malaria was 2,894+/-2,497 and 795+/-455 nmol/L for volunteers, and AUC(0-12) was 5,970+/-3,625 and 1,307+/-391 nmol hr/L, respectively (P < or = 0.05). In contrast, DHA parameter estimates for t1/2,z and tmax were similar between patients and healthy volunteers, with values of 0.80+/-0.30 versus 0.87+/-0.06 hr and 1.50+/-0.55 versus 1.13+/-0.52 hr, respectively (P > 0.5). Both drug metabolism and tissue protein binding could contribute to the differences between the antimalarial activity of artemisinin drugs in healthy volunteers and malaria infected patients.