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Atractylodes macrocephala Koidz (AMK) is a traditional Chinese medicine widely used in the treatment of various diseases, especially spleen deficiency. As the principle active constituents of AMK, however, the metabolites of Atractylenolide-III (A-lactone-III) have not been identified in rats yet. In this study, a three-step high throughput method based on UHPLC-Q-TOF-MS-MS was developed to profile and characterize the metabolites of A-lactone-III in rat feces, urine and plasma. The initial step was a full-scan that utilized a multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS). PeakView®1.2 and Metabolitepilot™1.5 software was then used to obtain data and seek possible metabolites. Finally, MS-MS spectra of the parent drug and possible metabolites were compared by the fragment ion peaks and retention times, which enabled metabolites to be identified. As a result, 53 metabolites were characterized in rats in vivo. The metabolic pathways of A-lactone-III were identified as including methylation, oxidation, hydroxylation, dihydroxylation, hydrogenation, glycosylation, sulfonation, and glucuronide, cysteine and N-acetylcysteine conjugation.

1,6-O,O-Diacetylbritannilactone is a natural sesquiterpene lactone isolated from Inula britannica that has displayed cytotoxic effects against several human cancer cell lines. In this study, a selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed for determination of 1,6-O,O-diacetylbritannilactone in rat plasma. Chromatographic separation was achieved on an Agilent C18 column (4.6 mm × 75 mm, 3.5 μm) with methanol and water (80:20, v/v) as the mobile phase. An ESI source was applied and operated in positive ion mode; selected-reaction monitoring was used for quantification using target fragment ions m/z 373.2→312.9 for 1,6-O,O-diacetylbritannilactone and m/z 331.2→144.1 for the IS. Calibration plots were linear in the range of 1.5-1350 ng/mL for 1,6-O,O-diacetylbritannilactone in rat plasma. Intra- and inter-day precisions were <8.5%, and the accuracy ranged from -2.7 to 12.8%. The LC-MS-MS method was successfully applied in a pharmacokinetic study of 1,6-O,O-diacetylbritannilactone in rats.

Objectives: Analysis of the biopharmaceutical properties of eremantholide C, sesquiterpene lactone with proven pharmacological activity and low toxicity, is required to evaluate its potential to become a drug., Methods: Preliminary analysis of the physicochemical characteristics of eremantholide C was performed in silico. Equilibrium solubility was evaluated using the shake-flask method, at 37.0 °C, 100 rpm during 72 h in biorelevant media. The permeability was analysed using parallel artificial membrane permeability assay, at 37.0 °C, 50 rpm for 5 h. The donor compartment was composed of an eremantholide C solution in intestinal fluid simulated without enzymes, while the acceptor compartment consisted of phosphate buffer., Key Findings: Physicochemical characteristics predicted in silico indicated that eremantholide C has a low solubility and high permeability. In-vitro data of eremantholide C showed low solubility, with values for the dose/solubility ratio (ml): 9448.82, 10 389.61 e 15 000.00 for buffers acetate (pH 4.5), intestinal fluid simulated without enzymes (pH 6.8) and phosphate (pH 7.4), respectively. Also, it showed high permeability, with effective permeability of 30.4 × 10 -6 cm/s, a higher result compared with propranolol hydrochloride (9.23 × 10 -6 cm/s)., Conclusions: The high permeability combined with its solubility, pharmacological activity and low toxicity demonstrate the importance of eremantholide C as a potential drug candidate., (© 2017 Royal Pharmaceutical Society.)

A rapid, sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was established and validated to assay the concentration of nardosinone, a main active compound isolated from Nardostachys chinensis, in rat plasma. Plasma samples were processed by protein precipitation with acetonitrile and separated on a Venusil MP-C18 column (50 × 2.1 mm, 5 µm) at an isocratic flow rate of 0.6 mL/min using methanol-0.1% formic acid in water (55 : 45, v/v) as mobile phase, and total run time was 2.5 min. MS-MS detection was accomplished in selected reaction monitoring mode with positive electrospray ionization. The calibration curve was linear over the concentration range of 9.60-320 ng/mL with lower limit of quantification of 9.60 ng/mL. The intra- and inter-day precisions were below 12.3% in terms of relative standard deviation, and the accuracy was within ±9.0% in terms of relative error. Extraction recovery, matrix effect and stability were also satisfactory in rat plasma. The developed method was successfully applied to a pharmacokinetic study of nardosinone following an intravenous injection at a dose of 1.04 mg/kg to Sprague-Dawley rats., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cholinergic transmission is altered by drugs of abuse and contributes to psychostimulant reinforcement. In particular, acetylcholinesterase inhibitors, like huperzine A, may be effective as treatments for cocaine use disorder., Methods: The current report describes results from a double-blind, placebo-controlled study in which participants (n=14-17/group) were randomized to huperzine A (0.4 or 0.8 mg) or placebo. Participants received randomized infusions of cocaine (0 and 40 mg, IV) on days 1 and 9. On day 10, participants received noncontingent, randomized infusions of cocaine (0 and 20mg, IV) before making 5 choices to receive additional infusions., Results: Huperzine A was safe and well-tolerated and compared with placebo, treatment with huperzine A did not cause significant changes in any cocaine pharmacokinetic parameters (all P>.05). Time-course and peak effects analyses show that treatment with 0.4 mg of huperzine A significantly attenuated cocaine-induced increases of "Any Drug Effect," "High," "Stimulated," "Willing to Pay," and "Bad Effects" (all P>.05)., Conclusions: The current study represents a significant contribution to the addiction field since it serves as the first published report on the safety and potential efficacy of huperzine A as a treatment for cocaine use disorder., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study investigated the use of a bioactive phytochemical, namely ginger extract (GE), for its antioxidant and antiulcer effects, and also for supporting probiotic growth and activity. Use of probiotics is limited in therapy because of their transience and inability to survive the adverse physiological conditions of the gastrointestinal tract. Packaging probiotics in a suitably designed pharmaceutical system with GE may facilitate their establishment in the stomach mucosa., Methods: A probiotic (Lactobacillus acidophilus) and GE were simultaneously and individually encapsulated/immobilized in alginate floating beads. The developed system was evaluated for diameter, buoyancy, entrapment, porosity, in-vitro viability/release and pharmacodynamics in a cold restraint stress induced gastric ulcer model in rats., Key Finding: The developed floating beads stayed in the stomach for more than 10 h and both agents were released slowly and over a prolonged period from these beads. Significant and promising results were obtained for the combination (synbiotic) system in terms of ulcer index, mucus secretion, oxidative stress and histopathological parameters, as compared with the individual agents. The developed system could completely revert the damage induced in ulcerated stomachs at physiological (ulcer index and mucus secretion), biochemical (oxidative stress) and histological levels., Conclusion: This study establishes that suitable packaging of GE and Lactobacillus acidophilus together in floating beads can help exploit their prospects as therapeutic curative agents rather than potential preventive agents., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

Objectives: Elemene is a chemical extracted from plants. It has demonstrated anti-tumour capability. Although widely studied, there has been little reported regarding its tissue distribution. Our aim was to rectify this., Methods: The tissue distribution of elemene was studied after intragastric or intravenous administration in rats. The effectiveness of elemene in treating brain tumours was studied using the G-422 tumour cell model in mice., Key Findings: Elemene had a higher concentration in the lungs, spleen and livers than other tissues of normal rats after intragastric and intravenous administration, while the concentration in the gastrointestinal tract was greater after intragastric administration. Elemene molecules were also detected in the rats' brain tissue. Elemene had a therapeutic effect on mice inoculated with G-422 cells both intracranially and subcutaneously. The best life-extending rate and the best tumour-inhibiting rate of elemene were 64.43% and 34.46%, respectively, when 80 mg/kg elemene was used for treatment., Conclusions: The results from the tissue distribution study showed that elemene can pass through the blood-brain barrier. The therapeutic experiments showed that elemene is effective in treating cerebral malignancy.

Objectives: Paediatric drug formulations of artemisinin combination therapies and pharmacokinetic data supporting their use in African children are urgently needed for the effective treatment of young children suffering from falciparum malaria in sub-Saharan Africa., Patients and Methods: In this study, the pharmacokinetic characteristics of a novel paediatric granule formulation of artesunate-mefloquine therapy were evaluated in comparison to the standard tablet formulation in the treatment of uncomplicated malaria in paediatric patients. Twenty-four patients were assigned to treatment according to body weight with either a fixed-dose paediatric granule co-formulation (10-20 kg body weight) or a free-dose co-blister tablet formulation of artesunate-mefloquine (>20-40 kg body weight)., Results: Median values for C(max) (861 and 930 ng/mL), T(max) (1.5 and 1.5 h) and AUC(0-)(t) (2,050 and 2,470 ng.h/mL) were comparable for dihydroartemisinin in the two groups. Exploratory analysis of mefloquine plasma levels revealed a trend towards higher concentrations in the younger age group during the absorption phase (2,550 and 1,815 ng/mL, 54 h after initiation of treatment, respectively). Median mefloquine concentrations at day 28 were 197 and 343 ng/mL, respectively., Conclusions: The pharmacokinetic characteristics of the two paediatric dosage forms, i.e. the novel fixed-dose co-formulation and the standard co-blister of artesunate-mefloquine show comparable results in the two treatment groups. The novel fixed-dose paediatric formulation is an interesting option for outpatient treatment of uncomplicated malaria in African children.

A new dihydroartemisinin (DHA) tablet formulation has been developed by the Thai Government Pharmaceutical Organization (GPO). In this report, its in vitro dissolution and in vivo pharmacokinetics as well as its safety in healthy volunteers were evaluated, using the DHA tablet made by Dafra Pharma NV as a reference. A two-period crossover clinical study design was utilised. Twenty-four volunteers were randomly allocated to two sequences (12 volunteers in each) to receive a 200mg single oral dose of either the GPO or Dafra formulation with a wash-out period of 5-7 days. In vitro, the GPO formulation dissolved more readily. In vivo, the GPO formulation had a higher maximum plasma concentration and approximately 149% (90% CI 125-179%) greater bioavailability. Both formulations were well tolerated. Interestingly, significant decreases in haemoglobin and haematocrit values (P<0.001) were noted following administration of one dose of DHA (decrease of 0.73 g/dl haemoglobin and 2.0% haematocrit compared with baseline) or two doses of DHA (decrease of 0.95 g/dl haemoglobin and 3.3% haematocrit compared with baseline). The second dose was associated with additional toxicity compared with one dose with regard to haematocrit (P<0.001) but not haemoglobin. This finding warrants further investigation, since the drug will be used for the treatment of malaria in which anaemia is a consequence.

Huperzine A (Hup A) is under investigation as a treatment of Alzheimer's disease because of its properties of reversible and specific AChE inhibition. It has additional interesting pharmacological effects such as the protection of primary neuronal cells isolated from embryonic rat brains from glutamate-induced toxicity. We have isolated a new compound which has similar absorbance characteristics as Hup A from blood of rats administered Hup A. Monitoring the effluent from reversed-phase high-performance liquid chromatography (RP-HPLC) of blood collected 60 min after Hup A treatment at an absorbance of 308 nm (lambdamax for Hup A), yielded a peak height and area for this compound that was approximately 1.4-fold the initial Hup A peak. The compound was isolated from RP-HPLC fractions from blood and liver for analysis by mass spectrometry and nuclear magnetic resonance (NMR). The compound gave an (M+H)+ ion with m/z 259 in positive ion mode, yielding a molecular weight (MW) of 258. If derived from Hup A (MW 242), the change in MW indicates a mass gain of 16. This would be consistent with the addition of a single oxygen or a hydroxylation. To determine the location of the modification, it was examined by 1H NMR, and it was found that the added mass was due to a single epoxidation yielding 13,14-epoxy Hup-A.

We have evaluated the therapeutic equivalence of a beta-cyclodextrin-artemisinin complex at an artemisinin dose of 150 mg, with a commercial reference preparation, Artemisinin 250 at a recommended dose of 250 mg. One hundred uncomplicated falciparum malarial patients were randomly assigned to orally receive either beta-cyclodextrin-artemisinin complex (containing 150 mg artemisinin) twice daily for five days or the active comparator (containing 250 mg artemisinin) twice daily for five days. The patients were hospitalized for seven days and were required to attend follow up assessments on days 14, 21, 28 and 35. All patients in both treatment groups were cured of the infection and achieved therapeutic success. At day seven of treatment, all patient blood was clear of the parasites and the sublingual temperature of all patients was less than 37.5 degrees C. Moreover, the parasite clearance time in both treatment groups was similar, being approximately three days after initiation of treatment. Comparable plasma artemisinin concentrations were observed between patients in both treatment groups at 1.5 and 3.0 h, although slightly higher levels were obtained with patients in the beta-cyclodextrin-artemisinin complex-treated group. The beta-cyclodextrin-artemisinin complex at a dose of 150 mg artemisinin was therapeutically equivalent to 250 mg Artemisinin 250. Additionally, patients receiving beta-cyclodextrin-artemisinin complex showed less variability in their plasma artemisinin concentrations at 1.5 h post-dosing, which suggested a more consistent rate of drug absorption.

The in-vivo anti-influenza-virus activity of Stachyflin derivatives (III and its phosphate ester, III-Phos), a new class of haemagglutinin fusion inhibitor, and the improvement of their absorption after oral or intranasal administration were studied in mice, rats, and ferrets. The absorption of III in PEG 4000 and III-Phos aqueous solution increased about three and four fold in AUC after oral administration to uninfected mice compared with that of 0.5% HPMC (hydroxypropyl-methylcellulose) suspension. Using a mouse influenza virus infection model, significant anti-influenza-virus activity was observed in infected mice treated orally with these compounds dissolved in PEG 4000 or distilled water, respectively, but not in mice treated with 0.5% HPMC. The in-vivo anti-influenza-virus activity in ferrets, a good model for influenza virus infection in man, was also studied. Although the concentration of III in plasma was above the IC50 against the influenza virus strain used for 6h after the oral administration of III in PEG 400 to uninfected ferrets, no in-vivo anti-influenza-virus activity was observed at the same dosage given 4 times daily for 3 days. The intranasal administration of III-Phos, which was expected to have a more notable in-vivo anti-influenza-virus activity, was examined. III-Phos, whose intranasal absorption had been improved by the modification of III with phosphate ester in rats, inhibited viral replication in the nasal cavity and suppressed influenza-virus-induced fever when administered intranasally to infected ferrets. This study demonstrates that intranasally administered compounds with anti-influenza-virus activity must permeate the nasal membranes to produce their anti-influenza-virus effect.

Eight male Vietnamese malaria patients received 600 mg of artemisinin in a single dose of 3 suppositories containing 200 mg each; 24 h later they received a single oral dose of mefloquine, 15 mg/kg. Plasma artemisinin concentrations were measured until 24 h after dosing, and parasites were counted until none could be detected. Artemisinin concentration versus time curves of all subjects were analysed with model-independent methods. Mean Cmax was 108 micrograms/L (SD = 60, range 29-169), mean tlag was 0.3 h (SD = 0), mean tmax was 6.5 h (SD = 3.9, range 2-14). By comparing the area under the concentration-time curve with that found in a previous study on oral artemisinin, average bioavailability relative to oral administration was estimated to be approximately 30%. Median parasite clearance time was 24 h (range 24-72). We concluded that therapeutic blood concentrations of artemisinin can be reached after rectal administration. There was a large inter-individual variation in blood concentrations attained. The dose given by rectal administration should probably be twice the usual oral dose, i.e., at least 20 mg/kg of body weight twice daily.

The pharmacokinetics, metabolism, protein binding, red blood cell (RBC) binding, stability in vitro, and acute and anorectic toxicity of artelinic acid (ARTL) were investigated in various animal species and human blood samples. Absorption and distribution following 10 mg/kg intramuscular or oral administration in dogs and rats were very rapid with t1/2 0.12-0.54; there were also a high AUC (11,262 ng/h/mL) and Vss (9.5 L/kg), low CL (15 mL/min/kg) and long elimination time (t1/2 = 2.6 h), compared with rat data. Oral bioavailability of ARTL was 79.7% in dogs and 30.1% in rats. The conversion of ARTL to dihydroartemisinin (DART) in dogs (0.1-0.5% of total dose) after 3 routes of administration (intravenous, intramuscular and oral) was 10-fold lower than that in rats. In rats dosed with [14C]ARTL, unchanged ARTL accounted for less than 13% of the total radioactivity after all 3 administration routes, suggesting that ARTL was extensively biotransformed. The half-lives of total radioactivity (21-49 h) in urine were much longer than that of unchanged ARTL in plasma (1.4-3.7 h), indicating that some long-lasting metabolites of ARTL were formed in rats. The mass balance data showed that 77-83% of total radioactivity was recovered in urine and faeces. High binding capacity (79-95%) and low binding affinity (1.1-9.3 x 10-7 M) of ARTL were measured in rat, rabbit, dog, monkey and human plasma. The RBC/plasma ratios of [14C]ARTL were 0.35 and 0.44 for dog and human plasma, respectively. ARTL was much more stable than artesunic acid (ARTS) in rat and dog plasma, and both ARTL and ARTS were more stable in dog plasma than in rat plasma in vitro. The 50% lethal dose (LD50) of ARTL in rats was about 535 mg/kg. Multiple intramuscular dosing for 7 d of 50 mg/kg/d of ARTL caused mild anorectic toxicity compared to ARTS in rats. In contrast to 4 other artemisinin derivatives, ARTL seems to be a good antimalarial candidate as it has the highest plasma concentration, the highest binding capacities in RBC, the highest oral bioavailability, the longest elimination half-life, the lowest metabolism rate and the lowest toxicity at equivalent dose levels.

The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.

The disposition of intramuscular artemether (AM) was studied in 26 Kenyan children with cerebral malaria. Antimalarial activity determined by bioassay was compared with total plasma AM plus dihydroartemisinin (DHA) determined by high power liquid chromatography (HPLC). Therapeutic levels were achieved in most subjects (21/26) within 1 h of receiving intramuscular AM (3.2 mg/kg), with close correlation between bioassay and HPLC measurements (r = 0.706). However, there was marked inter-individual variation, antimalarial activity was undetectable in 5 subjects ('non-absorbers'), and plasma concentrations were lower in subject with respiratory distress. The 50% parasite clearance time was significantly longer in non-absorbers (mean = 13.1 h, SD = 10.8 vs. mean = 7.8 h, SD = 5.5; P = 0.013). We conclude that the bioavailability of intramuscular AM in children with severe malaria may be highly variable, particularly in the presence of respiratory distress, and may be associated with an inadequate therapeutic response.

The pharmacokinetic properties of oral artesunate (3 mg/kg) were determined in 10 Vietnamese children, aged from 6 to 15 years, with acute falciparum malaria of moderate severity. Plasma concentrations were measured using a bioassay and expressed in terms of antimalarial activity equivalent to dihydroartemisinin, the principal biologically active metabolite. Oral artesunate was absorbed rapidly with a mean time to peak plasma bioactivity of 1.7 h (95% confidence interval [95% CI] 0.8-2.6). There was wide variation in peak plasma concentrations with a mean value equivalent to 664 ng of dihydroartemisinin/mL (95% CI 387-9410, range 179-1395) and a four-fold variation in the area under the plasma concentration-time curves. Elimination from plasma was rapid with a mean (95% CI) half-life of 1.0 h (95% CI 0.8-1.4). Plasma antimalarial levels were below the limit of detection in all cases by 12 h, despite the relatively high dose of artesunate used. Oral artesunate is rapidly absorbed and rapidly eliminated in children with moderately severe malaria but there is considerable variation between individuals.

The study compared the clinical efficacy and safety of oral artemisinin and oral artesunate as well as artemisinin pharmacokinetics during and after resolution of falciparum malaria. Forty adults with symptomatic falciparum malaria were allocated at random to treatment with either oral artemisinin (500 mg single dose on day 1 followed by 250 mg twice daily for 4 d and then another 500 mg single dose on day 6) or with oral artesunate (100 mg single dose on day 1 followed by 50 mg twice daily for 5 d). Patients were admitted to hospital at the Kibaha Designated District Hospital, Kibaha, Tanzania for the duration of treatment. The patients were seen once weekly for 3 more weeks. The time to parasite clearance (PCT) after oral artesunate (26.4 +/- 3.6 h) was shorter (P = 0.002) than after artemisinin (31 +/- 3.6 h). The fever subsidence time (FST) after oral artesunate (18.9 +/- 4.0 h) was also shorter (P = 0.04) than after artemisinin (21.8 +/- 4.6 h). Parasites were detected in 4 (20%) and 7 (35%) patients after completing treatment with artesunate and artemisinin respectively. In these patients the parasitaemia reappeared at the 3rd or 4th week of follow-up. Standard haematology, blood biochemistry and urinalysis, performed before drug intake and again on days 6 and 14, were normal. No clinical abnormality was observed during the study period. Artemisinin plasma concentrations, determined by high performance liquid chromatography with post-column derivatization and detection by ultraviolet light, were followed up to 8 h after drug administration on days 1 and 6. Artemisinin absorption was rapid, the maximum plasma concentrations (Cmax) being attained at about 3 h. Artemisinin areas under the plasma concentration-time curve (AUC) and the Cmax values were about 6 times higher after the first dose on day 1 than on day 6. This decrease in artemisinin plasma concentration is suggestive of an increase in metabolic capacity due to pronounced autoinduction.

Artesunate, the only artemisinin analogue that can be given intravenously, produces rapid parasite and fever clearance in falciparum malaria. A significant therapeutic problem is a high, late recrudescence rate, probably due to short half-lives of both artesunate and its active metabolite dihydroartemisinin relative to conventional dosing intervals. One method of extending the duration of action of artesunate could be to administer the drug by infusion rather than bolus injection, provided that it is chemically stable at ambient temperature. Artesunate was found to be stable in 0.9% w/v sodium chloride at 9 degrees C, 23 degrees C and 36.5 degrees C for 130, 10.6 and 1.6 h, respectively. Interpolating from an Arrhenius plot, artesunate should be stable for approximately 4 h at 30 degrees C, a temperature representative of ambient conditions in tropical countries. Exposure to light did not affect the degradation rate. Single compartment pharmacokinetic modelling was used to evaluate potential differences in artesunate and dihydroartemisinin plasma concentrations following administration of artesunate by intravenous bolus or infusion. A bolus injection of artesunate at a dose of 4 mg kg-1 gives a peak concentration of 5.3 mg L-1, falling to 0.005 mg L-1 at 5 h. The same dose infused over 4 h results in a peak concentration of 0.92 mg L-1, falling to 0.005 mg L-1 at 8 h. Simultaneous modelling of dihydroartemisinin showed that while its peak plasma concentration was reduced by 27% and the peak delayed by 2.5 h following artesunate administration by infusion, substantially higher concentrations were maintained compared with those predicted after bolus artesunate. These data indicate that artesunate can be administered as a high-dose intravenous infusion, thus avoiding high plasma concentrations. This strategy also has the potential to prolong the duration of antimalarial effect and reduce toxicity, and consequently improve clinical outcome in seriously ill patients.

Reliable and reproducible methods for the measurements of artemisinin and its derivatives in body fluids have proved difficult to develop. The available evidence suggests that all compounds are hydrolysed to a biologically active metabolite, dihydroartemisinin, which is eliminated rapidly. The role of other (hydroxylated) metabolites in humans requires further study. The hydrolysis of artesunate is so rapid that it may be considered a pro-drug for dihydroartemisinin. All the artemisinin compounds induce more rapid reduction of parasitaemia than other antimalarial drugs, indicating a direct effect on ring forms. This pharmacodynamic measure can be used in drug comparisons, and allows estimations of the number of parasites removed before sequestration.

The recently developed artemisinin derivative arteether was administered by intramuscular injection to healthy male subjects in a single dose (n = 23) and a multiple dose study (n = 27). The drug was well tolerated. Clinical, neurological, electrocardiographic and biochemical monitoring did not reveal significant toxicity. Apart from some increase in eosinophil numbers, no haematological abnormality was seen. Preliminary pharmacokinetic data showed a long elimination half life of 25-72 h and marked accumulation in the multiple dose study.

The efficacy of artelinic acid and artemisinin, orally administered at 10 and 50 mg kg-1 day-1, was compared in Plasmodium berghei infected mice. Subsequently, the pharmacokinetics of artelinic acid after intravenous, intramuscular, oral and rectal administration of a 20 mg kg-1 aqueous solution to rabbits were studied in a four-way randomized cross-over experiment. After intravenous administration, artelinic acid concentrations in blood plasma were high (C0: 76 +/- 15 mg L-1), and the drug was rapidly eliminated from the central compartment, showing linear elimination kinetics with an elimination half-life of 15 +/- 3 min. A large inter-subject variation appeared in the absorption rate and the extent of absorption (2-92%) over the 120 min interval after intramuscular administration. Also, a large inter-subject variation in individual rectal bioavailability (17-100%) was shown, which was dependent on the site of absorption in the rectum. The estimated oral bioavailability was low (4.6 +/- 1.7%), probably due to a high first-pass effect and possible decomposition in the acidic gastric environment.

The pharmacokinetics after oral, intramuscular and rectal administration of artemisinin, a new potent antimalarial drug, to healthy volunteers has been examined. The study was set-up as a four-way cross-over design with a wash-out period of one week between the test days. In ten volunteers artemisinin concentrations in serum were monitored using a reversed phase HPLC assay with UV detection after derivatization. After oral administration, artemisinin was rapidly but incompletely absorbed, the mean absorption time was 0.78 h and the bioavailability relative to the intramuscularly injected suspension in oil 32%. The mean residence time of the latter (10.6 h) was 3 times that of the oral formulation (3.4 h). This seems to enable a twice daily dosage regimen for the intramuscular oil injection, while the oral formulation necessitates a more frequent dosing interval. After intramuscular injection and rectal administration of an aqueous suspension, very low and variable artemisinin concentrations in serum were observed, probably indicating a poor and erratic absorption.