Dose Of Artesunate Research Articles

Reproductive profile of artemisinins in albino rats

Reproductive profile of artemisinins in albino rats

Effect Of Artesunate On The Nissl Bodies Of The Cerebellum Of Wistar Rats

The study was to assess the effect of the administration of different doses of artesunate on the Nissl bodies of the cerebellum of Wistar rats. Twenty adult albino Wistar rats weighing between 160-180g were equally assigned into four groups (A, B, C and D). Group A served as the control that received distilled water, while groups B, C and D were the experimental groups. Groups B and C received 2.86mg/kg and 5.71mg/kg of artesunate respectively for three days, while group D received 2.86mg/kg of artesunate for six days. Twelve hours after the last administration the animals were sacrificed. There was reduced staining intensity of Nissl bodies in groups B, C and D compared to the control. The reduction in staining was more in groups C and D especially in the granular and Purkinje cortical layers. These results revealed that artesunate cause reduced Nissl bodies of the cerebellum of Wistar rats, and these reductions were dose and time dependent.

Comparative study of artesunate, ACTs and their combinants on the biochemical parameters of male guinea-pigs

In this study, the effects of different doses of artesunate, artesunate/sulfadoxine/ pyrimethamine, artesunate/amodiaquine and their combinants (sulfadoxine/pyrimethamine and artesunate/ amodiaquine) on the biochemical parameters- alkaline phosphatase (ALP), total acid phosphatase (ACPT), prostatic acid phosphatase (ACPP), urea, creatinine, uric acid and total cholesterol of the male guinea-pig were investigated. Basal serum ACPP value was increased from 3.50 ± 0.42 to 4.75 ± 0.85 and 4.75 ± 0.48 IU/L by amodiaquine and sulfadoxine/pyrimethamine respectively at their subclinical doses. These values were significant at p 0.05) serum urea at the 3 doses, while the effects of artesunate and artesunate/amodiaquine were biphasic, decreasing basal serum urea level at lower doses and increasing at higher doses. However, basal serum creatinine level was increased from 62.5 ± 6.7 to 89.8 ± 4.8 imol/L by sulfadoxine/pyrimethamine and decreased to 53.0 ± 0 imol/L by artesunate/amodiaquine at their subclinical doses, while the other agents caused no significant (p respectively. Total blood cholesterol was also significantly reduced from 2.43 ± 0.13 to 2.1 ± 0 and 1.9 ±0 mmol/L after administration of clinical doses of amodiaquine and artesinate/amodiaquine, respectively. These biochemical changes may be due to oxidative effects induced by these agents.

Comparative Study Of Artesunate, ACTs And Their Combinants On The Spermatic Parameters Of The Male Guinea-Pig

In this study, the effects of half, normal and double clinical doses of artesunate; artesunate/sulfadoxine/pyrimethamine; artesunate/amodiaquine and their combinants [sulfadoxine/pyrimethamine and amodiaquine] on the basal serum levels of testosterone, FSH, LH and prolactin of the guinea-pig were investigated. The results of this study showed that the agents caused significant decreases [P<0.05] in serum testosterone level, with varying effects on LH, FSH and prolactin. Testosterone level was decreased by artesunate [37%], sulfadoxine/pyrimethamine [22%], amodiaquine [14%], artesunate/sulfadoxine/pyrimethamine [41%] and artesunate/amodiaquine [49%] at the clinical dose, compared to the serum levels in control animals. Furthermore, artesunate and amodiaquine also caused moderate decreases in the serum concentrations of LH and FSH, without an effect on prolactin. The effects of these agents may be due to oxidative stress on the reproductive system of the organism.

Artesunate causes relaxation of rat aortic rings and reduces the contractile response to noradrenaline

To study if the present widely used artemisin derived anti-malaria drugs have vascular effects. Aortic rings were obtained from adult male Sprague-Dawley rats. The rings were mounted in an organ bath and tension recorded using isometric force transducers. After pre-contraction with noradrenaline, cumulative doses of artesunate were added to the bath containing the rings. The effects of nitric oxide inhibition with L-NAME, on the responses to artesunate were also assessed. Lastly the effects on the contractile responses of the rings to noradrenaline (NA) were determined before and after incubation in artesunate. Cumulative addition of artesunate from 6 x 10(-4) to 6 x 10(-1) mg/ml resulted in relaxation of pre-contracted aortic rings. L-NAME significantly reduced the relaxation response to artesunate (P < 0.05). Vascular contraction response to NA was significantly reduced (P < 0.01) following the addition of artesunate. Artesunate causes relaxation of precontracted rat aortic rings which is partly mediated by Nitric Oxide (EDRF). It also reduces the contractile responses of the rings to noradrenaline.

Pharmacokinetics of chlorproguanil, dapsone, artesunate and their major metabolites in patients during treatment of acute uncomplicated Plasmodium falciparum malaria

Chlorproguanil (CPG)-dapsone (DDS)-artesunate was in development for the treatment of uncomplicated Plasmodium falciparum malaria. The pharmacokinetics of CPG, DDS, artesunate and their metabolites chlorcycloguanil (CCG), monoacetyl dapsone (MADDS) and dihydroartemisinin (DHA) were investigated in patients with P. falciparum given CPG-DDS alone or plus artesunate. Adult patients from Malawi and The Gambia taking part in a phase II clinical trial were randomised to receive a 3-day treatment of CPG-DDS alone (2/2.5 mg/kg/day) or plus 1, 2 or 4 mg/kg/day artesunate. Blood samples for pharmacokinetic analysis were collected up to 24 h post-first dose. The pharmacokinetic analysis included 115 patients. For CPG, there was no significant effect of artesunate on C(max) or AUC(0-24), except the 90% confidence interval (CI) for AUC(0-24) for the 4 mg/kg artesunate dose was slightly below that for the standard bioequivalence range (90% CI 0.78, 1.11); this was not considered clinically relevant. Artesunate increased the CCG AUC(0-24) by 6-17% and C(max) by 0-16%. Artesunate had no significant effect on the rate or extent of absorption of DDS. For MADDS, artesunate increased the AUC(0-24) by 13-47% and C(max) by 8-45%. For 1, 2 and 4 mg/kg artesunate dosing, artesunate AUC(0-infinity) was 64.6, 151 and 400 ng.h/ml and C(max) 48.9, 106 and 224 ng/ml respectively; DHA AUC(0-infinity) was 538, 1,445 and 3,837 ng.h/ml and C(max) 228, 581 and 1,414 ng/ml respectively. Using a power model, the point estimates of slope were greater than 1 for artesunate AUC(0-t) by 16% and C(max) by 5% and for DHA by 39 and 21% respectively. Artesunate did not significantly affect CPG or DDS pharmacokinetics. For CCG and MADDS, small to moderate increases in exposure with artesunate dosing were observed. There was a greater than proportional increase in artesunate and DHA exposure with increasing artesunate dose. These effects are not considered to be clinically relevant. It should be noted that the CPG-DDS-artesunate programme has now been stopped following unacceptable haematological toxicity in patients with glucose-6-phosphate dehydrogenase deficiency during a phase III trial. In addition, the CPG-DDS combination has been withdrawn from clinical use.

Anthelmintic activity of artesunate against Fasciola hepatica in naturally infected sheep

In light of rapidly spreading triclabendazole resistance alternative fasciocidal drugs are urgently needed. Following up on promising results obtained with artemether in Fasciola hepatica infected sheep, we here report the efficacy and safety of artesunate in sheep with a natural F. hepatica infection. Artesunate was administered intravenously and intramuscularly, adverse events were monitored and drug efficacy was elucidated by means of faecal egg and worm burden reductions. A single 40 mg/kg intravenous dose of artesunate induced an egg count reduction of 68.9% and a worm burden reduction of 77.4%. Intramuscular artesunate at 40 mg/kg reduced faecal egg count and worm burden by 97.6% and 91.9%, respectively; whereas at 60 mg/kg it caused 93.2% and 87.1% reduction in faecal egg count and worm burden, respectively. Three sheep died 24–72 h post-treatment with a double dose of 40 mg/kg intramuscular artesunate, showing lethargy, sialorrhoea, reduced rumination and tremors. Egg and worm burden reductions of 93.3% and 83.9%, respectively, were calculated in the three surviving sheep. In conclusion, the interesting fasciocidal properties of artesunate in sheep warrant further investigations with an emphasis on toxicity studies.

The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum

BackgroundArtesunate (AS) plus amodiaquine (AQ) is one artemisinin-based combination (ACT) recommended by the WHO for treating Plasmodium falciparum malaria. Fixed-dose AS/AQ is new, but its safety and efficacy are hitherto untested.MethodsA randomized, open-label trial was conducted comparing the efficacy (non-inferiority design) and safety of fixed (F) dose AS (25 mg)/AQ (67.5 mg) to loose (L) AS (50 mg) + AQ (153 mg) in 750, P. falciparum-infected children from Burkina Faso aged 6 months to 5 years. Dosing was by age. Primary efficacy endpoint was Day (D) 28, PCR-corrected, parasitological cure rate. Recipients of rescue treatment were counted as failures and new infections as cured. Documented, common toxicity criteria (CTC) graded adverse events (AEs) defined safety.ResultsRecruited and evaluable children numbered 750 (375/arm) and 682 (90.9%), respectively. There were 8 (AS/AQ) and 6 (AS+AQ) early treatment failures and one D7 failure (AS+AQ). Sixteen (AS/AQ) and 12 (AS+AQ) patients had recurrent parasitaemia (PCR new infections 10 and 6, respectively). Fourteen patients per arm required rescue treatment for vomiting/spitting out study drugs. Efficacy rates were 92.1% in both arms: AS/AQ = 315/342 (95% CI: 88.7–94.7) vs. AS+AQ = 313/340 (95% CI: 88.6–94.7). Non-inferiority was demonstrated at two-sided α = 0.05: Δ (AS+AQ – AS/AQ) = 0.0% (95% CI: -4.1% to 4.0%). D28, Kaplan Meier PCR-corrected cure rates (all randomized children) were similar: 93.7% (AS/AQ) vs. 93.2% (AS+AQ) Δ = -0.5 (95% CI -4.2 to 3.0%). By D2, both arms had rapid parasite (F & L, 97.8% aparasitaemic) and fever (97.2% [F], 96.0% [L] afebrile) clearances.Both treatments were well tolerated. Drug-induced vomiting numbered 8/375 (2.1%) and 6/375 (1.6%) in the fixed and loose arms, respectively (p = 0.59). One patient developed asymptomatic, CTC grade 4 hepatitis (AST 1052, ALT 936). Technical difficulties precluded the assessment and risk of neutropaenia for all patients.ConclusionFixed dose AS/AQ was efficacious and well tolerated. These data support the use of this new fixed dose combination for treating P. falciparum malaria with continued safety monitoring.Trial registrationCurrent Controlled Trials ISRCTN07576538

Antioxidant therapy: Reducing malaria severity?*

Ackerman, Hans C. MD, DPhil, MSc; Beaudry, Steven D. BS; Fairhurst, Rick M. MD, PhD Author Information

Pharmacokinetic parameters of artesunate and dihydroartemisinin in rats infected with Fasciola hepatica

The pharmacokinetic (PK) parameters of artesunate, recently discovered to possess promising trematocidal activity, and its main metabolite dihydroartemisinin (DHA) were determined in rats infected with hepatic and biliary stages of Fasciola hepatica and compared with uninfected rats after single intragastric and intravenous (iv) doses. Rats infected with F. hepatica for 25 and 83 days and uninfected rats were cannulated in the right jugular vein and blood samples were withdrawn at selected timepoints following 10 mg/kg of iv and a single 100 mg/kg oral dose of artesunate. Plasma was analysed for artesunate and DHA by liquid chromatography coupled to tandem mass spectrometry. Rats harbouring juvenile and adult F. hepatica infections revealed considerable changes in PK parameters of artesunate and DHA. Following oral administration, maximum plasma concentrations (C(max)) of artesunate and DHA were 1.8-2.3-fold higher in infected rats [artesunate: 1334 +/- 1404 ng/mL (no infection) versus 2454 +/- 1494 ng/mL (acute infection) and 2768 +/- 538 ng/mL (chronic infection); DHA: 3802 +/- 2149 ng/mL (no infection) versus 6507 +/- 3283 ng/mL (acute infection) and 9093 +/- 884 ng/mL (chronic infection)]. The AUCs of artesunate and DHA were 2.1-4.4-fold greater in infected rats. An opposite trend was observed after iv injection. C(max) and AUC of artesunate and DHA following iv dosing were 5784 +/- 3718 and 140 938 +/- 128 783 ng.min/mL and 3849 +/- 3060 and 86 107 +/- 41 863 ng.min/mL, respectively, in uninfected rats versus 2623 +/- 1554 and 21 617 +/- 12 230 ng.min/mL and 2835 +/- 980 and 64 290 +/- 29 057 ng.min/mL, respectively, in rats harbouring a chronic infection. The elimination half-lives (t(1/2)) of artesunate and DHA were considerably altered in infected rats following oral and iv administration of artesunate. F. hepatica infections strongly influence the disposition kinetics of artesunate and its metabolite in rats. The clinical implications of this finding need to be carefully studied.

Auditory assessment of patients with acute uncomplicated Plasmodium falciparum malaria treated with three-day mefloquine-artesunate on the north-western border of Thailand

BackgroundThe use of artemisinin derivatives has increased exponentially with the deployment of artemisinin combination therapy (ACT) in all malarious areas. They are highly effective and are considered safe, but in animal studies artemisinin derivatives produce neurotoxicity targeting mainly the auditory and vestibular pathways. The debate remains as to whether artemisinin derivatives induce similar toxicity in humans.MethodsThis prospective study assessed the effects on auditory function of a standard 3-day oral dose of artesunate (4 mg/kg/day) combined with mefloquine (25 mg/kg) in patients with acute uncomplicated falciparum malaria treated at the Shoklo Malaria Research Unit, on the Thai-Burmese border. A complete auditory evaluation with tympanometry, audiometry and auditory brainstem responses (ABR) was performed before the first dose and seven days after initiation of the antimalarial treatment.ResultsComplete auditory tests at day 0 (D0) and day 7 (D7) were obtained for 93 patients. Hearing loss (threshold > 25 dB) on admission was common (57%) and associated with age only. No patient had a threshold change exceeding 10 dB between D0 and D7 at any tested frequency. No patient showed a shift in Wave III peak latency of more than 0.30 msec between baseline and D7.ConclusionNeither audiometric or the ABR tests showed clinical evidence of auditory toxicity seven days after receiving oral artesunate and mefloquine.

Single-dose pharmacokinetic interaction between artesunate and amodiaquine: assembling the clues for the purported interaction

To the Editor – Due to the rampant development of resistance to most of the commonly used antimalarial drugs, the use of combination drug regimens is now strongly recommended. One of the interesting combination treatment includes the use of artesunate and amodiaquine as a first-line treatment option in several African countries [1, 2]. Whereas the safety, tolerability, and efficacy data have been gathered for this combination use, the pharmacokinetic data have been hitherto elusive. However, a recent paper published by Orrell and coworkers captures the pharmacokinetic data of the individually administered oral doses of artesunate/ amodiaquine as well as the combined entity in healthy African subjects in a well-planned and executed single-dose crossover design [3]. Generally, it appeared to be a well controlled study that ensured, among other things: rigorous study entry criteria, robust plasma sampling scheme, employment of sound bioanalytical assays, and reasonably adequate washout time between periods to remove any drug/metabolite(s) residues [3]. However, the single-dose data of the combined entity revealed the existence of pharmacokinetic interaction such that the total exposure of the two agents in combination treatment (parent and respective metabolites) were significantly reduced when compared with exposure data from the individual drug administrations [3]. As these new findings had not been published before, it would definitely add a new twist in trying to understand the pharmacokinetic play(s) when such combinations are being used to control the spread of the resistant malarial disease. More importantly, it brings into question the rationale in combining two agents that in combination may render it unsuitable in a combination situation from a clinical efficacy point of view due to loss of total drug exposure as a result of a very pronounced interaction. The intent of this note is to build some speculative clues by which to understand the nature of the observed pharmacokinetic interaction reported by Orrell and coworkers [3]. Typically, the loss of exposure of both agents following a mere single oral dose coadministration of the two agents is not a commonly observed pharmacokinetic interaction. However, opportunities do exist for single dose interaction in situations such as: (a) when there is a physicochemical interaction via chelation and/or degradation after oral ingestion; (b) when one and/or the combined entity can significantly alter gastrointestinal motility; (c) when one and/or the combined entity can hinder absorption by causing permeability issues and/or via efflux phenomenon. Although increased metabolism in the gut and/or autoinduction phenomenon may cause lowered exposure, it may be associated with increased exposure to one or more metabolite(s). It is interesting to note from limited pharmacokinetic reports available that artesunate did not alter the kinetics of compounds such as artemisinin [4], atovaquone–proguanil combination [5], and/or sulfadoxine/pyrimethamine combination [6] upon single/multiple dose coadministration. Mefloquine, another commonly used antimalarial, did not alter the pharmacokinetics of artesunate [7]. Similarly, amodiaquine did not alter the kinetics of halofantrine following pretreatment, although pharmacodynamically there appeared to be QTc prolongation attributable to the combination treatment [8]. Therefore, it appears that via documented pharmacokinetic data, neither artesunate nor Eur J Clin Pharmacol (2008) 64:1231–1233 DOI 10.1007/s00228-008-0539-x

Developmental toxicity of artesunate in the rat: comparison to other artemisinins, comparison of embryotoxicity and kinetics by oral and intravenous routes, and relationship to maternal reticulocyte count

The antimalarial, artesunate, is teratogenic and embryolethal in rats, with peak sensitivity on Days 10 and 11 postcoitum (pc). We compared the developmental toxicity of structurally related artemisinins, dihdyroartemisinin (DHA), artemether (ARTM), and arteether (ARTE) to that of artesunate after oral administration to rats on Day 10 pc. In separate studies, embryolethality was characterized after single intravenous (IV) administration of artesunate on Day 11 pc, and toxicokinetic parameters following oral and IV administration were compared. Lastly, to determine whether maternal hematologic effects occurred at doses that affect embryonic erythroblasts, artesunate was orally administered on Day 11 pc at a dose that caused 100% embryolethality. All artemisinins caused the same pattern of embryolethality and fetal cardiovascular and skeletal abnormalities as previously shown for artesunate. In the IV study, marked postimplantation loss occurred at 1.5 and 3 mg/kg artesunate, but not at 0.75 mg/kg. Among the toxicokinetic parameters evaluated, only the DHA AUC(0-t) was similar at embryolethal oral and IV doses of artesunate. An embryolethal dose of artesunate caused a 15% decrease in maternal reticulocyte counts and no other hematologic effects. Several structurally related artemisinins cause similar developmental toxicity, suggesting an artemisinin class effect. Equally embryotoxic oral and IV treatments of one artemisinin compound (artesunate) produced similar systemic exposure to the artesunate metabolite, DHA, suggesting that DHA may be the proximate developmental toxicant. Embryolethal doses of artesunate only caused minor changes in maternal reticulocyte counts indicating that adult hematology parameters are not as sensitive as embryonic erythroblasts.

Pharmacokinetics of artesunate in the domestic pig

The aim was to study the pharmacokinetic profile of artesunate and its metabolite dihydroartemisinin (DHA) in a pig model. Thirteen pigs received either intravenous (iv) or intramuscular (im) artesunate (60 mg), with the alternative preparation given 24 h later in an open crossover design. Five of them also received an additional intra-arterial (ia) artesunate dose (60 mg). The plasma concentrations of artesunate and DHA were determined by high-performance liquid chromatography with electrochemical detection. Population modelling was performed with NONMEM, using a two-compartment model. Plasma concentration-time profiles were comparable to those observed in humans, with a rapid and biphasic decline for both artesunate and DHA. Following an iv bolus, artesunate had a median maximum plasma concentration (C(max)) of 13.8 microM [interquartile range (IQR), 10.4-22.1 microM], elimination half-life (t(1/2)) = 18 min (IQR, 16-22 min), total plasma clearance (CL) = 5.58 L/h/kg (IQR, 3.31-5.91 L/h/kg) and volume of distribution (V(d)) = 1.85 L/kg (IQR, 1.27-3.20 L/kg). The median C(max) value for DHA was 3.30 microM (IQR, 2.08-5.95 microM), t(1/2) = 26 min (IQR, 23-31 min), CL/Fm = 4.37 L/h/kg (IQR, 3.29-6.87 L/h/kg) and V(d)/Fm = 2.56 L/kg (IQR, 1.93-4.49 L/kg). Artesunate and DHA pharmacokinetic parameters were similar after ia administration. Following im dosing, median artesunate C(max) was 4.81 microM (IQR, 3.74-5.40 microM), t(1/2) = 18 min (IQR, 16-28 min), CL = 4.37 L/h/kg (IQR, 4.13-4.68 L/h/kg) and V(d) = 2.07 L/kg (IQR, 1.83-2.79 L/kg); the bioavailability was 100%. For DHA, median C(max) was 1.43 microM (IQR, 1.00-1.92 microM), t(1/2) = 27 min (IQR, 25-37 min), CL/Fm = 4.68 L/h/kg (IQR, 3.35-6.73 L/h/kg) and V(d)/Fm = 3.31 L/kg (IQR, 2.89-4.27 L/kg). The pharmacokinetic properties of artesunate and DHA in pigs were similar to those reported in humans, suggesting that the swine model is suitable for determining the preclinical pharmacokinetics of artemisinin derivatives.

Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies

BackgroundRectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria.MethodsIndividual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success.ResultsArtemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether.ConclusionArtemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy.

Open-Label Comparative Clinical Study of Chlorproguanil−Dapsone Fixed Dose Combination (Lapdap™) Alone or with Three Different Doses of Artesunate for Uncomplicated Plasmodium falciparum Malaria

The objective of this study was to determine the appropriate dose of artesunate for use in a fixed dose combination therapy with chlorproguanil−dapsone (CPG−DDS) for the treatment of uncomplicated falciparum malaria.MethodsOpen-label clinical trial comparing CPG−DDS alone or with artesunate 4, 2, or 1 mg/kg at medical centers in Blantyre, Malawi and Farafenni, The Gambia. The trial was conducted between June 2002 and February 2005, including 116 adults (median age 27 years) and 107 children (median age 38 months) with acute uncomplicated Plasmodium falciparum malaria. Subjects were randomized into 4 groups to receive CPG–DDS alone or plus 4, 2 or 1 mg/kg of artesunate once daily for 3 days. Assessments took place on Days 0−3 in hospital and follow-up on Days 7 and 14 as out-patients. Efficacy was evaluated in the Day 3 per-protocol (PP) population using mean time to reduce baseline parasitemia by 90% (PC90). A number of secondary outcomes were also included. Appropriate artesunate dose was determined using a pre-defined decision matrix based on primary and secondary outcomes. Treatment emergent adverse events were recorded from clinical assessments and blood parameters. Safety was evaluated in the intent to treat (ITT) population.ResultsIn the Day 3 PP population for the adult group (N = 85), mean time to PC90 was 19.1 h in the CPG−DDS group, significantly longer than for the +artesunate 1 mg/kg (12.5 h; treatment difference −6.6 h [95%CI −11.8, −1.5]), 2 mg/kg (10.7 h; −8.4 h [95%CI −13.6, −3.2]) and 4 mg/kg (10.3 h; −8.7 h [95%CI −14.1, −3.2]) groups. For children in the Day 3 PP population (N = 92), mean time to PC90 was 21.1 h in the CPG−DDS group, similar to the +artesunate 1 mg/kg group (17.7 h; −3.3 h [95%CI −8.6, 2.0]), though the +artesunate 2 mg/kg and 4 mg/kg groups had significantly shorter mean times to PC90 versus CPG−DDS; 14.4 h (treatment difference −6.4 h [95%CI −11.7, −1.0]) and 12.8 h (−7.4 h [95%CI −12.9, −1.8]), respectively. An analysis of mean time to PC90 for the Day 14 PP and ITT populations was consistent with the primary analysis. Treatment emergent, drug-related adverse events were experienced in 35.3% (41/116) of adults and 70.1% (75/107) of children; mostly hematological and gastroenterological. The nature and incidence of adverse events was similar between the groups. No dose-related changes in laboratory parameters were observed. Nine serious adverse events due to any cause occurred in five subjects including two cases of hemolysis believed to be associated with drug treatment (one adult, one child). One adult died of anaphylactic shock, not associated with investigational therapy.ConclusionsCPG–DDS plus artesunate demonstrated advantages over CPG–DDS alone for the primary efficacy endpoint (mean time to PC90) except in children for the 1 mg/kg artesunate dose. Based on a pre-defined decision matrix, the primary endpoint in the child group supported an artesunate dose of 4 mg/kg. Secondary endpoints also supported a 4 mg/kg artesunate dose to take forward into the remainder of the development program.Trial RegistrationClinicalTrials.gov NCT00519467

COMPARATIVE EVALUATION OF PHAMACODYNAMICS AND NEURONAL OXIDATIVE STRESS ELICITED BY LARGE DOSES OF ARTESUNATE IN COMBINATION WITHMEFLOQUINE OR AMODIAQUINE IN Plasmodium berghei INFECTED MICE

Background: Artemisinins in combination with other conventional antimalarials have been found to elicit greater schizonticidal and gametocidal activity than other antimalarial drugs. However, their pharmacokinetic misfit has raised substantial concerns over their future pharmacodynamic potentials, which include restoration of neutrophil function during covalescence or at full recovery.Method: A total of forty‐five mice (Mean weight = 22.1g) intraperitoneally infected with P. berghei at a dose of 5 × 107 parasitized erythrocytes, were randomized into 3 treatment groups of 15 mice per dosing regimen. The animals were scored for mortality, clearance of parasitaemia and pigmented neutrophils. .Results: Administration of escalated doses of artesunate‐amodiaquine and artesunate – mefloquine resulted in dose‐dependent but non significant (P &lt; 0.05) decreases in parasite clearance time (12 – 28.8 h for artesunate + amodiaquine; 16.5 – 27 h for artesunate + mefloquine) and parasite reduction rate (0.65 – 074 % parasite/h and 0.64 −0.78 % parasite/h). While parasitaemia correlated positively but non‐significantly (r = 0.065; P &lt; 0.05), the neutropenia (4472.3 ± 240 vs. 1709.5 ± 17.8 cells/mm3; P &lt; 0.05) and pigmented neutrophils (308.2±2.4 cells/mm3) elicited by P. berghei infection was also not corrected by the two artesunate – based regimens.Conclusion: Based on the results of this study, it can be concluded that the artesunate based combination therapies lack neutrophil restoration ability and oxidative stress corrective function in spite of their antiparasitic efficacy.

Artemether, artesunate, praziquantel and tribendimidine administered singly at different dosages against Clonorchis sinensis: A comparative in vivo study

We comparatively assessed the in vivo efficacy of artemether, artesunate, praziquantel and tribendimidine against different stages of Clonorchis sinensis. Rats were infected with 40–50 C. sinensis metacercariae, and drugs were administered singly by the oral route at different dosages. Rats were dissected 2–4 weeks post-treatment and C. sinensis trematodes were removed from the liver and bile ducts and counted. We used a negative binomial regression model to test the effect of drug and dosage in terms of worm burden reduction. Single 150 mg/kg oral doses of artesunate, artemether, tribendimidine and praziquantel, administered to rats infected with adult C. sinensis, resulted in mean worm burden reductions of 100, 100, 89.5 and 80.7%, respectively (all P < 0.001). Halving the dose to 75 mg/kg still resulted in highly significant worm burden reductions for artesunate, artemether and tribendimidine (71.4–100%), but not for praziquantel (20.7%). In the juvenile infection model, a single 150 mg/kg oral dose of tribendimidine and praziquantel resulted in mean worm burden reductions of 99.1 and 90.0%, respectively, whereas considerably lower reductions were observed for artemether (59.2%) and artesunate (57.6%) when used at the same single dose. The in vivo results presented here with the artemisinins and tribendimidine provide further data for clinical investigations to assess the safety and efficacy of these drugs in clonorchiasis patients.

COMBINATION OF ARTESUNATE-AMODIAQUINE AS A TREATMENT FOR UNCOMPLICATED FALCIPARUM MALARIA IN CHILDREN

INTRODUCTION: Resistance of falciparum malaria to both chloroquine and pyrimethamine-sulfadoxine has been reported from Indonesia and other countries. Since the end of 2004, we have changed the standard treatment of uncomplicated falciparum malaria to use a combination of artesunate and amodiaquine. OBJECTIVE: Our aim was to evaluate the efficacy and adverse reactions of artesunate-amodiaquine as a treatment for uncomplicated falciparum malaria in children. METHODS: We conducted a cross-sectional study at Panyabungan, Mandailing Natal Regency, North Sumatera Province, Indonesia, from August to September 2006. The sample was school-aged children between 5 and 18 years old. The sample received an oral dose of artesunate (4 mg/kg body weight) combined with an oral dose of amodiaquine (10 mg/kg body weight) for 3 days. Parasitemia was assessed at days 0, 2, 7, and 28. RESULTS: Peripheral blood smears were performed for 376 school-aged children; 135 of them tested positive for falciparum malaria. At the end of the study (28 days), 121 cases completed a full course of study. From the peripheral blood smears on days 2, 7, and 28, we found a 100% cure rate. Adverse reactions included 20 children (16.5%) with headache, 10 (8.3%) with vomiting, and 1 (0.8%) with tinnitus. CONCLUSIONS: A combination of artesunate and amodiaquine can be used as treatment for uncomplicated falciparum malaria in children with the caution of headache as an adverse reaction of the drug combination.

Anti-malarial efficacy of pyronaridine and artesunate in combination in vitro and in vivo

Pyronaridine is a Mannich base anti-malarial with demonstrated efficacy against drug resistant Plasmodium falciparum, P. vivax, P. ovale and P. malariae. However, resistance to pyronaridine can develop quickly when it is used alone but can be considerably delayed when it is administered with artesunate in rodent malaria models. The aim of this study was to evaluate the efficacy of pyronaridine in combination with artesunate against P. falciparum in vitro and in rodent malaria models in vivo to support its clinical application. Pyronaridine showed consistently high levels of in vitro activity against a panel of six P. falciparum drug-sensitive and resistant strains (Geometric Mean IC 50 = 2.24 nM, 95% CI = 1.20–3.27). In vitro interactions between pyronaridine and artesunate showed a slight antagonistic trend, but in vivo compared to pyronaridine and artesunate administered alone, the 3:1 ratio of the combination, reduced the ED 90 of artesunate by ∼15.6-fold in a pyronaridine-resistant P. berghei line and by ∼200-fold in an artesunate-resistant line of P. berghei. Complete cure rates were achieved with doses of the combination above or equal to 8 mg/kg per day against P. chabaudi AS. These results indicate that the combination had an enhanced effect over monotherapy and lower daily doses of artesunate could be used to obtain a curative effect. The data suggest that the combination of pyronaridine and artesunate should have potential in areas of multi-drug resistant malaria.