Oral Artemether Research Articles

Treatment of Murine Toxoplasmosis with Oral and Parenteral Artemether and Following by Detection of B1 Gene by Quantitative Real-Time PCR (qPCR) for Evaluating Parasite Density.

Background:Toxoplasma gondii is an obligate intracellular parasite that can infect humans and animals. As the choice drug have shown side effects, development a new drug with low toxicity will be necessary.Methods:BALB/c mice were infected with tachyzoiets of T. gondii. After treatment by oral and parenteral artemether (250 μg/mice) and sulfadiazine (50 μg/mice), we evaluated the rates of survival in treated and control mice. The fold change of B1 gene (target gene) expression in liver and brain of mice treated with parenteral artemether (i.p.), oral artemether (via gavage) and sulfadiazine, were detected by using the Real-Time quantitative PCR.Results:Both treatment with sulfadiazine and artemether showed significant prolongation in time to death of the infected mice compared to the control group. Median survival days for parenteral artemether, oral artemether, sulfadiazine and control group were 8, 11, 12 and 6 d respectively. Expression of B1 gene in liver and brain of mice after treatment with artemether and sulfadiazine were reduced in comparison to housekeeping gene (β-tubulin gene). The fold change (comparing to control group) for parenteral artemether, oral artemether, sulfadiazine is 0.034, 0.027 and 0.111 for liver and 0.220, 0.425 and 0.366 for brain respectively.Conclusion:Artemether is effective to control the tachyzoites of T. godii in vivo conditions and oral treatment is more effective than parenteral treatment. Due to its low cytotoxicity and its high effective action against the tachyzoietes of T. godii in susceptible animals.

Arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a single-centre, open-label, randomised, non-inferiority trial

SummaryBackgroundTriple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children.MethodsIn this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2–12 years and had an asexual parasitaemia of 5000–250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane–piperaquine, arterolane–piperaquine–mefloquine, or artemether–lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether–lumefantrine was administered twice daily (target dose 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of bodyweight of lumefantrine), and oral arterolane–piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane–piperaquine–mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane–piperaquine–mefloquine versus artemether–lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was −7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed.FindingsBetween March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane–piperaquine (n=73), arterolane–piperaquine–mefloquine (n=72), or artemether–lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane–piperaquine–mefloquine (100%, 95% CI 95–100; 72/72) was non-inferior to that after treatment with artemether–lumefantrine (96%, 95% CI 88–99; 69/72; risk difference 4%, 95% CI 0–9; p=0·25). The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine was non-inferior to that of arterolane–piperaquine (100%, 95% CI 95–100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane–piperaquine (5%, 95% CI 2–9; ten of 203 drug administrations; p=0·0013) or arterolane–piperaquine–mefloquine (5%, 3–9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether–lumefantrine (1%, 0–2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether–lumefantrine; n=19 for arterolane–piperaquine–mefloquine; n=23 for arterolane–piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths.InterpretationThis study shows that arterolane–piperaquine–mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance.FundingUK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries

A case of blackwater fever with persistent Plasmodium falciparum parasitaemia detected by PCR after artemether\u2013lumefantrine treatment

BackgroundBlackwater fever is a complication of malaria infection consisting of a syndrome of febrile intra-vascular haemolysis with severe anaemia and intermittent passage of dark-red to black colour urine. Despite numerous reports and studies of this condition, its pathogenesis remains incompletely understood.Case presentationThis report describes a case of classic blackwater fever in a returning traveller, without prior history of malaria infection nor usage of anti-malarial prophylaxis, treated with two courses of oral artemether–lumefantrine combination therapy. Unusual persistence of submicroscopic Plasmodium falciparum parasitaemia was detected by PCR for 18 days after initiation of treatment.ConclusionTo the authors’ knowledge this is the first reported occurrence of a case of blackwater fever associated with prolonged submicroscopic parasitaemia. This unusual case challenges the current knowledge of the pathogenesis of this condition and opens questions that may have important diagnostic and treatment implications.

AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial

SummaryBackgroundChloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria.MethodsWe did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per μL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 μL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964.FindingsBetween Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2–4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93·9%] of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference −6·1%, 95% CI −14·7 to 2·4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84·8% for AQ-13 vs 31 of 33, 93·9% for artemether and lumefantrine; p=0·43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9·1%, 95% CI −5·6 to 23·8).InterpretationThe per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended.FundingUS Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs-Wellcome Fund, US State Department, and WHO.

Quality Testing of Artemisinin-Based Antimalarial Drugs in Myanmar.

Artemisinin-based combination therapies are the frontline treatment of Plasmodium falciparum malaria. The circulation of falsified and substandard artemisinin-based antimalarials in Southeast Asia has been a major predicament for the malaria elimination campaign. To provide an update of this situation, we purchased 153 artemisinin-containing antimalarials, as convenience samples, in private drug stores from different regions of Myanmar. The quality of these drugs in terms of their artemisinin derivative content was tested using specific dipsticks for these artemisinin derivatives, as point-of-care devices. A subset of these samples was further tested by high-performance liquid chromatography (HPLC). This survey identified that > 35% of the collected drugs were oral artesunate and artemether monotherapies. When tested with the dipsticks, all but one sample passed the assays, indicating that the detected artemisinin derivative content corresponded approximately to the labeled contents. However, one artesunate injection sample was found to contain no active ingredient at all by the dipstick assay and subsequent HPLC analysis. The continued circulation of oral monotherapies and the description, for the first time, of falsified parenteral artesunate provides a worrisome picture of the antimalarial drug quality in Myanmar during the malaria elimination phase, a situation that deserves more oversight from regulatory authorities.

A Physiologically Based Pharmacokinetic Model to Describe Artemether Pharmacokinetics in Adult and Pediatric Patients

Artemether is co-administered with lumefantrine as part of a fixed-dose combination therapy for malaria in both adult and pediatric patients. However, artemether exposure is higher in younger infants (1-3 months) with a lower body weight (<5 kg) as compared to older infants (3-6 months) with a higher body weight (≥5 to <10 kg), children, and adults. In contrast, lumefantrine exposure is similar in all age groups. This article describes the clinically observed artemether exposure data in pediatric populations across various age groups (1 month to 12 years) and body weights (<5 or ≥5 kg) using physiologically based pharmacokinetic (PBPK) mechanistic models. A PBPK model was developed using artemether physicochemical, biopharmaceutic, and metabolic properties together with known enzyme ontogeny and pediatric physiology. The model was verified using clinical data from adult patients after multiple doses of oral artemether, and was then applied to simulate the exposure in children and infants. The simulated PBPK concentration-time profiles captured observed clinical data. Consistent with the clinical data, the PBPK model simulations indicated a higher artemether exposure for younger infants with lower body weight. A PBPK model developed for artemether reliably described the clinical data from adult and pediatric patients.

Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda.

Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether–lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether–lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women.

In Vitro and In Vivo Studies of Antileishmanial Effect of Artemether on Leishmania infantum

Background: Visceral leishmaniasis is the most acute form of leishmaniasis. Instead of administering usual drugs with different side effects, applying a herbal drug can put forward a novel horizon in dealing with this parasite. Artemether is one of the derivatives of artemisinin, a new anti-malarial drug, and can be activated by heme to produce free radicals which, in turn, have toxic effect on the parasite. Objectives: In this study we used artemether as a new drug for treatment of visceral leishmaniasis. Materials and Methods: In the present study, BALB/c mice infected with Leishmania infantum (MHOM/TN/80/IPI1) were treated with the most effective dose of artemether assessed with In Vitro assay. Artemether was given in parenteral and oral forms. Parasite burdens in the spleen and liver were determined by homogenizing and counting the parasite rate and were compared with those in the untreated mice. To evaluate the apoptotic properties of artemether by FACS flowcytometry, annexin-V FLUOS staining was performe. Results: IC50 of the drug on Leishmania infantum was determined to be 25 μg/mL after 24 h. In Vivo experiments indicated that oral artemether treatment of mice, during 3 days and every 6 h (0.625 mg/kg) was more significant than parenteral (0.625 mg/kg IP) treatment. Artemether exerts its cytotoxic effect on this parasite via apoptosis-related mechanism. Accordingly, parasite burden in the current study decreased in the liver and spleen of mice by oral treatment. Conclusions: Artemether especially in oral treatment is an effective and simple method and may be used as a new method to treat visceral leishmaniasis.

Haemolytic anaemia after oral artemether–lumefantrine treatment in a patient affected by severe imported falciparum malaria

Artemisinin and its derivatives are essential components of artemisinin-based combination therapies for treating severe falciparum malaria. In this paper, we describe the occurrence of haemolysis after oral artemether-lumefantrine treatment. To the best of our knowledge, this is the second reported case of a patient affected by severe falciparum malaria with haemolytic anaemia that is likely associated with oral artemether-lumefantrine treatment.

Locomotor and Exploratory Behaviour in Mice with Treated Oral Artemether Suspension

Previous studies with intramuscular Artemether reveal dose dependent neurotoxicity with specific concern on the nuclei of the brain stem. This study was aimed at assessing the effect of oral Artemether suspension on locomotor and exploratory behaviour in mice. The study was conducted using a total of 30 mice randomly divided into 3 groups. Group 1 served as the control and was administered with neither drug nor placebo. Groups 2 and 3 were administered with 30mg/kg/day (low dose) and 60mg/kg/day (high dose) respectively of oral Artemether suspension for 17 days. Behavioural tools used were Open Field Maze, ElevatedPlus maze and Light/Dark transition box. Parameters measured were centre square duration/ entries, frequency of rearing, frequency of line crosses, open arm duration / entries and head dips. In the Open Field test, centre square duration and entries were significantly higher in the low dose group but lower in the high dose group compared to the control. The frequency of line crosses in the Open Field test was also significantly lower in the high dose group compared to control. The frequency of rearing was significantly lower in high dose group compared to the control in all the 3 behavioural tools used. There was no significant difference between the control and the experimental mice in the frequency of head dips and open arm duration/entries. In conclusion, oral Artemether causes reduce exploratory and locomotor activity.

Efficacy of Artemether in Unresolving Plasmodium Falciparum Malaria

The emergence of possible resistant Plasmodium falciparum malaria to artemisinin known for its immense benefit in malaria chemotherapy is worrisome. We report a case of unresolving Plasmodium falciparum malaria to Artesunate treatment in a 29- year old man in Enugu Nigeria. Plasmodium falciparum count of Giemsa stained blood films was 3000 parasites /il on the first day, and 2400 parasites /il on the 14 th day following treatment with oral Artesunate. On administering oral Artemether to the patient, the parasite count dropped from 2400 parasites /il to zero as at day 14 with normal body temperature and marked clinical improvement. The use of Artesunate as monotherapy against malaria infection is common practice in our community. Health care providers should have a re-think and use artemisinin based combination therapy Keywords: Malaria, Artesunate, Resistance Nigerian Medical Practitioner Vol. 62 No 5-6, 2012

Efficacy and Safety of Artemether in the Treatment of Chronic Fascioliasis in Egypt: Exploratory Phase-2 Trials

BackgroundFascioliasis is an emerging zoonotic disease of considerable veterinary and public health importance. Triclabendazole is the only available drug for treatment. Laboratory studies have documented promising fasciocidal properties of the artemisinins (e.g., artemether).MethodologyWe carried out two exploratory phase-2 trials to assess the efficacy and safety of oral artemether administered at (i) 6×80 mg over 3 consecutive days, and (ii) 3×200 mg within 24 h in 36 Fasciola-infected individuals in Egypt. Efficacy was determined by cure rate (CR) and egg reduction rate (ERR) based on multiple Kato-Katz thick smears before and after drug administration. Patients who remained Fasciola-positive following artemether dosing were treated with single 10 mg/kg oral triclabendazole. In case of treatment failure, triclabendazole was re-administered at 20 mg/kg in two divided doses.Principal FindingsCRs achieved with 6×80 mg and 3×200 mg artemether were 35% and 6%, respectively. The corresponding ERRs were 63% and nil, respectively. Artemether was well tolerated. A high efficacy was observed with triclabendazole administered at 10 mg/kg (16 patients; CR: 67%, ERR: 94%) and 20 mg/kg (4 patients; CR: 75%, ERR: 96%).Conclusions/SignificanceArtemether, administered at malaria treatment regimens, shows no or only little effect against fascioliasis, and hence does not represent an alternative to triclabendazole. The role of artemether and other artemisinin derivatives as partner drug in combination chemotherapy remains to be elucidated.

Efficacy of artesunate and artemether against Clonorchis sinensis in rabbits

Artesunate and artemether display promising clonorchicidal properties in rats. In this study, we assessed the efficacy of artesunate and artemether against Clonorchis sinensis in rabbits. Rabbits were each fed with 300 C. sinensis metacercariae. At day 28 postinfection, the rabbits were administered oral artesunate at doses of 7.5-120 mg/kg and oral artemether of 15-120 mg/kg. Two groups of rabbits were treated with single oral praziquantel at 75 and 150 mg/kg. Untreated rabbits served as controls. Fourteen days after treatment, all rabbits were sacrificed, and C. sinensis adults were collected from the bile ducts and counted. At the highest doses tested (120 mg/kg) artesunate and artemether achieved statistical significant worm burden reductions of 88.8% and 67.2%, respectively. These rates were lower than worm burden reductions observed with praziquantel (88% and 100%, respectively). It is suggested that artesunate and artemether have moderate anthelminthic efficacy against C. sinensis in rabbits.

Efficacy and acceptability of oral artemether (Artemos&lt;sup&gt;TM&lt;/sup&gt;) for the treatment of acute uncomplicated malaria in Ghana

Efficacy and acceptability of oral artemether (Artemos&lt;sup&gt;TM&lt;/sup&gt;) for the treatment of acute uncomplicated malaria in Ghana

A double-blind field trial on the effects of artemether on Schistosoma japonicum infection in a highly endemic focus in southern China

To further strengthen the evidence-base of artemether for the control of schistosomiasis japonica, a randomised controlled trial was carried out in the Poyang Lake region, a highly endemic area in southern China. A total of 783 individuals, aged 6–60 years, were enrolled. They were first given a single oral dose of praziquantel (50 mg/kg). Then, they were randomly assigned oral artemether (6 mg/kg) or placebo, administered once every 2 weeks for 9–11 doses, covering the entire transmission season for Schistosoma japonicum in 2004. Stool examination 1 month after the final dosing revealed eggs of S. japonicum in 3/373 (0.8%) of the artemether recipients and 56/361 (15.0%) in placebo recipients ( χ 2 = 53.69, P < 0.001). Compared to the baseline, the geometric mean intensity of S. japonicum infection had decreased by 96.1% in the artemether group, and increased by 50.8% in the placebo group. No acute cases of schistosomiasis japonica were observed in the artemether group, whereas three such cases were reported from the placebo group. Compliance with regard to multi-doses of artemether and placebo was 84.9, and 77.9%, respectively. This study confirms that repeated oral artemether produces no drug-related adverse effects, significantly reduces incidence and intensity of patent S. japonicum infection and results in high compliance. Hence it can be used as an additional tool for the control of schistosomiasis japonica in the lake regions of China.

Successful co-artemether (artemether–lumefantrine) clearance of falciparum malaria in a patient with severe cholera in Mozambique

Background. Both falciparum malaria and cholera occur in Mozambique and other resource poor African countries. We report successful parasite clearance by oral co-artemether of coincidental falciparum malaria in a patient suffering severe cholera. Methods. A case report. Results. Parasite clearance was observed at day 3. Conclusions. Oral artemether is sufficiently absorbed in the face of co-existent severe cholera to effect parasitological clearance of P. falciparum. This may be of relevance in resource poor tropical settings when a malaria patient presents with a simultaneous secretory diarrhoea, and a limited drug choice is available.

RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF ORAL ARTEMETHER FOR THE PREVENTION OF PATENT SCHISTOSOMA HAEMATOBIUM INFECTIONS

Artemether is an efficacious antimalarial drug that also displays antischistosomal properties. Laboratory studies have found that artemether curtails the development of adult worms of Schistosoma japonicum, S. mansoni and S. haematobium, and thus prevents morbidity. These findings have been confirmed in clinical trials for the former two parasites; administered orally once every 2-3 weeks, artemether significantly reduced the incidence and intensity of patent infections. Here, we present the first randomized, double-blind, placebo-controlled trial of artemether against S. haematobium, done in a highly endemic area of Côte d'Ivoire. Urine specimens from 440 schoolchildren were examined over 4 consecutive days, followed by two systematic praziquantel treatments 4 weeks apart. S. haematobium-negative children were randomized to receive 6 mg/kg artemether (N = 161) or placebo (N = 161). Medication was administered orally for a total of six doses once every 4 weeks. Adverse events were assessed 72 hours after medication, and perceived illness episodes were monitored throughout the study period. Incidence and intensity of S. haematobium infections, and microhematuria and macrohematuria were assessed 3 weeks after the final dosing. We also monitored malaria parasitemia and treated positive cases with sulfadoxine-pyrimethamine (SP). Oral artemether was well tolerated. The incidence of patent S. haematobium infections in artemether recipients was significantly lower than in placebo recipients (49% versus 65%, protective efficacy: 0.25, 95% CI: 0.08-0.38, P = 0.007). The geometric mean infection intensity in the artemether group was less than half that of the placebo recipients (3.4 versus 7.4 eggs/10 mL urine, P < 0.001). Heavy S. haematobium infections, microhematuria and macrohematuria, and the incidence of malaria parasitemia were all significantly lower in artemether recipients. In conclusion, previous findings of efficacy of artemether against S. japonicum and S. mansoni were confirmed for S. haematobium, although the protective efficacy was considerably lower. These findings enlarge the scope and potential of artemether and further contribute to discussions of its role as an additional tool for integrated schistosomiasis control.

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Intramuscular administration of high doses of artemether and arteether to experimental mammals produces selective damage to brain stem centers involved predominantly in auditory processing and vestibular reflexes. The relationship between clinical signs of neurotoxicity and neuropathologic toxicity was studied in the mouse. Intramuscular artemether (50-100 mg/kg/day for 28 days) caused dose-dependent neuropathologic damage to the brain stem. There was no pathologic evidence of neuronal death in mice receiving either oral artemether, or oral or intramuscular artesunate, in doses up to 300 mg/kg/day. The neurons in the lower brain stem trapezoid nucleus, the gigantocellular reticular nucleus, and the inferior cerebellar peduncle were the most sensitive to the toxic effects of artemether. All mice with neuropathologic changes also showed behavioral changes, whereas in some mice with gait disturbance, no corresponding histopathologic damage could be detected. Thus clinical assessment was a sensitive measure of neurotoxicity. There may be a reversible component to artemether neurotoxicity.

Assessment of the neurotoxicity of oral dihydroartemisinin in mice

High doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether, given by intramuscular injection to experimental mammals, produce an unusual pattern of selective damage to brainstem centres predominantly involved in auditory processing and vestibular reflexes. We have shown recently, in adult Swiss albino mice, that constant exposure either from depot intramuscular injection of oil-based artemisinin derivatives, or constant oral intake carries relatively greater neurotoxic potential than other methods of drug administration. Using the same model, oral dihydroartemisinin suspended in water was administered once or twice daily at different doses ranging from 50 to 300 mg/kg/day for 28 days. The neurotoxic potential of the oral dihydroartemisinin was assessed and compared to that of oral artemether and artesunate. Oral artemether, artesunate, and dihydroartemisinin had similar neurotoxic effects with no significant clinical or neuropathological evidence of toxicity at doses below 200 mg/kg/day. These data indicate that once and twice daily oral administration of artemether, artesunate and dihydroartemisinin is relatively safe when compared to intramuscular administration of the oil-based compounds.

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential.