Use Of Artemether Research Articles

Clinical isolates of uncomplicated falciparum malaria from high and low malaria transmission areas show distinct pfcrt and pfmdr1 polymorphisms in western Ethiopia

BackgroundPfcrt gene has been associated with chloroquine resistance and the pfmdr1 gene can alter malaria parasite susceptibility to lumefantrine, mefloquine, and chloroquine. In the absence of chloroquine (CQ) and extensive use of artemether–lumefantrine (AL) from 2004 to 2020 to treat uncomplicated falciparum malaria, pfcrt haplotype, and pfmdr1 single nucleotide polymorphisms (SNPs) were determined in two sites of West Ethiopia with a gradient of malaria transmission.Methods230 microscopically confirmed P. falciparum isolates were collected from Assosa (high transmission area) and Gida Ayana (low transmission area) sites, of which 225 of them tested positive by PCR. High-Resolution Melting Assay (HRM) was used to determine the prevalence of pfcrt haplotypes and pfmdr1 SNPs. Furthermore, the pfmdr1 gene copy number (CNV) was determined using real-time PCR. A P-value of less or equal to 0.05 was considered significant.ResultsOf the 225 samples, 95.5%, 94.4%, 86.7%, 91.1%, and 94.2% were successfully genotyped with HRM for pfcrt haplotype, pfmdr1-86, pfmdr1-184, pfmdr1-1042 and pfmdr1-1246, respectively. The mutant pfcrt haplotypes were detected among 33.5% (52/155) and 80% (48/60) of isolates collected from the Assosa and Gida Ayana sites, respectively. Plasmodium falciparum with chloroquine-resistant haplotypes was more prevalent in the Gida Ayana area compared with the Assosa area (COR = 8.4, P = 0.00). Pfmdr1-N86Y wild type and 184F mutations were found in 79.8% (166/208) and 73.4% (146/199) samples, respectively. No single mutation was observed at the pfmdr1-1042 locus; however, 89.6% (190/212) of parasites in West Ethiopia carry the wild-type D1246Y variants. Eight pfmdr1 haplotypes at codons N86Y–Y184F–D1246Y were identified with the dominant NFD 61% (122/200). There was no difference in the distribution of pfmdr1 SNPs, haplotypes, and CNV between the two study sites (P > 0.05).ConclusionPlasmodium falciparum with the pfcrt wild-type haplotype was prevalent in high malaria transmission site than in low transmission area. The NFD haplotype was the predominant haplotype of the N86Y–Y184F–D1246Y. A continuous investigation is needed to closely monitor the changes in the pfmdr1 SNPs, which are associated with the selection of parasite populations by ACT.

Synthesis of Artemether-Loaded Albumin Nanoparticles and Measurement of Their Anti-Cancer Effects.

Colorectal cancer is the third most common cancer in the world. Due to the side effects of common treatments such as chemotherapy and radiotherapy, the use of herbal medicines has received much attention. Artemether (ARM) is an herbal medicine derived from artemisinin, which has many anti-tumor properties. However, factors such as low solubility and short half-life have limited the use of artemether in clinical practice. In this study, we aimed to reduce these limitations by encapsulating artemether in human serum albumin (HSA). The hydrodynamic diameter and the zeta potential value of ARM-ALB nanoparticles (NPs) were 171.3 ± 5.88 nm and -19.1 ± 0.82 mV, respectively. Comparison of the effect of free and encapsulated artemether on CT 26 cell line showed that the use of artemether in capsulated form can reduce the effective concentration of the drug. Additionally, in vivo studies have also shown that albumin-artemether nanoparticles can control tumor growth by increasing the production of cytokine IFN-γ and decreasing the production of IL4. Therefore, ARM-ALB nanoparticles have greater anti-tumor effects than free artemether.

Mechanisms of artemether toxicity on single cardiomyocytes and protective effect of nanoencapsulation.

The artemisinin derivative, artemether, has antimalarial activity with potential neurotoxic and cardiotoxic effects. Artemether in nanocapsules (NC-ATM) is more efficient than free artemether for reducing parasitaemia and increasing survival of Plasmodium berghei-infected mice. NCs also prevent prolongation of the QT interval of the ECG. Here, we assessed cellular cardiotoxicity of artemether and how this toxicity was prevented by nanoencapsulation. Mice were treated with NC-ATM orally (120 mg·kg-1 twice daily) for 4 days. Other mice received free artemether, blank NCs, and vehicle for comparison. We measured single-cell contraction, intracellular Ca2+ transient using fluorescent Indo-1AM Ca2+ dye, and electrical activity using the patch-clamp technique in freshly isolated left ventricular myocytes. The acute effect of free artemether was also tested on cardiomyocytes of untreated animals. Artemether prolonged action potentials (AP) upon acute exposure (at 0.1, 1, and 10 μM) of cardiomyocytes from untreated mice or after in vivo treatment. This prolongation was unrelated to blockade of K+ currents, increased Ca2+ currents or promotion of a sustained Na+ current. AP lengthening was abolished by the NCX inhibitor SEA-0400. Artemether promoted irregular Ca2+ transients during pacing and spontaneous Ca2+ events during resting periods. NC-ATM prevented all effects. Blank NCs had no effects compared with vehicle. Artemether induced NCX-dependent AP lengthening (explaining QTc prolongation) and disrupted Ca2+ handling, both effects increasing pro-arrhythmogenic risks. NCs prevented these adverse effects, providing a safe alternative to the use of artemether alone, especially to treat malaria.

Artemether Regulates Metaflammation to Improve Glycolipid Metabolism in db/db Mice.

BackgroundArtemether, a commonly used artemisinin derivative, has been shown to possess potential antidiabetic activities. However, only limited information is available on the mechanisms of artemether in type 2 diabetes. Therefore, in this study, we examined some of the possible mechanisms of artemether (ATM) upon glycolipid metabolism in the db/db mouse model of diabetes.Materials and MethodsMale C57BL/KsJ-db/db and C57BL/KsJ-db/+ mice at 4 weeks of age were divided into four groups (N=6/group): (1) NC (normal control – db/+ mice, 1% methylcellulose, intragastric administration), (2) DM (diabetic model – db/db mice, 1% methylcellulose, intragastric administration), (3) ATM 100 (DM + 100 mg/kg of artemether) and (4) ATM 200 (DM + 200 mg/kg of artemether). A number of assays related to diabetes were then performed following a 4-week period of these treatments.ResultsArtemether at both doses significantly reduced rates of weight gain and fasting blood glucose levels, improved islet function and insulin resistance and reduced serum lipid levels to varying degrees in db/db mice. Artemether exerted a positive effect on islet vacuolar degeneration and hepatic steatosis, and increased expressions of AMP-activated protein kinase, glucose transporter 4 and Insulin receptor β protein in the liver of these db/db mice. With the use of liver protein chip detection, we found that artemether significantly improved the immune microenvironment, down-regulated the expression of inflammatory factors and activated the cytokine-mediated signaling pathway through cytokine–cytokine receptor interactions.ConclusionArtemether may regulate glycolipid metabolism in db/db mice by improving the immune microenvironment. The results of this study provide important new information that can serve as the foundation for future research into the use of artemether as a means to improve glycolipid metabolism.

Selective sweeps and genetic lineages of Plasmodium falciparum multi-drug resistance (pfmdr1) gene in Kenya

BackgroundThere are concerns that resistance to artemisinin-based combination therapy might emerge in Kenya and sub-Saharan Africa (SSA) in the same pattern as was with chloroquine and sulfadoxine–pyrimethamine. Single nucleotide polymorphisms (SNPs) in critical alleles of pfmdr1 gene have been associated with resistance to artemisinin and its partner drugs. Microsatellite analysis of loci flanking genes associated with anti-malarial drug resistance has been used in defining the geographic origins, dissemination of resistant parasites and identifying regions in the genome that have been under selection.MethodsThis study set out to investigate evidence of selective sweep and genetic lineages in pfmdr1 genotypes associated with the use of artemether–lumefantrine (AL), as the first-line treatment in Kenya. Parasites (n = 252) from different regions in Kenya were assayed for SNPs at codons 86, 184 and 1246 and typed for 7 neutral microsatellites and 13 microsatellites loci flanking (± 99 kb) pfmdr1 in Plasmodium falciparum infections.ResultsThe data showed differential site and region specific prevalence of SNPs associated with drug resistance in the pfmdr1 gene. The prevalence of pfmdr1 N86, 184F, and D1246 in western Kenya (Kisumu, Kericho and Kisii) compared to the coast of Kenya (Malindi) was 92.9% vs. 66.7%, 53.5% vs. to 24.2% and 96% vs. to 87.9%, respectively. The NFD haplotype which is consistent with AL selection was at 51% in western Kenya compared to 25% in coastal Kenya.ConclusionSelection pressures were observed to be different in different regions of Kenya, especially the western region compared to the coastal region. The data showed independent genetic lineages for all the pfmdr1 alleles. The evidence of soft sweeps in pfmdr1 observed varied in direction from one region to another. This is challenging for malaria control programs in SSA which clearly indicate effective malaria control policies should be based on the region and not at a country wide level.

The use and preference of artemether as a first-choice treatment for malaria: results from a cross-sectional survey in the Bata district, Equatorial Guinea

BackgroundMalaria is endemic in Equatorial Guinea with stable transmission, and it remains a major cause of morbidity and mortality in children under 5 years of age. Adherence to artemisinin-based combination therapy (ACT) as a first-line treatment for uncomplicated malaria is critical to malaria control. Six years after the introduction of artesunate-amodiaquine (AS/AQ) therapy in Equatorial Guinea, adherence to the first-line treatment seems to be low in the Bata district. The factors associated with the choice of malaria treatment have not been studied previously in this area; therefore, this study aimed to analyse the preference and use of artemether as malaria treatment and its related factors in the Bata district of Equatorial Guinea.MethodsIn 2013, a cross-sectional study was conducted in the Bata district, which involved 428 households. Bivariate and multivariate statistical analyses were conducted to determine the relevance of socio-economic, geographical, and behavioural factors that played a role in the preference and use of artemether as malaria treatment.ResultsArtemether was considered the best treatment for malaria by 110 caregivers (26%), and was the antimalarial most administrated in the Bata district. It was prescribed to 117 children (27.34%); while, only 6.78% were administered AS/AQ. Caregivers living ≤ 3 km from the nearest health facility were almost two times more likely to consider artemether as the best treatment than those living farther away (95% CI 0.31–0.86). Caregivers with at least a secondary school education were 2.7 times more likely to consider artemether as the best treatment than those less educated. Children whose caregivers considered artemether the best treatment against malaria were five times more likely to be treated with artemether than children with caregivers who did not consider it the best (OR 5.07, 95% CI 2.93–8.78). In contrast, children that reported weakness as a symptom were less likely to be treated with artemether than those with other symptoms (OR 0.47, 95% CI 0.28–0.78).ConclusionCaregivers, public and private health staff, and drug sellers need to understand the importance of using ACT to treat uncomplicated malaria and the dangers of using artemisinin monotherapy.

Use of artemether–lumefantrine to treat malaria during pregnancy: what do we know and need to know?

Artemether–lumefantrine is a fixed-dose combination containing 20 mg artemether/120 mg lumefantrine per tablet, used for treating uncomplicated malaria in patients weighing ≥5 kg. It is the first artemisinin-based combination registered in some European countries and in the USA. It is marketed in Europe as Riamet® (Novartis, Basel, Switzerland) and in malaria-endemic countries as Coartem® (Novartis). Safety concerns prevent early pregnancy usage, while limited postmarketing surveillance has delayed safety assessment and policy development. Large clinical studies, postmarketing surveillance and pharmacovigillance ongoing in some countries may soon bridge safety issues. Fatty diet requirements for optimal absorption, pregnancy-induced changes in pharmacokinetics, pregnancy-related anorexia and food taboos, and emerging reduced parasite sensitivity to artemisinin, challenges optimal artemether–lumefantrine dosing and efficacy during pregnancy. This evaluation addresses drug usage, safety concerns following early exposure, implications for changed pharmacokinetics and reduced parasite susceptibility. Clinical-use updates and strategies to address some knowledge gaps including key operational research are discussed.

No hearing loss associated with the use of artemether–lumefantrine to treat experimental human malaria

Artemisinin derivatives are becoming the first-line treatment for uncomplicated malaria in areas with widespread resistance to chloroquine. Although generally safe and well tolerated, it has been suggested from animal experiments, and more recently from one human study with artemether-lumefantrine, that these compounds are potentially neurotoxic, affecting particularly the brainstem auditory pathways. We report here the auditory analyses of 15 volunteers who underwent an experimental human malaria infection and were treated with artemether-lumefantrine. The subjects underwent audiological examination before the start of the study, during infection, and after treatment. Examination included standard tone audiometry, high frequency tone audiometry and auditory brainstem response (ABR). No effects on hearing loss that were deemed to be caused by drug treatment were found using tone audiometry. ABR analysis similarly failed to demonstrate any auditory pathway damage in the volunteers after treatment. We have thus not found any clear evidence of a detrimental effect on the auditory system by artemether-lumefantrine treatment in uncomplicated malaria. Our results support the continued implementation of artemisinin derivatives in the fight against drug-resistant malaria.

Ultrastructural alterations in adult Schistosoma mansoni caused by artemether.

Progress has been made over the last decade with the development and clinical use of artemether as an agent against major human schistosome parasites. The tegument has been identified as a key target of artemether, implying detailed studies on ultrastructural damage induced by this compound. We performed a temporal examination, employing a transmission electron microscope to assess the pattern and extent of ultrastructural alterations in adult Schistosoma mansoni harboured in mice treated with a single dose of 400 mg/kg artemether. Eight hours post-treatment, damage to the tegument and subtegumental structures was seen. Tegumental alterations reached a peak 3 days after treatment and were characterized by swelling, fusion of distal cytoplasma, focal lysis of the tegumental matrix and vacuolisation. Tubercles and sensory organelles frequently degenerated or collapsed. Typical features of subtegumental alterations, including muscle fibres, syncytium and parenchyma tissues, were focal or extensive lysis, vacuolisation and degeneration of mitochondria. Severe alterations were also observed in gut epithelial cells and vitelline cells of female worms. Our findings of artemether-induced ultrastructural alterations in adult S. mansoni confirm previous results obtained with juvenile S. mansoni and S. japonicum of different ages.

Current progress in the development and use of artemether for chemoprophylaxis of major human schistosome parasites.

Human schistosomiasis, a chronic and debilitating parasitic disease of the tropics, is ranked second after malaria in terms of public health importance. At present, there is no vaccine available, and chemotherapy is the cornerstone of schistosomiasis control. Praziquantel is the drug of choice. Oxamniquine has become difficult to obtain and metrifonate has recently been withdrawn from the market. Rapid re-infection following treatment and concern about praziquantel resistance called for the search of novel drugs for prevention and cure of schistosomiasis. Significant progress has been made with artemether, the methyl ether of dihydroartemisinin, already widely used for the treatment of malaria. The present article reviews the literature that led to the development of artemether for chemoprophylaxis in schistosomiasis, and it summarises the experiences so far obtained with its use to control schistosomiasis in different endemic settings. Topics covered include an overview of the global burden of schistosomiasis and approaches for its control; the nature and features of artemisinin and related derivatives, initially discovered as antimalarials, other bioactivities, and their recent discovery of antischistosomal properties; a historic account disclosing the antischistosomal activity of artemether; in vivo assessment of drug susceptibility of different developmental stages of schistosome parasites; artemether-induced pathology evidenced by scanning and transmission electron microscopy; the possible mechanism of action; in vivo studies with combination therapy of artemether and praziquantel; results of randomised controlled clinical trials of oral artemether for the prevention of patent infection and morbidity; and, ultimately the translation of this knowledge into public health action in different endemic settings towards a more integrated approach of schistosomiasis control.

Lack of activity of artemether for prophylaxis and treatment oftoxoplasma gondiiandPneumocystis cariniiinfections in rat

Artemisinin and its derivatives have been found effective in vivo against Plasmodium and in vitro against Toxoplasma gondii and Pneumocystis carinii. We tested the activity of artemether for prophylaxis and treatment in the rat model of concurrent T. gondii and P. carinii infection. Artemether at doses of 18 and 100 mg/kg administered (s.c.) in prophylaxis did not prevent toxoplasmosis or pneumocystosis, while trimethoprimsulfamethoxazole (reference treatment) was effective for prevention of both infections. Similar results were obtained in curative studies. These results do not support the use of artemether for prevention or treatment of toxoplasmosis or pneumocystosis.

Extraction of artemisinin and artemisinic acid: preparation of artemether and new analogues

The preparation of artemether from artemisinin is reviewed. Firstly, the extraction of artemisinin from Artemisia annua is described and an estimation of the yield per hectare based on literature data is given. Artemisinin is reduced with sodium borohydride to produce dihydroartemisinin as a mixture of epimers. The mixture is treated with methanol and an acid catalyst to provide artemether. Increasing demand for use of artemether places pressure on the supply of artemisinin, and an alternative means of preparing the drug from artemisinic acid, an abundant constituent of A. annua, which could triple current yields, is described. In anticipation of problems of drug resistance emerging with the continued use of artemether and artesunate to treat malaria, development of new derivatives of artemisinin which have enhanced stability is required. Examples of such derivatives which have been prepared in our laboratories, or proposed, are described.

The combined use of artemether, sulfadoxine and pyrimethamine in the treatment of uncomplicated falciparum malaria

29 male patients (14 from Taunggyi, 6 from Rangoon and 9 from Tharrawaddy in Burma) were treated simultaneously with 200 mg artemether (Single intramuscular dose), 1500 mg sulfadoxine and 750 mg pyrimethamine (orally). The mean parasite clearance time was 106 · 7 ± 48 · 7 h. Side effects were few and self-limiting. 13 of 29 patients had recrudescences before day 28; as all the patients were living in towns, reinfection was unlikely. This parasite clearance time was longer than that in patients treated with artemether alone (600 mg total dose), and the recrudescence rate was higher. This drug combination is not recommended for patients in areas where sulfadoxine/pyrimethamine resistance is already established.