Oral artemisinin derivatives in combination with one or more other anti-ma- larial ingredients are recommended for the treatment of uncomplicated Plasmo- dium falciparum malaria in clinical and community settings by trained, super- vised Community Health Workers (CHWs)  . They are generally safe, well tolerated, and highly effective in rapidly clearing parasitemia and ultimately in- fection, and the preferred alternative for the treatment of multidrug-resistant Falciparum malaria    . Herein we report one case of severe acute al- lergic reaction that was attributed to the combination of oral artesunate and amodiaquine.
Background: Currently, population pharmacokinetic (PK) studies of anti-malarial drugs are designed primarily by the logistical and ethical constraints of taking blood samples from patients, and the statistical models that are fitted to the data are not formally considered. This could lead to imprecise estimates of the target PK parameters, and/or designs insufficient to estimate all of the parameters. Optimal design methodology has been developed to determine blood sampling schedules that will yield precise parameter estimates within the practical constraints of sampling the study populations. In this work optimal design methods were used to determine sampling designs for typical future population PK studies of dihydroartemisinin, the principal biologically active metabolite of oral artesunate.
Lot quality assurance sampling (LQAS) was recently pro- posed as the first step in assessing drug quality , but, as convenience sampling already suggested that there was a severe problem of counterfeit artesunate in Laos, a con- ventional randomized survey was performed. The major- ity of the details listed in the Medicine Quality Assessment Reporting Guidelines (MEDQUARG)  are reported. Limitations of this study include that we did not sample itinerant sellers who may also stock oral artesunate, the number of shops selling medicines sampled was relatively small and may have been underestimated, that we did not perform dissolution tests and urban and rural districts were not formally defined. Apart from a larger number of outlets in urban than rural districts there were no clear dif- ferences between the two district types. Although, a for- mal definition of urban districts was not used, there is no agreed definition of 'urban'  and all the urban districts sampled included rural farming areas. Of note the median (range) population of the six cities in the second collec- tion was only 65,592 (20,239–200,462). Figure 2 includes both 'cities' and the urban and rural districts –
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Malaria is one of the deadliest infectious diseases in the world, causing nearly a million deaths among more than three billion people who were at risk in 2006 . Unfor- tunately, given the high burden of the disease, the number of available anti-malarial drugs is relatively small. On top of that, the emergence of resistance to the most affordable anti-malarial drugs has seriously undermined the global effort to control malaria. As the result of chloroquine and sulphadoxine-pyrimethamine resistance, millions of lives that could otherwise be saved were sacrificed over the past 30 years . Artemisinin-based combination therapy (ACT) is now being widely used as the first-line treatment for Plasmodium falciparum malaria throughout the world. Artemisinin (ARN) and its derivatives, dihydroartemisi- nin (DHA), artesunate (AS), artemether and arteether are fast acting anti-malarial drugs producing the most rapid reduction in parasitaemia . These agents also have gametocytocidal activity, which contributes to the reduc- tion in the disease transmission [4,5]. Among the availa- ble derivatives, AS has the most appealing physicochemical and pharmacological properties. It is more water soluble, thermally and chemically more sta- ble, and rapidly converted in vivo to its active metabolite DHA, which is responsible for most of the anti-malarial activity [6,7].
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Artemisinin (qinghaosu) and its derivatives are a major ad- vance in antimalarial treatment (8). These drugs are increas- ingly used in southeast Asia for the treatment of multidrug- resistant Plasmodium falciparum malaria (2, 8, 15, 22). Artesunate, the most widely available of the artemisinin-re- lated compounds, is a hemisuccinate derivative of dihydroar- temisinin (DHA). It may be given parenterally, intravenously, intramuscularly, orally, or rectally. Oral artesunate is used ei- ther alone or in combination, usually with mefloquine (15). Despite considerable use in areas where malaria is endemic, there are relatively few data on the pharmacokinetics of arte- sunate in the treatment of malaria (2–4, 6, 9, 13, 21, 27). There are concerns that the various artesunate formulations may have different bioavailabilities and that the development of resistance will be accelerated if suboptimal doses are used (13, 24). Optimization of dosing recommendations is also impor- tant because of evidence that high doses of parenteral arte- misinin derivatives (artemether, arteether) are neurotoxic in experimental mammals (16).
In Malaysia, the reported number of falciparum malaria cases has decreased from around 5000 in 2010 to less than 20 in 2017; with progress on track to meet the national WHO elimination goal for human-only malaria by 2020 . Malaysia borders Thailand where arte- misinin-resistant P. falciparum is established. At the time of study design, no previous studies had evaluated the presence of artemisinin resistance in Malaysia, particu- larly in East Malaysia on the island of Borneo where the majority of P. falciparum transmission occurs [10, 11]. To determine whether artemisinin-resistant P. falciparum was present in Sabah, Eastern Malaysia, a clinical efficacy study of oral artesunate was conducted with complemen- tary parasite molecular studies to genotype kelch13 poly- morphisms associated with artemisinin resistance.
parasite metabolism in concentrations within the lower nano-molar range and killing parasite more quickly than any other antimalarial drug . The emergence of multidrug resistant Plasmodium and the potential threat to the artemisinins lead to the strong recommendation of Artemisinin combination therapy by WHO and authorities of endemic countries for the treatment of severe malaria. Artesunate being the most widely distributed and used makes it a major candidate for adulteration and counterfeiting just like any other very successful drug. There has been reports of widespread distribution of fake and counterfeit artesunate in South East Asia [8,9,10). East Africa . The widespread distribution of counterfeit Artesunate is not likely to be localized in South East Asia and East Africa alone and since fake drug syndicates are sophisticated chances are that fake and adulterate artesunate may soon follow the genuine ones into the West Africa sub region, if not already here [12,13,14]. The fight against widespread distribution of counterfeit/fake artesunate tablets demand the use of sensitive, accurate and reliable methods and equipment. In the international pharmacopoeia Artesunate is assayed by HPLC and acid base titration . Some workers have assayed artemisinin and its derivatives using HPLC [16,17,18]. Unfortunately most pharmaceutical outlet involved in the sales and distribution of Artesunate in this region can ill afford HPLC equipment. The second method acid-base titration is simple, accurate, affordable and reproducible. The application of this proposed iodometric titrimetric method can serves as complimentary while the application of the proposed spectrophotometric method could serve as a confirmatory method. In pharmaceutical analysis titrimetric and spectrophotometric methods are usually methods of choice for some drugs owing to their simplicity, accuracy, affordability and reproducibility. In the proposed titrimetric method Artesunate is reacted with potassium iodides in acid medium, iodine is liberated in situ which is then titrated against a standardized sodium thiosulphate using boiled starch as the indicator. In the proposed spectrophotometric method Artesunate is reacted with sodium hydroxide resulting in the opening of the lactone ring of the molecule and production of alkali decomposition product which is then measured spectrophotometrically. Both proposed method are versatile cost effective and environmentally friendly, devoid of the use of toxic solvents which could be hazardous to the analyst and the environment.
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As one of the most active endoplasmic reticulum cha- perone protein, GRP78 is overexpressed in different kinds of cancers and involved in tumorigenesis, metastasis, and angiogenesis. 10 GRP78 conferred breast cancer cells resis- tance BIK-mediated apoptosis. Overexpression of GRP78 decreases the sensitivity of glioma cells to cisplatin- induced cell death. Zhu et al reported that GRP78 formed complex with GPX4 in pancreatic cancer cells which further mediating erastin induced ferroptosis resistance. Our study ﬁ rstly con ﬁ rmed that GRP78 could also con- ferred KRAS mutant pancreatic cancer cells resistance to artesunate induced ferroptosis. The exact mechanism needs further investigation.
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Safe, rapid, and reliably effective, the combination of AS and MQ is one of five forms of ACT currently recom- mended by the WHO as a first-line anti-malarial treat- ment. The WHO also recommends that fixed-dose combinations (FDC) be used whenever possible  to in- crease compliance to treatment. In 2002, in order to ad- dress the treatment needs of people most threatened by malaria and underscoring the need for public leadership, the Fixed-Dose Artesunate-Based Combination Therapies (FACT) Consortium, created by the Drugs for Neglected Diseases initiative (DNDi) and the Special Programme for Research and Training in Tropical Diseases (TDR), devel- oped ASMQ as a (FDC). Within the FACT Consortium, Farmanguinhos was the first manufacturing partner of ASMQ FDC. By developing a FDC of well-established use, DNDi and its partners aimed to improve treatment com- pliance, extend its use in malaria endemic countries and fight more efficiently against resistance development. [9,10]. This user-friendly new tablet co-formulation, which simplifies treatment with a single daily dose of 1 or 2 tablets for three days, represents an innovation that could have considerable impact in the treatment of uncompli- cated P. falciparum malaria. Fixed-dose combinations eliminate the possibility of patients taking only one com- ponent of the combination and are expected to improve patient compliance. With specific presentations for children aged between 6 months and 11 years, ASMQ FDC addresses the needs of children, the primary victims of malaria worldwide.
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Artesunate bulk drug, tablets (50 mg) and injection (60 mg) were obtained as a gift sample from Skymax Laboratories Pvt. Ltd., Gujarat. Another samples of artesunate tablets (50 mg) and combination dosage form containing artesunate (100 mg), sulfadoxine (500 mg) and pyramethamine (25 mg) was from Medicamen Biotech Ltd. All other chemicals and reagents used were of AR/HPLC grade. The instrument used in the present study was Camag- HPTLC system (Switzerland) comprising Camag Linomat V automatic sample applicator, Camag TLC Scanner III with Wincats software. The samples were spotted in the form of bands of width 5 mm using a Camag microlitre syringe on precoated silica gel 60 F 254 TLC precoated aluminium plates (E.Merck), 10 cm×10 cm size with 200 µm layer thickness using a Camag Linomat V applicator. A constant application rate of 150 nl/s was employed and space between two bands was 5.5 mm. The slit dimension was kept at 4 mm×0.1 mm and 20 mm/s scanning
Artesunate-amodiaquine (AS-AQ) is currently the first line treatment in 24 countries, mainly in sub-Saharan Africa, and the second most widely used ACT globally after artemether-lumefantrine . AS-AQ is available in three formulations: non-fixed dose combinations (NFDC) either as loose NFDC or as co-blistered NFDC, and as a fixed dose combination (FDC). The efficacy of AS-AQ has been evaluated in a range of epidemiological settings, and although high cure rates have been re- ported in several studies [4,5], some studies have re- ported low efficacy rates [6-11]. It has been suggested that the reduced efficacy observed with AS-AQ in some trials is due to amodiaquine resistance selected by prior use of AQ monotherapy, mainly in East Africa [12-14] and Asia [6,7,13,14]. However, the efficacy of AS-AQ has varied between clinical trials even within the same regions [5,15,16], suggesting that different designs and methodology of clinical trials or other confounding fac- tors are responsible for the varying treatment efficacy.
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Stepniewska et al  described the PopPK of DHA following oral AS administration in children (6 months - 5 years) with uncomplicated falciparum malaria. AS and DHA pharmacokinetic data were obtained from 70 children who received AS and amodiaquine, but only DHA data could be modelled. Samples were collected once in the first dosing interval and once in the third dosing interval. The authors modelled DHA data using a one-compartment model with first-order input. They estimated DHA CL/F as 0.636 L/kg/hr for the first dos- ing period, with a substantial additive increase of 0.760 L/kg/hr being associated with the third dosing period. The authors speculated that this modelled increase in clearance reflected pharmacokinetic changes related to resolution of acute illness. DHA apparent volume of dis- tribution, which was not modelled as varying between dosing periods, was estimated as 2.285 L/kg, with age modelled as a covariate on volume. The authors noted that either age or weight explained a significant portion of the variability on volume, but that the two covariates were not independent. Inter-individual variability was modelled on DHA apparent volume of distribution (% CV = 47%), but no other parameter.
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Therefore, the block of clozapine-induced CRP increase by artesunate suggests a protective action of this antimalarial on liver functions of the rats. Indeed, co-administration of artesunate and clozapine was shown to prevent rats from the clozapine-induced hepatic steatosis and cirrhosis along with increased plasma levels of triglycerides in the present study. These findings are in accordance with the results of a recent animal study in which artesunate decreased the plasma triglyceride while it attenuated liver steatosis and reduced the area of aortic root lesions in New Zealand rabbits fed a western-type diet developing hyperlipidemia. 35 These pro-
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Results of both the in vivo and in vitro studies showed that artesunate caused reversible adverse effects on male reproductive functions in a dose and duration dependent manner. The study of biological phenomena in-vivo is often compli- cated by various interactions operative within a living organism. Although highly artificial, tissue culture models provide valuable systems in which the environmental conditions can be controlled and the effects of various factors on a specific cell type can be directly investigated, however, mor- phological and functional characteristics are fre- quently subject to alteration in culture due to changes in pH, temperature, culture medium and atmospheric conditions, but care was taken to maintain these factors at physiological conditions suitable to the cultured cells in this study. The present in-vitro studies were, therefore, supported at least and in part by the in-vivo experiments. Moreover, the long term use of artesunate might have to be done with caution because the greatest adverse effect was observed during the long-term administration of the drug. Sertoli cells are very important in spermatogenesis because they nour- ish the germ cells and form the blood-testis barrier which protects the germ cells and developing spermatocytes from direct contact with the exter- nal environment. However, if this barrier is breached, there would be a greater tendency for the infiltration of toxic substances into the interior of the seminiferous tubules, thereby, affecting the process of spermatogenesis. Further studies could be aimed at co-culturing Sertoli cells with germ cells and then treating them with artesunate. This will shed more light as to how these drugs affect the protective function of Sertoli cells on germ cells.
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Apoptosis is a tightly regulated physiological process in which cells establish an inducible cellular death of non-necrotic type. Apoptosis has a major role in balancing cell proliferation and remodeling tissue activities in many or- ganisms (34). The present study was planned to study the hepatocyte induced apoptosis in experimentally infected mice with S. mansoni using immunohistochemical expression of P53 and Bcl-2 markers, to evaluate the therapeutic effect of PZQ, artesunate and their combina- tions in treatment of schistosomiasis mansoni.
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A literature review was conducted in PubMed in March 2013 and updated in 2014 to identify all published clinical trials of antimalarials since 1960. All antimalarial clinical trials published since 1960 were identified by the application of the key terms ((malaria OR plasmod*) AND (amodiaquine OR atovaquone OR artemisinin OR arteether OR artesunate OR artemether OR artemotil OR azithromycin OR artekin OR chloroquine OR chlor- proguanil OR cycloguanil OR clindamycin OR coartem OR dapsone OR dihydroartemisinin OR duo-cotecxin OR doxycycline OR halofantrine OR lumefantrine OR lariam OR malarone OR mefloquine OR naphthoquine OR naphthoquinone OR piperaquine OR primaquine OR proguanil OR pyrimethamine OR pyronaridine OR quinidine OR quinine OR riamet OR sulphadoxine OR tetracycline OR tafenoquine)) through the PubMed library. All references containing any mention of anti- malarial drugs were tabulated and manually checked to confirm prospective clinical trials. Studies on prevention or prophylaxis, reviews, animal studies or studies of patients with severe malaria or in pregnant women were excluded. When pdfs were available further details of the publications were reviewed, and basic details on the study methodology, treatment arms assessed and the study locations were documented. These are provided in the WorldWide Antimalarial Resistance Network (WWARN) publication library . Specific details of the studies with ACTs are available in Additional files 1 and 2. The year of the study was taken as the year in which the paper was published, although the start and end date of patient enrolment were also recorded. Where a specific site was not reported in the manuscript, the capital city of the country was used as the default location. Countries were grouped into four sub-regions: East; West; Central; and South Africa, as reported in the WHO World malaria report 2014 .
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The artemisinin derivatives, characterized by Chinese sci- entists in the early 1970s [19-21], have been associated with CNS toxicity in animals. In one study, dogs treated with high doses of intramuscular artemether or arteether developed gait disturbances, loss of spinal and pain response reflexes, and prominent loss of brain stem and eye reflexes. This lead to cardiorespiratory depression and death in five out of six animals, as a result of selective damage to the brain stem, particularly to the reticular for- mation, the vestibular system and nuclei related to the auditory system . Rats and Rhesus monkey given arteether or artemether showed a similar selective pattern of brain stem pathology [23,24]. These neurotoxic effects have not been found in human trials that have examined coordination (heel-toe ataxia), fine finger dexterity, hear- ing, nystagmus and balance (Romberg's test) in patients (>5 years) treated with artemether or artesunate as mono- therapy or with mefloquine . Selected testing for audi- ometry and auditory evoked potentials in patients treated with artemisinin derivatives [26,27] or with the combina- tion of artesunate and mefloquine  also failed to find any detrimental artemisinin effect. In addition, brain- stems of adults who died after treatment with high dose artemether or quinine for severe falciparum malaria showed no evidence of selective neuronal damage. This aim of this study was to examine, in a resource-poor setting, the potential neurotoxicity of treatment doses of artesunate and mefloquine given to young children (< 5 years age) with acute falciparum malaria. No single stand- ardized test that focused on ataxia, irritability, behav- ioural and tone change in children of this age, and could be easily applied in remote clinics by local health workers, existed for this problem. Hence items of interest that spe- cifically examined for coordination and behaviour were selected from previously standardized tests. Age-matched healthy children from the same community were included as controls to elucidate practice effects and as a compara- tor group for normal neurological test results in this age group.
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The Y-maze is a behavioral model that can be used to investigate locomotor activity as well as learning and memory; it assesses hippocampus-dependent naviga- tional behaviors of rodents . The radial arm maze is an appetitive motivated task useful in assessing spatial reference as well as spatial working memory perform- ance and factors affecting these processes . The re- sults of both the Y maze and radial arm maze studies showed a reduction in spatial memory scores in all groups that received drug compared to vehicle, although the artesunate amodiaquine group performed better than either the artesunate or amodiaquine groups. This effect of artesunate amodiaquine combination on spatial mem- ory task is for us a source of curiosity as it is obvious from the study that when combined, these drugs show less impairment of cognition than when used singly. The neurotransmitter acetylcholine (ACh) is known to be important in learning and memory processes in the hip- pocampus. Cholinergic activity in the hippocampus is correlated with memory, with lower than normal activity associated with spatial memory impairment as shown with drugs that impair cholinergic transmission. In the study, the memory impairments seen after administering these drugs is comparable to that seen in scopolamine group, and while we do not know the exact mechanism yet we hope that further studies will provide the answers that we need.
In Yunnan, 61 cases with falciparum malaria were treated by an oral total dosage of 2.0 g divided into five doses (two doses on the first day, one dose daily for the next three days). The average times of fever subsidence and parasite clearance were within 60 h. Two days after treatment, four out of 61 cases showed a high fever (39°–40.4°C) and with the rate of asexual forms being 48–261%. The four cases failed treatment. The recrudes- cence rate was 9.8% (five out of 51 cases), followed-up for 28 days. The occurrence rate of gametocytes was 3.9% 28 days after treatment . The failed four cases might be induced by the lower sensibility of P. falcip- arum to the drug or by a lower dosage of the drug. The side effects of the drug included diarrhea, abdominal pain, vomiting, dizziness, etc., which could disappear after a nap.
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Clinical studies including thousands of patients con- firmed that artemisinin-based combination therapies were safe and well tolerated in patients [6,7]. However, in animal studies, artemisinin derivatives have been consist- ently associated with neuronal damage, particularly in areas of the brainstem involved in hearing and gait con- trol [8-13]. Neuropathological lesions were seen after pro- longed administration of oral, intra-muscular and parental artemisinin compounds, but were more frequent after intra-muscular injection of oil-based arteether and artemether, than after parental or oral administration of artesunate [14-16]; clinical manifestations following oral administration of artemisinin derivatives were seen only at high doses . In 1997, retrospective studies in Thai- land  and in Vietnam  have specifically investi- gated the potential adverse effect on brainstem function in patients having been exposed to artemisinins. Patients were, in both studies, compared to controls who had not been treated with an artemisinin and who were living in the same environment and they were matched by age and sex; audiology results were similar in both groups and no neurological anomalies were found. However, concerns about safety of the artemisinin-based combinations have been raised following a retrospective study in Mozam- bique published in 2004 . The authors reported a mild hearing loss across all but the two lowest audible fre- quencies in a non-randomised retrospective study of 150 construction site workers who had received artemether- lumefantrine. Audiograms were routinely performed on induction and cessation of employment. Audiology results of patients having received artemether-lumefan- trine were compared to those from employees unexposed to this drug combination and matched by age, gender, weight and race. A negative change between the two audi- ograms was systematically seen among those having received artemether-lumefantrine, varying from -6.50 dBL to – 0.07 dBL. To further explore this issue the auditory function of 68 subjects treated with artemether-lumefan- trine within the previous five years, and 68 age and sex- matched controls were assessed by the Shoklo Malaria Research Unit (SMRU), between October 2004 and March 2005. This retrospective study failed to show any differ- ence in auditory function between the two groups . More recently, two prospective studies evaluated the potential audiotoxicity of a standard oral dose of arte- mether-lumefantrine; one in 15 healthy volunteers fol- lowed up 8 days after treatment  and one in Ethiopian patients followed up for a period of 90 days ; neither study found pathological changes in audiometric pure-