***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND In the treatment of severe malaria , intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance , is safer , and is simpler to administer , but whether it can reduce mortality is uncertain . METHODS We did an open-label r and omised controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh , India , Indonesia , and Myanmar . We assigned individuals intravenous artesunate 2.4 mg/kg bodyweight given as a bolus ( n=730 ) at 0 , 12 , and 24 h , and then daily , or intravenous quinine ( 20 mg salt per kg loading dose infused over 4 h then 10 mg/kg infused over 2 - 8 h three times a day ; n=731 ) . Oral medication was substituted when possible to complete treatment . Our primary endpoint was death from severe malaria , and analysis was by intention to treat . FINDINGS We assessed all patients r and omised for the primary endpoint . Mortality in artesunate recipients was 15 % ( 107 of 730 ) compared with 22 % ( 164 of 731 ) in quinine recipients ; an absolute reduction of 34.7 % ( 95 % CI 18.5 - 47.6 % ; p=0.0002 ) . Treatment with artesunate was well tolerated , whereas quinine was associated with hypoglycaemia ( relative risk 3.2 , 1.3 - 7.8 ; p=0.009 ) . INTERPRETATION Artesunate should become the treatment of choice for severe falciparum malaria in adults AIMS To obtain pharmacokinetic data for  artesunate ( ARTS )  and its active metabolite dihydroartemisinin ( DHA )  following i.m . ARTS and rectal DHA administration . METHODS Twelve Vietnamese patients with uncomplicated falciparum malaria were r and omized to receive either i.v . or i.m . ARTS ( 120 mg ) , with the alternative preparation given 8 h later in an open crossover design . A further 12 patients were given i.v . ARTS ( 120 mg ) at 0 h and rectal DHA ( 160 mg ) 8 h later . RESULTS Following i.v . bolus , ARTS had a peak concentration of 42 microm ( 16 mg l(-1 ) , elimination t1/2 = 3.2 min , CL = 2.8 l h(-1 ) kg(-1 ) and V = 0.22 l kg(-1 ) . The Cmax for DHA  was 9.7 microm ( 2.7 mg l(-1 ) ) , t1/2 = 59 min , CL = 0.64 l h(-1 ) kg(-1 ) and V = 0.8 l kg(-1 ) . Following i.m . ARTS , Cmax was 2.3 microm ( 3.7 mg l(-1 ) ) , the apparent t1/2 = 41 min , CL = 2.9 l h(-1 ) kg(-1 ) and V = 2.6 l kg(-1 ) . The relative bioavailability of DHA was 88 % , Cmax was 4.1 microm ( 1.16 mg l(-1 ) ) and t1/2 = 64 min . In the rectal DHA study , relative bioavailability of DHA was 16 % . CONCLUSIONS For patients with uncomplicated falciparum malaria i.m . ARTS is a suitable alternative to i.v . ARTS , at equal doses . To achieve plasma  DHA concentrations equivalent to parenteral administration of ARTS , rectal DHA should be given at approximately four-fold higher milligram doses . Further studies are needed to determine whether these recommendations can be applied to patients with severe malaria Summary Background Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa .  Quinine is still the established treatment of choice , although evidence from Asia suggests that artesunate is associated with a lower mortality . We compared parenteral treatment with either artesunate or quinine in African children with severe malaria . Methods This open-label , r and omised trial was undertaken in 11 centres in nine African countries . Children ( < 15 years ) with severe falciparum malaria were r and omly assigned to parenteral artesunate or parenteral quinine . R and omisation was in blocks of 20 , with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes . The trial was open label at each site , and none of the investigators or trialists , apart from for the trial statistician , had access to the summaries of treatment allocations . The primary outcome measure was in-hospital mortality , analysed by intention to treat . This trial is registered , number IS RCT N50258054 . Findings 5425 children were enrolled ; 2712 were assigned to artesunate and 2713 to quinine . All patients were analysed for the primary outcome . 230 ( 8·5 % ) patients assigned to artesunate treatment died compared with 297 ( 10·9 % ) assigned to quinine treatment ( odds ratio [ OR ] stratified for study site 0·75 , 95 % CI 0·63–0·90 ; relative reduction 22·5 % , 95 % CI 8·1–36·9 ; p=0·0022 ) . Incidence of neurological sequelae did not differ significantly between groups , but the development of coma ( 65/1832 [ 3·5 % ] with artesunate vs 91/1768 [ 5·1 % ] with quinine ; OR 0·69 95 % CI 0·49–0·95 ; p=0·0231 ) , convulsions ( 224/2712 [ 8·3 % ] vs 273/2713 [ 10·1 % ] ; OR 0·80 , 0·66–0·97 ; p=0·0199 ) , and deterioration of the coma score ( 166/2712 [ 6·1 % ] vs 208/2713 [ 7·7 % ] ; OR 0·78 , 0·64–0·97 ; p=0·0245 ) were all significantly less frequent in artesunate recipients than in quinine recipients . Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine ( 48/2712 [ 1·8 % ] vs 75/2713 [ 2·8 % ] ; OR 0·63 , 0·43–0·91 ; p=0·0134 ) . Artesunate was well tolerated , with no serious drug-related adverse effects . Interpretation Artesunate substantially reduces mortality in African children with severe malaria . These data , together with a meta- analysis of all trials comparing artesunate and quinine , strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide . Funding The Wellcome Trust Abstract Objective : The pharmacokinetics and bioavailability of artemether and dihydroartemisinin  were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether ( 300 mg ) in a r and omized two-way cross-over study . Results : Both oral and intramuscular artemether were well-tolerated . In most cases , artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration , oral administration of artemether result ed in a relatively rapid but incomplete absorption [ Cmax : 474 vs 540 ng · ml−1 ; tmax : 2.0 vs 3.9 h ; AUC : 2.17 vs 5.20 μg · h · ml−1 ] . Geographic means of lag-time and absorption half-life ( t1/2a ) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h , respectively . t1/2z was significantly shortened after the oral dose [ 2.8 vs 6.9 h ] . Mean oral bioavailability relative to intramuscular administration was 43.2 % . The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose ( geometric mean : 0.29 vs 0.60 ) This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence ABSTRACT The first-dose pharmacokinetic properties of intramuscular ( i.m . ) artesunate ( ARTS ; 2.4 mg/kg immediately [ stat ] , followed by 1.2 mg/kg i.m . daily ) and artemether ( ARM ; 3.2 mg/kg i.m . stat , followed by 1.6 mg/kg i.m . daily ) were compared in Vietnamese adults with severe falciparum malaria . A total of 19 patients were studied ; 9 received ARTS , and 10 received ARM . ARTS was absorbed very rapidly ; concentrations in plasma peaked between 1,362 and 8,388 nmol/liter ( median , 5,710 nmol/liter ) within 20 min of injection and then declined with a median ( range ) half-life ( t1/2 ) of 30 ( 3 to 67 ) min . ARTS was hydrolyzed rapidly and completely to the biologically active metabolite dihydroartemisinin ( DHA ) . Peak DHA concentrations in plasma ranged between 1,718 and 7,080 nmol/liter ( median , 3,060 nmol/liter ) and declined with a t1/2 of 52 ( 26 to 69 ) min . In contrast , ARM was slowly and erratically absorbed . The absorption profile appeared biphasic . Maximum ARM concentrations in plasma ranged between 67 nmol/liter ( a value close to the 50 % inhibitory concentration for some Plasmodium falciparum isolates ) and 1,631 nmol/liter ( median , 574 nmol/liter ) and occurred at a median ( range ) of 10 ( 1.5 to 24 ) h. There was relatively little conversion to DHA . After i.m . injection in cases of severe malaria , absorption of the water-soluble ARTS is rapid and extensive , whereas the oil-based ARM is slowly and erratically absorbed , with relatively little conversion to the more active DHA . On the basis of this pharmacological study , parenteral ARTS is preferable to ARM as an initial antimalarial therapy , particularly in the most seriously ill patients . These findings should be formally assessed by a r and omized clinical trial ABSTRACT Artesunate ( ARS ) is a water-soluble artemisinin derivative that is a potential alternative to quinine for the treatment of severe childhood malaria . We studied the pharmacokinetics and bioavailability of ARS  given by the intramuscular ( i.m . ) route in an open crossover study design . Fourteen children were r and omized to receive intravenous ( i.v . ) ARS  in a loading dose ( 2.4 mg/kg of body weight ) followed 12 h later by an i.m . dose ( 1.2 mg/kg ) ( group I ) , and 14 children were r and omized to receive i.m . ARS ( 2.4 mg/kg ) followed by an i.v . dose of ARS ( 1.2 mg/kg ) ( group II ) . We carried out a two-compartment analysis of  ARS and dihydroartemisinin ( DHA ; the principal antimalarial metabolite ) levels in 21 children ( groups I and II combined ) . Absorption of i.m . ARS was rapid , with the maximum concentration of DHA in serum being achieved in less than 1 h in most children ( median time to the maximum concentration of drug in serum , 35.1 min ; range , 10.8 to 71.9 min ) . The absolute bioavailability of DHA was a median of 86.4 % ( range , 11.4 to 462.1 % ) , the median steady-state volume of distribution was 1.3 liters/kg ( range , 0.5 to 7.9 liters/kg ) , and the median clearance was 0.028 liters/kg/min ( range , 0.001 to 1.58 liters/kg/min ) . There were no major adverse events attributable to ARS . Parasite clearance kinetics were comparable between the two treatment groups . These results support the 
    Output:
    
Authors ' conclusions Artemether appears to be more effective than quinine in children and adults .
Artemether compared to artesunate has not been extensively studied , but in adults it appears inferior .
These findings are consistent with the WHO recommendations that artesunate is the drug of choice , but artemether is acceptable when artesunate is not available .