***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: OBJECTIVE To evaluate the efficacy of different antipyretic agents and their highest recommended doses for preventing febrile seizures . DESIGN R and omized , placebo-controlled , double-blind trial . SETTING Five hospitals , each working as the only pediatric hospital in its region . PARTICIPANTS A total of 231 children who experienced their first febrile seizure between January 1 , 1997 , and December 31 , 2003 . The children were observed for 2 years . INTERVENTIONS All febrile episodes during follow-up were treated first with either rectal diclofenac or placebo . After 8 hours , treatment was continued with oral ibuprofen , acetaminophen , or placebo . MAIN OUTCOME MEASURE Recurrence of febrile seizures . RESULTS The children experienced 851 febrile episodes , and 89 of these included a febrile seizure . Febrile seizure recurrences occurred in 54 of the 231 children ( 23.4 % ) . There were no significant differences between the groups in the main measure of effect , and the effect estimates were similar , as the rate was 23.4 % ( 46 of 197 ) in those receiving antipyretic agents and 23.5 % ( 8 of 34 ) in those receiving placebo ( difference , 0.2 ; 95 % confidence interval , -12.8 to 17.6 ; P = .99 ) . Fever was significantly higher during the episodes with seizure than in those without seizure ( 39.7 degrees C vs 38.9 degrees C ; difference , 0.7 degrees C ; 95 % confidence interval , -0.9 degrees C to -0.6 degrees C ; P < .001 ) , and this phenomenon was independent of the medication given . CONCLUSIONS Antipyretic agents are ineffective for the prevention of recurrences of febrile seizures and for the lowering of body temperature in patients with a febrile episode that leads to a recurrent febrile seizure A descriptive profile for antipyretic drug action has been documented for children . However , a linked pharmacokinetic – pharmacodynamic ( PK/PD ) model is central to the underst and ing of antipyretic drug action in febrile children . This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen ( APAP ) ( 12.5 mg/kg ) , ibuprofen ( IBU ) ( 5 or 10 mg/kg ) , or placebo .  Rectal temperatures and plasma levels ( μg/ml ) of APAP and IBU were measured for up to 12 hr after drug administration . Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK , link , and SigmoidEmaxeffect model in 102/153 febrile children given APAP or IBU . The PK parameters ( tlag , ka , β , T1/2β , AUC0–∞,Vd/F , and Clp/F ) were not different than those reported previously , except the APAPkawas significantly lower . The link component yieldedkeos of 0.58±0.06 ( X±SE ) , 0.70±0.11 and 0.57 ± 0.11 hr-1for APAP , IBU05 , and IBU10 , respectively : the SigmoidEmaxcomponent yieldedEC50s ( μg/ml ) and sigmoidicity ( γ ) of 4.63±0.39 and 3.98±0.42 for APAP , 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10 . On visual inspection of the efficacy – time profiles of the febrile children , a number of them had an apparent linear function ( slope ; Δ ° C/hr ) and /or a sinusoidal cyclic function “ confounding ” st and ard approaches to PD analysis . Thus , the temperature profiles of 91/102 children  given APAP or IBU required the addition of a slope ( Δ ° C/hr ) and /or a sinusoidal cyclic function to the SigmoidEmaxcomponent to fit the data satisfactorily . All 22 children  given a placebo also required a slope and /or a cyclic function in their PD model . The residual Δ ° Cs ( observed-predicted ) of the placebo group were not significantly different from 0 . Thus , no placebo antipyretic effect was observed . Dose dependency of IBUAUC0–∞was confirmed ; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞by only 1.5-fold . The confounding effect of initial temperature ( Tempi ) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics . A significant ( p=0.03 ) contribution ofTempi(but not age ) on the value of the slope function was found . There was no consistent effect of age orTempi , on the cyclic component of the integrated model of antipyresis . In addition , a multiple linear relationship of age and Tempiwas observed with a large number of the PK , link , and PD variables in those who received IBU .  Dose , age , and Tempiinteracted with β in a significant multiple linear relationship withAUC0–∞. The effects of IBU dose , age , and Tempiare pervasive and cascade down the chain of events leading to the PD response . The etiology of pyresis may create the slope function , the magnitude of which may be partially due to the underlying disease . In some cases , the cyclic function may be explained by temperature regulation . Regardless of their cause , both confound analysis of drug action and make the simple , unmodified SigmoidEMaxeffect model less than satisfactory for interpretation of antipyretic drug effects . The influence of Tempion the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications . In children receiving IBU  , dose and age are also confounders , in addition toTempi . A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children BACKGROUND Many pediatricians recommend , and many parents administer , alternating or combined doses of ibuprofen and acetaminophen for fever . Limited data support this practice with st and ard US doses . OBJECTIVE This study compared the antipyretic effect of 3 different treatment regimens in children , using either ibuprofen alone , ibuprofen combined with acetaminophen , or ibuprofen followed by acetaminophen over a single 6-hour observation period . METHODS Febrile episodes from children aged 6 to 84 months were r and omized into the 3 treatment groups : a single dose of ibuprofen at the beginning of the observation period ; a single dose of ibuprofen plus a single dose of acetaminophen at the beginning of the observation period ; or ibuprofen followed by acetaminophen 3 hours later . Ibuprofen was administered at 10 mg/kg ; acetaminophen at 15 mg/kg . Temperatures were measured hourly for 6 hours using a temporal artery thermometer . The primary outcome was temperature difference between treatment groups . Adverse-event data were not collected in this single treatment period study . RESULTS Sixty febrile episodes in 46 children were assessed . The mean ( SD ) age of the children was 3.4 ( 2.2 ) years , and 31 ( 51.7 % ) were girls .  Differences among temperature curves were significant ( P < 0.001 ; the combined and alternating arms had significantly better antipyresis compared with the ibuprofen-alone group at hours 4 to 6 ( hour 4 , P < 0.005 ; hours 5 and 6 , P < 0.001 ) . All but one of the children in the combined and alternating groups were afebrile at hours 4 , 5 , and 6 . In contrast , for those receiving ibuprofen alone , 30 % , 40 % , and 50 % had temperatures > 38.0 ° C at hours 4 , 5 , and 6 , respectively ( hour 4 , P = 0.002 ; hours 5 and 6 , P < 0.001 ) . CONCLUSION During a single 6-hour observation period for these participating children , combined and alternating doses of ibuprofen and acetaminophen provided greater antipyresis than ibuprofen alone at 4 to 6 hours . Clinical Trials.gov identifier : NCT00267293 A comparison of different antipyretics in children with malaria showed a small effect of naproxen , but not of metamizol , on the reduction of fever peaks .  Antipyretic treatment had no effect on fever clearance and therefore should be used cautiously in the treatment of malaria Purpose LATIN is a multinational case – control study design ed to identify risk factors for agranulocytosis and to estimate the incidence rate of the disease in some Latin American countries . Methods Each study site in Brazil , Argentina and Mexico conducted an active search of agranulocytosis patients in hematology clinics and looked for possible associations with drug use . Results The overall incidence rate was 0.38 cases per 1 million inhabitant – years . Agranulocytosis patients more often took medications already associated with agranulocytosis than controls ( p = 0.01 ) , mainly methimazole ( OR 44.2 , 95 % CI 6.8 to infinity ) . The population attributable risk percentage ( etiologic fraction ) was 56 % . The use of nutrient supplements  was more frequent among patients than controls ( p = 0.03 ) . Conclusions Agranulocytosis seems to be very rare in Latin America . The lower than expected number of cases identified during the study period precluded estimation of the risk associated to individual drugs , with the exception of methimazol . However , this is the longest series of agranulocytosis cases ever gathered in Latin America , and information on drug exposures was collected prospect ively . The conclusion is that drug-induced agranulocytosis does not seem to be a major public health problem in the study regions OBJECTIVE To compare the antipyretic benefit of acetaminophen or ibuprofen monotherapy with an alternating regimen of both drugs in young children aged 6 to 36 months . DESIGN R and omized , double-blind , parallel-group trial . SETTING Three primary pediatric community ambulatory centers in central Israel . PARTICIPANTS A total of 464 children aged 6 to 36 months with fever . INTERVENTION Infants were assigned to receive either acetaminophen ( 12.5 mg/kg per dose every 6 hours ) ( n = 154 ) or ibuprofen ( 5 mg/kg per dose every 8 hours ) ( n = 155 ) or to receive alternating acetaminophen and ibuprofen ( every 4 hours ) ( n = 155 ) for 3 days after a loading dose . MAIN OUTCOME MEASURES Temperature , stress score , amount of antipyretic received , total days that the infant or caregiver was absent from day care or work , respectively , at the 3-day time point , recurrence of fever , and number of emergency department visits . RESULTS The group given the alternating regimen was characterized by a lower mean temperature , more rapid reduction of fever , receiving less antipyretic medication , less stress , and less absenteeism from day care as compared with the other groups ; all of the differences were statistically significant ( P < .001 ) . None of the regimens were associated with a significantly higher number of emergency department visits ( P = .65 ) or serious long-term complications ( P = .66 ) . The drug used for initial loading had no effect on outcome in any of the groups . CONCLUSIONS An alternating treatment regimen of acetaminophen ( 12.5 mg/kg per dose ) and ibuprofen ( 5 mg/kg per dose ) every 4 hours for 3 days , regardless of the initial loading medication , is more effective than monotherapy in lowering fever in infants and children The antipyretic effect of nimesulide has not been adequately compared with paracetamol and ibuprofenparacetamol combination in children . Hence , a r and omized , double blind , and parallel groups ’ design and multicenter study was conducted on children with respiratory tract infections . Eighty-nine patients with temperatures above 38.5 ° C were r and omly administered nimesulide  ( 1.5 mgJkgJdose ) , paracetamol ( 10.0 mgJkgJdose ) , or ibuprofen- patients combination ( 10.0 mgJkgJdose ) , thrice daily for five days . The axillary temperature was recorded at the baseline and at different time intervals post administration of drugs . The hematological and biochemical investigations were performed at the basal level and at the end of the treatment period . The adverse drug reactions were monitored during the trial . All the drugs produced a significant fall in temperature as compared to their respective basal values ( p<0.001 ) . However , on looking at the change in temperatures at different time intervals from the respective basal levels , no significant difference was found among all the drugs . Surprisingly , nimesulide had a tendency to raise serum glutamate pyruvate transaminase and serum glutamate oxaloacetate transaminase levels as compared to its baseline values . There was no marked adverse effect of the drugs on other hematological and biochemical parameters investigated . No other serious adverse reaction occurred in the study . Ibuprofen-paracetamol combination , nimesulide , and paracetamol had almost similar antipyretic effects in children Abstract Objective : To compare the effectiveness and rate of temperature reduction of three antipyretic medications in febrile children . Design : 
    Output:
    
Overall , the articles pointed to a tendency of lower mean temperatures in groups with alternating therapy .
Few adverse effects were reported .
Although there was a tendency towards the reduction of mean temperatures with alternating antipyretics compared to the use of one antipyretic alone , there is not enough evidence to say that alternating antipyretic therapy is more effective than monotherapy