***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: Cyclosporine (  CsA )  blood concentrations measured 2 h after Neoral ® administration ( c 2 ) are a sensitive predictor of clinical outcome in organ transplantation , as suggested by a recent prospect i ve clinical trial in liver transplant patients ( 1 ) . c 2 is now recommended as the target exposure index for the therapeutic drug monitoring ( TDM ) of CsA (2)(3)(4)(5)(6)(7)(8 ) . The aim of this study was to investigate , for different types of grafts , the concentration – time relationships around c 2 to evaluate the concentration error as a function of the sampling-time error and to identify the sampling-time range compatible with acceptable performance of this c 2 TDM strategy . Data obtained from three different clinical trials were studied retrospectively . Each patient gave written informed consent , and each trial was approved by a local ethics committee (9)(10)(11 ) . The three population s were as follows Background . Cyclosporine monitoring using the 2-hr postdose sample , C2 , has been shown to have advantages in monitoring de novo renal transplant recipients . The purpose of this study was to assess cyclosporine exposure , using C2 , in stable renal transplant patients previously monitored by C0 to determine the effect of dose reduction on patients with C2 more than 10 % above target and the course of those with C2 at and more than 10 % below target , whose dose was not modified . Methods . One hundred and seventy-five patients , three or more months after transplantation , had C2 assessed . The relationship of C2 to C0 and of both to renal function was analyzed by linear regression . Blood pressure , serum creatinine level , and lipids were followed for a mean of 15±2.6 months . Results . Eighty-five patients had values more than 10 % above target , 42 were within 10 % of target , and 48 were more than 10 % below target  . Cyclosporine dose was reduced in all patients above target . In this group , serum creatinine level was stable overall , but fell significantly in 46 ( 54 % ) of 85 from 153±55 to 132±49 & mgr;M. Blood pressure also fell in that group from 135/82 to 131/77 . Serum creatinine level was stable in the remaining two groups of patients . Conclusions . These data suggest that dose reduction in many overexposed patients leads to improvements in renal function and blood pressure . Further study is required to confirm the long-term benefits of this strategy Background . A prospect i ve , open-label , study was conducted at 29 centers in 9 countries , involving 307 de novo liver transplant patients to compare the clinical usefulness of monitoring 2-hr post-dose cyclosporine ( CsA ) levels ( C2 ) with conventional trough cyclosporine blood levels ( pre-dose ) ( C0 ) . Methods . Neoral oral therapy was initiated at 15 mg/kg/day and dose adjusted according to predetermined C2 or C0 target level ranges . The primary efficacy variable was treatment failure at 3 months , where evaluation was based on a composite endpoint of biopsy-proven rejection , treatment for rejection , graft loss , death , or premature withdrawal/discontinuation from the study . Results . Baseline characteristics were similar between groups . Graft loss at 12 weeks ( retransplantation or death ) occurred in 6.8 % C2 and in 7.0 % C0 patients . Overall incidence of treated acute rejection was lower for C2 ( 23.6 % ) than C0 patients ( 31.6 % ) ( P = 0.144 , Cochran-Mantel-Haenszel [ CMH ] test ) . In hepatitis C virus (HCV)-negative patients , the incidence of rejection in the C2 group was significantly less than in the C0 group ( 21.2 % vs. 33.0%;P < 0.05 ) , whereas in HCV-positive patients , the rejection rate was similar in both groups ( 26.7 % for C2 group vs. 27.3 % for C0 group : P = 0.81 ) . C2 patients ( n=16 ) who reached minimum target CsA levels by day 3 had a notably low incidence of rejection ( 12.5 % ) , whereas there was no difference in the incidence of rejection in C0 patients , irrespective of time to reach target level . For biopsy-proven acute rejections ( 21.6 % for C2 vs. 30.4 % for C0 ) , the incidence of moderate and severe histological diagnosis was significantly lower in the C2 group than in the C0 group ( 47 % vs. 73%;P = 0.01 ) . Safety profiles were similar between the two groups , with few patient withdrawals due to adverse events ( 9.5 % for C2 ; 7.0 % for C0 ) . Conclusions . Using C2 monitoring , the overall incidence of acute cellular rejection was lower compared with the C0 group , and the histological severity of acute rejections was shown to be significantly milder for the C2 group , indicative of good long-term prognosis . These data demonstrate that the use of C2 monitoring is superior to C0 and results in a reduction in the incidence and severity of acute cellular rejection without detrimental effect on the drug safety profile Background . The clinical utility of C2 monitoring of cyclosporine A microemulsion ( CsA-ME ) was evaluated in a prospect i ve study of 110 patients more than 12 months posttransplant who demonstrated stable graft function and were receiving CsA-ME and steroids .  Methods . Patients were converted to C2 monitoring with the CsA-ME dose adjusted to a target C2 range of 800 to 1,000 ng/mL and followed for 40 + 11 months . Results . At the time of conversion , 57 % of patients exceeded the C2 target , 20 % of patients were below the C2 target , and 23 % of patients were within the C2 target range . The mean dose of CsA-ME  decreased from 258 + 88 to 202 + 76 mg/day ( P<0.0001 ) , and the mean C2 level decreased from 1,052 + 292 ng/mL to 896 + 233 ng/mL ( P<0.0002 ) . There were no episodes of rejection . At last follow-up , 7.3 % of patients had developed chronic renal allograft dysfunction . Use of antihypertensive agents decreased significantly ( P=0.0004 ) , and mean total cholesterol decreased from 6.4 + 1.3 to 5.8 + 1.1 ( P=0.0009 ) after adoption of C2 monitoring . Conclusion . These findings suggest that conversion of maintenance renal transplant recipients from C0 to C2 monitoring of CsA-ME offers the clinical benefits of better control of hypertension and dyslipidemia , with effective protection against chronic renal allograft dysfunction . A target C2 range of 800 to 1,000 ng/mL in maintenance patients receiving CsA-ME dual therapy seems appropriate The registry of r and omized trials in organ transplantation reported between 1 January and 30 June 2004 and an evaluation of the quality of the trial methodology was published in an earlier issue ( 1 ) . In an editorial accompanying this registry of trials , it was noted that the methodology of many trials was less than adequate ( 2 ) . In this issue , we are publishing an analysis of the trials published between 1 July and 31 December 2004 , namely 44 trials described in 58 publications . In the future , the registry of trials published for the first and second six months of each year will appear in March and July respectively in the following year . The methodology has been evaluated again on the basis of the Jadad score , together with two other components required in a good trial , namely an adequate description of the concealment of allocation of the intervention and an analysis based on the intention to treat . These were described in some detail in the initial registry publication ( 1 ) . There was little difference in the overall quality of trial methodology published in the second six months of 2004 . The quality of the methodology of the trials over the whole year is summarized in Table 1 . A Jadad score equal to or greater than 3 is generally regarded as a good quality trial . As can be seen , only 40 % of r and omized trials could be regarded of adequate quality based on the Jadad score . Furthermore , with respect to two other key components of a good trial , in only 31 % of trials was there concealment of allocation and in only 44 % was the analysis based on intention to treat . This has to be regarded as rather disappointing and there is a need for better planning and reporting of r and omized trials in the field of transplantation . As in the first report , we did correspond with the authors not only to obtain agreement with our analysis of their paper but also to seek further information , which was also forthcoming . It has also generated an interesting dialog with a number of authors who have drawn to our attention that often there was editorial pressure to reduce the length of the manuscript , and quite often it was the description of the trial methodology that suffered . Where the authors have provided additional information , this has again been included in this report . As indicated in the initial introduction , we have begun to examine the quality of reporting of outcomes especially in the light of an analysis of outcome reporting bias by Chan and Altman ( 3 ) . Their conclusion was “ incomplete reporting of outcomes within published articles of r and omized trials is common and is associated with statistical non significance . The medical literature therefore represents a selective and biased subset of study outcomes , and trial protocol s should be made publicly available . ” Thus , in this second registry of r and omized trials in solid organ transplantation , we have assessed the reporting of a number of items included in the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement ( 4 ) . Several medical journals have endorsed the CONSORT statement , including the New Engl and Journal of Medicine , The Lancet , and JAMA . Furthermore , a number of publications have recommended the use of these guidelines in transplantation trials ( 2 , 5–7 ) Background . C2 monitoring of cyclosporine ( CsA ) has been promoted as improving the results of organ transplantation . No r and omized , controlled studies in de novo kidney transplant recipients are available . Methods . Between June 2003 and August 2004 , 160 consecutive cadaveric kidney recipients allocated to CsA , mycophenolate and steroids  were r and omized to either C0 or C2 monitoring of CsA for the first 3 weeks posttransplant . Both levels were measured , keeping the other level blinded until 3 weeks . Altogether , 1451 double measurements were done . The target C0 was 200–300 & mgr;g/L and C2 1500–2000 & mgr;g/L. From the fourth week on , only C0 monitoring was used . Median follow up time was 505 days . Results . The overall 3-month rejection rate was 7.5 % in Group C0 vs. 10.8 % in Group C2 and the one-year graft survival rates were 92.5 % vs. 94.6 % ( NS ) . Rate of delayed graft function was similar in the groups . Plasma creatinine tended to be higher in group C2 at 3 weeks , but not thereafter . During the first three weeks posttransplant , the mean CsA dose was 57 % , mean C2 levels were 55 % , and mean C0 levels were 98 % higher in group C2 than in group C0 ( P<0.00001 ) . Conclusion . This pilot study showed no advantages of C2 monitoring but led to significantly higher CsA doses and blood levels than C0 monitoring Pescovitz , MD , Barbeito , R for the Simulect US01 Study Group . Two‐hour post dose cyclosporin level is a better predictor than trough level of acute rejection of renal allografts . Clin Transplant 2002 : 16 : 378–382 . © Blackwell Munksgaard , BACKGROUND Cyclosporine monitoring using 2-hour post-dose sample s ( C2 ) is thought to be more efficacious than using pre-dose levels ( C0 ) in managing immunosuppression for transplant patients . We evaluated the effect of C2 monitoring on cyclosporine dose and clinical parameters in stable heart transplant patients . METHODS 125 stable heart transplant patients were r and omized to C0 or C2 monitoring of cyclosporine levels  for a period of six months . All patients had both C0 and C2 sample s taken , and clinicians were blinded to one of the sample s depending on r and omization . The primary endpoint was the relative change in cyclosporine ( Neoral ) dose during the study period and secondary endpoints were change in creatine clearance , mortality , infection , and acute rejection . RESULTS There was a significant decrease in the  cyclosporine dose for the C2 group as compared with the C0 group ( -11 mg/day and -26 mg/day respectively , p = 0.0025 ) . No proven rejection episodes occurred in either group and there was no significant difference in the incidence of infection ( C0 6 , C2 10 ; p = 0.14 ) , the change in renal function ( change in creatine clearance C(0 ) + 0.54 ml/min ; C2 -0.16 ml/min ; p = 0.61 ) , the number of blood tests or dose adjustments between groups over the study period . Analysis of the blinded sample s revealed that the reduction of  cyclosporine dose in the C2 group could not be accounted for by reduced immunosuppression . CONCLUSION C2 monitoring allows a significant  cyclosporine dose reduction without compromising patient outcome in stable heart transplant patients . Further studies are required to ascertain whether this dose reduction can be translated into clinical benefit BACKGROUND We reported that cyclosporine 2-hr postdose levels ( C2 ) correlate better with the AUC0 - 4 hr than trough levels ( C0 ) 
    Output:
    
The most consistent finding in de novo renal , hepatic , and cardiac transplant recipients is a higher mean cyclosporine dose in the early postoperative period in C2 monitored patients .
There is no clear evidence that this leads to impaired renal function .
In the majority of studies , the monitoring strategy had no significant effect on the rate of acute rejection .
In stable transplant recipients , the majority of studies show a reduction in mean cyclosporine dose with adoption of C2 monitoring .
No obvious clinical benefit was derived from this reduction in dose .
In de novo transplant patients , there is little evidence from prospect i ve studies to support the theoretical benefits of C2 monitoring .
Potential dose reductions in stable patients may reduce costs , but no short-term clinical benefit is seen .