 |
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
|
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
*
Kidney Transplant Program and the Department of Urology, Queen Elizabeth
II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Kidney Transplant Program and the Department of Medicine, Queen Elizabeth
II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Kidney Transplant Program and the Department of Pathology, Queen Elizabeth
II Health Sciences Centre, Halifax, Nova Scotia, Canada.
§
Kidney Transplant Program and the Department of Pharmacy, Queen Elizabeth
II Health Sciences Centre, Halifax, Nova Scotia, Canada.
||
Kidney Transplant Program and the Department of Surgery, Queen Elizabeth
II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Correspondence to Dr. Philip Belitsky, Room 210, 5 South, Victoria General Site, Queen Elizabeth II Health Sciences Centre, 1278 Tower Road, Halifax, Nova Scotia B3H 2Y9, Canada. Phone: 902-473-4027; Fax: 902-492-2437; E-mail: Philip.Belitsky{at}Dal.Ca
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
A new galenic formulation of CyA, Neoral (Novartis Pharmaceuticals, Basel, Switzerland), has more predictable and consistent pharmacokinetic characteristics than Sandimmune. It was hoped that with Neoral, C0 would better reflect true drug exposure, resulting in better immunosuppression with fewer side effects (5,6,7). Subsequent randomized clinical trials in new kidney transplant patients showed a comparable tolerability and side effect profile for the two CyA formulations and a lower but still significant rate of AR (35 to 45%) (8,9,10) with Neoral. Better pharmacokinetic characteristics of Neoral, however, allow AUC determination with fewer blood samplings (11,12,13,14). A 4-h AUC (AUC0-4), shown to correlate very closely with a full 12-h AUC (r2 = 0.94) (11), is a more practical monitoring tool and is very effective in differentiating between patients with normal and impaired absorption of CyA (11). On the basis of this relationship, we analyzed and reported (15) a cohort of 156 de novo kidney transplant recipients who received Neoral-based triple immunosuppression and had an AUC0-4 measured on days 2 to 4 after starting Neoral. In this cohort, the Neoral dose was monitored by C0 levels, not AUC0-4. This early AUC0-4 displayed a significant correlation with AR and CyANT during the first 3 mo posttransplantation, whereas C0 did not. An AUC0-4 range of 4400 to 5500 µg/h per L was associated with the lowest rate of AR and CyANT (15). Given the demonstrated crucial importance of early exposure to therapeutic levels of CyA as measured by AUC0-4, we conducted this pilot study in which we prospectively monitored and adjusted Neoral doses in de novo renal transplant patients by serial AUC0-4 determinations rather than by C0. The objective of the study was to assess efficacy, safety, and feasibility of achieving and maintaining therapeutic ranges of CyA as measured by AUC0-4 (4400 to 5500 µg/h per L) in the first 3 mo posttransplantation.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Logistic feasibility was measured by the ratio of AUC performed to AUC planned during the first 2 wk. During this time, each patient had five AUC scheduled, compared with only once a week to once a month afterward. AR was the primary efficacy end point. Primary safety end points were 3-mo serum creatinine and episodes of CyANT. Neurotoxicity and hepatotoxicity were secondary safety end points.
Definitions
The diagnosis of AR was confirmed by percutaneous core needle
biopsy. All patients with >30% rise in serum creatinine that was not due to
an identifiable cause, e.g., dehydration, and was confirmed with two
consecutive measurements underwent percutaneous needle biopsy. In addition,
patients with delayed graft function underwent needle biopsy on days 4 to 7
and weekly thereafter until renal function recovered. Severity of AR episodes
was classified according to the Banff criteria
(16,17).
CyANT was defined as >30% increase in serum creatinine that was not attributed to any other identifiable cause and that improved with decrease in the Neoral dose. Biopsies performed for renal dysfunction in these patients were free of acute rejection changes. Hepatotoxicity was arbitrarily defined as a 2x increase in aspartate aminotransferase and/or alanine aminotransferase above the normal values or any elevation in direct or indirect bilirubins. Neurotoxicity was defined as seizures, severe headache, or moderate-severe tremors. Delayed graft function (DGF) was defined as lack of >10% spontaneous drop in serum creatinine by the third postoperative day regardless of the need for dialysis. All CyA blood concentration values refer to whole-blood concentrations, determined by a monoclonal, parent compound-specific RIA test (Incstar Cyclo-Trac whole blood RIA kit, Stillwater, MN).
Immunosuppression
None of the patients received antilymphocyte antibody treatment. Recipients
of HLA-identical living related transplants (4 patients) were treated by
prednisone (Pred) and Neoral only. The other 55 patients received Pred,
Neoral, and a third immunosuppressive drug according to one of the following
protocols: (1) Pred, Neoral, mycophenolate mofetil (MMF; 35 patients
[59%]; (2) Pred, Neoral, and either SDZ RAD
(40-O-[2-hydroxyethyl]-rapamycin) or MMF (as part of a randomized,
double-blind study; 12 patients [20%]); or (3) Pred, Neoral,
rapamycin (as a part of open-label, multicenter study; 8 patients [14%]).
In all patients, CyA was initiated in the recovery room immediately after transplantation by continuous intravenous infusion at a dose of 3 mg/kg per d, which was maintained until the next Neoral dosing time or until they were deemed able to take oral medication (usually 8 to 16 h). Neoral was started at 9 to 14 mg/kg per d in two divided doses. We progressively increased the starting dose in an effort to increase the proportion of patients who exceeded the 4400 µg/h per L AUC0-4 target threshold within the first 5 d posttransplantation. AUC0-4 was performed on days 3, 5, 7, 10, and 14 and at week 3, 4, 6, 8, and 12. Blood for CyA levels was drawn before (C0) and at 1, 2, 3, and 4 h after the Neoral morning dose (C1, C2, C3, and C4, respectively). AUC0-4 was determined by the following regression formula obtained from our retrospective study database (15), using only C1, C2, and C3: AUC0-4 = 256 + C1 + 0.9 x C2 + 1.4 x C3. C0 and C4 values were obtained and stored for later calculation of actual AUC0-4. The Neoral dose was adjusted to achieve an AUC0-4 target range of 4400 to 5500 µg/h per L (15), regardless of C0. Assuming an almost linear relationship between dose and systemic exposure for Neoral within the same patient, dose adjustments were made by multiplying the ratio of mid-range target AUC0-4 (5000 µg/h per L) to patient's AUC0-4 by the previous Neoral dose to obtain the new dose (New dose = 5000/current AUC0-4 x previous dose).
Methylprednisolone 500 mg intravenously was given intraoperatively followed by Pred 1 mg/kg per d orally and tapered by 5 mg every other day to 20 mg/d for the first month, 15 mg/d for the second month, and 10 mg/d for the third month. MMF 1 g orally twice a day was started as soon as oral medication could be tolerated and adjusted to maintain white blood cells > 4000/mm3. Patients who were receiving SDZ RAD/MMF were part of a randomized, double-blind study and were assigned to receive either MMF 1 g orally twice a day, SDZ RAD 0.75 mg orally twice a day, or SDZ RAD 1.5 mg orally twice a day. Rapamycin was given as a 6-mg loading dose on postoperative day 1 followed by rapamycin 2 mg/d orally and adjusted to keep rapamycin trough blood levels above 5 ng/ml.
Statistical Analyses
A t test was used to compare means of continuous numeric values.
Stepwise logistic regression analysis was done to explore the relation of
source of transplant, HLA mismatch, type of immunosuppression, DGF,
C0, AUC0-4, and Neoral dose to incidence of AR and renal
function at 3 mo. Fisher's exact test was used to compare incidence of AR
between different groups. In all statistical analyses, P < 0.05
was considered significant. Statistical calculations were performed with
SAS/STAT (SAS institute Inc., Cary, NC).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Logistic Feasibility
Of 295 planned AUC for 59 patients within the first 2 wk, 260 (88%) were
performed on the scheduled days. An additional 16 (5%) AUC were obtained
within 4 d of the scheduled AUC.
Pharmacokinetic Analysis
A total of 489 AUC0-4 were performed. AUC0-4
calculated by the regression formula based on C1, C2,
and C3 showed excellent correlation with the actual
AUC0-4 (r2 = 0.99). C0 correlated poorly with
AUC0-4 (r2 = 0.22), as did the weight-adjusted Neoral
dose (r2 = 0.08). The single sampling point concentration that
correlated best with AUC0-4 was C2 (r2 =
0.76).
Clinical Parameters
Efficacy. Four recipients of HLA-identical living donor kidney
recipients were deliberately excluded from the acute rejection efficacy
analysis, leaving 55 patients for analyses regarding AR. In 33 of 55
recipients (60%), AUC0-4 >4400 µg/h per L was achieved on
postoperative day 3 and maintained afterward (group 1). In 22 of 55 recipients
(40%), AUC0-4 on day 3 and/or day 5 (AUC0-4) was
<4400 µg/h per L (group 2). Only 1 patient (3%) in group 1
versus 10 patients (45%) in group 2 had AR (P = 0.0002).
Virtually all AR episodes occurred early, within 26 d of transplantation
(Figure 1). The only patient in
group 1 who had AR was a highly sensitized (panel reactive antibody, 60%)
recipient with severe DGF. Protocol biopsy on day 6, while the graft was still
not functioning, showed vascular rejection. In group 2, 10 patients had 12
episodes of AR. Eight of them had AR within 20 d posttransplantation. Two
patients had AR on days 26 and 87, respectively, when their Neoral dose was
decreased because of assumed neurotoxicity (severe tremors) and
nephrotoxicity, despite AUC0-4 in the low target range. Reducing
the Neoral dose led to AUC0-4 values below target levels, which was
followed by AR within 14 d, without an interval fall in serum creatinine. Two
of these 10 patients had recurrent rejection on days 40 and 54, respectively,
both with AUC0-4 < 4400 µg/h per L. The Neoral dose had been
decreased because of severe tremors and assumed nephrotoxicity, but again, the
Neoral dose reduction did not lead to a reduction in serum creatinine.
|
Stepwise logistic regression analysis of variables that affect AR showed that only AUC0-4 (P = 0.0001) and DGF (P = 0.04) were significant predictors of AR. Age, gender, C0, weight-adjusted Neoral dose, HLA mismatch, source of transplantation (cadaver versus living), and type of third immunosuppressive drug were not significant.
Figures 2, 3, and 4 show mean serum creatinine, AUC, and weight-adjusted Neoral dose, respectively, in both group 1 and group 2 patients during the first 3 mo after transplantation. Group 1 patients had lower mean serum creatinine levels throughout (Figure 2), despite higher mean AUC0-4 for most of the 3 mo (Figure 3). The influence of early AUC0-4 on AR and 3-mo serum creatinine was seen in both cadaveric and live donor kidney recipients (Table 2), but because of the small number of patients in the cadaveric group, the difference did not reach statistical significance despite a strong trend. The dose of Neoral required to maintain target AUC0-4 diminished over time to 4.5 ± 1.3 mg/kg per d in group 1 patients and to 5.1 ± 1.4 mg/kg per d in group 2 patients at 3 mo posttransplantation (P = 0.29; Figure 4). The dose of Neoral in 156 historic patients monitored by C0 in our center was 4.6 ± 1.6 mg/kg per d at 3 mo posttransplantation.
|
|
|
|
Safety. Nephrotoxicity. None of the patients experienced CyANT with AUC0-4 < 5500 µg/h per L. Four patients had episodes of CyANT while AUC0-4 was in the range of 6200 to 8500 µg/h per L. In all four patients, CyANT was reversed by appropriate reduction in the Neoral dose.
Multiple regression analysis showed that AUC0-4 and DGF were the only two independent variables measured that affected serum creatinine at 3 mo. Higher early AUC0-4 was associated with lower serum creatinine at 3 mo (P = 0.001). Presence of DGF was associated with higher serum creatinine at 3 mo (P = 0.02). Source of transplantation, C0, weight-adjusted Neoral dose, recipient's diabetes mellitus, HLA mismatch, and type of third immunosuppressive drug were not significant.
Hepatotoxicity. Twenty-two patients (37%) had transient elevations of aminotransferase, alanine aminotransferase, and/or bilirubin. All patients were asymptomatic. None of the patients had the Neoral dose reduced specifically because of elevated liver enzymes. By adjusting the Neoral dose according to AUC0-4, however, 20 of the 22 patients had normal liver enzymes at the end of the first month and another by the end of the second month. One patient, although completely asymptomatic, had persistently high bilirubin levels.
Neurotoxicity. None of the patients had seizures or reported severe headaches. Five patients (8%) developed moderate to severe tremors after transplantation. In one patient, tremors resolved spontaneously despite increasing Neoral doses. Three patients had tremors associated with AUC0-4 > 5500 µg/h per L, and all improved on achieving target AUC0-4 range with decreasing Neoral doses. Only one patient (1.7%) had persistent tremors, even with AUC0-4 in the low target range.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Using the original Sandimmune CyA preparation, CyA exposure measured by AUC had been reported to affect AR rate and/or graft survival in kidney transplant recipients (3,4). Lindholm and Kahan (3) dosed CyA-Sandimmune by serial AUC monitoring in 160 kidney transplant recipients and showed that average CyA blood concentration of <400 ng/ml on the first posttransplant pharmacokinetic study, usually on postoperative day 7, was associated with higher AR rate and poorer graft survival. Only approximately one third of patients achieved the targeted AUC levels, and even in this group the 1-yr AR rate was 34%. No correlation was found between pharmacokinetic parameters and CyANT. In an extension of that study, Senel et al. (4) reported that an average CyA blood concentration >550 ng/ml on day 7 after renal transplantation was associated with higher graft survival for up to 6 yr posttransplantation, although it did not influence the incidence of acute rejection. C0 did not correlate well with graft or rejection-free survival.
Despite an abundance of information in the literature regarding correlation between limited sampling AUC and AUC0-12 for Neoral, there are very limited data on the influence of AUC0-12 or of any limited sampling strategy on the incidence of AR in kidney transplant recipients. Also, we were unable to find any reports that compared the differential influence of AUC0-4 and AUC0-12 on clinical events posttransplantation.
On the basis of excellent correlation established between AUC0-4 and AUC0-12 in stable kidney transplant recipients (11) and also because it provides an accurate estimate of CyA bioavailability from the Neoral formulation and was demonstrated to be a useful tool for the determination of CyA absorption characteristics in a broad range of renal transplant recipients (11), our group recently reported a retrospective study of 156 first kidney transplant recipients who received Neoral-based triple immunosuppression and who were monitored by C0 but had AUC0-4 measured during the first posttransplantation week. We demonstrated that achieving an AUC0-4 range of 4400 to 5500 µg/h per L as early as days 2 to 4, even with C0 monitoring, was associated with the lowest rate of AR (7%) and CyANT (6%) at 3 mo posttransplantation. Although patients received different immunosuppressive regimens, the association among AUC0-4, AR, and CyANT was independent of which third immunosuppressive agent was used. Again, C0 correlated very poorly with AR (15).
Although the association of early AUC0-4 with AR and CyANT was observed in patients who were monitored by CyA C0, the feasibility and safety of dosing Neoral to maintain an AUC0-4 range of 4400 to 5500 µg/h per L in the first 3 mo after kidney transplantation was unknown. The purpose of the current study was to assess the feasibility, safety, and efficacy of AUC0-4 monitoring in different Neoral-based triple immunosuppressive protocols. For this reason, no attempt was made to change the ongoing immunosuppressive protocols during this study. AUC0-4 rather than C0 was used to monitor Neoral dosing. This was achieved without significant inconvenience to patients, to laboratory staff, or to nursing staff on the wards or in the outpatient clinic. Requirements for abbreviated AUC monitoring were reviewed with laboratory and nursing staff before initiating the study, and their collaboration allowed potential pitfalls to be identified and eliminated beforehand. As a consequence, 94% of scheduled AUC were actually completed, 88% on the scheduled days. Missed or incomplete AUC were usually due to patients' being off the ward for other investigations. Virtually none of the infrequent later AUC was missed. Although for the purpose of the study five blood samples were drawn, only three blood levels—C1, C2, and C3—proved to be necessary to calculate accurately AUC0-4 for clinical decision making. The C0 and C4 samples were used to confirm the validity of 3-point sampling versus 5-point sampling in calculating AUC0-4 (r2 = 0.99) and to archive data for later determination of whether even fewer sampling points later after transplantation would reflect adequately true CyA exposure. Changes in the Neoral dose were rational and made in direct proportion to AUC0-4 values.
None of the patients, including eight patients with DGF, experienced CyANT with an AUC0-4 < 5500 µg/h per L. Achieving and maintaining AUC0-4 levels of 4400 to 5500 µg/h per L were not associated with deterioration of renal function at 3 mo. On the contrary, early exposure to CyA as measured by AUC0-4 had a very significant inverse relationship with 3-mo serum creatinine. This effect might be related to prevention of subclinical immunologic injury to the graft with proper CyA exposure (21,22). The absence of nephrotoxicity may also be related in part to rapid and appropriately rational reduction of the Neoral dosage to prevent prolonged overexposure to CyA. This is possible with AUC monitoring but not with C0 monitoring, because the latter does not reflect accurately true drug exposure, and low or "normal" C0 levels may actually be associated with high exposure to CyA. This may help explain the anachronistic findings of nephrotoxicity with "low" C0 and excellent renal function with "high" C0. It is also interesting that at the end of 3 mo, the mean Neoral dose in mg/kg in patients who were monitored by AUC0-4 was similar to the mean Neoral dose in our historic patients who were monitored by C0. Although the mean dose was similar, the distribution of dosage was more appropriately allocated in AUC-monitored patients because AUC monitoring allows for more rational adjustment of the Neoral dose to maintain optimal CyA exposure. In addition, with AUC monitoring, clinical hepatotoxicity was not seen in our 59 patients. Elevated liver enzymes were seen in 37% of patients, but it was asymptomatic in all and normalized with Neoral dose adjustments designed to maintain CyA exposure within the target range. Similarly, neurotoxicity was not a clinical problem when CyA exposure was maintained within the target AUC range.
Our experience also suggests that rapidly achieving and maintaining AUC0-4 within the 4400 to 5500 µg/h per L range may effectively prevent AR. In this group, only one highly sensitized patient with severe DGF had early vascular AR. Prevention of this type of AR arguably might not be possible with any currently available oral immunosuppressive agents, all of which act by inhibiting T-cell activation or function in some way. The poor correlation between C0 and AUC0-4 may help to explain the occurrence of AR with "high" or target C0 levels and its absence in many patients with "low" C0. Interestingly, four patients developed AR when their Neoral dose was decreased because of assumed toxicity despite an AUC0-4 at the low end of the target range. This decrease in dose, attributable to early inexperience with AUC0-4 monitoring, resulted in AUC0-4 <4400 µg/h per L. The subsequent AR occurred without any previous reduction in serum creatinine, suggesting that CyANT had not been present before dose reduction. All four of these patients were in group 2, with early subthreshold exposure to CyA during the first 5 postoperative days. This experience emphasizes the importance of not only rapidly reaching adequate levels of CyA exposure as measured by AUC0-4 but also maintaining it, especially in patients who may have experienced early donor-specific T-cell activation as a result of inadequate early exposure to CyA.
This study shows for the first time that with Neoral, therapeutic drug monitoring by AUC0-4 is feasible; safe in terms of renal, hepatic, and neurologic function; and efficacious in prevention of AR. By AUC0-4 monitoring, rapidly achieving and maintaining proper CyA drug exposure may essentially eliminate AR and CyANT. If confirmed by subsequent larger experience, these findings may have a significant impact on our understanding and management of CyA immunosuppression in clinical renal transplantation.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  C. Sommerer, T. Giese, S. Meuer, and M. Zeier Pharmacodynamic monitoring of calcineurin inhibitor therapy: Is there a clinical benefit? Nephrol. Dial. Transplant., October 15, 2008; (2008) gfn556v2. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Schiff, E. Cole, and M. Cantarovich Therapeutic Monitoring of Calcineurin Inhibitors for the Nephrologist Clin. J. Am. Soc. Nephrol., March 1, 2007; 2(2): 374 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Scholten, A. T. Rowshani, S. Cremers, F. J. Bemelman, M. Eikmans, E. van Kan, M. J. Mallat, S. Florquin, J. Surachno, I. J. ten Berge, et al. Untreated Rejection in 6-Month Protocol Biopsies Is Not Associated with Fibrosis in Serial Biopsies or with Loss of Graft Function J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2622 - 2632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J Curtis, P. Jones, and R. Barbeito Large Within-Day Variation in Cyclosporine Absorption: Circadian Variation or Food Effect? Clin. J. Am. Soc. Nephrol., May 1, 2006; 1(3): 462 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Buchler, S. Chadban, E. Cole, K. Midtvedt, E. Thervet, H. Prestele, and P. Keown Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases Nephrol. Dial. Transplant., January 1, 2006; 21(1): 197 - 202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T. Rowshani, E. M. Scholten, F. Bemelman, M. Eikmans, M. Idu, M. C.R. van Groningen, J. S. Surachno, M. J.K. Mallat, L. C. Paul, J. W. de Fijter, et al. No Difference in Degree of Interstitial Sirius Red-Stained Area in Serial Biopsies from Area under Concentration-over-Time Curves-Guided Cyclosporine versus Tacrolimus-Treated Renal Transplant Recipients at One Year J. Am. Soc. Nephrol., January 1, 2006; 17(1): 305 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Einecke, M. Schutz, I. Mai, L. Fritsche, M. Giessing, P. Glander, H.-H. Neumayer, and K. Budde Limitations of C2 monitoring in renal transplant recipients Nephrol. Dial. Transplant., July 1, 2005; 20(7): 1463 - 1470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Marcen, J. J. Villafruela, J. Pascual, J. L. Teruel, J. Ocana, M. T. Tenorio, F. J. Burgos, and J. Ortuno Clinical outcomes and C2 cyclosporin monitoring in maintenance renal transplant recipients: 1 year follow-up study Nephrol. Dial. Transplant., April 1, 2005; 20(4): 803 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. di Paolo, A. Teutonico, G. Stallone, B. Infante, A. Schena, G. Grandaliano, M. Battaglia, P. Ditonno, and P. F. Schena Cyclosporin exposure correlates with 1 year graft function and histological damage in renal transplanted patients Nephrol. Dial. Transplant., August 1, 2004; 19(8): 2107 - 2112. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
HOME
CURRENT ISSUE
ARCHIVES
JASN Express
ONLINE SUBMISSION
AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP |
