Protopic
Tacrolimus enhances irritation in a 5-day human irritancy in vivo model.

Fuchs M, Schliemann-Willers S, Heinemann C, Elsner P.

Department of Dermatology, Friedrich-Schiller-University, Jena, Germany. silke.fuchs derma.uni-jena-de

Tacrolimus (FK 506) is a macrolide discovered in 1984 as a metabolic product of Streptomyces tsukabaensis. It has been used successfully in treating atopic dermatitis, allergic contact dermatitis, lichen planus mucosae and pyoderma gangrenosum. In the present study, we evaluated the anti-inflammatory activity of FK 506 in 2 human skin inflammation models. FK 506 as Protopic(R) cream was tested (i) in a 4-day repetitive irritation test with 2 x daily application of sodium lauryl sulphate (SLS), and (ii) in a UVB erythema model. The effect was evaluated visually and quantified by non-invasive bioengineering methods, namely chromametry and tewametry (TEWL). When FK 506 was applied 30 min after SLS irritation, an increased inflammation in comparison to controls was observed with all 3 methods, with only the TEWL data reaching statistical significance. 1 x daily application of FK 506 for 5 days, starting at the end of the 4-day irritation period, was without any effect. Similarly, no effect of FK 506 was seen in the UVB model. In conclusion, FK 506 was shown to enhance experimentally induced irritant contact dermatitis and not to accelerate healing of irritant contact dermatitis and UVB erythema.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12084083&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus and cyclosporine differ in their capacity to overcome ongoing allograft rejection as a result of their differential abilities to inhibit interleukin-10 production.

Jiang H, Wynn C, Pan F, Ebbs A, Erickson LM, Kobayashi M.

Fujisawa Research Institute of America, Northwestern University Research Park, 1801 Maple Avenue, Evanston, IL 60201-3135, USA. hongsi_jiang fujisawa.com

BACKGROUND: Accumulated evidence from clinical transplantation has suggested that tacrolimus-based treatment can reverse ongoing allograft rejection in patients treated with cyclosporine (CsA)-based immunosuppression, even when a high dose of antirejection rescue therapy has failed. This evidence prompted us to investigate whether these two compounds, which share an in vitro mechanism, would differ in their abilities to regulate in situ cellular and molecular events during ongoing allograft rejection. METHODS: The equivalent effective doses of tacrolimus (3.2 mg/kg/day) and CsA (10 mg/kg/day), when administered orally to Lewis rats for 10 days (day 0-9), were predetermined and defined as the ability of the drug to induce a similar survival of Brown Norway rat heart allografts with an equal suppression of intragraft interleukin (IL)-2 mRNA expression. To investigate the ability of each drug to rescue ongoing allograft rejection, Lewis recipients of Brown Norway rat heart grafts were left untreated for the first 5 days after transplantation. Tacrolimus or CsA was then administered at the equivalent effective dose for 10 days (days 5-14). Heart grafts and blood samples, harvested on days 3, 5, 7, and 10, were analyzed by reverse transcriptase-polymerase chain reaction, real-time quantitative polymerase chain reaction, ELISA, and immunohistology. RESULTS: Ongoing allograft rejection was found to be rescued by tacrolimus but not by CsA at the equivalent dose (median survival time: untreated, 6 days; tacrolimus, 18 days; and CsA, 7 days). A significant suppression of local intragraft IL-10 mRNA expression and serum protein production along with a dramatic down-regulation of functional CD8+ T and NKR-P1a+ natural killer cell local infiltration by means of decreased of cytotoxic factor release, including granzyme B and perforin 1, was found to be associated with tacrolimus but not CsA treatment. However, both drugs inhibited other immune cells (CD4+ T cell, ED2+ macrophage) and cytokines (IL-1beta, IL-2, IL-4, IL-6, IL-12, interferon-gamma, transforming growth factor-beta, and tumor necrosis factor-alpha) at almost the same levels. The inability of CsA to overcome ongoing allograft rejection could be rescued by cotreating recipients with neutralizing anti-IL-10 antibody on day 5 and day 6 after transplantation: anti-IL-10 antibody alone did not show such an effect. CONCLUSIONS: Inhibition of IL-10 production is a critical factor in the ability of tacrolimus to reverse ongoing allograft rejection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12085006&dopt=Abstract tacrolimus Protopic



Protopic
Cyclosporine microemulsion and tacrolimus are associated with decreased chronic allograft failure and improved long-term graft survival as compared with sandimmune.

Meier-Kriesche HU, Kaplan B.

University of Michigan Health System, Department of Internal Medicine, Nephrology, Ann Arbor 48109-0364, USA.

Tacrolimus and cyclosporine in the microemulsion formulation Neoral have demonstrated improvements in acute rejection rates after renal transplantation compared with conventional cyclosporine formulation, Sandimmune. To evaluate whether these drugs are also associated with improvements in chronic allograft failure (CAF) rates, we retrospectively analyzed 32,040 primary renal allograft recipients reported to the United States Renal Data System (USRDS) between 1994 and 1997. Graft loss secondary to CAF was defined as graft loss beyond 6 months post-transplant, censored for death, acute rejection, thrombosis, infections and noncompliance. A Cox proportional hazard model was used to investigate the relationship between graft loss secondary to CAF and the use of conventional cyclosporine formulation, as opposed to cyclosporine microemulsion and tacrolimus (Prograf). The analysis was corrected for confounding variables, such as acute rejection, sex, race, human leukocyte antigen (HLA) mismatch, % panel reactive antibodies (PRA), delayed graft function (DGF), cold ischemia time, induction therapy, dialysis time, etiology of end-stage renal disease, cytomegalovirus (CMV) risk group, donor source, era effect, and mycophenolate mofetil (MMF) use. Cyclosporine microemulsion use was associated with a significantly lower relative risk (RR = 0.6, Cl = 0.5-0.7) for CAF as opposed to conventional cyclosporine formulation. Likewise tacrolimus as compared with conventional cyclosporine formulation was associated with a significantly lower relative risk (RR = 0.7, CI = 0.6-0.8) for CAF. Conventional cyclosporine formulation treatment was associated with a 87.6% adjusted CAF-free survival rate at 4 years. Both tacrolimus and cyclosporine microemulsion were associated with a significantly better adjusted CAF-free survival at 4years (91.4 and 92.4%, respectively). Both cyclosporine microemulsion and tacrolimus are associated with improved graft survival and a decreased relative risk for CAF when compared with the older conventional cyclosporine formulation. This association is independent of the use of MMF or changes in era.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12095048&dopt=Abstract tacrolimus Protopic



Protopic
Downregulation of both interleukin-12 and interleukin-2 in heart allografts by pretransplant host treatment with granulocyte colony-stimulating factor and tacrolimus.

Egi H, Hayamizu K, Kitayama T, Ohmori I, Okajima M, Asahara T.

Department of Surgery II, Hiroshima University Faculty of Medicine, Hiroshima, Japan.

Since recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been reported to induce immune deviation, we examined the effects of pretransplant treatment of recipients with rhG-CSF on heart allograft survival. Before heterotopic heart transplantation from DA to Lewis rats, recipients were given rhG-CSF (125microg/kg s.c. twice a day from day -5 to 0) and/or tacrolimus (2mg/kg i.m. on day 0). Combined treatment with both rhG-CSF and tacrolimus prolonged graft survival significantly (P<0.05), while rhG-CSF or tacrolimus alone did not. At 24h after transplantation, cytokine mRNA levels in the grafts were measured by reverse transcription and real-time polymerase chain reaction. IL-12 p35 expression was highly inhibited by rhG-CSF treatment, but tacrolimus did not change the levels. Conversely, rhG-CSF treatment did not affect IL-2 levels, while tacrolimus completely blocked its expression. Combined pretreatment was effective for suppressing acute rejection reaction by downregulating these two key type-1 cytokines, IL-12 and IL-2, with unchanged levels of IL-10.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12126653&dopt=Abstract tacrolimus Protopic



Protopic
Subclinical rejection in tacrolimus-treated renal transplant recipients.

Gloor JM, Cohen AJ, Lager DJ, Grande JP, Fidler ME, Velosa JA, Larson TS, Schwab TR, Griffin MD, Prieto M, Nyberg SL, Sterioff S, Kremers WK, Stegall MD.

Transplant Center, Mayo Foundation and Clinic, Rochester, Minnesota 55905, USA. gloor.james mayo.edu

BACKGROUND: Subclinical rejection, defined as histologic acute rejection in the absence of graft dysfunction, has been suggested as a cause of chronic allograft rejection. In cyclosporine-treated patients, the incidence of subclinical rejection 3 months after transplant is reported to be approximately 30%. The intent of our study was to determine the incidence of subclinical rejection in tacrolimus-treated renal allograft recipients. METHODS: We prospectively studied the incidence of subclinical rejection on surveillance biopsies performed 3 months after transplantation in 114 patients transplanted between September 1, 1998 and November 30, 2000. All patients received tacrolimus, mycophenolate mofetil, and prednisone, and 56% received antibody induction. RESULTS: Subclinical rejection was detected in 2.6% of patients (3/114, 95% confidence interval 0.5-7.5%). Borderline changes were detected in 11% (12/114). Subclinical rejections were treated with bolus methylprednisolone. CONCLUSIONS: The incidence of subclinical rejection early after kidney transplantation is extremely low in tacrolimus-treated patients in whom early rejections are aggressively treated, suggesting that surveillance biopsies may not be necessary with this regimen.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12131699&dopt=Abstract tacrolimus Protopic



Protopic
Conversion from cyclosporine to tacrolimus after renal transplantation improves cardiovascular risk factors.

Hohage H, Welling U, Heck M, Zeh M, Gerhardt U, Suwelack BM.

Nephrologisches Zentrum Emsland, Gymnasialstr. 6, 49808 Lingen, Germany.

BACKGROUND: It is vital that after, renal transplantation, immunosuppression is efficacious and causes few complications. It is especially important that hyperlipidaemia, hypertension and toxic influences should be avoided because these conditions can reduce patient and transplant survival. Many studies have demonstrated beneficial effects of tacrolimus in comparison with cyclosporine with regard to these conditions. These results have suggested that a conversion to tacrolimus from cyclosporine is advantageous. Our study investigated whether patients with deteriorating renal functions can profit from this conversion. METHODS: Thirty patients with a renal transplant were studied retrospectively, using data recorded from 3 years before to 3 years after conversion from cyclosporine to tacrolimus. RESULTS: While renal function (glomerular filtration rate [GFR]) deteriorated progressively under cyclosporine, it stabilised and even improved under tacrolimus (creatinine: Delta(Cyc)=+1.4 mg/d; Delta(Tac=)-0.7 mg/dl; GFR: Delta(Cyc)=-35 ml/min; Delta(Tac)=14 ml/min). In addition, uric acid level (7.0 vs. 6.4 mg/dl, p<0.05) and cholesterol level (258 vs. 225 mg/dl, p<0.05) were both significantly lower under tacrolimus. CONCLUSION: Conversion from cyclosporine to tacrolimus is recommended for patients with a kidney transplant, in which there has been a progressive fall in renal function. It leads to stabilisation or even improvement of transplant function and a reduction in cardiovascular risk factors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15589469&dopt=Abstract tacrolimus Protopic



Protopic
Interference of hematocrit in the tacrolimus II microparticle enzyme immunoassay.

Kuzuya T, Ogura Y, Motegi Y, Moriyama N, Nabeshima T.

Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Nagoya, Japan. t-kuzuya med.nagoya-u.ac.jp

The authors studied the effect of hematocrit, bilirubin, and alkaline phosphatase on microparticle enzyme immunoassay for tacrolimus II (MEIA II) using specimens of whole blood obtained from 33 patients undergoing cyclosporine treatment. Tacrolimus was added to these samples at a final concentration of 7.5 microg/L and 15 microg/L. Both coefficients of variation were over 20% (21% at 7.5 macrog/L of tacrolimus and 22% at 15 microg/L of tacrolimus). No correlation was found between bilirubin and tacrolimus concentrations or between alkaline phosphatase and tacrolimus concentrations. On the other hand, negative correlations were found between hematocrit values and tacrolimus concentrations (r2 = 0.47; P < 0.0001 at 7.5 microg/L tacrolimus, r2 = 0.54; P < 0.0001 at 15 microg/L tacrolimus). Negative correlations were also found between hematocrit and the tacrolimus concentration using normal human red blood cells diluted with physiological saline solution (r2 = 0.93; P < 0.0001 at 7.5 microg/L tacrolimus, r2 = 0.91; P < 0.0001 at 15 microg/L tacrolimus). The results showed that the hematocrit interferes with the MEIA II for tacrolimus, and the magnitude of the interference is clinically significant. Beyond the normal range of hematocrit values, caution should be exercised in interpreting results as one may need to compensate for the levels of tacrolimus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12142635&dopt=Abstract tacrolimus Protopic