Protopic
Response of oral lichen planus to topical tacrolimus in 37 patients.

Byrd JA, Davis MD, Bruce AJ, Drage LA, Rogers RS 3rd.

Department of Dermatology, Mayo Clinic, Rochester, MN 55905, USA.

BACKGROUND: Topical tacrolimus has been reported to be effective for the treatment of oral lichen planus. This article describes our experience with topical tacrolimus in patients treated for symptomatic oral lichen planus. OBSERVATIONS: A survey was mailed to 40 patients with symptomatic oral lichen planus treated with topical tacrolimus. Surveys were completed by 37 patients (93%) a mean of 1.3 years after initiation of treatment. Thirty-three (89%) of the 37 patients reported symptomatic improvement, and 31 (84%) reported partial to complete lesion clearance while using topical tacrolimus. On average, patients noted improvement in 1 month. Twelve patients (32%) reported adverse effects consistent with those reported previously (ie, burning, irritation, and tingling). Among the 28 patients still using the medication, 15 patients (54%) apply it at least once daily. Of the 9 patients who discontinued using the medication, 5 experienced recurrence. CONCLUSIONS: Topical tacrolimus is effective for the treatment of oral lichen planus. Most patients experienced symptomatic improvement in less than 1 month. However, the effect is temporary; when topical tacrolimus is discontinued, oral lichen planus may flare again.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15611431&dopt=Abstract tacrolimus Protopic



Protopic
Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection.

Theruvath TP, Saidman SL, Mauiyyedi S, Delmonico FL, Williams WW, Tolkoff-Rubin N, Collins AB, Colvin RB, Cosimi AB, Pascual M.

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

BACKGROUND: In renal transplantation, chronic rejection is a major cause of late allograft loss. Recent studies indicate that a subset of chronic rejection is associated with anti-HLA donor specific antibodies (DSA) and complement C4d deposition in peritubular capillaries (PTC). Since rescue therapy with tacrolimus and mycophenolate mofetil has been found to limit antidonor B-cell responses in recipients with acute humoral rejection, we sought to determine whether a similar immunosuppressive regimen might be effective in patients with 'chronic humoral rejection'. METHODS: Four renal allograft recipients with 'chronic humoral rejection' were prospectively identified. The diagnosis was based on: (1) progressive rise in serum creatinine over 12 months; (2) typical pathologic features by light microscopy (transplant arteriopathy and glomerulopathy); (3) widespread C4d deposits in PTC by immunofluorescence; (4) detection of 'de novo' DSA at the time of biopsy. Maintenance immunosuppression was CsA, prednisone and azathioprine (n=3) or prednisone and azathioprine (n=1). Rescue therapy with tacrolimus and mycophenolate mofetil was initiated in all patients, 12 hr after cyclosporine and azathioprine discontinuation. RESULTS: At diagnosis, the mean serum creatinine was 3.9 mg/dl (range: 3.3 to 5.4 mg/dl). DSA was an IgG directed against HLA class II (n=3) or class I (n=2), that is one patient had both anti-HLA class I and class II antibodies. Pretreatment antibody titers varied between 1:8 and 1:128. Rescue therapy was associated with a rapid and sustained decrease in antibody titers. In two patients, DSA became undetectable after 9 months and a repeat biopsy performed after 12 months revealed a decrease in C4d deposition in PTC. CONCLUSION: These results suggest that a decrease in DSA production can be induced in renal allograft recipients with 'chronic humoral rejection' by using an immunosuppressive regimen that combines tacrolimus and mycophenolate mofetil. Limitation of antidonor antibody synthesis may be important for the treatment or the prevention of chronic rejection in organ transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11468538&dopt=Abstract tacrolimus Protopic



Protopic
Quantitation of immunosuppression by tacrolimus using flow cytometric analysis of interleukin-2 and interferon-gamma inhibition in CD8(-) and CD8(+) peripheral blood T cells.

Ahmed M, Venkataraman R, Logar AJ, Rao AS, Bartley GP, Robert K, Dodson FS, Shapiro R, Fung JJ, Zeevi A.

Departments of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

The authors have determined the frequency of intracellular interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) synthesis by T-cell subsets in whole blood (WB) and isolated lymphocytes in 16 transplant recipients treated with tacrolimus and 10 control patients who were not transplant recipients. The authors also determined the impact of varying amounts of red blood cells (RBC) on immunosuppression by tacrolimus. Samples were analyzed by two-color flow cytometry, and the results were expressed as a ratio of whole blood to isolated lymphocytes. In healthy subjects who were not transplant recipients, the frequency of IL-2--producing CD8(-) and CD8(+) cells was higher in WB than in isolated lymphocytes (mean +/- SD of whole blood to lymphocytes ratio: 1.24 +/- 0.5 and 1.67 +/- 0.62, respectively). Adding varying amounts of RBC had no significant impact on IL-2 production by CD8(-) and CD8(+) T cells. Adding tacrolimus (10 ng/mL) to lymphocyte cultures inhibited (90%) IL-2 production in isolated T cells but not in the whole-blood assay. The dose of tacrolimus required for a 50% inhibition of IL-2 release in T cells was 10-fold higher in cultures with RBC than without. Peripheral blood mononuclear cells (PBMC) isolated from tacrolimus-treated whole blood (WB) showed less IL-2 inhibition than did lymphocytes in the WB. The authors also tested cytokine production in WB and PBMCs in 16 transplant recipients and observed various patterns of reactivity. The frequency of IL-2--producing CD8(-) and CD8(+) cells was similar using two different methods in 10 of 16 patients tested. By contrast, in the remaining six patients the authors observed a significant inhibition of IL-2 production in both CD8(-) and CD8(+) T-cell subsets in the whole-blood assay but not in the isolated lymphocytes. The frequency of CD8(-) IFN-gamma--producing cells was significantly lower in 9 of 16 patients, but the same individuals showed no inhibition of their CD8(+) IFN-gamma T cells. The trough levels of tacrolimus did not predict the level of cytokine inhibition in the whole-blood assay in these patients. The authors' results show that the whole-blood assay for cytokine production can be used for monitoring the in vivo effect of tacrolimus in transplant recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11477316&dopt=Abstract tacrolimus Protopic



Protopic
No effect of water deprivation for 48 hours on the pharmacokiinetics of intravenous tacrolimus in rats.

Son IJ, Moon YJ, Lee MG, Sohn YT.

Department of Pharmacy, College of Pharmacy, Duksung Women's University, Tobong-Gu, Seoul, South Korea.

Because the physiological changes that occur in patients with water deprivation could alter the pharmacokinetics of drugs, the pharmacokinetics of tacrolimus were investigated after 1-min intravenous administration of the drug (1 mg/kg) to control rats and rats with water deprivation for 48 h. In rats with dehydration, kidney function seemed to be impaired slightly. Kidney weight (0.800 versus 0.676% body weight) increased significantly and the renal tissue showed only total and mild tubular dilatation and flattening of tubular epithelial cells based on kidney microscopy. However, hepatic function seemed not to be impaired in rats with dehydration. After intravenous administration of tacrolimus, the pharmacokinetic parameters were not significantly different between two groups of rats and the results were expected since tacrolimus was almost completely metabolized in rats (impaired kidney function could not affect considerably the pharmacokinetics of tacrolimus) and hepatic function was not impaired in rats with dehydration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11484882&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus is not associated with gingival overgrowth in renal transplant patients.

James JA, Jamal S, Hull PS, Macfarlane TV, Campbell BA, Johnson RW, Short CD.

University Dental Hospital of Manchester, Higher Cambridge Street, Manchester, M15 6FH, UK. jackie.james man.ac.uk

BACKGROUND: Cyclosporin A is used extensively to prevent the rejection of allogenic renal transplants. However, it is associated with a variety of undesirable side effects including gingival overgrowth. Tacrolimus (FK506), has been marketed as an effective alternative immunosuppressant to cyclosporin A and recent subjective reports suggest patients taking it complain infrequently of gingival problems. This clinical investigation was undertaken to confirm whether or not tacrolimus adversely affected the gingival health of renal transplant recipients. METHODS: Renal transplant patients (RTPs) under the care of the Renal Transplantation Service at the Manchester Royal Infirmary, who had received a renal allograft at least 18 months earlier, were recruited for this study. All but one of the RTPs had been taking tacrolimus since transplantation. The other had commenced tacrolimus therapy two months after receiving her allograft. A hospital based control group was recruited from non transplanted individuals attending the Turner Dental School, Manchester. Each patient underwent a detailed dental assessment and had dental impressions taken. The extent of gingival overgrowth was determined from plaster models. RESULTS: 25 renal transplant recipients and 26 control patients were included in the study. None of the individuals in either the tacrolimus or control groups had clinically significant overgrowth. The patients in the tacrolimus group with the highest overgrowth scores were those also taking calcium antagonists as treatment for hypertension. CONCLUSION: This study demonstrates that tacrolimus has no adverse effects on the gingival tissues and thus has potential as an alternative immunosuppressant for individuals susceptible to developing cyclosporin A-induced gingival overgrowth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11493354&dopt=Abstract tacrolimus Protopic



Protopic
Bone marrow augmentation in kidney transplantation: a large animal study.

Gruessner RW, Zhang KY, Dunning M, Nakhleh RE, Gruessner AC.

Department of Surgery, University of Minnesota, Minneapolis 55455, USA.

Specific immunomodulatory strategies are required to eliminate the need for lifelong dependence on debilitating immunosuppressants. One proposed strategy is to simultaneously transplant the kidney and infuse donor-specific bone marrow cells. We prospectively studied the effect of unmodified donor-specific bone marrow infusion (DSBMI) on rejection, infection, graft-versus-host disease (GvHD), and graft survival. We performed 57 kidney transplants in mixed lymphocyte culture (MLC)-reactive, outbred pigs. The groups of recipient pigs differed according to the use of (1) indefinite versus short-term tacrolimus-based immunosuppression, (2) DSBMI, and (3) recipient preconditioning (RPC: whole body irradiation with 400 rads on day 0 and horse anti-pig thymocyte globulin (ATG) on days -2, -1, and 0). In all, we studied eight groups: group 1, nonimmunosuppressed control pigs (n = 8); group 2, nonimmunosuppressed DSBMI pigs (n = 7); group 3, nonimmunosuppressed RPC + DSBMI pigs (n = 5); group 4, tacrolimus (indefinite) pigs (n = 11); group 5, tacrolimus (10 days only) pigs (n = 5); group 6, DSBMI + tacrolimus (indefinite) pigs (n = 8); group 7, DSBMI + tacrolimus (10 days only) pigs (n = 6); and group 8, RPC + DSBMI + tacrolimus (indefinite) pigs (n = 7). DSBMI alone (group 2) or in combination with RPC (group 3) did not prolong graft survival, as compared with nonimmunosuppressed controls (group 1). In groups 1, 2, and 3, all but one pig died from rejection; in group 3 only, 45% of the pigs died from concurrent infection or GvHD, indicating that RPC in combination with DSBMI aggravated the risk of generalized infection and GvHD. Post-transplant immunosuppression--irrespective of indefinite or short-term administration--was required for prolonged graft survival. With indefinite use of immunosuppression, graft survival rates and death rates from rejection were not different for pigs with (group 6) versus without (group 4) DSBMI; however, the death rate from infection was higher in group 6, suggesting that the bone marrow inoculum increased the risk of systemic infection. With short-term use of immunosuppression, graft survival rates were higher and death rates from rejection lower for pigs with (group 7) versus without (group 5) DSBMI. But DSBMI and short-term immunosuppression (group 7) failed to prolong survival beyond that achieved with indefinite immunosuppression (groups 4 and 6). Although the combination of DSBMI and short-term immunosuppression (group 7) reduced the risk of infection, it did not avert severe rejection. The addition of RPC to DSBMI and indefinite immunosup- pression (group 8) significantly decreased graft survival, as compared with groups 4, 6, and 7. It also increased the incidence of death from rejection, GvHD, and infection, or a combination thereof. Unmodified DSBMI did not prolong graft survival after kidney transplantation, nor did it decrease the incidence of rejection. But it aggravated the risk of GvHD and infection. Short-term immunosuppression with DSBMI reduced the incidence of death from infection or GvHD, but it resulted in a higher incidence of death from rejection (as compared with indefinite use of immunosuppression). RPC, combined with DSBMI and indefinite immunosuppression, increased the death rate from rejection, GvHD, infection, or a combination thereof. In this large animal study, the effect of unmodified DSBMI has been disappointing. The search continues for the optimal way to successfully perform bone marrow augmentation in solid organ transplants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11499905&dopt=Abstract tacrolimus Protopic



Protopic
Basiliximab induction improves the outcome of renal transplants in children and adolescents.

Swiatecka-Urban A, Garcia C, Feuerstein D, Suzuki S, Devarajan P, Schechner R, Greenstein S, Tellis V, Kaskel F.

Department of Pediatrics, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10467, USA. ajaswurban001 worldnet.att.net

Thirty-two children and adolescents received their renal transplant at the Montefiore Medical Center, in New York, between October 1996 and May 2000. Twenty-four patients received basiliximab, in addition to tacrolimus and steroids (basiliximab group). The remaining eight patients received only tacrolimus and steroids (non-basiliximab group). The 1-year patient survival rate was 100% in both groups. The 1-year graft survival rate was 87.5% for the basiliximab group and 75% for the non-basiliximab group (P=0.45). The rates of acute rejection in the basiliximab and non-basiliximab groups were 26% and 43%, respectively (P=0.36). However, in recipients with <or=3 HLA mismatches, the rate of acute rejection was zero in the basiliximab group, and 40% in the non-basiliximab group (P=0.04). The beneficial effect occurred despite the fact that tacrolimus was maintained at below the target levels. There were no adverse events directly attributable to the administration of basiliximab. There were no cases of opportunistic infections or post-transplant lymphoproliferative disease. In summary, addition of basiliximab to tacrolimus and prednisone significantly decreased the rate of acute rejection in well-matched patients. Moreover, this effect was manifest at lower, and therefore less toxic, tacrolimus levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11511978&dopt=Abstract tacrolimus Protopic