Protopic
Comparing renal transplant patients' adherence to free cyclosporine and free tacrolimus immunosuppressant therapy.

Chisholm MA, Mulloy LL, DiPiro JT.

University of Georgia College of Pharmacy, Augusta, GA 30912, USA. Mchishol mail.mcg.edu

BACKGROUND: The purpose of this study is to determine if there is a difference in renal transplant patients' (RTPs) adherence to cyclosporine compared to tacrolimus when medications are supplied free to the RTPs. METHODS: Adult primary RTPs were included in the study if they received a renal transplant at the Medical College of Georgia (MCG) from June 1998 through August 2001 and received their first post-transplant year of follow-up care at MCG and free cyclosporine or free tacrolimus from the MCG outpatient pharmacy. Adherence was estimated by comparing each RTPs' tacrolimus or cyclosporine pharmacy refill records to the prescribed regimen for 12 months after transplant. Patients' cyclosporine and tacrolimus serum concentrations were used to validate adherence. Kaplan-Meier analysis was used to estimate the fraction of RTPs remaining adherent and to compare the mean time RTPs were adherent in each group (cyclosporine vs. tacrolimus). RESULTS: Thirty-three RTPs were included in the study, 25 (76%) received cyclosporine and eight received tacrolimus. The mean time to the first non-adherent month was 8 months post-transplant. At 12-months post-transplant, approximately 42% of the patients remained adherent. A greater percentage of the patients who received tacrolimus remained adherent compared with those who were taking cyclosporine (63% vs. 33%, p < 0.05). Approximately 75% of non-adherent patients were found to have subtarget drug concentrations, and only 24% of adherent patients had subtarget levels (p < 0.01). CONCLUSIONS: When provided free, patients are more adherent to tacrolimus than cyclosporine. Regardless of treatment, intensive efforts to increase adherence should be implemented.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15659138&dopt=Abstract tacrolimus Protopic



Protopic
A novel management strategy of steroid-free immunosuppression after liver transplantation: efficacy and safety of tacrolimus and mycophenolate mofetil.

Ringe B, Braun F, Schutz E, Fuzesi L, Lorf T, Canelo R, Oellerich M, Ramadori G.

Klinik fur Transplantationschirurgie, Abteilung Klinische Chemie, Georg-August-Universitat Gottingen, Germany.

BACKGROUND: Corticosteroids have been used traditionally for immunosuppression after solid organ transplantation. The variety of modern immunosuppressive agents offers the chance to replace drugs with an unfavorable risk-benefit ratio. The objective of this prospective pilot study was to investigate a novel steroid-free immunosuppressive regimen after clinical liver transplantation. METHODS: 30 adult liver graft recipients were included in an intent-to-treat analysis. Dual induction immunosuppression consisted of tacrolimus and mycophenolate mofetil. Prophylactic steroids were not given. Efficacy and safety parameters analyzed were patient and graft survival, incidence and severity of rejection, and adverse events in correlation to immunosuppressive drug levels. RESULTS: Patient and graft survival at 2 years was 86.7 and 83.9%, respectively. Acute rejection occurred in 26.2%, and was associated with subtherapeutic tacrolimus blood levels and diarrhea. All rejections were completely reversible by temporary addition of steroids. Acute renal failure was seen in 10/30 patients, and was related to high tacrolimus blood levels together with primary liver graft dysfunction. 43% of all patients never received any steroids, and 73% were on a steroid-free maintenance regimen. CONCLUSIONS: These results confirm that corticosteroids can be completely avoided from the beginning after liver transplantation. Double drug immunosuppression with tacrolimus and mycophenolate mofetil is effective and safe in terms of patient and graft survival as well as incidence and severity of rejection. In order to avoid under- or over-immunosuppression, which may be caused by impaired absorption or metabolism, close drug monitoring is advised.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11258429&dopt=Abstract tacrolimus Protopic



Protopic
Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy.

Weir MR, Ward MT, Blahut SA, Klassen DK, Cangro CB, Bartlett ST, Fink JC.

Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA. mweir medicine.umaryland.edu

BACKGROUND: Chronic allograft nephropathy is the major cause of progressive renal failure in renal transplant recipients. It has no definitive treatment. METHODS: One hundred eighteen renal transplant recipients with declining kidney function and biopsy-proven chronic allograft nephropathy had their cyclosporine or tacrolimus dose reduced or discontinued with either the addition or continuation of mycophenolate mofetil and low-dose steroids at a mean of 853.3 days post-transplantation. Their renal function was modeled before and after this intervention by two methods: A least-square regression was used to assess the decay of renal function after the intervention and to compare that with the slope pre-intervention, whereas a hinge regression line method was used to assess the correlation of the intervention with the inflection point and the impact of the intervention on the decay of renal function. Mean follow-up was 651.0 days after the intervention. Serum creatinine at the time of intervention was 2.8 +/- 0.9 mg/dL in the reduced dose cyclosporine (N = 67) and reduced dose tacrolimus (N = 33) groups, and was 2.7 +/- 0.7 mg/dL in the group with discontinued calcineurin inhibitor (N = 18). RESULTS: Using the least-square method, 91.7% of the no calcineurin inhibitor group, 51.6% of the reduced dose cyclosporine group, and 59.3% of the reduced dose tacrolimus group had improved or lack of deterioration in slope after the intervention. Using the hinge regression line method, there was a statistically significant correlation of the inflection point with the intervention (P = 0.001). Moreover, there was a similar relationship with stabilized or improved graft function observed with the hinge regression line method and the least-square method, as 72.2% of the calcineurin inhibitor withdrawal group, 54.4% of reduced-dose cyclosporine group, and 40% of the reduced-dose tacrolimus group had improved the slope of decay of renal function or lack of deterioration after the inflection point. The difference between the calcineurin inhibitor withdrawal group and the reduced-dose cyclosporine/tacrolimus groups on the decay in renal function was significant (P = 0.038) with the least-square method and nearly significant (P = 0.056) using the hinge regression line method. CONCLUSION: This intervention was safe, well tolerated, and associated with a minimal risk of acute rejection. We conclude that the reduction and possible withdrawal of calcineurin inhibitors may be necessary to slow the rate of loss of renal function in patients with chronic allograft nephropathy and deteriorating renal function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11260422&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus: the good, the bad, and the ugly.

Chand DH, Southerland SM, Cunningham RJ 3rd.

Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

The aim of this study was to evaluate the efficacy and side-effects of tacrolimus in pediatric transplant patients previously receiving cyclosporin A (CsA). This study was a retrospective chart review strengthened by a concomitant patient interview. Eleven pediatric cardiac or renal transplant patients, who had been converted from CsA to tacrolimus from October 1995 to January 1999 at The Cleveland Clinic Foundation, were included; there were six renal and five cardiac transplant patients. Each chart was reviewed to assess transplanted organ function pre- and post-conversion. For the six renal transplant patients, creatinine levels and biopsy findings were evaluated. For the five cardiac transplant patients, cardiac catheterization and routine biopsy data were analyzed likewise. Epstein Barr virus (EBV) status was also evaluated in each patient. In addition, each parent or patient was interviewed to ascertain dates of transplant, current medications, and side-effects. The patients' ages ranged from 6 to 20 yr (mean age 14.6 yr). All patients had been converted to tacrolimus. Eight patients were converted for treatment of refractory rejection, two were converted because of CsA-associated side-effects, and one patient was converted empirically for a history of multiple previous transplant rejections. Seven out of eight patients who received tacrolimus for rejection therapy improved. One patient had complete resolution of gingival hyperplasia. Another patient who previously developed hemolytic uremic syndrome on CsA had no further evidence of hemolysis. Four patients were weaned off steroid therapy. Despite conversion, two renal transplant patients progressed to chronic rejection. Five patients exhibited no side-effects. Side-effects experienced included transient hyperglycemia in conjunction with steroid use, headaches, and tremors that subsided rapidly. Four of 11 patients developed post-transplant lymphoproliferative disease (PTLD). Fortunately, reducing the dose of tacrolimus and/or surgical resection of the mass (if present), eradicated the disease. In conclusion, conversion therapy successfully provides an alternate treatment for acute rejection. It also enabled some patients to discontinue steroid therapy, maximizing growth potential. PTLD is a severe, potentially life-threatening complication that needs to be recognized and monitored closely. In conclusion, tacrolimus has been shown to be a very effective agent for the treatment of refractory organ rejection, but must be used cautiously.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11260486&dopt=Abstract tacrolimus Protopic



Protopic
Effects of hematocrit value on microparticle enzyme immunoassay of tacrolimus concentration in therapeutic drug monitoring.

Tomita T, Homma M, Yuzawa K, Ohkohchi N, Hori T, Kaneko M, Hasegawa Y, Kojima H, Nagasawa T, Kohda Y.

Department of Pharmacy, Tsukuba University Hospital, Tsukuba, Ibaraki 305-8576, Japan.

The effects of hematocrit (Ht) value on microparticle enzyme immunoassay (MEIA) of tacrolimus concentration were examined in 1063 whole-blood samples from 42 transplant recipients (13 liver, 20 kidney, and 9 bone marrow transplantations). MEIA guarantees the test's assay quality for blood tacrolimus in samples with Ht values of 25% to 45%. However, 129 samples (29.3%) obtained from liver transplant recipients and 107 samples (61.5%) from bone marrow transplant recipients had lower Ht (<25%). Further, 81 blood samples (18.1%) with Ht > 45% were observed in kidney transplant patients. Twenty-five whole-blood samples with low Ht were tested by 3 assay methods for tacrolimus: MEIA, modified, corrected MEIA (cMEIA), and enzyme-linked immunosorbent assay (ELISA). MEIA gave higher blood concentrations of tacrolimus than ELISA (16.1 versus 11.0 ng/mL, P < 0.001). This difference was generated by overestimation in MEIA and was not observed in samples with normal Ht. This overestimation was eliminated by using cMEIA on samples with low Ht values: there was no difference in blood tacrolimus concentration between cMEIA and ELISA (12.3 versus 11.0 ng/mL). ELISA or cMEIA should be used for tacrolimus assay in samples obtained from bone marrow transplant recipients with anemia and from liver and kidney transplant recipients with unstable Ht values.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15665753&dopt=Abstract tacrolimus Protopic



Protopic
Formulary review of therapeutic alternatives for atopic dermatitis: focus on pimecrolimus.

Weinberg JM.

Department of Dermatology, St. Luke's-Roosevelt Hospital Center, 1090 Amsterdam Ave., Suite 11D, New York, NY 10025, USA. jmw27 columbia.edu

OBJECTIVE: Atopic dermatitis (AD), often called eczema, is characterized by intense pruritus, erythema, dry skin, and inflammation. The condition is chronic and relapsing, and often occurs in patients with a family history of the atopic triad (asthma, allergic rhinitis, and AD). Use of topical steroids has been the mainstay of medical treatment for AD. Steroid-free treatments for AD, with a more favorable safety profile, have become available within the past 2 years. Tacrolimus ointment, a topical immunomodulator, became available in early 2001 and is indicated for moderate-to-severe AD. A similar but highly skinselective cytokine inhibitor, pimecrolimus cream 1%, became available in March 2002. Pimecrolimus is indicated for mild-to-moderate AD. The objective of this article is to review the key characteristics that differentiate pimecrolimus from steroids and tacrolimus in the treatment of AD. METHODS: Using secondary resources, the clinical aspects and conventional treatment strategies for AD are reviewed as are the pivotal clinical studies with pimecrolimus and literature on quality of life and economic burden of disease for AD patients and families. SUMMARY: Pimecrolimus is an effective, steroid-sparing therapy for mild-tomoderate AD. Early treatment prevents flares, the agent works quickly to reduce signs and symptoms of more advanced AD, and it is safe and appropriate for intermittent long-term therapy. Pimecrolimus has fewer side effects than topical steroids and a better side-effect profile than tacrolimus. It can also be used as a first-line therapy. In studies with patients aged 2 to 17 years, it has been shown to be particularly effective in improving eczema of the face and neck, and its use may improve quality of life for many patients, especially children. A single-strength dose (1%) is safe and medically beneficial for pediatric, adolescent, and adult patients. The direct drug cost of pimecrolimus compares favorably with tacrolimus, but it is significantly more expensive than generic topical steroid creams.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15667233&dopt=Abstract tacrolimus Protopic



Protopic
Low-dose tacrolimus treatment in thymectomised and steroid-dependent myasthenia gravis.

Kawaguchi N, Yoshiyama Y, Nemoto Y, Munakata S, Fukutake T, Hattori T.

Department of Neurology, Chiba University Graduate School of Medicine, Chiba, Japan. kawaguchi faculty.chiba-u.jp

OBJECTIVES: The effects of tacrolimus, a new immunosuppressive drug, which inhibits calcineurin pathway and also might enhance corticosteroid (CS) receptor-mediated gene expressions, on clinical outcome and biochemical data were evaluated in thymectomised and steroid-dependent myasthenia gravis (MG) patients. PATIENTS AND METHODS: We administrated low-dose tacrolimus (3 mg/day orally) to 17 steroid-dependent thymectomised MG patients. They were followed for 4 to 58 months, average 19.2 months. The MG activities of daily living (MGADL) scores and the dosage of prednisolone (PSL) were assessed at baseline and 4 months later. RESULTS: The average MGADL scores improved from 6.8 to 5.0 (p < 0.01) at 4 months; to 3.5 at the last visit (p < 0.01) as well as the average dosage of PSL reducing from 31.6 to 24.1 mg/alternate day (p < 0.01) at 4 months; 14.6 mg at the last visit (p < 0.01). CONCLUSIONS: The additional low dose tacrolimus therapy for steroid-dependent thymectomised MG is effective in improving symptoms as well as allowing the tapering of CSs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15324529&dopt=Abstract tacrolimus Protopic