Protopic
Conversion from tacrolimus to cyclosporine microemulsion therapy in liver transplant recipients.

Ogino S, Hashikura Y, Katsuyama Y, Ikegami T, Nakazawa Y, Urata K, Terada M, Miyagawa S, Kawasaki S.

Division of Liver Transplantation, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.

The calcineurin inhibitors cyclosporine and tacrolimus have distinct advantages and drawbacks. Therefore it is important to tailor their use to the patient's tolerance. In some patients, the need to ameliorate the adverse effects of tacrolimus may necessitate a switch to cyclosporine-based therapy. Rescue therapy with a cyclosporine microemulsion (Neoral)-based regimen for transplant patients intolerant of tacrolimus has been evaluated to assess the best method of switching and determine the initial and maintenance doses of Neoral in children and adults. Our aims were to evaluate not only these facets, but also the pharmacokinetics of Neoral in stable patients, including target 2-hour postdose blood concentrations (C2) of cyclosporine in liver transplant recipients. Eighteen liver transplant patients switched from tacrolimus to Neoral underwent a program of cyclosporine blood level monitoring. The conversions were conducted safely; the incidence of acute rejection episodes was low (11.1%). Statistical analysis showed that the C2 correlated with the area under the time-blood concentration curve of cyclosporine for 0 to 4 hours after dosing (R=0.970). We determined the maintenance doses of Neoral for pediatric and adult patients as well as the feasibility of C2 quantitated monitoring in liver transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15041357&dopt=Abstract tacrolimus Protopic



Protopic
A pharmacodynamic investigation of tacrolimus in pediatric liver transplantation.

Staatz CE, Taylor PJ, Lynch SV, Tett SE.

School of Pharmacy, University of Queensland, Princess Alexandra Hospital, Queensland, Australia.

Although monitoring of tacrolimus blood concentrations is standard clinical practice following liver transplantation, a greater understanding of the relationship between trough concentrations and clinical outcome is required. The aim of this study was to perform a pharmacodynamic investigation of tacrolimus in pediatric liver transplant recipients. A retrospective analysis was performed on 35 pediatric liver recipients who received oral tacrolimus as the primary immunosuppressant. Outcome data were recorded corresponding to the times that tacrolimus trough concentrations had been determined (using a validated high-performance liquid chromatography-tandem mass spectrometry assay). A Mann-Whitney rank sum test was used to investigate differences between median concentrations at which drug toxicity, infection, and organ rejection did and did not occur. Outcome data and trough concentrations were recorded from the immediate post-transplant time to over 3 years (656 concentration-effect measures). Seventy one percent of data was obtained after the first 90 days post-transplant. Patients were identified as having experienced hypomagnesemia (20), hypertension (14), hyperkalemia (12), infection (11), nephrotoxicity (8), diarrhea (6), hyperglycemia (3), neurotoxicity(3), and rejection (3) during retrospective follow-up. Median trough concentrations were significantly higher (P <.05) at times patients experienced tacrolimus toxicity compared to no toxicity for nephrotoxicity (11.8 vs. 6.1 ng/mL) and neurotoxicity (15.1 vs. 6.2 ng/mL) and at times when patients suffered from diarrhea (8.9 vs. 6.0 ng/mL). No significant difference could be found between median trough concentrations at which hypertension, hyperkalemia, hyperglycemia, infection and organ rejection did and did not occur. A statistically significant relationship exists between some tacrolimus toxicities and tacrolimus trough concentrations. To minimize toxicity in the later post-transplant period, we propose a target trough tacrolimus concentration of 6 ng/mL.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15048793&dopt=Abstract tacrolimus Protopic



Protopic
The colon displays an absorptive capacity of tacrolimus.

Nishi K, Ishii T, Wada M, Amae S, Sano N, Nio M, Hayashi Y.

Department of Pediatric Surgery, Tohoku University School of Medicine, Sendai, Japan. nishi ped-surg.med.tohoku.ac.jp

PURPOSE: In our previous study, blood levels of orally administered tacrolimus were significantly higher in short bowel piglets than in control animals. It has been reported that the blood levels of tacrolimus are influenced by the metabolic activity of intestinal CYP3A4. If tacrolimus may be absorbed in the colon, direct administration of drug into this organ might be useful to augment bioavailability since the expression of CYP3A4 is low at this site. In the present study we evaluated the absorptive capacity of tacrolimus in the colon. MATERIALS AND METHODS: Piglets were divided into four groups: groups 1 and 2 were controls (n = 11 and 3, respectively); group 3 underwent resection of the entire small intestine (n = 8); and group 4 had a catheter placed in the cecum (n = 4). In groups 1 and 3, tacrolimus was administered orally; in group 2 it was given intravenously; and in group 4 it was injected into cecum through the catheter from postoperative days 3 to 7. On day 7, blood samples were obtained for drug measurements to calculate the area under the concentration time curve (AUC) values. RESULTS: The trough level and AUC values of tacrolimus in group 4 as well as in group 3 were significantly higher than those in group 1. In Group 4 animals showed a 60-minute time to peak concentration. CONCLUSIONS: Tacrolimus is absorbed by the colon. Since the blood levels were not influenced by the metabolic activity in the graft bowel, direct administration of tacrolimus into the colon might be useful in small intestinal transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15050160&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus therapy according to mucosal MDR1 levels in small-bowel transplant recipients.

Masuda S, Uemoto S, Goto M, Fujimoto Y, Tanaka K, Inui K.

Departmnet of Pharmacy, Kyoto University Hospital, Kyoto, Japan. inui kuhp.kyoto-u.ac.jp

To clarify the clinical applicability of intestinal absorptive barriers, we have quantified messenger ribonucleic acid (mRNA) expression levels of multidrug resistance 1 (MDR1) protein and cytochrome P450 (CYP) 3A4 in intestinal biopsy specimens from 2 small-bowel transplant recipients. Postoperative immunosuppressive therapy was started with intravenous and oral administrations of tacrolimus and a small amount of steroids. The daily dosage of tacrolimus was modified mainly on the basis of trough levels. After confirmation that the enterocyte MDR1 level was decreasing, tacrolimus was administered via the oral route only. The mRNA levels in the biopsy specimens varied widely throughout the period. With high-dose steroid-pulse treatment, the enterocyte mRNA expression of CYP3A4, but not of MDR1, was markedly enhanced. The mRNA levels of MDR1, but not CYP3A4, correlated well with the concentration/oral dose ratio and the oral dosage of tacrolimus. The good progress after transplantation in both cases suggested that monitoring the change in expression of MDR1 mRNA in the graft intestine might be helpful for understanding the pharmacokinetic profile and determining when to change the route of tacrolimus administration in small-bowel transplant recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15060513&dopt=Abstract tacrolimus Protopic



Protopic
Effects of antiasthmatic agents on the functions of peripheral blood monocyte-derived dendritic cells from atopic patients.

Saeki S, Matsuse H, Kondo Y, Machida I, Kawano T, Tomari S, Obase Y, Fukushima C, Kohno S.

Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.

BACKGROUND: Dendritic cells (DCs), the antigen-presenting cells in the airway, play a critical role in asthma. Nevertheless, there is little information on the effects of antiasthmatic agents on DCs. OBJECTIVES: The purpose of the present study was to determine the effects of representative antiasthmatic agents, including cysteinyl leukotriene (cysLT) 1 receptor antagonists, corticosteroid, and tacrolimus, on DCs in inducing allergy. METHODS: Human peripheral blood monocyte-derived DCs (MoDCs) generated from atopic and healthy subjects were pulsed with Dermatophagoides farinae allergen in the presence of medium alone, pranlukast, montelukast, dexamethasone, or tacrolimus. The mRNA expressions of cysLT receptor, cysLTs producing enzymes, and various surface markers on MoDCs, as well as the concentrations of cysLTs, IL-10, and IL-12 in cultured supernatants, were determined. MoDCs were also cocultured in vitro with autologous CD4(+) T cells, and IL-5 and IFN-gamma production was measured. RESULTS: MoDCs of atopic patients expressed mRNAs of cysLT1 receptor and cysLT-producing enzymes, and allergen pulsing significantly increased cysLT production. MoDCs of atopic patients showed a T(H)2-favoring phenotype and induced T(H)2-skewed cytokine production from autologous CD4(+) T cells. Dexamethasone and tacrolimus inhibited allergen-pulsed MoDC-induced cytokine production by autologous CD4(+) T cells without and with IL-10 inhibition, respectively. CysLT1 receptor antagonists had no effect on MoDC functions. CONCLUSION: Our results indicate that MoDCs of atopic patients induce a T(H)2 reaction. Corticosteroid and tacrolimus, but not cysLT1 receptor antagonists, inhibit T(H)2 reactions, and this effect is probably mediated through different pathways.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15356554&dopt=Abstract tacrolimus Protopic



Protopic
Rapid inhibitory effect of tacrolimus on T cell migration by suppressing CD29-related functions.

Munakata Y, Saito T, Watanabe T, Fujii H, Morimoto C.

Division of Rheumatology and Hematology, Tohoku University Graduate School of Medicine, Sendai, Japan. mnkt mail.tains.tohoku.ac.jp

OBJECTIVE: To clarify the direct effect of Tacrolimus (FK506) on T cell function in relation to CD29. METHODS: Human T cell line H9 and phytohemagglutinin (PHA)-activated T cells were incubated with or without Tacrolimus. The cells underwent cell migration assay by using fibronectin-coated trans-wells, and at the same time the degree of adherence by cultured cells to fibronectin-coated plastic wells was measured. For H9 cells, intracellular filamentous actin formation and the cell surface expression of CD3, CD11a, CD25, CD26, CD44, CD29 were measured by using flow cytometry. Intracellular tyrosin-phosphorylation induced by fibronectin by CD29 stimulation in H9 cells was analyzed by immunoblotting. RESULTS: The ability of H9 cells and PHA-activated T cells incubated with Tacrolimus for 2 hours (hrs) to migrate and to adhere to fibronectin was significantly suppressed. However, the inhibiton was transient, because the ability of cells incubated with Tacrolimus for 24 hrs to migrate was not affected despite the suppression of cell replication. Tacrolimus showed slight but significant reduction of cell surface expression of CD29 within 4 hrs, but CD3, CD11a, CD25, CD26 and CD44 were not affected. Tacrolimus rapidly inhibited intracellular filamentous actin formation; the maximum inhibition was within 2 hrs and the effect was not observed at 6 hrs. Intracellular tyrosin-phosphorylation induced by CD29 stimulation was also inhibited by, Tacrolimus in H9 cells. CONCLUSION: Tacrolimus appeared to have transient early phase inhibitory effects on CD29-related function that may be associated with T cell migration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15083887&dopt=Abstract tacrolimus Protopic



Protopic
Biodegradable microsphere-loaded tacrolimus enhanced the effect on mice islet allograft and reduced the adverse effect on insulin secretion.

Wang Q, Uno T, Miyamoto Y, Hara Y, Kitazawa Y, Lu FZ, Funeshima N, Fujino M, Yamamoto H, Takenaka H, Kawashima Y, Li XK.

Laboratory of Transplantation Immunology, Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo, Japan.

The adverse effects of tacrolimus have limited the use of this potent immunosuppressive drug in clinical transplantation. To improve the therapeutic effects, we developed a new type of tacrolimus with biodegradable microsphere technology and examined the immunosuppressive effects on allogeneic islet transplantation and the side-effects on insulin secretion in vivo. With a single subcutaneous injection, mouse blood concentrations of tacrolimus (M-FK) carried in biodegradable microspheres remained flat for 2 weeks (only 10 h for conventional tacrolimus). A single subcutaneous administration of 20 mg/kg of M-FK significantly prolonged the survival of islet allografts (MST = 28 days) compared with the control group (MST = 10 days). Series administration of 10 mg/kg of M-FK at 7-day intervals markedly prolonged the survival of islet grafts, and resulted in 60% allograft acceptance. In mice with syngeneic islet transplantations, a single administration of 30 mg/kg of tacrolimus inhibited insulin secretion, whereas a single administration of an equal dosage of M-FK did not. The results suggested that M-FK enhanced the immunosuppressive effects on islet allograft rejection more effectively with reduced side-effects on insulin secretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15084166&dopt=Abstract tacrolimus Protopic