Protopic
Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials.

Ashcroft DM, Dimmock P, Garside R, Stein K, Williams HC.

School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL. darren.ashcroft manchester.ac.uk

OBJECTIVE: To determine the efficacy and tolerability of topical pimecrolimus and tacrolimus compared with other treatments for atopic dermatitis. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic searches of the Cochrane Library, Medline, and Embase. STUDY SELECTION: Randomised controlled trials of topical pimecrolimus or tacrolimus reporting efficacy outcomes or tolerability. DATA EXTRACTION: Efficacy: investigators' global assessment of response; patients' global assessment of response; proportions of patients with flares of atopic dermatitis; and improvements in quality of life. Tolerability: overall rates of withdrawal; withdrawal due to adverse events; and proportions of patients with burning of the skin and skin infections. DATA SYNTHESIS: 4186 of 6897 participants in 25 randomised controlled trials received pimecrolimus or tacrolimus. Both drugs were significantly more effective than a vehicle control. Tacrolimus 0.1% was as effective as potent topical corticosteroids at three weeks and more effective than combined treatment with hydrocortisone butyrate 0.1% (potent used on trunk) plus hydrocortisone acetate 1% (weak used on face) at 12 weeks (number needed to treat (NNT) = 6). Tacrolimus 0.1% was also more effective than hydrocortisone acetate 1% (NNT = 4). In comparison, tacrolimus 0.03% was more effective than hydrocortisone acetate 1% (NNT = 5) but less effective than hydrocortisone butyrate 0.1% (NNT = -8). Direct comparisons of tacrolimus 0.03% and tacrolimus 0.1% consistently favoured the higher strength formulation, but efficacy differed significantly between the two strengths only after 12 weeks' treatment (rate ratio 0.80, 95% confidence interval 0.65 to 0.99). Pimecrolimus was far less effective than betamethasone valerate 0.1% (NNT = -3 at three weeks). Pimecrolimus and tacrolimus caused significantly more skin burning than topical corticosteroids. Rates of skin infections in any of the comparisons did not differ. CONCLUSIONS: Both topical pimecrolimus and topical tacrolimus are more effective than placebo treatments for atopic dermatitis, but in the absence of studies that show long term safety gains, any advantage over topical corticosteroids is unclear. Topical tacrolimus is similar to potent topical corticosteroids and may have a place for long term use in patients with resistant atopic dermatitis on sites where side effects from topical corticosteroids might develop quickly. In the absence of key comparisons with mild corticosteroids, the clinical need for topical pimecrolimus is unclear. The usefulness of either treatment in patients who have failed to respond adequately to topical corticosteroids is also unclear.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15731121&dopt=Abstract tacrolimus Protopic



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Neuroprotective effect of tacrolimus (FK506) on ischemic brain damage following permanent focal cerebral ischemia in the rat.

Noto T, Ishiye M, Furuich Y, Keida Y, Katsuta K, Moriguchi A, Matsuoka N, Aramori I, Goto T, Yanagihara T.

Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa, Osaka, 532-8514, Japan.

We investigated the neuroprotective effect of tacrolimus (FK506) on the ischemic cell death with respect to cytochrome c translocation and DNA fragmentation, which are pivotal events in the necrotic and apoptotic signaling pathway, using permanent focal cerebral ischemia in rats. Immunohistochemically, cytochrome c was observed in the cytoplasm as early as 1 h after middle cerebral artery (MCA) occlusion in the infarcted hemisphere. Cytosolic release of cytochrome c after MCA occlusion was also confirmed by Western blot analysis and enzyme immunoassay. Terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) showed DNA fragmentation evolving in the ipsilateral cortex and the caudate putamen after 3 and 6 h, respectively, following MCA occlusion. Tacrolimus (1 mg/kg, i.v.), administered immediately after MCA occlusion, significantly attenuated the release of cytochrome c in the ischemic region, the number of TUNEL-positive cells in the ischemic penumbra zone, and the size of cortical ischemic lesions. This study demonstrated that tacrolimus ameliorated the accumulation of cytochrome c in the cytosol and the increase of TUNEL-positive cells induced by cerebral ischemia, indicating that the neuroprotective action of tacrolimus on ischemic brain injury caused by permanent focal cerebral ischemia could partially be attributed to the attenuation of the activation of the apoptotic execution machinery.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15337315&dopt=Abstract tacrolimus Protopic



Protopic
Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results.

Kramer BK, Montagnino G, Del Castillo D, Margreiter R, Sperschneider H, Olbricht CJ, Kruger B, Ortuno J, Kohler H, Kunzendorf U, Stummvoll HK, Tabernero JM, Muhlbacher F, Rivero M, Arias M.

Klinik und Poliklinik fur Innere Medizin II - Nephrologie, University of Regensburg, Germany.

BACKGROUND: Comparison studies of calcineurin inhibitors as cornerstone immunosuppressants in renal transplantation have demonstrated that tacrolimus consistently reduces acute rejection rates and, in some studies, also improves long-term renal outcome in comparison to cyclosporin A (CsA). The aim of the present 2 year follow-up of the European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was to investigate long-term clinical outcome in terms of rate of acute rejection, graft and patient survival and graft function. METHODS: The European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was a randomized, comparative 6 month trial of the calcineurin inhibitors tacrolimus and CsA in combination with both azathioprine and steroids. The intent-to-treat population (ITT) consisted of 286 patients in the tacrolimus arm and 271 in the CsA microemulsion (CsA-ME) arm. Whereas whole blood level targets were 10-20 and 5-15 ng/ml for tacrolimus and 100-400 and 100-200 ng/ml for CsA during months 0-3 and 4-6, respectively, during the investigator-driven follow-up after termination of the main study (months 7-24) no specific calcineurin inhibitor target levels were required. Follow-up data were collected at 2 years post-transplantation from 237 (82.9% of the ITT population) patients who received tacrolimus and 222 (81.9% of the ITT population) patients who received CsA-ME. RESULTS: Calculated on ITT populations, mortality (2.0% vs 3.3%; P<0.05 in Kaplan-Meier analysis) was lower, but rate of graft loss (9.3% vs 11.2%; P = 0.12 in Kaplan-Meier analysis) was not significantly different after 2 years with tacrolimus- vs CsA-ME-based immunosuppression. Biopsy-proven acute rejection was significantly lower (19.6%) with tacrolimus than with CsA-ME (37.3%) during months 0-6 (P<0.0001), but was not significantly different during months 7-12 and 13-24 of follow-up (1.7% and 0.8% with tacrolimus and 4.7% and 0.9% with CsA-ME, respectively). A composite endpoint consisting of graft loss, patient death and biopsy-proven acute rejection occurred significantly more frequently in CsA-ME patients than in tacrolimus patients (42.8% vs 25.9%; P<0.001) during 24 months follow-up. Renal function 2 years post-transplant, measured by serum creatinine concentrations, was significantly better in tacrolimus-based compared with CsA-ME-based immunosuppression (136.9 vs 161.6 micromol/l; P<0.01). Cornerstone immunosuppression remained unchanged in 82.5% and 66.2% of patients treated with tacrolimus and CsA-ME, respectively. At 2 years, more patients in the tacrolimus arm were off steroids and received calcineurin inhibitor monotherapy, and fewer tacrolimus patients remained on a triple immunosuppressive regimen. The cardiovascular risk profile was affected favourably in the tacrolimus arm, with lower cholesterol and triglyceride concentrations (despite less use of cholesterol-lowering drugs); no significant difference in requirement for antidiabetic medication was noted. CONCLUSIONS: The 2 year study results confirm that tacrolimus is a highly efficacious cornerstone immunosuppressant in kidney transplantation. Tacrolimus-based immunosuppression may induce long-term benefits with regard to graft function and graft survival. The overall side-effect profile is considered to be favourable.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15741208&dopt=Abstract tacrolimus Protopic



Protopic
Patient satisfaction after the treatment of vulvovaginal erosive lichen planus with topical clobetasol and tacrolimus: a survey study.

Jensen JT, Bird M, Leclair CM.

Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, USA.

OBJECTIVE: The purpose of this study was to compare patient satisfaction with the topical immune system modulator tacrolimus to topical clobetasol during treatment for vulvovaginal erosive lichen planus. STUDY DESIGN: Subjects who had been diagnosed with vulvovaginal erosive lichen planus between June 2000 and May 2001 received a mail survey regarding clinical satisfaction and response to treatment with clobetasol and tacrolimus. Satisfaction was assessed with a 100-mm visual analogue scale (very unsatisfied, 0; very satisfied, 100). Satisfaction was compared with the use of a paired t-test. RESULTS: Nineteen subjects met the inclusion criteria; 17 subjects (89%) returned completed surveys. Sixteen of the 17 women reported clobetasol therapy, and 11 of the 17 subjects acknowledged the use of tacrolimus therapy. All but 1 of the women who received tacrolimus had been treated previously with clobetasol therapy. All subjects reported experiencing sexual pain before their initial examination. After treatment with clobetasol, 2 of 16 women reported pain-free intercourse. Two additional women reported pain-free intercourse after switching to tacrolimus therapy. Ten subjects who had used both treatments rated tacrolimus therapy as significantly more satisfactory than clobetasol therapy (63 vs 38 mm; P=.03). CONCLUSION: The use of topical tacrolimus improves satisfaction and may result in better clinical outcomes than therapy with clobetasol for the treatment of vulvovaginal erosive lichen planus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15284791&dopt=Abstract tacrolimus Protopic



Protopic
Increased bioavailability of tacrolimus after rectal administration in rats.

Sakai M, Hobara N, Hokama N, Kameya H, Ohshiro S, Sakanashi M, Saitoh H.

Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, 207 Aza Uehara, Nishihara-cho, Nakagami-gun, Okinawa 903-0215, Japan.

The oral bioavailability of tacrolimus is low and varies considerably in humans due to first-pass metabolism by cytochrome P450 (CYP) 3A4 and the active efflux mediated by P-glycoprotein. This study was undertaken to elucidate the usefulness of rectal administration of tacrolimus as an alternative route to improve its bioavailability. Tacrolimus powder was suspended in a suppository base (witepsol H-15) and the tacrolimus suppository was inserted into the anus of the rats. For comparison, tacrolimus was suspended in 0.5% sodium methylcellulose solution and administered orally to rats. The dose of tacrolimus was fixed to 2 mg/kg. Blood samples were collected periodically up to 24 h after dosing, and tacrolimus concentrations were assayed by microparticle enzyme immunoassay. The whole blood concentrations of tacrolimus after rectal administration were much greater than those after oral administration. The C(max) and AUC(0-24 h) values after rectal administration were 3.9- and 6.9-fold greater than those after oral administration, respectively. These results clearly suggest a possibility that rectal administration of tacrolimus is capable of improving its bioavailability and cutting the costs of tacrolimus treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15340245&dopt=Abstract tacrolimus Protopic



Protopic
Conversion from cyclosporin A to tacrolimus as a non-surgical alternative to reduce gingival enlargement: a preliminary case series.

Hernandez G, Arriba L, Frias MC, de la Macorra JC, de Vicente JC, Jimenez C, de Andres A, Moreno E.

Department of Oral Medicine and Buccofacial Surgery, School of Dentistry, Complutense University, Madrid, Spain. ghervall odon.ucm.es

BACKGROUND: Gingival enlargement (GE) is a frequent side effect that occurs in organ transplant recipients (OTR) after the administration of cyclosporin A (CsA). The availability of new drugs used to suppress graft rejection in OTR offers an opportunity to manage GE non-surgically. This preliminary case series aimed to analyze the effect of CsA withdrawal and its substitution by another immunosuppressant in OTR with severe GE. METHODS: Four organ transplant recipients who had received a liver or renal allograft were recruited for this study. All OTR had developed clinically severe CsA-induced GE. GE scores were assessed for each patient at baseline and at weeks 2, 4, 8, 12, 16, and 54 following conversion to tacrolimus. Scaling and root planing were initially performed and repeated monthly during the first 6 months. Careful polishing of the teeth was carried out once every 2 weeks until month 6 and then monthly until month 12. Hygiene instructions and reinforcement to optimize oral hygiene were maintained throughout the study. RESULTS: The four patients showed a rapid decrease in their gingival symptoms and in the size of the gingivae. This change was clinically evident 8 weeks after conversion to tacrolimus. One year later, all the patients experienced GE regression, although some anatomic irregularities persisted in the interdental papillae of one of the patients. No adverse effects from tacrolimus were observed during the study except in one patient who presented headaches. CONCLUSION: It seems that CsA withdrawal and its conversion to tacrolimus in organ transplant recipients who develop severe gingival enlargement, together with an extensive plaque control program, provide an effective means to control/eliminate gingival hyperplasia, with minimal risk of graft dysfunction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14974825&dopt=Abstract tacrolimus Protopic



Protopic
Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats.

Kobayashi M, Saitoh H, Kobayashi M, Tadano K, Takahashi Y, Hirano T.

Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.

The onset of diarrhea after the administration of mycophenolate mofetil (MMF) is possibly associated with the biliary excretion of its metabolite, mycophenolic acid glucuronide (MPAG). This study was undertaken to clarify the mechanism underlying the biliary excretion of MPAG. Intravenously administered mycophenolic acid (MPA, 5 mg/kg) rapidly disappeared from plasma and was efficiently excreted as MPAG in the bile of Wistar (26% of dose) and Sprague-Dawley rats (21% of dose) over 1 h. On the other hand, in spite of the rapid disappearance of MPA from plasma, the biliary excretion of MPAG was very limited in Eisai hyperbilirubinemic rats (EHBRs), which display mutations in multidrug resistance-associated protein 2 (Mrp2)/canalicular multispecific organic anion transporter, and constituted only 0.5% of dose. Instead, high levels of MPA were noted in the plasma of EHBRs. Intravenous administration of CsA (5 mg/kg) to Wistar rats significantly lowered the biliary excretion of MPAG. However, intravenously administered tacrolimus (0.1 mg/kg) failed to produce such effect. In conclusion, it is suggested that there is an efficient MPAG transport mediated by Mrp2 on the bile canalicular membrane of rat hepatocytes and that the therapeutic range of CsA potentially interferes with Mrp2. However, the therapeutic range of tacrolimus does not inhibit the transporter. Thus, it should be noted that MMF coadministered with tacrolimus instead of CsA might increase the occurrence of diarrhea related to the biliary excretion of MPAG in transplant recipients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14978191&dopt=Abstract tacrolimus Protopic