Protopic
Design of pH-sensitive microspheres for the colonic delivery of the immunosuppressive drug tacrolimus.

Lamprecht A, Yamamoto H, Takeuchi H, Kawashima Y.

Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, Gifu, Japan.

Recently, tacrolimus was shown to be effective in mitigating inflammatory bowel disease (IBD). In the treatment of IBD, oral drug delivery using pH-dependent polymers is one of the most successful therapeutic strategies. Eudragit P-4135F, a pH-sensitive polymer for colonic delivery was used to prepare tacrolimus microparticles using an oil/oil emulsification or an oil/water emulsification technique combined with a solvent extraction or evaporation step. Although the pH-dependent drug release was similar for all types of microspheres, it was generally found that encapsulation rates of oil/water systems (extraction 38.8 +/- 9.4%; evaporation 56.3 +/- 1.9%) were superior to the oil/oil emulsification (4.8 +/- 0.4%). Eudragit P-4135F was found to limit drug leakage at pH 6.8 to levels lower than 10% within 6 h. At pH 7.4, almost immediate release (within 30 min) was observed. From differential scanning calorimetry and X-ray analyses, the drug inside the polymeric microsphere matrix was concluded to be present in a molecular dispersion. Generally, all formulations proved their applicability in vitro as a promising device for pH-dependent colonic delivery of tacrolimus, however, the oil/water technique was found to be superior to the oil/oil approach and among them solvent evaporation seemed to be more advisable, due to the higher encapsulation rate. Copyright 2004 Elsevier B.V.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15207535&dopt=Abstract tacrolimus Protopic



Protopic
Recalcitrant symptomatic vulvar lichen planus: response to topical tacrolimus.

Byrd JA, Davis MD, Rogers RS 3rd.

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

BACKGROUND: Topical tacrolimus has been reported to be an effective treatment for genital lichen planus in small case series. We retrospectively reviewed the medical records of 16 patients with symptomatic vulvar lichen planus who received treatment with tacrolimus ointment. OBSERVATIONS: All patients had symptomatic vulvar lichen planus recalcitrant to other treatments. Of 16 patients, 15 (94%) experienced a symptomatic response to tacrolimus treatment within 3 months (mean, 4.2 weeks) and had a partial or complete resolution of the lesions. Six patients (38%) reported mild adverse effects, including irritation, burning, and tingling. With continued use of the medication, these adverse effects resolved. When patients stopped treatment, lichen planus returned in 10 (83%) of 12 patients within 6 months after discontinuation of therapy (median, 1 week; range, 0.3-24 weeks), but in 6 patients the lesions were less severe than the lesions before treatment; all 10 patients resumed use of topical tacrolimus. CONCLUSIONS: In this retrospective series of 16 women with vulvar lichen planus, topical tacrolimus therapy effectively controlled symptoms and improved lesions in all but 1 patient. The effect may be temporary, requiring continued use of tacrolimus, which appears to be safe and effective in controlling disease activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15210463&dopt=Abstract tacrolimus Protopic



Protopic
Multiple modes of action of tacrolimus (FK506) for neuroprotective action on ischemic damage after transient focal cerebral ischemia in rats.

Furuichi Y, Noto T, Li JY, Oku T, Ishiye M, Moriguchi A, Aramori I, Matsuoka N, Mutoh S, Yanagihara T.

Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, 2-1-6, Kashima, Osaka 532-8514, Japan. yasuhisa_furuichi po.fujisawa.co.jp

While the immunosuppressant tacrolimus (FK506) is known to be neuroprotective following cerebral ischemia, the mechanisms underlying its neuroprotective properties are not fully understood. To determine the mode of action by which tacrolimus ameliorates neurodegeneration after transient focal ischemia, we therefore evaluated the effect of tacrolimus on DNA damage, release of cytochrome c, activation of microglia and infiltration of neutrophils following a 60-min occlusion of the middle cerebral artery (MCA) in rats. In this model, cortical brain damage gradually expanded until 24 h after reperfusion, whereas brain damage in the caudate putamen was fully developed within 5 h. Tacrolimus (1 mg/kg) administered immediately after MCA occlusion significantly reduced ischemic damage in the cerebral cortex, but not in the caudate putamen. Tacrolimus decreased both apoptotic and necrotic cell death at 24 h and reduced the number of cytochrome c immunoreactive cells at 8 h after reperfusion in the ischemic penumbra in the cerebral cortex. In contrast, tacrolimus did not show significant neuroprotection for necrotic cell death and reduction of cytochrome c immunoreactive cells in the caudate putamen. Tacrolimus also significantly decreased microglial activation at 8 h and inflammatory markers (cytokine-induced neutrophil chemoattractant and myeloperoxidase [MPO] activity) at 24 h after reperfusion in the ischemic cortex but not in the caudate putamen. These results collectively suggest that tacrolimus ameliorates the gradually expanded brain damage by inhibiting both apoptotic and necrotic cell death, as well as suppressing inflammatory reactions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15212998&dopt=Abstract tacrolimus Protopic



Protopic
A numerical scale comparison of renal transplant recipient experience with and opinions about calcineurin inhibitors.

Prasad GV, Nash MM, McFarlane PA, Zaltzman JS.

Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Ont., Canada. prasadr smh.toronto.on.ca

BACKGROUND: Many studies compare the relative benefits of cyclosporine and tacrolimus with respect to graft and patient outcomes, but comparative renal transplant recipient opinion on calcineurin inhibitor (CI) use has not been directly sought. METHODS: We administered a confidential clinic-distributed written questionnaire to adult single-organ recipients pertaining to CI use and related physical side effects experienced. Sixteen common immunosuppressive therapy-related side effects were rated on a 1-10 Likert numerical scale, with 1 meaning complete disagreement and 10 complete agreement with their own CI experience. Comparisons were made among recipients on cyclosporine, tacrolimus, and those with a dual drug experience. RESULTS: The questionnaire was filled by 316 patients. The efficacy of cyclosporine and tacrolimus was considered equivalent (p = 0.99), while the overall side effect profile reported was greater for cyclosporine (p = 0.001). The side effect profile for cyclosporine was greater in the dual group than the cyclosporine-only group (p = 0.01). Cyclosporine was perceived as more difficult to swallow (p = 0.001), nephrotoxic (p = 0.005), and to cause more hypertension (p = 0.04) and hyperlipidemia (p = 0.001), while tacrolimus was perceived to be more neurotoxic (p < 0.0001), but not causing more diabetes (p = 0.64). CONCLUSIONS: Renal transplant recipients experience fewer and less severe side effects with tacrolimus. Further contemporaneous study of CI preferences in this population is warranted. Transplant centers should consider patient opinion in tailoring their own immunosuppressive strategies and regimens. Copyright 2004 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15218328&dopt=Abstract tacrolimus Protopic



Protopic
Quantitative evaluation of eyelid elasticity using the cutometer SEM575 and its clinical application in assessing the efficacy of tacrolimus ointment treatment in eyelid atopic dermatitis.

Kawakita T, Takano Y, Asano-Kato N, Tanaka M, Dogru M, Goto E, Tsubota K, Takahashi S, Fukagawa K, Fujishima H.

Department of Ophthalmology, Tokyo Dental College, Ichikawa, Chiba, Japan.

PURPOSE: To study the clinical efficacy of a noninvasive suction device that measures eyelid skin elasticity in the treatment of eyelid atopic dermatitis using tacrolimus (FK-506) ointment. METHODS: Ten patients with eyelid atopic dermatitis treated with tacrolimus ointment and 10 normal volunteers participated in this study. The cutometer SEM575 was used to quantitatively evaluate eyelid skin elasticity. Severity of the eyelid atopic dermatitis was scored, and comparisons were made before and after treatment. RESULTS: Skin elasticity of patients with eyelid atopic dermatitis was significantly lower than that of normal volunteers (31.3 +/- 5.2% vs 40.2 +/- 7.8%, respectively). Skin elasticity of patients with eyelid atopic dermatitis improved significantly to 37.5 +/- 6.3% after treatment with tacrolimus ointment. The total severity score for eyelid atopic dermatitis also improved from 2.77 +/- 1.11 to 1.77 +/- 1.15. CONCLUSION: Measurement of skin elasticity using the cutometer SEM575 is a useful and reliable method for objective and quantitative evaluation of eyelid skin condition in patients with eyelid atopic dermatitis. The efficacy of short-term tacrolimus ointment treatment in patients with eyelid atopic dermatitis was confirmed quantitatively using this apparatus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15220731&dopt=Abstract tacrolimus Protopic



Protopic
[Case of inflammatory vasculopathy and encephalopathy caused by treatment with tacrolimus]

[Article in German]

Ringelstein A, Bongs K, Sorge-Hadicke B, Berlit P.

Neurologische Klinik, Alfried Krupp-Krankenhaus, Essen.

The case of inflammatory vasculopathy and encephalopathy caused by treatment with tacrolimus is reported. This 49-year-old woman developed progressive gait ataxia and right-sided hemiparesis after 7 years of tacrolimus therapy for focal sclerosing glomerulonephritis. MRI presented multifocal cerebral lesions with contrast enhancement. Oligoclonal banding was positive. When the treatment with tacrolimus was stopped, the clinical symptoms resolved completely and the MRI findings improved with corticoid monotherapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15221068&dopt=Abstract tacrolimus Protopic



Protopic
CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation.

Goto M, Masuda S, Kiuchi T, Ogura Y, Oike F, Okuda M, Tanaka K, Inui K.

Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University.

OBJECTIVES: Tacrolimus is widely used for immunosuppressive therapy after organ transplantation, but its pharmacokinetics shows such great interindividual variation that control of its blood concentration is difficult. We have previously reported that an intestinal P-glycoprotein (MDR1) contributes to this variation as an absorptive barrier, but the role of hepatic metabolism is not clear. METHODS: In this study, we have evaluated the genotypes of MDR1 and cytochrome P450 (CYP) 3A in donor and recipient, and the influence of polymorphisms on mRNA expression and the tacrolimus concentration/dose (C/D) ratio in recipients of living-donor liver transplantation (LDLT). RESULTS: The expression level of MDR1 and tacrolimus C/D ratio were not affected by either MDR1 C3435T or G2677T/A. The CYP3A4*1B genotype was not detected, but the CYP3A5*3 genotype had an allelic frequency of 76.3%. The mRNA level of CYP3A5 was significantly reduced by the *3/*3 genotype, and the tacrolimus C/D ratio was decreased in recipients engrafted with partial liver carrying CYP3A5*1/*1 genotype. An analysis of the combination of intestinal MDR1 level and liver CYP3A5 genotype revealed that the tacrolimus C/D ratio was lower in the group with higher MDR1 levels regardless of CYP3A5 genotype during postoperative week 1. CONCLUSIONS: These results indicate that in recipients of LDLT, the pharmacokinetics of tacrolimus is influenced by flux via P-glycoprotein in the intestine during the first week; after that, it is mostly the hepatic metabolism that contributes to the excretion of tacrolimus, and carriers of the CYP3A5*1/*1 genotype require a high dose of tacrolimus to achieve the target concentration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15226679&dopt=Abstract tacrolimus Protopic