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Concept: Tacrolimus


PURPOSE: The administration of topical tacrolimus (FK506) eye drops or ointment is effective in treating certain immunologic corneal diseases and in the prevention of rejection of high-risk corneal grafts. The purpose of this study is to determine the optimal formulation of tacrolimus 0.06% eye drops. A procedure for preparation is presented and discussed. METHODS: Tacrolimus monohydrate powder and virgin castor oil are used in this new formulation. The manufacturing process guarantees consistency of product sterility. Measurement by high-performance liquid chromatography allows precise control of the concentration of tacrolimus. RESULTS: The manufacture and packaging of tacrolimus 0.06% eye drops involve numerous controls allowing for guaranteed sterility and stability. The drops remained sterile and stabile for 28 days after opening regardless of storage conditions and can be stored for 3 months after manufacture. Tolerability studies are currently being performed.

Concepts: Eye, Chromatography, High performance liquid chromatography, Analytical chemistry, Cornea, Lens, Iris, Tacrolimus


PURPOSE: The objective of the study was to investigate the relative bioavailability between the generic tacrolimus products that are presently authorized in Spain by adjusted indirect comparison. This was based on demonstration of bioequivalence with the reference product (Prograf, Astellas Pharma), which makes these generic tacrolimus products prescribable, switchable and therapeutically equivalent to the reference product; yet, according to Spanish legislation, only prescribers can switch tacrolimus-containing products. METHODS: Data from independent bioequivalence studies that compare each generic product with the reference product were combined by adjusted indirect comparisons to investigate the relative bioavailability between generic drug products, since there is no direct bioequivalence study comparing generics to each other. RESULTS: Eight generic tacrolimus products in the form of capsules are presently authorized in Spain, but only five are marketed. These eight products represent only three different generic product developments. One product is authorized with four different names/companies, while another is authorized under three different names/companies. The adjusted indirect comparisons between generic products show bioequivalence within the conventional 80-125 % confidence interval acceptance criteria for area under the curve (AUC) and maximum concentration (Cmax). CONCLUSION: Not only are the generic products bioequivalent with the reference product, but also with each other.

Concepts: Comparison, Generic drug, Comparisons, Marketing, Bioavailability, Bioequivalence, Tacrolimus, Astellas Pharma


Abstract Background: Pruritus ani (PA) is defined as intense chronic itching affecting perianal skin. Objective: We aimed to determine the efficacy of topical tacrolimus treatment in atopic dermatitis (AD) patients who have PA. Methods: The study included 32 patients with AD who were suffering PA. Patients were randomized into two groups. In total, 16 patients used 0.03% tacrolimus ointment and 16 patients used Vaseline® as placebo. All groups applied topical treatments to their perianal area twice daily for 4 weeks. The treatments were then reversed for 4 weeks after a 2 weeks wash out period. Results: In total, 32 patients with AD who had refractory anal itching were enrolled in the present study. None of the patients had obtained successful results with previous treatments. There was a statistically significant decrease in the recorded EASI, DLQI and itching scores for the tacrolimus group compared to the placebo groupat weeks 4 and 6 of treatment (p < 0.05). Conclusion: Topical tacrolimus treatment was well tolerated and effective in controlling persistent PA in AD patients.

Concepts: Allergy, Symptoms, Tacrolimus, Hemorrhoid, Itch, Anal fissure, Atopic dermatitis, Pruritus ani


Although topical tacrolimus (FK506) is known to promote repigmentation by increasing the pigmentation and migration of melanocytes, the mechanism through which FK506 regulates cell migration remains unclear. Here, we report that FK506 treatment enhanced cell spreading on laminin-332 and increased migration in both melanocytes and melanoma cells. Interestingly, FK506 also increased the expression of syndecan-2, a transmembrane heparan sulfate proteoglycan through JNK activation. Moreover, siRNA-mediated reduction of syndecan-2 expression decreased FK506-mediated cell spreading and migration in melanoma cells, and decreased FAK phosphorylation in both melanocytes and melanoma cells. Consistent with these effects on syndecan-2 expression, FK506 enhanced the membrane and melanosome localizations of PKCβII, a regulator of tyrosinase activity. This suggests that FK506 may play a dual regulatory role by affecting both melanogenesis and migration in melanocyte-derived cells. Interestingly, however, FK506 failed to show any synergistic effect on the migration of UVB-treated melanocyte-derived cells. Taken together, these data indicate that FK506 regulates cell migration by enhancing syndecan-2 expression, further suggesting that syndecan-2 could be a potential target for the treatment of vitiligo patients. This article is protected by copyright. All rights reserved.

Concepts: Cell membrane, Melanoma, Heparan sulfate, Melanin, All rights reserved, Tacrolimus, Copyright, Melanocyte


Topical calcineurin inhibitors (TCIs), commercially available since 2000-2001, are the first and only topical medications approved for chronic treatment of atopic dermatitis (AD) in pediatric patients and remain a welcomed alternative to topical corticosteroids. In January 2006, the US Food and Drug Administration (FDA) issued a boxed warning requirement based on a theoretical risk of malignancy (including lymphoma) with TCI use. However, in the years since, analyses of epidemiologic and clinical data have failed to demonstrate a causal relationship between TCI use and malignancy or lymphoma risk, especially for pimecrolimus cream. In fact, the observed number of malignancies and lymphomas observed both in post-marketing surveillance and reported to the FDA using its adverse events reporting system is much lower among TCI-exposed patients than the expected number for the general population. Furthermore, among children enrolled in post-marketing pediatric registry studies for both tacrolimus and pimecrolimus followed for up to 5.5 years [10,724 patient-years (PY)] or 6.5 years (16,219 PY), respectively, the observed number of malignancies and lymphomas is very low and similar to the number expected for a sample of similar size in the general population. In addition to reporting these comparative malignancy and lymphoma data, this article provides a historical overview of the boxed warning requirement and critically evaluates the preclinical, clinical, and epidemiological evidence that has thus far failed to substantiate a relationship between TCI use and malignancy. The authors also provide practical clinical advice for optimizing AD management and patient care in the context of the boxed warning.

Concepts: Epidemiology, Cancer, Food and Drug Administration, Hematological malignancy, Tacrolimus, Atopic dermatitis, Calcineurin, Pimecrolimus


Atopic dermatitis (AD) is a condition frequently encountered in medical practices across the country. Arming ourselves with appropriate and safe treatment modalities to provide relief for this chronic and relapsing inflammatory condition is of utmost importance to our patients and their families. Utilizing topical calcineurin inhibitors (TCIs) for the treatment of AD not responsive to high-potency corticosteroids, or low-potency corticosteroids and localized to the face, eyelids, and skin folds of patients >2 years, is reasonable to include in common practice. Despite the FDA¿s Black Box warning, to date no evidence has been published linking the TCIs to an increased incidence of malignancy in either children or adults that establishes causation. The Canadian Society of Allergy and Clinical Immunology (CSACI) therefore recognizes that the benefits of TCIs should be carefully weighed with the theoretical risks in advising patients, and acknowledges that long-term studies remain in progress. The safety and efficacy of topical tacrolimus and pimecrolimus should therefore be considered when treating children and adults with AD in Canadian allergy and immunology practices.

Concepts: Asthma, Medical terms, Allergy, Atopy, Tacrolimus, Atopic dermatitis, Calcineurin, Pimecrolimus


The genus Malassezia includes yeasts that are commonly found on the skin or hair of animals and humans as commensals and are associated with a number of skin disorders. We have previously developed an Agrobacterium tumefaciens transformation system effective for both targeted gene deletion and insertional mutagenesis in Malassezia furfur and M. sympodialis In the present study, these molecular resources were applied to characterize the immunophilin FKBP12 as the target of tacrolimus (FK506), ascomycin, and pimecrolimus, which are calcineurin inhibitors that are used as alternatives to corticosteroids in the treatment of inflammatory skin disorders such as those associated with Malassezia species. While M. furfur and M. sympodialis showed in vitro sensitivity to these agents, fkb1Δ mutants displayed full resistance to all three of them, confirming that FKBP12 is the target of these calcineurin inhibitors and is essential for their activity. We found that calcineurin inhibitors act additively with fluconazole through an FKBP12-dependent mechanism. Spontaneous M. sympodialis isolates resistant to calcineurin inhibitors had mutations in the gene encoding FKBP12 in regions predicted to affect the interactions between FKBP12 and FK506 based on structural modeling. Due to the presence of homopolymer nucleotide repeats in the gene encoding FKBP12, an msh2Δ hypermutator of M. sympodialis was engineered and exhibited an increase of more than 20-fold in the rate of emergence of resistance to FK506 compared to that of the wild-type strain, with the majority of the mutations found in these repeats.IMPORTANCEMalassezia species are the most abundant fungal components of the mammalian and human skin microbiome. Although they belong to the natural skin commensal flora of humans, they are also associated with a variety of clinical skin disorders. The standard treatment for Malassezia-associated inflammatory skin infections is topical corticosteroids, although their use has adverse side effects and is not recommended for long treatment periods. Calcineurin inhibitors have been proposed as a suitable alternative to treat patients affected by skin lesions caused by Malassezia Although calcineurin inhibitors are well-known as immunosuppressive drugs, they are also characterized by potent antimicrobial activity. In the present study, we investigated the mechanism of action of FK506 (tacrolimus), ascomycin (FK520), and pimecrolimus in M. furfur and M. sympodialis and found that the conserved immunophilin FKBP12 is the target of these drugs with which it forms a complex that directly binds calcineurin and inhibits its signaling activity. We found that FKBP12 is also required for the additive activity of calcineurin inhibitors with fluconazole. Furthermore, the increasing natural occurrence in fungal pathogen populations of mutator strains poses a high risk for the rapid emergence of drug resistance and adaptation to host defense. This led us to generate an engineered hypermutator msh2Δ mutant strain of M. sympodialis and genetically evaluate mutational events resulting in a substantially increased rate of resistance to FK506 compared to that of the wild type. Our study paves the way for the novel clinical use of calcineurin inhibitors with lower immunosuppressive activity that could be used clinically to treat a broad range of fungal infections, including skin disorders caused by Malassezia.

Concepts: DNA, Gene, Genetics, Agrobacterium, Tacrolimus, Malassezia, Calcineurin, Pimecrolimus


We sought to explore the architecture of trials of calcineurin inhibitors for atopic eczema to document the extent to which comparisons with active treatments such as topical corticosteroids (TCS) might have been included or avoided. We identified all eligible randomized controlled trials (RCTs) using the Global Resource for EczemA Trials database. Network plots were produced where the nodes represented a treatment type and the lines between the nodes represented the number of trials or participants that were involved in the various treatment comparisons. A total of 174 RCTs for atopic eczema treatments were identified where pimecrolimus, tacrolimus or topical corticosteroids were compared with another intervention or a vehicle/emollient. Of 39 trials involving pimecrolimus and of 41 trials involving tacrolimus, 8 (20.5%) and 13 (31.7%) respectively made comparisons with topical corticosteroids, and 25 (64.1%) and 15 (36.6%) respectively were vehicle-controlled studies. The high rate of comparisons with vehicle controls in RCTs assessing the efficacy of pimecrolimus or tacrolimus long after efficacy had been established is a matter of concern. Active comparators (mild TCS for pimecrolimus and moderate to potent TCS for tacrolimus) are best placed to inform how topical calcineurin inhibitors compare to established clinical practice.

Concepts: Clinical trial, Asthma, Randomized controlled trial, Eczema, Tacrolimus, Atopic dermatitis, Calcineurin, Pimecrolimus


Eczema (syn. Atopic Eczema or Atopic Dermatitis) is a chronic, relapsing, itchy skin condition which probably results from a combination of genetic and environmental factors. The Global Resource of EczemA Trials (GREAT) is a collection of records of randomised controlled trials (RCTs) for eczema treatment produced from a highly sensitive search of six reference databases. We sought to assess the sensitivity of the GREAT database as a tool to save future researchers repeating extensive bibliographic searches.

Concepts: Asthma, Randomized controlled trial, Allergy, Atopy, Eczema, Psoriasis, Tacrolimus, Atopic dermatitis


Medication non-adherence after liver transplantation (LT) is associated with adverse clinical outcomes such as graft rejection and graft loss. Few studies have examined non-adherence and the impact on clinical outcomes in LT. Study objectives were to evaluate: 1) medication understanding (using treatment knowledge and demonstrated regimen use scores) and medication (non)-adherence of entire regimens among LT recipients, and 2) examine associations of these exposures with clinical outcomes. We conducted a two-site study of 105 recipients between 2011 and 2012 at two transplant centers in Chicago, IL and Atlanta, GA. Data were collected via detailed in-person interviews and medical record review. Study participants were middle aged and predominantly male; 15% of the sample had limited literacy. On average, patients were taking 11 (SD=4) medications and 39% had a medication change within the last month. Average scores for the entire medication regimen were: 86% (SD=22) for treatment knowledge and 78% (SD=22) for demonstrated regimen use. The mean score for self-reported non-adherence to the entire regimen was 14% (SD=20), whereas 32% of patients were non-adherent by tacrolimus levels. In multivariate analyses, lower income, less time since transplant, a higher number of medications, and limited literacy were inversely associated with treatment knowledge scores (all p<0.05), whereas limited literacy was associated with non-adherence by tacrolimus levels (p<0.05). In multivariate models, higher scores for treatment knowledge (IRR 0.85, 95% CI, 0.74-0.97) and demonstrated regimen use (IRR 0.87, 95% CI 0.77-0.98) were independently associated with a 15% and 13% reduction in the number of post-transplant re-hospitalizations, respectively. Inadequate treatment knowledge and improper regimen use may be significant determinants of unintentional non-adherence among liver transplant recipients and are associated with adverse clinical outcomes. Liver Transpl , 2014. © 2014 AASLD.

Concepts: Medicine, Cirrhosis, Liver, Organ transplant, Mycophenolic acid, Liver transplantation, Tacrolimus, Liver dialysis