Application Of Tacrolimus Ointment Research Articles

An Unusual Presentation of Lichen Striatus.

An Unusual Presentation of Lichen Striatus.

Tacrolimus suppresses itch-related response in diet-induced atopic dermatitis model mice by reducing chloroquine-sensitive sensory neurons

Introduction: Itch (or pruritus) is a common symptom of atopic dermatitis (AD), which significantly decreases the patient’s quality of life. Tacrolimus ointment reduces pruritus in AD; however, the underlying mechanism is not fully understood. Methods: In the present study, we used a diet-induced AD mouse model to examine the antipruritic mechanism of tacrolimus. After induction of AD symptoms, the tacrolimus-containing ointment was applied once daily for 7 days. Responsiveness of isolated dorsal root ganglion (DRG) cells to various stimuli was examined by monitoring intracellular Ca2+ levels. Results: Repeated application of tacrolimus ointment attenuated spontaneous itch-related responses, even when skin barrier dysfunction, skin inflammation, and epidermal nerve sprouting were not ameliorated. Tacrolimus-treated mice also exhibited reduced scratching behavior induced by several pruritogens, such as histamine, SLIGRL-NH2, and chloroquine (CQ), although capsaicin-induced pain behavior was not affected. DRG cells from tacrolimus-treated mice showed significantly lower Ca2+ responses to CQ. Furthermore, a reduction in CQ-sensitive DRG neurons was observed after in vitro treatment with either tacrolimus or rapamycin. Discussion: CQ-sensitive (MrgprA3-expressing) DRG neurons are implicated as itch-specific sensory neurons. Therefore, topically applied tacrolimus may act directly on itch-signaling neurons, consequently suppressing various itch responses in AD mice.

Different methods of enhancing the efficacy of topical tacrolimus in extra-facial vitiligo: A comparative study.

Vitiligo is an acquired pigmentation disorder due to loss of melanocytes. Topical tacrolimus is effective in vitiligo treatment with minimal effect on extra-facial lesions. To assess different methods of enhancing the absorption of topical tacrolimus in extra-facial vitiligo sites using microneedling and occlusion. This study included 20 adult patients of both sexes with non-segmental vitiligo. Four extra-facial vitiligo lesions in each patient were randomly labeled A, B, C, and D and treated as follows: area A: tacrolimus ointment (0.03%) application twice/day, area B: microneedling once/week and tacrolimus ointment application directly after microneedling and twice/day the rest of the week, area C: microneedling once/week alone, and area D: tacrolimus ointment application twice/day under occlusion by polyethylene foil. The evaluation was done clinically by calculating the re-pigmentation percent after 6months of treatment. Responders in area B were 45%, and 35% in area C, and 25% in both areas A and D. No statistically significant difference was detected regarding the re-pigmentation percent between the four areas (p>0.05). No correlations were detected between re-pigmentation percent and patients' data. Combination of microneedling and topical tacrolimus has an edge over monotherapy in vitiligo, and further studies are needed to verify such results.

Topical tacrolimus in adult atopic dermatitis: a consensus based on a 15-year experience.

Atopic dermatitis (AD) is one of the most common cutaneous inflammatory diseases both in adults and in children. It is a chronic, remitting-relapsing dermatitis, primarily managed by dermatologists, but also by allergists and primary care physicians. Due to coexistence of comorbidities, often a multidisciplinary team is required. Topical calcineurin inhibitors (TCIs - i.e. tacrolimus and pimecrolimus) are a class of steroid-sparing, anti-inflammatory agents that have been shown to be efficacious for the treatment of AD acute flares and in maintenance therapy. In particular, the application of tacrolimus ointment twice daily reduces AD severity and pruritus. Moreover, maintenance therapy with an intermittent application of tacrolimus to recurrent skin sites (proactive therapy) decreases frequency and severity of relapses. Many studies have also assessed the efficacy of TCIs in disorders other than AD. Although US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued a "black box warning" regarding the possible cancerogenic activity of these drugs, there is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. A panel of dermatologists have thoroughly discussed the use of tacrolimus in AD after 15-year experience. The experts focused on AD flare treatment, maintenance therapy and management of side effects. Consensus was reached on some areas of interest, namely the stages of AD in which tacrolimus is recommended, the amount of drug to be applied, how to manage side effects, and how to improve patient's compliance. Moreover, the panel of experts recommended to perform randomized clinical trials to confirm the efficacy of tacrolimus off-label use, which led to successful outcomes in other skin diseases.

An Unusual Presentation of Sensitive Skin Syndrome over the Lips of a Female Chinese Patient after Dental Procedure Managed and Improved with 0.03% and 0.1% Topical Tacrolimus Ointment Application as Assessed by the SS-10 Questionnaire

Sensitive skin syndrome (SSS) is a prevalent skin condition reported globally in most ethnic groups which may occur in any skin location. The cause and pathogenesis of SSS is still unresolved and controversial. Albeit the head and neck region including the face and scalp are reported as the commonest sites of SSS, the lips as the only region of the face affected has been rarely reported in the literature. We report a case of a 30 years old Chinese women with a positive family history of nasopharyngeal carcinoma who reported to have significant neurological, nociceptive and pruritoceptive symptoms solely over the lips lasting for more than one year complicated by psychological and sleep disturbances after dental procedure. She was followed up and monitored by the validated 10-items Sensitive Skin Scale questionnaire (SS–10) in the clinic setting, treated and managed by topical tacrolimus ointment, emollients, counselling, education and psychological supports.

Corneal Toxicity of Topical Tacrolimus Ointment in Mice with Corneal Epithelial Injury.

Purpose: To investigate the effect of tacrolimus ointment on corneal epithelium. Methods: Eight-week-old male BALB/c mice were divided into 3 groups. In group 1, no injury was made. In group 2, the central 2-mm corneal epithelium was scraped off. In group 3, the whole corneal and limbal epithelium was removed after absolute ethanol application. In each group, the corneas were observed and treated daily with 0.03% or 0.1% tacrolimus ointment (Protopic®). The viability of cultivated human corneal epithelial cells was also examined after 24-h incubation with various concentrations of tacrolimus. Results: Tacrolimus ointment significantly delayed the epithelial healing in corneas with epithelial injuries (groups 2 and 3) in dose- and frequency-dependent manners, whereas it did not have any effects on uninjured corneas (group 1). The proportion of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive cells and mRNA levels of inflammatory cytokines were higher in tacrolimus-treated corneas, compared with controls. Tacrolimus did not directly reduce the viability of corneal epithelial cells in culture. Conclusions: Topical application of tacrolimus ointment onto the ocular surface induced toxicity in the cornea with epithelial defects through the impairment of epithelial healing and induction of apoptosis.

Tacrolimus ointment for the treatment of adult and pediatric atopic dermatitis: Review on safety and benefits.

Atopic dermatitis (AD) requires long‐term management, mainly with topical anti‐inflammatory agents. Topical corticosteroids (TCS) and tacrolimus ointment (TAC‐O) are recommended as first‐line treatments for AD. However, the long‐term use of TCS is limited by cutaneous adverse events such as skin atrophy. For TAC‐O, Japanese and US labelings were updated in 2003 and 2006, respectively, to include a boxed warning about a theoretical risk of skin cancer and lymphoma in patients treated with topical calcineurin inhibitors. However, TAC‐O has been used worldwide for longer than 15 years to treat adult and pediatric patients with AD. Available data suggest that TAC‐O is effective and well tolerated, and can improve quality of life. TAC‐O has successfully been used in the proactive management of AD consisting of long‐term intermittent use to prevent, delay or reduce the occurrence of AD flares. Systemic drug absorption after TAC‐O application is negligible and unlikely to result in systemic immunosuppression. There is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. In the absence of robust evidence, the warning about the carcinogenic potential in the Japanese labeling for TAC‐O does not appear justified and should be reconsidered. This mitigation of description would allow adult and pediatric patients with AD to receive the effective treatment more appropriately.

The onset risk of carcinoma in patients continuing tacrolimus topical treatment for oral lichen planus: a case report

Oral lichen planus is a chronic inflammatory mucocutaneous disease. Topical use of steroids and other immuno-modulating therapies have been tried for this intractable condition. Nowadays, tacrolimus ointment is used more commonly as a choice for treatment. However, a number of discussions have taken place after tacrolimus was reported to be carcinogenic. This report describes a patient who applied tacrolimus ointment to the lower lip after being diagnosed with oral lichen planus in 2008, and whose lesion developed squamous cell carcinoma in 2010. Since the relationship between tacrolimus and cancer development has been reported in only a few cases, including this case report, the clinician must be careful selecting tacrolimus as a second-line treatment for oral lichen planus.

EXPERIENCE OF SUCCESSFUL ACNEFORM ERUPTIONS TREATMENT IN PATIENT WITH MULTIPLE MELANOMA

Objective: to describe the results of the joint monitoring and diversified treatment of oncologists and dermatologists those patient with multiple recurrent melanoma who received over a long period a targeted anti-cancer therapy, which was complicated by side-effect as widespread acneform rush, resistant to traditional treatment. Patient A., born in 1988, was followed up and got a treatment more than 2 years in oncology out-patient clinic diagnosed with “Melanoma of the front surface of the left leg T2bN0M0 IIA”. Subsequently, the patient was verified metastasis in the inginal lymph nodes, in the soft tissues of the hips, to liver. Acute adverse reaction has developed in a short time after getting the anti-tumor target therapy as generalized acneform rush and itching of the skin. Skin symptoms accompanied by pronounced psychological and emotional stress, therefore, dermatologists have been invited to provide additional medical assistance to this patient. Due to the fact that subsequent traditional anti-acne algorithms of topical and oral treatment was not such effective, there was made a decision to use an alternative supporting external therapy, which did not have similar examples of usage previously. Results. External application of tacrolimus ointment in combination with other drugs and then as a mono-therapy, allows us in a rather short period achieve a stable and pronounced regression of skin pathological lesions, to return to the previously cancelled initial drug dose of the anti-tumor target therapy, to change significantly components of the patient’s quality of life. Conclusion. The search for additional and alternative treatment approaches for similar patients, as in our case, remains relevant for specialists and patients themselves. This case is an example of alternative approach to the tacrolimus topical application in patient with drug-mediated acneform rush.

Olopatadine hydrochloride suppresses hot flashes induced by topical treatment with tacrolimus ointment in rats

Tacrolimus ointment is prescribed for patients with atopic dermatitis, although it is known to cause transient burning sensations and hot flashes in the applied skin. The aim of this study was to evaluate the effects of olopatadine hydrochloride (olopatadine), an antiallergic agent with a histamine H1 receptor (H1R) antagonistic activity, on the incidence of hot flashes induced by topical treatment with tacrolimus ointment in rats. Consequently, the skin temperature was increased by the topical application of tacrolimus ointment in rats, and the rise in skin temperature was inhibited by pretreatment with olopatadine in a dose-dependent manner. Inhibitory effect of olopatadine on tacrolimus-induced skin temperature elevation was significantly more potent than that of cetirizine hydrochloride, other antiallergic agent with H1R antagonistic activity, at doses in which both agents exhibit comparable H1R antagonistic activity in rats. These results suggest that H1R antagonistic activity-independent mechanism contribute to the inhibitory effect of olopatadine on tacrolimus-induced skin temperature elevation. Olopatadine also significantly inhibited increases in vascular permeability and nerve growth factor production in the skin induced by topical tacrolimus treatment. Thus, the onset of hot flashes in rats is quantitatively determined by measuring the skin temperature and olopatadine attenuates hot flashes induced by topical tacrolimus ointment in rats, suggesting that the combination application with olopatadine and tacrolimus ointment is useful for improving medication adherence with tacrolimus ointment treatment in patients with atopic dermatitis.

Efficacy of topical application of 0.03% tacrolimus eye ointment in the management of allergic conjunctivitis.

Background:Allergic conjunctivitis is commonly observed eye diseases in Sikkim, India due to the abundance of seasonal pollens, environmental pollutants, and house dust. We evaluated the efficacy of topical 0.03% tacrolimus eye ointment in the management of simple allergic conjunctivitis.Materials and Methods:A prospective observational study was designed consisting of 41 patients with refractory simple allergic conjunctivitis, whose condition responded very poorly to conventional anti-allergic eye drops (azelastine, olopatadine, chlorpheniramine maleate, sodium chromoglycate). Simple allergic conjunctivitis cases were diagnosed and followed up evaluating both subjective and objective findings (itching, photophobia, tearing, chemosis, conjunctival congestion, tarsal papilla, and eyelid edema). Existing ocular treatment was discontinued at enrolment and 0.03% tacrolimus ointment was applied into the conjunctival sac of the affected eyes twice daily for 4 weeks followed by a 2 weeks washout period. Patients were followed up at the end of 1st week, 4th week, and at 7th week (2 weeks washout period).Results:Symptoms of simple allergic conjunctivitis (itching, tearing and photophobia) were significantly reduced at the end of 1st week. Signs such as conjunctival chemosis, congestion, tarsal papillae, and eyelid edema were effectively treated in all cases at the end of 1st week. At the end of 4th week, all cases were fully cured and none of the patient had any recurrences up to 7th week. Mean score at 1st day (9.6 ± 3.27) was significantly (P < 0.0001) reduced by 7th day (1.35 ± 1.19) of treatment.Conclusion:Topical application of tacrolimus ointment is an excellent alternative to anti-allergic and steroids eye drops for the treatment of simple allergic conjunctivitis as it significantly reduces recurrences.

Effects of 0.1% Tacrolimus on Canine Skin Mast Cells and Eosinophils

Five dogs were used to determine whether 0.1% tacrolimus ointment application for one day would inhibit IgE-mediated late-phase reactions (LPRs). It was consisted of three periods: one period without therapeutic administration (control) and two periods of treatment with either the tacrolimus ointment or vehicle. Induction of IgEmediated LPRs was induced by intradermal injections of 0.05 ml (0.14 mg/ml) of solution of goat anti-canine IgE polyclonal antibodies. Each section for mast cells (MCs) and eosinophils (EPs) was stained with acidified toluidine blue, and Luna’s stain, respectively. Assessment of anti-inflammatory effect of tacrolimus ointment composed of cell counts of MC and EP from lesions of induced LPR. In normal canine biopsies, the number of dermal MCs and EPs were 12.3 ± 1.4 cells/㎟ and 3.1 ± 1.3 cells/㎟, respectively. MC counts dramatically decreased at time dependent manner after anti-IgE administration. However, the number of MCs on 6 hours after challenge was significantly less decreased in the groups treated with the tacrolimus, as compared with control and vehicle group. The number of EPs on 24 hours after challenge was significantly lower in the group treated with the tacrolimus than in the control and vehicle groups. In conclusion, this study revealed that 0.1% tacrolimus ointment in dogs may exert a potent antiinflammatory effect on inhibition of MC degranulation and also secondary prevention of EP infiltration during LPR.

The proactive treatment of atopic dermatitis with tacrolimus ointment in Korean patients: a comparative study between once-weekly and thrice-weekly applications

Funding sources: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2012 RIAIB 3002196 and No. 2012 ‐ 0004228) and by a grant from Amore Pacific Co. Ltd., 2011. Conflicts of interest: none declared. Madam, Atopic dermatitis (AD) typically runs a chronic course of flares and remissions. A proactive approach, with long‐term treatment of AD using low‐dose, intermittent, topical anti‐inflammatory agents has been shown to control acute disease and prevent relapses.1, 2 Tacrolimus ointment is a topical calcineurin inhibitor (TCI) that has been demonstrated to be efficient in the treatment of AD; the effectiveness of proactive treatment with tacrolimus has been confirmed in previous clinical trials.3–6 To date, no study has compared the efficacy and tolerability of different proactive treatment regimens, such as the frequency of tacrolimus ointment application. We compared the effectiveness of proactive treatment with tacrolimus ointment administered either once weekly or thrice weekly in delaying and reducing the occurrence of AD exacerbations.

Balanitis Xerotica Obliterans, the Topical Application of Tacrolimus Ointment, and the Result: An Institutional Study

Balanitis Xerotica Obliterans, the Topical Application of Tacrolimus Ointment, and the Result: An Institutional Study

Therapeutic Hotline: Ulcerative lichen planus - treatment challenges

Ulcerative lichen planus of the sole is an unusual variant of lichen planus, with only a few reported cases in the literature. The present authors present the case of a 77-year-old woman with relapsing erosive lichen planus of the feet with large, ill-defined and painful ulcers of the soles, which were present for 24 months and made her walking almost impossible. Ulcerative lichen planus is remarkably known as unresponsive to usual local and systemic therapies, and the cutaneous plantar lesions are even more difficult to treat. In our patient, we achieved very good results with topically applied tacrolimus ointment 0.1%, twice a day. The pain disappeared at the end of the first week of treatment, and after 4 weeks, the ulcerations were 95% epithelized, and the patient was able to walk without any discomfort. During the treatment, the present authors did not notice any undesirable secondary effects.

Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis

Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis

The Use of Topical Tacrolimus 0.1% Skin Ointment for Anterior Segment Conditions: A Case Series

Tacrolimus (FK 506) is a macrolactam derivative with immunomodulatory and anti-inflammatory activity. Topical tacrolimus 0.03% has been used for inflammatory conditions of the anterior segment. This article adds to the literature on the off-license application of tacrolimus ointment, by describing the safe and effective use of the higher strength of 0.1% topical tacrolimus skin ointment in four patients. To our knowledge this is the first report of topical tacrolimus 0.1% ointment applied to the conjunctival sac for the treatment of atopic keratoconjunctivitis, vernal keratoconjunctivitis and the post-operative management of trabeculectomy and graft rejection in steroid responders.

Long-term prospective evaluation of topically applied 0.1% tacrolimus ointment for treatment of perianal sinuses in dogs

To evaluate effectiveness of a combination of topically applied tacrolimus, orally administered prednisone, and a novel-protein diet for treatment of perianal sinuses in dogs and to monitor clinical progress and owner management of the condition for 2 years. Noncontrolled clinical trial. Animals-19 dogs with perianal sinuses. Procedures-Perianal sinuses were diagnosed during physical examination, and dogs were placed on a 16-week treatment protocol consisting of topically applied 0.1% tacrolimus ointment, orally administered prednisone (tapering dose), and a novel-protein diet. Metronidazole was orally administered for the first 2 weeks. Anal sacculectomy was recommended whenever anal sacs were involved. Dogs were evaluated every month for the first 4 months and then every 6 to 12 weeks for 2 years. Perianal sinuses resolved completely in 15 of 19 dogs during the 16 weeks. In the remaining 4 dogs, the lesions markedly improved but failed to completely resolve. Three of these had anal sac involvement, and the owner of 1 dog had complied poorly with treatment instructions. During the 2 years following treatment, all dogs were maintained on intermittently applied tacrolimus ointment, 4 dogs also received prednisone every other day, and 11 dogs remained on the novel-protein diet. At the conclusion of the study, 13 of the 15 dogs that survived to that point were free of perianal disease. The described protocol was effective and economical for resolving perianal sinuses. Dogs maintained on intermittent medications were unlikely to redevelop lesions. When the anal sacs were involved, anal sacculectomy appeared to improve the outcome.

Tacrolimus hydrate ointment inhibits skin plasma extravasation in rats induced by topical m-xylene but not capsaicin

Tacrolimus ointment is used to treat various chronic inflammatory skin diseases. However, the effect of this ointment on acute neurogenic inflammation in the skin remains to be fully elucidated. Topical capsaicin and m-xylene produce tachykinin release from sensory nerves in the skin, resulting in skin plasma leakage. We investigated the effect of tacrolimus ointment (0.1%) on skin microvascular leakage induced by topical capsaicin (10 mM) and m-xylene (neat), and intracutaneous compound 48/80 (c48/80) (10 μg/ml, 50 μl/site) in two groups of rats pretreated with excessive capsaicin or its vehicle. The amount of leaked Evans blue dye reflected skin plasma leakage. Capsaicin, m-xylene or c48/80 was applied to the shaved abdomens of rats 8 h after topical application of tacrolimus ointment or its base. Desensitization with capsaicin reduced the skin response to capsaicin and m-xylene by 100% and 65%, respectively, but not to c48/80. Tacrolimus ointment significantly inhibited the skin response induced by m-xylene and c48/80, regardless of pretreatment with capsaicin. However, topical tacrolimus did not influence the skin response induced by capsaicin. We also evaluated whether topical capsaicin and m-xylene, and intracutaneous c48/80 cause mast cell degranulation in skin treated with tacrolimus. Mast cell degranulation was microscopically assessed. Topical tacrolimus only significantly suppressed degranulation induced by m-xylene and c48/80. Our data shows that tacrolimus ointment partially inhibits plasma leakage and mast cell degranulation in rat skin induced by m-xylene and c48/80 but not capsaicin, suggesting that the inhibitory effect is not associated with a reduction in neurogenic-mediated mechanisms.

Dermatophagoides farinae extract induces severe atopic dermatitis in NC/Nga mice, which is effectively suppressed by the administration of tacrolimus ointment

Atopic dermatitis (AD) is a chronic inflammatory skin disease, which is accompanied by marked increases in the levels of inflammatory cells, including mast cells and eosinophils as well as T cells and macrophages. To investigate the expression pattern of chemokines in AD, a house dust mite, Dermatophagoides farinae extracts (DfE)-induced NC/Nga AD model was developed in mice , and this model was used to determine the expression levels of chemokines in atopic lesions using DNA microarrays and RT-PCR. When NC/Nga mice were repeatedly treated with DfE for 4 to 7 weeks on the back skin, the mRNA expression levels of CCL20/LARC, CCL24/eotaxin-2, CCL17/TARC, and CCL11/eotaxin-1 were markedly induced and lesser of CCL2/MCP-1, within the inflammatory lesion of the back skin. Immunohistochemical staining revealed the expression of these chemokines in the epidermis and dermis of DfE-treated NC/Nga mice. Interestingly, repeated application of tacrolimus ointment potently inhibited DfE-induced atopic dermatitis in NC/Nga mice concomitant with the inhibition of these changes in chemokine gene and protein expression levels particularly of CCL20/LARC, CCL17/TARC, and CCL11/eotaxin-1. These data indicate that severe atopic dermatitis induced by DfE accompanies elevated chemokine levels, and it was proposed that tacrolimus ointment is beneficial for the treatment of severe AD.