Ayumi Nakamura

Long-Term Administration of Intranasal Oxytocin Is a Safe and Promising Therapy for Early Adolescent Boys with Autism Spectrum Disorders

OBJECTIVE Oxytocin (OT) has been a candidate for the treatment of autism spectrum disorders (ASD), and the impact of intranasally delivered OT on ASD has been investigated. However, most previous studies were conducted by single-dose administration to adults; and, therefore, the long-term effect of nasal OT on ASD patients and its effect on children remain to be clarified. METHODS We conducted a singled-armed, open-label study in which OT was administered intranasally over the long term to eight male youth with ASD (10-14 years of age; intelligence quotient [IQ] 20-101). The OT administration was performed in a stepwise increased dosage manner every 2 months (8, 16, 24 IU/dose). A placebo period (1-2 weeks) was inserted before each step. The outcome measures were autism diagnostic observation schedule--generic (ADOS-G), child behavior checklist (CBCL), and the aberrant behavior checklist (ABC). In addition, side effects were monitored by measuring blood pressure and examining urine and blood samples. RESULTS Six of the eight participants showed improved scores on the communication and social interaction domains of the ADOS-G. However, regarding the T-scores of the CBCL and the scores of the ABC, we could not find any statistically significant improvement, although several subcategories showed a mild tendency for improvement. Caregivers of five of the eight participants reported certain positive effects of the OT therapy, especially on the quality of reciprocal communication. All participants showed excellent compliance and no side effects. CONCLUSIONS Although our results on the efficacy of long-term nasal OT therapy still remain controversial, to the best of our knowledge, this is the first report documenting the safety of long-term nasal OT therapy for children with ASD. Even though our data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, promising, and worthy of a large-scale, double-blind placebo-controlled study.

A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity

Background  Dysregulation of mTOR signalling by mutations in tuberin and/or hamartin leads to the formation of tuberous sclerosis complex (TSC). Trials to treat TSC using mTOR inhibitors, including rapamycin, have been performed. Although rapamycin improves many TSC lesions, significant side‐effects appear after systemic administration. Topical administration has been recommended.

A Novel Application of Topical Rapamycin Formulation, an Inhibitor of mTOR, for Patients With Hypomelanotic Macules in Tuberous Sclerosis Complex

T uberous sclerosis complex (TSC) is an autosomal dominant disease characterized by systemic hamartomas.Twogenes,TSCIandTSCII,whichencode hamartinandtuberin,areresponsible forTSC.Thecomplex of hamartin and tuberin inhibits the mammalian target of rapamycin(mTOR), whichhasnumerous functions in the regulationofprotein synthesis andcell growth.Theconstitutive activation of mTOR is associated with abnormal cellularproliferation,whichcausesTSC-relatedhamartomas. Recent reports suggest that inhibitors of mTOR, such as rapamycin, may be effective for the treatment of TSCrelated tumorigenesis, including facial angiofibroma. However, the efficacy of rapamycin for hypomelanotic macules is still unknown. We herein report 2 cases of hypomelanotic macules in TSC successfully treated with a topical rapamycin, 0.2%, formulation.

First left-right comparative study of topical rapamycin vs. vehicle for facial angiofibromas in patients with tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder causing multiple hamartomas. Treatment of TSC lesions with mammalian target of rapamycin inhibitors is effective. Recently, several reports have shown the efficacy of topical rapamycin (sirolimus) for angiofibromas. However, almost all studies have been case studies and the 0·1% solution caused skin irritation. A comparative study of topical rapamycin and a vehicle has not yet been reported.

Efficacy and Safety of Topical Sirolimus Therapy for Facial Angiofibromas in the Tuberous Sclerosis Complex : A Randomized Clinical Trial

Importance Inhibitors of mammalian target of rapamycin complex 1, such as sirolimus, effectively target skin lesions in tuberous sclerosis complex (TSC). However, systemic treatment causes adverse effects, and topical sirolimus has shown promise in the treatment of facial angiofibromas. Objective To evaluate the efficacy, safety, and optimal concentration of a topical sirolimus gel vs placebo for treatment of facial angiofibromas in TSC. Design, Setting, and Participants A double-blind, placebo-controlled, parallel-group, dose-escalation, phase 2 randomized clinical trial using 3 sirolimus gel concentrations was performed at Osaka University Hospital, Osaka, Japan. Thirty-six patients with TSC and facial angiofibromas, including 18 aged 3 to 18 years (children) and 18 aged 19 to 65 years (adults), were enrolled from December 10, 2013, to July 17, 2014. Analysis was by intention to treat. Interventions The adult and child groups were each subdivided into 3 groups (n = 12 each) and randomized to receive sirolimus gel concentrations of 0.05%, 0.1%, or 0.2% or placebo using a web-response system in a 2:1 fashion. The medication was applied to the patient’s lesions twice per day for 12 weeks. Each patient underwent assessment at 2, 4, 8, and 12 weeks during treatment and at 4 weeks after discontinuation of the treatment (16 weeks). Main Outcomes and Measures The primary end point, planned before starting data collection, was an improvement factor, represented as a variable composed of tumor size reduction and a lessening of the redness of the 3 target tumors at 12 weeks relative to baseline. Results All 36 patients (13 male and 23 female; median age, 40 years; range, 6-47 years) completed the study analyses. The improvement factor was statistically significant in all active treatment groups receiving 0.2% sirolimus (mean [SD], 1.94 [0.68]; P < .001) and not in the adult subgroups receiving 0.1% (mean [SD], 0.88 [0.85]; P = .31) and 0.05% (mean [SD], 1.63 [1.11]; P = .09) concentrations of sirolimus. No significant adverse effects were observed. Mild skin dryness (13 patients [36%]) and irritation (11 patients [31%]) were observed. Low blood levels of sirolimus (<0.25 ng/mL) were detected in adults (1 patient [25%] in the 0.1% adult subgroup and 2 patients [50%] in the 0.2% adult subgroup) and particularly in children (1 patient [25%] in the 0.05% child subgroup, 2 patients [50%] in the 0.1% child subgroup, and 4 patients [100%] in the 0.2% child subgroup). Conclusions and Relevance Topical sirolimus gel is safe and effective for facial angiofibromas in TSC. The optimal concentration of sirolimus was 0.2%. Trial Registration umin.ac.jp Identifier: UMIN000012420

Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex

IMPORTANCE Tuberous sclerosis complex (TSC) is an autosomal dominant disorder leading to the aberrant activation of the mammalian target of rapamycin complex 1. Although the efficacy of mammalian target of rapamycin complex 1 inhibitors against tumors in patients with TSC, including facial angiofibroma, has been well investigated, their efficacy against hypomelanotic macules in patients with TSC is unknown. OBJECTIVES To evaluate objectively the efficacy of topical rapamycin treatment of hypomelanotic macules in patients with TSC and to elucidate the mechanisms of how rapamycin improves the macules. DESIGN, SETTING, AND PARTICIPANTS We performed a prospective, baseline-controlled trial of 6 patients with TSC and hypomelanotic macules in non-sun-exposed and sun-exposed skin at the Department of Dermatology, Osaka University, from August 4, 2011, through September 27, 2012. Rapamycin gel, 0.2%, was applied to the lesions twice a day for 12 weeks. Histologic examinations and blood tests were conducted at the start and completion of treatment. Blood rapamycin levels were analyzed at completion. EXPOSURES Topical rapamycin treatment for hypomelanotic macules. MAIN OUTCOMES AND MEASURES Objective evaluation of rapamycin treatment of hypomelanotic macules in TSC with δ-L (L indicates the brightness of the color) levels on spectrophotometry at the start and completion (12 weeks) of treatment and at 4 and 12 weeks after discontinuation of treatment (16 and 24 weeks, respectively). RESULTS Improvement of hypomelanotic macules (in δ-L values) was significant at 12 weeks (mean [SD], 2.501 [1.694]; P < .05), 16 weeks (1.956 [1.567]; P < .01), and 24 weeks (1.836 [1.638]; P < .001). Although efficacy tended to be prominent in sun-exposed skin, we did not observe significant differences (in δ-L values) between sun-exposed and non-sun-exposed skin at 12 weeks (mean [SD], 1.859 [0.629] and 3.142 [2.221], respectively), 16 weeks ( 1.372 [0.660] and 2.539 [2.037], respectively), and 24 weeks (1.201 [0.821] and 2.471 [2.064], respectively). No adverse events were observed, and rapamycin was not detected in the blood of any patient. Electron microscopic analysis of hypomelanotic macules revealed that topical rapamycin treatment significantly improved the uniformity of the melanosome numbers in the TSC melanocytes (pretreatment macules: mean [SD], 25.71 [21.90] [range, 5-63]; posttreatment macules: 42.43 [3.60] [range, 38-49]; P < .001). Moreover, rapamycin treatment induced the recovery of melanosomes in TSC-knocked-down melanocytes from depleted amounts (mean [SD], 16.43 [11.84]) to normal levels (42.83 [14.39]; P < .001). CONCLUSIONS AND RELEVANCE Topical rapamycin treatment was effective and safe against hypomelanotic macules arising from TSC. This efficacy of rapamycin was corroborated as stemming from the improvement of impaired melanogenesis in TSC melanocytes.

Topical application of rapamycin ointment ameliorates Dermatophagoides farina body extract-induced atopic dermatitis in NC/Nga mice.

Atopic dermatitis (AD), a chronic inflammatory skin disease characterized by relapsing eczema and intense prurigo, requires effective and safe pharmacological therapy. Recently, rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, has been reported to play a critical role in immune responses and has emerged as an effective immunosuppressive drug. In this study, we assessed whether inhibition of mTOR signalling could suppress dermatitis in mice. Rapamycin was topically applied to inflamed skin in a murine AD model that was developed by repeated topical application of Dermatophagoides farina body (Dfb) extract antigen twice weekly for 7 weeks in NC/Nga mice. The efficacy of topical rapamycin treatment was evaluated immunologically and serologically. Topical application of rapamycin reduced inflammatory cell infiltration in the dermis, alleviated the increase of serum IgE levels and resulted in a significant reduction in clinical skin condition score and marked improvement of histological findings. In addition, increased mTOR phosphorylation in the lesional skin was observed in our murine AD model. Topical application of rapamycin ointment inhibited Dfb antigen‐induced dermatitis in NC/Nga mice, promising a new therapy for atopic dermatitis.

Examination of purification methods and development of intravitreal injection of triamcinolone acetonide.

PurposeIntravitreal injection of triamcinolone acetonide (TA) is used in ophthalmic treatment, but the reliability of commercially available TA preparations has still not been established. We evaluated two previously reported purification methods, and developed a more reliable TA injection which can be prepared in a hospital pharmacy.MethodsWe tested the two methods previously reported for purifying commercial TA preparations, the sedimentation and the filtration and backflushing methods. We developed a new TA injection made of pure TA suspended in 0.5% sodium hyaluronate. We measured the TA content in each preparation by high-performance liquid chromatography to evaluate the three methods.ResultsIn the sedimentation purification method, the TA content of a nominal 4-mg preparation varied from 1.43 to 7.37 mg, and the average recovery rate was 91.6%. In the filtration and backflushing method, TA content was 0.10–10.33 mg and recovery was 59.5%. In the TA injection we developed, the mean TA content was 102.5% (SD, 0.24; CV, 2.9%). The stability of this preparation was 99% after sterilization, and 97% after 3 months of storage.ConclusionsThe results of our investigation showed that the purification methods used for commercial preparations are simple and easy but not precise enough for an intravitreal injection. In contrast, the TA injection prepared by our method is reliable, stable, and safe enough for clinical use. Jpn J Ophthalmol 2005;49:384–387

Physician‐initiated first‐in‐human clinical study using a novel angiogenic peptide, AG30/5C, for patients with severe limb ulcers

In patients with diabetes or ischemia, angiogenesis and infection control are required for chronic leg ulcers, which substantially impair patients’ quality of life. We developed a novel functional peptide, named AG30/5C, with angiogenic and anti‐microbial properties. Treatment with AG30/5C significantly accelerated the wound healing of full‐thickness defects in mice. To evaluate the safety of AG30/5C in the treatment of leg ulcers, a physician‐initiated clinical study was carried out.

Physician-initiated clinical study of limb ulcers treated with a functional peptide, SR-0379: from discovery to a randomized, double-blind, placebo-controlled trial

SR-0379 is a functional peptide that has wound healing effect with anti-microbial action, making it an ideal drug to prevent infection. To evaluate the safety, efficacy, and pharmacokinetics of SR-0379 for the treatment of leg ulcers, a physician-initiated, phase I/IIa, first-in-patient clinical study was designed. A multi-center, double-blind, randomized clinical study was conducted from October 2015 to September 2016. The inclusion criteria for leg ulcers were (1) diabetes or critical limb ischemia and (2) wound size <6 cm in diameter. Twelve patients were randomized into four groups and administered 0.02%, 0.1%, or 0.5% SR-0379 or placebo treatment on skin ulcers once per day for 28 days. Efficiency was evaluated by determining the rate of wound size reduction as a primary endpoint at 4 weeks after the first treatment compared with the pre-treatment wound size. As a secondary endpoint, the DESIGN-R score index, time to wound closure, and the 50% wound size reduction ratio were also evaluated. The safety of SR-0379 was evaluated during the study period. In the evaluation of efficiency, the skin ulcer reduction rates at the last evaluation were 44.73% for the 0.02% SR-0379 group, 68.25% for the 0.1% group, and 71.61% for the 0.5% group, compared with 9.95% for the placebo group. Six adverse events were reported in four patients, of which one occurred in the placebo group, and causal relationships to study drugs were denied for all six events. Treatment with SR-0379 for chronic leg ulcers was safe, well tolerated, and effective.Dermatology: peptide drug development for skin ulcersChronic leg ulcers result in substantial impairment of patient quality of life with a socioeconomic impact both in terms of medical care and missed work days. A teams led by Hironori Nakagami at Osaka University originally identified a functional peptide, SR-0379, and evaluated the safety and efficacy of SR-0379 for the treatment of leg ulcers in a physician-initiated, first-in-patient, a multi-center, double-blind, randomized clinical study. In the evaluation of efficiency, the skin ulcer reduction rates were improved for the SR-0379 treated groups in a dose-dependent manner, compared for the placebo group with no causal adverse events. Since treatment with SR-0379 for chronic leg ulcers was safe, well tolerated, and effective in this initial clinical trial, the clinical trial on next stage will be designed toward peptide drug development.