Topical rapamycin combined with pulsed dye laser in the treatment of capillary vascular malformations in Sturge-Weber syndrome: Phase II, randomized, double-blind, intraindividual placebo-controlled clinical trial (original) (raw)
Lasers in Surgery and Medicine, 2010
Background and Objectives: Complete blanching of port wine stain (PWS) birthmarks after laser therapy is rarely achieved for most patients. We postulate that the low therapeutic efficacy or treatment failure is caused by regeneration and revascularization of photocoagulated blood vessels due to angiogenesis associated with the skin's normal wound healing response. Rapamycin (RPM), an antiangiogenic agent, has been demonstrated to inhibit growth of pathological blood vessels. Our objectives were to (1) investigate whether topical RPM can inhibit reperfusion of photocoagulated blood vessels in an animal model and (2) determine the effective RPM concentration required to achieve this objective. Study Design/Materials and Methods: For both laseronly and combined laser and RPM treated animals, blood vessels in the dorsal window chambers implanted on golden Syrian hamsters were photocoagulated with laser pulses. Structural and flow dynamics of blood vessels were documented with color digital photography and laser speckle imaging to evaluate photocoagulation and reperfusion. For the combined treatment group, topical RPM was applied to the epidermal side of the window daily for 14 days after laser exposure. Results: In the laser-only group, 23 out of 24 photocoagulated blood vessels reperfused within 5-14 days. In the combined treatment group with different RPM formulae and concentrations, the overall reperfusion rate of 36% was much lower as compared to the laser-only group. We also found that the reperfusion rate was not linearly proportional to the RPM concentration. Conclusions: With topical RPM application, the frequency of vessel reperfusion was considerably reduced, which implies that combined light and topical antiangiogenic therapy might be a promising approach to improve the treatment efficacy of PWS birthmarks. Lasers Surg.
Background and Objectives: Facial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas. Patients and Methods: The study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any...
JAMA dermatology, 2018
Facial angiofibromas occur in approximately 75% of individuals with tuberous sclerosis complex (TSC), causing substantial morbidity and disfigurement. Current therapies are partially effective, uncomfortable, produce scarring, and need repeating to treat recurrence. To evaluate the efficacy and safety of topical rapamycin for TSC-related facial angiofibromas. This prospective, multicenter, randomized, double-blind, vehicle-controlled trial with 6 monthly clinic visits enrolled 179 patients with TSC-related facial angiofibromas not treated within 6 months from May 2012 to March 2014 in 9 clinical sites in the United States and 1 in Australia. Patients were randomized (1:1:1) to topical formulation containing 0.3 g per 30 g (1%) rapamycin, 0.03 g per 30 g (0.1%) rapamycin, or vehicle alone. Participants applied 1.0 mL to designated areas daily at bedtime. Angiofibroma Grading Scale (AGS) change from baseline scored from photographs by independent masked dermatologists. Safety analyses...
Plastic and Aesthetic Research, 2016
How to cite this article: Palmetun Ekbäck M, Wiegleb Edström D. Topical rapamycin for angiofibromas in patients with tuberous sclerosis: how does it work in clinical practice? Plast Aesthet Res 2016;3:328-34. Aim: Topical rapamycin for angiofibromas has been reported to be a new promising treatment. This study aims to report the outcome in clinical practice. Methods: A retrospective clinical follow-up on twenty-three patients who had been prescribed an oral solution of 0.1% rapamycin, to be applied on facial lesions once a day. Results: Seventeen of 23 patients continued the treatment. Papules and nodules were improved in 8 patients (47%) and erythema in 12 (70%). Side effects, such as stinging and redness were reported in 35% of patients. Blood samples were taken from 5 patients and no rapamycin could be detected. All patients who paused the treatment relapsed. Conclusion: Topical rapamycin has a positive effect on angiofibromas with improvement in both erythema and papules even if only applied every second to third day, but continuous treatment is needed. ABSTRACT Article history:
PLoS ONE, 2014
Background: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR). Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas) in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD.
Journal of Cutaneous Pathology, 2010
Port-wine stains (PWS) represent a group of vascular malformations that are usually accompanied by psychological distress for affected patients, often reflected in high treatment demand. Although the pulsed-dye laser (PDL) was established as standard therapy for PWS more than a decade ago, therapeutic outcome may be unsatisfactory. One of the main drawbacks to successful PDL therapy is PWS revascularization shortly after laser exposure. Therefore, inhibition of revascularization should improve therapeutic outcome of PDL therapy. In this study, we first evaluated the effects of various light energies on normal cutaneous vessels over a period of 14 days, particularly the proliferation and stem cell marker expression of dermal endothelial cells, which were found to be highest 8 days following laser exposure. We found that PDL exposure induced dose-dependent damage of dermal vessels up to energy densities of 6 J/cm 2 , above which no increase in PDLinduced effects were observed with the energies employed in this study. In dermal endothelial cells of PDL-exposed skin, we found strong expression of the proliferation marker Ki-67 as well as the stem cell marker nestin but not other stem cell markers such as CD133 and CD166. The influence of rapamycin (RPM), used as an adjuvant to PDL exposure, was also investigated. RPM administration reduced Ki-67 and nestin expression in dermal endothelial cells and increased PDL-induced destruction of dermal vessels, indicating that the use of RPM after PDL exposure may be an interesting new approach for prolonging and improving PWS laser therapeutic outcome.
Child Neurology Open
Facial angiofibromas, composed of fibrous tissue and blood vessels appearing on the face, are closely associated with tuberous sclerosis complex. Historically, oral rapamycin, a mammalian target of the rapamycin inhibitor of cell proliferation, has been used to treat visceral tuberous sclerosis–related tumors; however, the side effect profile of this medicine generally precludes its use in patients lacking significant internal involvement. The authors developed a novel topical formulation of rapamycin cream to treat the facial angiofibroma without exposing patients to possible systemic side effects. We followed 11 patients in a long-term, open-label, prospective study to evaluate the safety and effectiveness of rapamycin cream when used chronically. All of the patients showed an improvement in the appearance of their facial angiofibroma which was maintained in long-term follow-up without safety concerns or systemic absorption. The novel rapamycin cream was tolerated well by all pati...
Topical rapamycin (sirolimus) for facial angiofibromas
Indian Dermatology Online Journal, 2013
Rapamycin (sirolimus) is a fungal fermentation product that inhibits the proper functioning of a serine/threonine protein kinase in mammalian cells eponymously named mammalian target of rapamycin, or mTOR. Rapamycin is a novel class of anticancer and immunosuppressant drugs targeting the proteins at molecular level. Rapamycin (sirolimus) is routinely incorporated in drug-eluting stents used for cardiac angioplasty. In recent years, rapamycin was found to be efficacious in managing the symptom complex of tuberous sclerosis, i.e. renal angiomyolipoma, giant cell astrocytoma and pulmonary lymphangiomyomatosis. Various investigators have also proved that topically applied rapamycin causes regression of facial angiofibromas, giving better cosmetic results.
Lasers in surgery and medicine, 2014
Administration of topical rapamycin (RPM) suppresses the regeneration and revascularization of photocoagulated blood vessels induced by pulsed dye laser (PDL). To systematically elucidate the molecular pathophysiology of the inhibition of PDL-induced angiogenesis by topical RPM in a rodent model. The mRNA expression profiles of 86 angiogenic genes and phosphorylation levels of ribosomal protein S6 kinase (P70S6K) in rodent skin were examined with or without topical RPM administration post-PDL exposure. The PDL-induced systematic increases in transcriptional levels of angiogenic genes showed a peak expression at days 3-7 post-PDL in rodent skin. Topical application of 1% RPM significantly and systematically suppressed the PDL-induced increase in mRNA levels of the examined angiogenic genes during the first five days post-PDL. The phosphorylation levels of P70S6K increased after PDL exposure but those increases were suppressed by the topical RPM. After topical application, RPM penetra...
Effect of Rapamycin on Wound Healing: An Experimental Study
2007
The aim of this study was to investigate the effects of rapamycin (RAPA) on the healing of bladder and abdominal wound closures. Fourteen male Sprague Dawley rats were randomized to receive either RAPA (3 mg/d) or placebo. A midline laparotomy was performed. The bladder was cut and closed with 4-0 Vicryl in a double layer. The fascia was closed with 0 nylon suture, and the skin closed with a subcuticular 2-0 nylon suture. The mean RAPA level was 9.1 ng/mg. Eosinophil and neutrophil infiltration, and the presence and degree of myofibroblast proliferation were significantly higher in the bladder, fascia, and dermis of the control group. Lymphocyte infiltration was similar in each group. Mean microvessel density as well as the percentage of cells expressing vascular endothelial growth factor in the bladder, fascia, and dermis were significantly lower among the RAPA group. Both proliferating cell nuclear antigen labeling indices for inflammatory cells in the fascia, dermal fibroblasts, and epithelial cells in the placebo group were significantly higher. No difference was observed for hydroxyproline levels in both the bladder and fascia between the groups. In conclusion, we found that RAPA treatment affected all steps of the wound healing process by decreasing the inflammatory cell number, angiogenesis, and myofibroblast proliferation, so the wound healing process was delayed and consequently the tensile strength of the wound decreased.
The horizon for treating cutaneous vascular lesions
Seminars in cutaneous medicine and surgery, 2012
Dermatologists encounter a wide range of cutaneous vascular lesions, including infantile hemangiomas, port-wine stain birthmarks, arteriovenous malformations, venous malformations, Kaposi sarcomas, angiosarcomas, and angiofibromas. Current treatment modalities to reduce these lesions include topical and/or intralesional steroids, laser therapy, surgical resection, and endovascular therapy. However, each method has limitations owing to recurrence, comorbidities, toxicity, or lesion location. Photodynamic therapy, antiangiogenic therapy, and evolving methods of sclerotherapy are promising areas of development that may mitigate limitations of current treatments and offer exciting options for patients and their physicians.
2010
BACKGROUND Dermatosis papulosa nigra (DPN) is a common variant of seborrheic keratoses in darkly pigmented individuals. Treatment options include cryosurgery, curettage, electrosurgery, and shave removal. OBJECTIVE To compare the efficacy and complications of pulsed dye laser (PDL) therapy for the treatment of DPN with those of curettage and electrodesiccation. METHODS AND MATERIALS Randomized, controlled, single-center, evaluator-blinded trial of 10 patients with at least four clinically diagnosed lesions. RESULTS All 10 patients completed the study. Mean lesion clearance was 96% for curettage, 92.5% for electrodesiccation, and 88% for laser. There was no significant difference between the three treatment modalities. All three techniques had an overall cosmetic outcome of good for most patients. Five of the 10 patients preferred electrodesiccation. Patients rated the laser as the most painful treatment method. The most common adverse outcome was hyperpigmentation. There were no significant differences between the treatment groups for any of the measured outcomes. CONCLUSION The efficacy of PDL in the treatment of DPN is not significantly different from the already established treatment modalities of electrodesiccation and curettage.
PLoS ONE, 2014
Fibrous papules of the face are hamartomas characterized by stellate-shaped stromal cells, multinucleated giant cells, and proliferative blood vessels in the dermis. The pathogenesis of fibrous papules remains unclear. There is a striking microscopic resemblance between fibrous papules and tuberous sclerosis complex (TSC)-associated angiofibromas. A germline mutation of the TSC1 or TSC2 gene, leading to activation of the mammalian target of rapamycin (mTOR) pathway, accounts for the pathogenesis of TSC-associated angiofibromas. Activated mTOR subsequently activates p70 ribosomal protein S6 kinase (p70S6K) and ribosomal protein S6 (S6) by phosphorylation. Rapamycin, a mTOR inhibitor, is effective in treating TSC-associated angiofibromas. The aim of this study was to understand whether the mTOR pathway is activated in fibrous papules. We studied immunoexpressions of phosphorylated (p-) mTOR effectors in fibrous papules, TSC-associated angiofibromas, and normal skin controls. P-mTOR, p-p70S6K and p-S6 were highly expressed in dermal stromal cells and epidermal keratinocytes in fibrous papules and TSC-associated angiofibromas but not in fibroblasts and epidermal keratinocytes of normal skin controls (p,0.001). The results suggest topical rapamycin may be a novel treatment option for fibrous papules.
Topical Simvastatin as Treatment of Digital Ulcer in Systemic Scleroderma
2018
Systemic Scleroderma (SS) is a connective tissue disease characterized by extensive fibrosis, vascular damage, immunologic disorder, and organ involvement. 1 digital ulcer (DU) is a common clinical condition in SS which occurred in 30% of the patients. Simvastatin, a HMG-CoA reductase competitive inhibitor, is known to have anti-inflammatory potency and could accelerate the healing of chronic wound. We report a case of UD in SS that improved with topical simvastatin treatment. A 61 years old woman came to the clinic with a complaint of wounds on the tip of fingers and toes that has not healed for two weeks. The wound initially appeared at the tip of finger, extended, and then similar wound appeared at the tip of toe. The patient was diagnosed with systemic scleroderma since three years ago and treated with methylprednisolone and a vasodilator agent. From physical examination, there were shallow ulcers at the right middle toe and left thumb sized 1x1-2 cm, with irregular border and covered with necrotic tissues. DU management in SS consisted of non-pharmacological, pharmacological, and operative methods. Simvastatin, a statin class drug, was proven to have anti-inflammatory, immune modulatory, and wound healing effects in several studies. The benefit of statin in wound healing process was shown by its ability to improve vascularization in chronic wound through increased VEGF concentration which is disturbed in abnormal wound healing process. Topical simvastatin was also proven to have antimicrobial effect which could potentially prevent bacteria from disrupting epithelialization and wound healing process. The patient was given normal saline compression twice daily followed by application of 0.5% simvastatin in gentamicin ointment twice daily after saline compression. After two weeks of treatment, the ulcers on both fingers and toes improved.
Photobiomodulation Therapy: A New Light in the Treatment of Systemic Sclerosis Skin Ulcers
Rheumatology and therapy, 2022
Introduction: Skin ulcers (SU) represent one of the most frequent manifestations of systemic sclerosis (SSc), occurring in almost 50% of scleroderma patients. SSc-SU are often particularly difficult to treat with conventional systemic and local therapies. In this study, a preliminary evaluation of the role and effectiveness of blue light photobiomodulation (PBM) therapy with EmoLED Ò in the treatment of scleroderma skin ulcers (SSc-SU) was performed. Methods: We retrospectively analyzed 12 consecutive SSc patients with a total of 15 SU on finger hands. All patients were treated with adequate systemic therapy and local treatment for SU; after a standard skin ulcer bed preparation with debridement of all lesions, EmoLED Ò was performed. All patients were locally treated every week during 2 months of follow-up; SU data were collected after 4 weeks (T4) and 8 weeks (T8). Eight SSc patients with comparable SU were also evaluated as controls. Results: The application of EmoLED Ò in addition to debridement apparently produced faster healing of SU. Complete healing of SU was recorded in 41.6% cases during EmoLED Ò treatment. Significant improvements in SU area, length, and width, wound bed, and related pain were observed in EmoLED Ò patients from T0 to T8. Control subjects treated with standard systemic/local therapies merely showed an amelioration of SU area and width at the end of the follow-up. No procedural or post-procedural adverse events were reported. Conclusions: The positive clinical results and the absence of side effects suggest that EmoLED Ò could be a promising tool in the management of SSc-SU, with an interesting role to play in the healing process in addition to conventional systemic and local treatments.