The Role of Ingenol Mebutate in the Treatment of Actinic Keratoses

Ali, Fahad; Wlodek, Christina; Lear, John T.

doi:10.1007/s13555-012-0008-4

Cited by 18 publications

(18 citation statements)

References 39 publications

(48 reference statements)

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“…AKs are the commonest pre-malignant skin condition, included in the larger population of NMSCs [7,15]. Treatments for AKs include physically destructive measures (cryotherapy, curettage, excision), chemically destructive means (including PDT and topical agents such as 5-FU and ingenol mebutate) and immunomodulatory agents (such as imiquimod).…”

Section: Actinic Keratosismentioning

confidence: 99%

“…Ingenol mebutate is a topical medicament used to treat AKs [15]. A 68-year-old gentleman with multiple occipital AKs received topical ingenol mebutate treatment to the right side of the occiput, whilst the left side underwent Er:YAG-AFXL (spot size 350 μm, density 10 %, fluence 63 J/cm 2 , one pass) prior to application of ingenol mebutate [19].…”

Section: Actinic Keratosismentioning

confidence: 99%

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Laser-assisted drug delivery in dermatology: from animal models to clinical practice

Ali

Al‐Niaimi

2015

Lasers Med Sci

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Topical medicaments are the mainstay of the dermatologists' therapeutic arsenal. Laser-assisted drug delivery enhances the ability of topically applied medicaments to penetrate the skin. We discuss the mechanisms of laser-assisted drug delivery and animal models that have informed clinical practice. We review clinical studies that have employed laser-assisted drug delivery for a range of indications to date including non-melanoma skin cancer, vitiligo, scarring, vaccination, local anaesthesia, analgesia, viral warts, infantile haemangiomas and cosmetic uses. Studies thus far suggest that laser pre-treatment improves transepidermal absorption of topical agents and allows for a much deeper penetration of drugs than is possible with topical medicaments alone. This may allow more efficacious action of current treatments, such that conventional duration of treatment can be shortened or lower concentrations of active agents be used, potentially obviating side effects of treatment. The prospect of using laser technologies to facilitate transdermal vaccination and as an adjunct for inflammatory dermatoses and cosmetic indications remains in its infancy. As larger trials are published, involving greater numbers of patients and utilising various laser and topical medicament parameters, we will enhance our understanding of this nascent modality of treatment delivery.

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Section: Actinic Keratosismentioning

confidence: 99%

Section: Actinic Keratosismentioning

confidence: 99%

Laser-assisted drug delivery in dermatology: from animal models to clinical practice

Ali

Al‐Niaimi

2015

Lasers Med Sci

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“…It is a natural product metabolite found in a number of members of the Eurphorbia family, 118 first described in 1980 as a component of E. paralias. 122,123 Originally used in traditional medicine to treat the precancerous skin condition actinic keratosis and basal cell carcinomas, 124,125 evaluation to determine whether there was a realistic pharmacological basis for traditional treatments, began in Australia in 2004. 122,123 Originally used in traditional medicine to treat the precancerous skin condition actinic keratosis and basal cell carcinomas, 124,125 evaluation to determine whether there was a realistic pharmacological basis for traditional treatments, began in Australia in 2004.…”

Section: Ingenol Mebutatementioning

confidence: 99%

“…A 100% cure rate was shown for three day topical application in mouse models of mouse and human skin cancer lines. 124,125 The initial cell line studies indicated that, upon application cancerous cells were much more sensitive to rapid mitochondrial disruption and cell death by primary necrosis than normal cells. 128 Preclinical and clinical study data were employed to elucidate the mechanism of action of ingenol mebutate.…”

Section: Ingenol Mebutatementioning

confidence: 99%

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

2015

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Numerous variations on structural motifs exist within pharmaceutical compounds that have entered the clinic. These variations have amounted over many decades based on years of drug development associated with screening natural products and de novo synthetic systems. Caged (or bridged) bicyclic structural elements offer a variety of diverse features, encompassing three-dimensional shape, and assorted pharmacokinetic properties. This review highlights approximately 20 all carbon cage containing pharmaceuticals, ranging in structure from bicyclo[2.2.1] through to adamantane, including some in the top-selling pharmaceutical bracket. Although, a wide variety of human diseases, illnesses and conditions are treated with drugs containing the bicyclic motif, a common feature is that many of these lipophilic systems display CNS and/or neurological activity. In addition, to an extensive overview of the history and biology associated with each drug, a survey of synthetic methods used to construct these entities is presented. An analysis section compares natural products to synthetics in drug discovery, and entertains the classical caged hydrocarbon systems potentially missing from the clinic. Lastly, this unprecedented review is highly pertinent at a time when big pharma is desperately trying to escape flatland drugs.

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“…Recently, ingenol mebutate gel (Picato ® , LEO Pharma A/S) was introduced to the market for topical field treatment of AK in a contiguous skin area of approximately 25 cm 2 [7, 8]. Ingenol mebutate ( 1 ) is a naturally occurring 3-monoester of ingenol ( 2 ) and angelic acid (Fig.…”

Section: Introductionmentioning

confidence: 99%

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

Bertelsen

Stahlhut

Grue-Sørensen

et al. 2016

Dermatol Ther (Heidelb)

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IntroductionIngenol mebutate gel (Picato®, LEO Pharma A/S) is approved for the field treatment of actinic keratosis and is characterized by high sustained clearance of actinic lesions. The inherent propensity of ingenol mebutate towards chemical rearrangement necessitates refrigeration of the final product. We sought to identify novel ingenol derivatives with enhanced chemical stability and similar or improved in vitro potency and in vivo efficacy.MethodsA number of ingenol esters were synthesized with full regiocontrol from ingenol. Chemical stability was determined in aqueous buffer at physiological pH and hydroalcoholic gel at lower pH. Acute cytotoxicity was determined in HeLa or HSC-5 cells. Keratinocyte proliferation, viability and caspase 3/7 activation was measured in primary epidermal keratinocytes. Relative gene expression levels were determined by real-time quantitative PCR. Evaluation of in vivo tumor ablating potential was performed in the murine B16 melanoma mouse model and in the UV-induced skin carcinogenesis model in hairless SKH-1 mice following topical treatment for two consecutive days with test compounds formulated at 0.1% in a hydroalcoholic gel.ResultsThis work resulted in the identification of ingenol disoxate (LEO 43204) displaying increased stability in a clinically relevant formulation and in aqueous buffer with minimal pH-dependent acyl migration degradation. Ingenol disoxate exhibited a significantly higher cytotoxic potency relative to ingenol mebutate. Likewise, cell growth arrest in normal human keratinocyte was more potently induced by ingenol disoxate, which was accompanied by protein kinase C dependent transcription of markers of keratinocyte differentiation. Most notably, ingenol disoxate possessed a superior antitumor effect in a B16 mouse melanoma model and significantly increased median survival time relative to ingenol mebutate. A significant effect on tumor ablation was also observed in a murine model of ultraviolet irradiation-induced skin carcinogenesis.ConclusionThese data illustrate that the favorable in vitro and in vivo pharmacological properties driving ingenol mebutate efficacy are either preserved or improved in ingenol disoxate. In combination with improved chemical stability to potentially facilitate storage of the final product at ambient temperatures, these features support further development of ingenol disoxate as a convenient and efficacious treatment modality of non-melanoma skin cancers.FundingLEO Pharma A/S.Electronic supplementary materialThe online version of this article (doi:10.1007/s13555-016-0137-2) contains supplementary material, which is available to authorized users.

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The Role of Ingenol Mebutate in the Treatment of Actinic Keratoses

Cited by 18 publications

References 39 publications

Laser-assisted drug delivery in dermatology: from animal models to clinical practice

Laser-assisted drug delivery in dermatology: from animal models to clinical practice

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers

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