The human papillomavirus vaccine as a treatment for human papillomavirus-related dysplastic and neoplastic conditions: A literature review.

BACKGROUND: Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE: To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS: A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS: A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS: This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION: The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.

Adverse Events of Injectable Deoxycholic Acid.

BACKGROUND: Injectable deoxycholic acid (DCA) may be used to remove excess submental fat and off-label for local adipose reduction. Despite DCA's widespread use, rare incidences of severe, systemic, long-term adverse events (AEs) have been reported. OBJECTIVE: To evaluate the potential side effects associated with injectable DCA. METHODS AND MATERIALS: A systematic review was conducted using PubMed, Cochrane, CINAHL, and Web of Science using PRISMA guidelines to gather the literature relating to DCA or deoxycholate-associated AEs and their management. RESULTS: Twenty-eight manuscripts were included after full article review. Most commonly, patients experienced mild localized AEs, whereas a small number of patients experienced severe pain, alopecia, nasopharyngitis, dysphagia, dizziness/lightheadedness, and gastrointestinal upset. Severe, long-term AEs were reported as rare in the evaluated literature. Deoxycholic acid injections in large volumes were more likely to cause severe adverse effects. CONCLUSION: Self-resolving, mild side effects and severe but rare adverse effects have been reported with DCA use making it a safe treatment for local adipose reduction. Further studies are necessary to determine its safety profile, especially when using DCA in off-label areas.

Oral Metformin for Treating Dermatological Diseases: A Systematic Review.

Introduction:Metformin is an antihyperglycemic medication most commonly used to treat Type II Diabetes Mellitus with promising off-label application for the treatment of hidradenitis suppurativa, psoriasis, acne, acanthosis nigricans, and hirsutism. Objective: To comprehensively assess evidence regarding the use of metformin for treating primary cutaneous disorders. Materials and Methods: A systematic literature search was conducted through PubMed, Cochrane, Web of Science, and CINAHL to identify the role of metformin in primary skin disease. Results: Sixty-four studies met inclusion criteria. Metformin demonstrates promising clinical response and favorable safety profile for treatment of HS, with most patients experiencing a decrease in frequency or severity of HS flares, and some experiencing full resolution of HS lesions. Patients with psoriasis treated with metformin experienced quantifiable clinical responses. Application of metformin on polycystic ovarian disease (PCOS) related acne, acanthosis nigricans, and hirsutism yielded mixed clinical results. No serious adverse effects were reported. Conclusion: Metformin is safe and efficacious and may be considered as an adjunctive therapy for the treatment of psoriasis and hidradenitis suppurativa in addition to first line therapies as well as PCOS related acne, acanthosis nigricans, and hirsutism. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.4874.

Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte-derived chemokine expression and neutrophil infiltration.

Psoriasis is an inflammatory autoimmune skin disorder possessing a complex etiology related to genetic and environmental triggers. Keratinocytes show a potential role for the origin of psoriasis. In this study, we estimated the efficiency of 2 anthranilate derivatives-(E)-4-( N-{2-[1-(hydroxyimino)ethyl]phenyl}sulfamoyl)phenyl pivalate (HFP031) and butyl 2-[2-(2-fluorophenyl)acetamido]benzoate (HFP034)-on psoriasis amelioration in a mouse model. The results showed that topical treatment with both compounds could attenuate epidermal thickness and scaling in an imiquimod (IMQ)-induced psoriasis mouse model via decreased expression of cytokines and chemokines [C-X-C chemokine ligand (CXCL)1 and CXCL2], leading to the reduction of neutrophilic abscess in the skin. The in vivo cutaneous absorption of HFP034 was 7.6-fold greater than that of HFP031. Both compounds caused negligible irritation on healthy mouse skin. In addition, we examined the effect of the anthranilate derivatives on chemokine expression in IMQ-treated HaCaT keratinocytes. Our results elucidated a mechanism for anti-inflammatory activity of HFP034 that involved the elevation of intracellular cAMP concentration, suppression of NF-κB activity, and attenuation of neutrophil chemoattractant expression. These results suggest that HFP034 could increase the cutaneous concentration of cAMP to suppress neutrophil infiltration into the skin. Topically applied HFP034 may demonstrate a potential for future clinical application as a novel therapy for psoriasis treatment.-Lin, Z.-C., Hsieh, P.-W., Hwang, T.-L., Chen, C.-Y., Sung, C. T., Fang, J.-Y. Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte-derived chemokine expression and neutrophil infiltration.

Non-Submental Applications of Injectable Deoxycholic Acid: A Systematic Review

Introduction: Injectable deoxycholic acid (DCA; Kybella; Allergan, Irvine, CA) is currently approved only for treatment of persistent submental fat (SMF). Many cosmetic surgeons use DCA off-label to treat fat tissue in other areas of the body. There is no review summarizing the off-label uses of injectable DCA. Methods: A systematic literature search was conducted through PubMed, Cochrane, CINAHL, and Web of Science databases using search terms "ATX-101 OR Kybella OR deoxycholic OR deoxycholate NOT amphotericin NOT bile" in accordance to PRISMA guidelines to identify off-label uses for injectable DCA or ATX-101. Results: Ten pertinent articles were identified for review. Anatomic areas treated include the face, brassiere line, foot, and gluteotrochanteric region. Indications include facial contouring, paradoxical adipose hyperplasia, HIV/HAART-associated buccal fat pad lipodystrophy, and reduction of lipomatous tumors. DCA is efficacious at causing lipolysis and safe with minimal side effects. Most patients treated for cosmetic indications reported high patient satisfaction. Conclusion: Off-label use of injectable DCA demonstrate a similar safety profile, effectiveness, and overall patient satisfaction compared to FDA-approved use for persistent SMF. DCA appears to be a safe and efficacious alternative to surgical reduction of unwanted adipose tissue in non-submental areas. Larger-scale studies are warranted to explore further cosmetic and potential medical applications. J Drugs Dermatol. 2019;18(7):675-680.

The Efficacy of Topical Minoxidil for Non-Scarring Alopecia: A Systematic Review

Introduction: Topical minoxidil is the first-line therapy for treating both male and female androgenetic alopecia. Currently there are no comprehensive reviews on the clinical efficacy of minoxidil on hair loss. Method: A literature search was conducted to identify clinically relevant studies regarding the efficacy of topical minoxidil for human subjects for hair loss. Results: Twenty-three pertinent studies were identified for inclusion in this review. Topical minoxidil has been studied in concentrations ranging from 0.01% to 15% for the treatment of AGA resulting in hair growth ranging from 17% to 70%. Concentrations from 3% to 5% have been used to treat alopecia areata, 2% to treat traction alopecia, and 1% to 5% for congenital hair disorders with varying levels of treatment success. Efficacy varies by ethnic groups, but topical minoxidil has been demonstrated to significantly improve quality of life even in the absence of hair regrowth. Conclusion: Topical minoxidil is efficacious for the treatment of hair loss due to male and female androgenic alopecia, alopecia areata, with case-by-case application for traction alopecia, hair transplantation, and congenital hair disorders. Combination therapies using minoxidil with systemic, topical, and injectable therapies demonstrate increased effectiveness over monotherapies. J Drugs Dermatol. 2019;18(2):155-160.

Oral Collagen Supplementation: A Systematic Review of Dermatological Applications

Importance: The use of nutraceuticals such as collagen for skincare has been rising, but regulations are lacking on quality, absorption, and efficacy. To address this knowledge gap, clinical studies regarding the potential effects of collagen-based dietary supplements on skin are being completed. Objective: To review the literature and assess available randomized-controlled trials using collagen supplementation for treatment efficacy regarding skin quality, anti-aging benefits, and potential application in medical dermatology. Evidence Review: A literature search was conducted with PubMed using search criteria (collagen) AND (supplement OR food OR nutrition). No lower limit on the year of publication was set. Inclusion criteria were: randomized, placebo-controlled trials using collagen supplementation in human subjects related to dermatology and written in English. Findings: Eleven studies with a total of 805 patients were included for review. Eight studies used collagen hydrolysate, 2.5g/d to 10g/d, for 8 to 24 weeks, for the treatment of pressure ulcers, xerosis, skin aging, and cellulite. Two studies used collagen tripeptide, 3g/d for 4 to 12 weeks, with notable improvement in skin elasticity and hydration. Lastly, one study using collagen dipeptide suggested anti-aging efficacy is proportionate to collagen dipeptide content. Conclusions and Relevance: Preliminary results are promising for the short and long-term use of oral collagen supplements for wound healing and skin aging. Oral collagen supplements also increase skin elasticity, hydration, and dermal collagen density. Collagen supplementation is generally safe with no reported adverse events. Further studies are needed to elucidate medical use in skin barrier diseases such as atopic dermatitis and to determine optimal dosing regimens. J Drugs Dermatol. 2019;18(1):9-16.

Is the Fractional Laser Still Effective in Assisting Cutaneous Macromolecule Delivery in Barrier-Deficient Skin? Psoriasis and Atopic Dermatitis as the Disease Models.

PURPOSE: Most of the investigations into laser-assisted skin permeation have used the intact skin as the permeation barrier. Whether the laser is effective in improving cutaneous delivery via barrier-defective skin is still unclear. METHODS: In this study, ablative (Er:YAG) and non-ablative (Er:glass) lasers were examined for the penetration of peptide and siRNA upon topical application on in vitro skin with a healthy or disrupted barrier. RESULTS: An enhanced peptide flux (6.9 fold) was detected after tape stripping of the pig stratum corneum (SC). A further increase of flux to 11.7 fold was obtained after Er:YAG laser irradiation of the SC-stripped skin. However, the application of Er:glass modality did not further raise the flux via the SC-stripped skin. A similar trend was observed in the case of psoriasiform skin. Conversely, the flux was enhanced 3.7 and 2.6 fold after treatment with the Er:YAG and the Er:glass laser on the atopic dermatitis (AD)-like skin. The 3-D skin structure captured by confocal microscopy proved the distribution of peptide and siRNA through the microchannels and into the surrounding tissue. CONCLUSIONS: The fractional laser was valid for ameliorating macromolecule permeation into barrier-disrupted skin although the enhancement level was lower than that of normal skin.

Allergic Contact Dermatitis Evaluation: Strategies for the Preschooler.

PURPOSE OF REVIEW: The environment for the developing children is complex as they are exposed to a variety of activities and settings where potential environmental allergens may be encountered. Recent evidence supports the clinical benefit of patch testing young children suffering from recalcitrant dermatitis. While patch testing has been recently approved by the Food and Drug Administration in children ages 6-18 years old, patch testing strategies for young children of preschool age (between 2 and 6 years old) have yet to be defined. RECENT FINDINGS: Allergic contact dermatitis is underdiagnosed among pediatric patients, particularly those suffering from concomitant atopic dermatitis as the interplay between the two diseases is complex. Recent reports in literature supported the clinical value, safety, and efficacy of patch testing pediatric patients. This review provides an overview of specific pediatric allergens, special considerations, practical modifications, and systematic exposure-driven guidance approaches toward patch testing preschoolers.

Intravenous anti-MRSA phosphatiosomes mediate enhanced affinity to pulmonary surfactants for effective treatment of infectious pneumonia.

The aim of this study was to develop PEGylated phosphatidylcholine (PC)-rich nanovesicles (phosphatiosomes) carrying ciprofloxacin (CIPX) for lung targeting to eradicate extracellular and intracellular methicillin-resistant Staphylococcus aureus (MRSA). Soyaethyl morphonium ethosulfate (SME) was intercalated in the nanovesicle surface with the dual goals of achieving strengthened bactericidal activity of CIPX-loaded phosphatiosomes and delivery to the lungs. The isothermal titration calorimetry (ITC) results proved the strong association of SME phosphatiosomes with pulmonary surfactant. We demonstrated a superior anti-MRSA activity of SME phosphatiosomes compared to plain phosphatiosomes and to free CIPX. A synergistic effect of CIPX and SME nanocarriers was found in the biofilm eradication. SME phosphatiosomes were readily engulfed by the macrophages, restricting the intracellular MRSA count by 1-2 log units. SME phosphatiosomes efficiently accumulated in the lungs after intravenous injection. In a rat model of lung infection, the MRSA burden in the lungs could be decreased by 8-fold after SME nanosystem application.

Overexpression of a three-gene conidial pigment biosynthetic pathway in Aspergillus nidulans reveals the first NRPS known to acetylate tryptophan.

Fungal nonribosomal peptide synthetases (NRPSs) are megasynthetases that produce cyclic and acyclic peptides. In Aspergillus nidulans, the NRPS ivoA (AN10576) has been associated with the biosynthesis of grey-brown conidiophore pigments. Another gene, ivoB (AN0231), has been demonstrated to be an N-acetyl-6-hydroxytryptophan oxidase that putatively acts downstream of IvoA. A third gene, ivoC, has also been predicted to be involved in pigment biosynthesis based on publicly available genomic and transcriptomic information. In this paper, we report the replacement of the promoters of the ivoA, ivoB, and ivoC genes with the inducible promoter alcA in a single cotransformation. Co-overexpression of the three genes resulted in the production of a dark-brown pigment in hyphae. In addition, overexpression of each of the Ivo genes, ivoA-C, individually or in combination, allowed us to isolate intermediates and confirm the function of each gene. IvoA was found to be the first known NRPS to carry out the acetylation of the amino acid, tryptophan.

Cationic amphiphile in phospholipid bilayer or oil-water interface of nanocarriers affects planktonic and biofilm bacteria killing.

A cationic amphiphile, soyaethyl morpholinium ethosulfate (SME), immobilized in liposomes or nanoemulsions, was prepared in an attempt to compare the antibacterial activity between SME intercalated in the phospholipid bilayer and oil-water interface. Before antibacterial assessment, the size of the liposomes and nanoemulsions was respectively recorded as 75 and 214 nm. The data of minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC) and live/dead cell count demonstrated a superior antimicrobial activity of nanoemulsions compared to liposomes against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Staphylococcus epidermidis. Nanoemulsion incubation reduced biofilm thickness by 2.4-fold, whereas liposomes showed a 1.6-fold decrease in thickness. SME insertion in the oil-water phase was found to induce bacterial membrane disruption. SME nanosystems were nontoxic to keratinocytes. In vivo topical application of the cationic nanosystems reduced skin infection, MRSA load, and inflammation in mice. The deteriorated skin barrier function evoked by MRSA was recovered by nanoemulsion treatment.

Anti-PDGF receptor ß antibody-conjugated squarticles loaded with minoxidil for alopecia treatment by targeting hair follicles and dermal papilla cells.

This study developed lipid nanocarriers, called squarticles, conjugated with anti-platelet-derived growth factor (PDGF)-receptor ß antibody to determine whether targeted Minoxidil (MXD) delivery to the follicles and dermal papilla cells (DPCs) could be achieved. Squalene and hexadecyl palmitate (HP) were used as the matrix of the squarticles. The PDGF-squarticles showed a mean diameter and zeta potential of 195 nm and -46 mV, respectively. Nanoparticle encapsulation enhanced MXD porcine skin deposition from 0.11 to 0.23 µg/mg. The antibody-conjugated nanoparticles ameliorated follicular uptake of MXD by 3-fold compared to that of the control solution in the in vivo mouse model. Both vertical and horizontal skin sections exhibited a wide distribution of nanoparticles in the follicles, epidermis, and deeper skin strata. The encapsulated MXD moderately elicited proliferation of DPCs and vascular endothelial growth factor (VEGF) expression. The active targeting of PDGF-squarticles may be advantageous to improving the limited success of alopecia therapy. FROM THE CLINICAL EDITOR: Topical use of minoxidil is only one of the very few treatment options for alopecia. Nonetheless, the current delivery method is far from ideal. In this article, the authors developed lipid nanocarriers with anti-platelet-derived growth factor receptor ? antibody to target dermal papilla cells, and showed enhanced uptake of minoxidil.

An efficient system for heterologous expression of secondary metabolite genes in Aspergillus nidulans.

Fungal secondary metabolites (SMs) are an important source of medically valuable compounds. Genome projects have revealed that fungi have many SM biosynthetic gene clusters that are not normally expressed. To access these potentially valuable, cryptic clusters, we have developed a heterologous expression system in Aspergillus nidulans . We have developed an efficient system for amplifying genes from a target fungus, placing them under control of a regulatable promoter, transferring them into A. nidulans , and expressing them. We have validated this system by expressing nonreducing polyketide synthases of Aspergillus terreus and additional genes required for compound production and release. We have obtained compound production and release from six of these nonreducing polyketide synthases and have identified the products. To demonstrate that the procedure allows transfer and expression of entire secondary metabolite biosynthetic pathways, we have expressed all the genes of a silent A. terreus cluster and demonstrate that it produces asperfuranone. Further, by expressing the genes of this pathway in various combinations, we have clarified the asperfuranone biosynthetic pathway. We have also developed procedures for deleting entire A. nidulans SM clusters. This allows us to remove clusters that might interfere with analyses of heterologously expressed genes and to eliminate unwanted toxins.

Nanocomposite liposomes containing quantum dots and anticancer drugs for bioimaging and therapeutic delivery: a comparison of cationic, PEGylated and deformable liposomes.

Multifunctional liposomes loaded with quantum dots (QDs) and anticancer drugs were prepared for simultaneous bioimaging and drug delivery. Different formulations, including cationic, PEGylated and deformable liposomes, were compared for their theranostic efficiency. We had evaluated the physicochemical characteristics of these liposomes. The developed liposomes were examined using experimental platforms of cytotoxicity, cell migration, cellular uptake, in vivo melanoma imaging and drug accumulation in tumors. The average size of various nanocomposite liposomes was found to be 92­134 nm. Transmission electron microscopy confirmed the presence of QDs within liposomal bilayers. The incorporation of polyethylene glycol (PEG) and Span 20 into the liposomes greatly increased the fluidity of the bilayers. The liposomes provided sustained release of camptothecin and irinotecan. The cytotoxicity and cell migration assay demonstrated superior activity of cationic liposomes compared with other carriers. Cationic liposomes also showed a significant fluorescence signal in melanoma cells after internalization. The liposomes were intratumorally administered to a melanoma-bearing mouse. Cationic liposomes showed the brightest fluorescence in tumors, followed by classical liposomes. This signal could last for up to 24 h for cationic nanosystems. Intratumoral accumulation of camptothecin from free control was 35 nmol g(−1); it could be increased to 50 nmol g(−1) after loading with cationic liposomes. However, encapsulation of irinotecan into liposomes did not further increase intratumoral drug accumulation. Cationic liposomes were preferable to other liposomes as nanocarriers in both bioimaging and therapeutic approaches.

Proteinase K/Retinoic Acid-Loaded Cationic Liposomes as Multifunctional Anti-Acne Therapy to Disorganize Biofilm and Regulate Keratinocyte Proliferation.

Background: Simultaneous anti-Cutibacterium acnes and anti-inflammatory actions are highly beneficial in treating acne vulgaris. In this study, we present novel anti-acne nanovesicles based on liposomes loaded with proteinase K (PK), retinoic acid (RA), and soyaethyl morpholinium ethosulfate (SME) to achieve an effective and safe treatment. Materials and Methods: This study examined in vitro planktonic and biofilm C. acnes elimination, as well as the keratinocyte proliferation suppression by liposomes. The multifunctional liposomes for treating C. acnes in mice were also evaluated. Results: We acquired multifunctional liposomes with a size of 71 nm and zeta potential of 31 mV. The antimicrobial activity of SME was enhanced after liposomal encapsulation according to the reduction of minimum bactericidal concentration (MBC) by 6-fold. The multifunctional liposomes exhibited a synergistically inhibitory effect on biofilm C. acnes colonization compared with the liposomes containing PK or those containing SME individually. The adhesive bacterial colony in the microplate was lessened by 62% after multifunctional liposome intervention. All liposomal formulations tested here demonstrated no cytotoxicity against the normal keratinocytes but inhibited C. acnes-stimulated cell hyperproliferation. The in vitro scratch assay indicated that the liposomal RA-but not free RA-restrained keratinocyte migration. The animal study showed that free RA combined with SME and multifunctional nanovesicles had a similar effect on diminishing C. acnes colonies in the skin. On the other hand, liposomes exhibited superior performance in recovering the impaired skin barrier function than the free control. We also found that RA-loaded nanovesicles had greater skin tolerability than free RA. Conclusion: The cationic liposomes containing dual PK and RA represented a potential treatment to arrest bacterial infection and associated inflammation in acne.

Laser-assisted nanocarrier delivery to achieve cutaneous siRNA targeting for attenuating psoriasiform dermatitis.

Psoriasis is an autoimmune skin disorder presenting the excessive expression of interleukin (IL)-6. The topical use of small interfering RNA (siRNA) has been increasingly discovered for treating skin diseases. A delivery system capable of protecting siRNA while facilitating both skin targeting and cellular entrance is critical for the successful medication of topically-applied siRNA. Herein, we developed a delivery system for siRNA based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles and combined this system with an ablative laser to promote skin absorption for topical psoriasis therapy. The siRNA absorption enhancement was compared by two laser modalities: a fractional CO2 laser and a fully-ablative Er:YAG laser. We characterized the effect of the delivery system by the cellular uptake, IL-6 silencing, in vitro skin absorption, cutaneous biodistribution, and in vivo psoriasiform dermatitis in mice. The nanocarriers showed minimal cytotoxicity and facile cellular uptake to knock down the IL-6 expression. The nanoformulation containing a cationic surfactant (Forestall) for ion pairing with siRNA achieved a 66% and 77% IL-6 knockdown efficiency toward keratinocytes and macrophages, respectively. In the Franz cell absorption, the lasers increased the naked siRNA penetration to the receptor compartment by 3.7-5.0-fold but remarkably reduced skin deposition using imiquimod (IMQ)-treated psoriasiform skin as the barrier. The fractional laser facilitated nanoparticle-associated siRNA skin deposition up to 3.3-fold, whereas the transport of the nanocarriers to the receptor was negligible. Qualitatively, the lasers increased nanoparticle delivery in the epidermis with limited effect to elevate the penetration depth. The fractional-mediated nanocarrier delivery dramatically attenuated the erythema and scaly lesions of psoriasiform dermatitis. The histological examination displayed a reduction of epidermal hyperplasia and macrophage infiltration by the combination of laser and nanosystem. The passive and laser-assisted naked siRNA delivery was less effective in mitigating dermatitis. The topical delivery of fractional laser-assisted nanoparticles on mice resulted in a 56% IL-6 knockdown. Our results manifested the benefit of cutaneous siRNA targeting using ablative lasers to deliver nanocarriers for treating psoriatic inflammation.