-
Therapeutics and Clinical Risk... 2016The fixed-dose combination adapalene 0.1%/benzoylperoxide 2.5% (A/BPO) was introduced as an acne vulgaris therapeutic in 2007. It combines anti-inflammatory,... (Review)
Review
The fixed-dose combination adapalene 0.1%/benzoylperoxide 2.5% (A/BPO) was introduced as an acne vulgaris therapeutic in 2007. It combines anti-inflammatory, keratolytic, comedolytic, and antibacterial properties. Thus, it addresses several pathophysiological factors involved in the pathophysiology of acne. This review highlights the rationale for the use of this fixed-dose combination product, its therapeutic efficacy including effects on adherence and quality of life, its use for different forms of acne, and the side-effect profile. In summary, the fixed-dose combination of A/BPO gel can be regarded as a highly effective and safe formulation. It is not associated with antibiotic resistance. It reduces factors that cause nonadherence and has positive effects on the quality of life of affected patients. The tolerance is good. The initial mild irritation potential can be addressed by adequate counseling. A/BPO can be used for all forms of inflammatory acne, including severe forms, as part of a combination with systemic antibiotics. Finally, it can also be used for the long-term treatment of chronic acne. Thus, it is a very valuable therapeutic option in daily practice, which is reflected by its strong recommendation in the "European S3-guidelines".
PubMed: 27757036
DOI: 10.2147/TCRM.S94062 -
Cancers Aug 2023The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene...
The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of -7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (K value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC, 1 × IC, 2 × IC) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G/M phase and increased the portion of cells in the sub-G/G phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM.
PubMed: 37627164
DOI: 10.3390/cancers15164136 -
Molecular Diversity Feb 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been significantly paralyzing the societies, economies and health care systems around the globe. The...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been significantly paralyzing the societies, economies and health care systems around the globe. The mutations on the genome of SARS-CoV-2 led to the emergence of new variants, some of which are classified as "variant of concern" due to their increased transmissibility and better viral fitness. The Omicron variant, as the latest variant of concern, dominated the current COVID-19 cases all around the world. Unlike the previous variants of concern, the Omicron variant has 15 mutations on the receptor-binding domain of spike protein and the changes in the key amino acid residues of S protein can enhance the binding ability of the virus to hACE2, resulting in a significant increase in the infectivity of the Omicron variant. Therefore, there is still an urgent need for treatment and prevention of variants of concern, particularly for the Omicron variant. In this study, an in silico drug repurposing was conducted through the molecular docking of 2890 FDA-approved drugs against the mutant S protein of SARS-CoV-2 for Omicron variant. We discovered promising drug candidates for the inhibition of alarming Omicron variant such as quinestrol, adapalene, tamibarotene, and dihydrotachysterol. The stability of ligands complexed with the mutant S protein was confirmed using MD simulations. The lead compounds were further evaluated for their potential use and side effects based on the current literature. Particularly, adapalene, dihydrotachysterol, levocabastine and bexarotene came into prominence due to their non-interference with the normal physiological processes. Therefore, this study suggests that these approved drugs can be considered as drug candidates for further in vitro and in vivo studies to develop new treatment options for the Omicron variant of SARS-CoV-2.
Topics: Humans; Antiviral Agents; SARS-CoV-2; Dihydrotachysterol; Adapalene; COVID-19; Drug Repositioning; Molecular Docking Simulation
PubMed: 35507211
DOI: 10.1007/s11030-022-10440-6 -
Briefings in Bioinformatics Mar 2024Gliomas are the most common type of malignant brain tumors, with glioblastoma multiforme (GBM) having a median survival of 15 months due to drug resistance and relapse....
Gliomas are the most common type of malignant brain tumors, with glioblastoma multiforme (GBM) having a median survival of 15 months due to drug resistance and relapse. The treatment of gliomas relies on surgery, radiotherapy and chemotherapy. Only 12 anti-brain tumor chemotherapies (AntiBCs), mostly alkylating agents, have been approved so far. Glioma subtype-specific metabolic models were reconstructed to simulate metabolite exchanges, in silico knockouts and the prediction of drug and drug combinations for all three subtypes. The simulations were confronted with literature, high-throughput screenings (HTSs), xenograft and clinical trial data to validate the workflow and further prioritize the drug candidates. The three subtype models accurately displayed different degrees of dependencies toward glutamine and glutamate. Furthermore, 33 single drugs, mainly antimetabolites and TXNRD1-inhibitors, as well as 17 drug combinations were predicted as potential candidates for gliomas. Half of these drug candidates have been previously tested in HTSs. Half of the tested drug candidates reduce proliferation in cell lines and two-thirds in xenografts. Most combinations were predicted to be efficient for all three glioma types. However, eflornithine/rifamycin and cannabidiol/adapalene were predicted specifically for GBM and low-grade glioma, respectively. Most drug candidates had comparable efficiency in preclinical tests, cerebrospinal fluid bioavailability and mode-of-action to AntiBCs. However, fotemustine and valganciclovir alone and eflornithine and celecoxib in combination with AntiBCs improved the survival compared to AntiBCs in two-arms, phase I/II and higher glioma clinical trials. Our work highlights the potential of metabolic modeling in advancing glioma drug discovery, which accurately predicted metabolic vulnerabilities, repurposable drugs and combinations for the glioma subtypes.
Topics: Humans; Glioma; Cannabidiol; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Animals; Models, Biological; Cell Line, Tumor; Organophosphorus Compounds
PubMed: 38701414
DOI: 10.1093/bib/bbae199 -
Gels (Basel, Switzerland) Feb 2023Retinoids are considered the mainstay treatment for moderate to severe acne. Adapalene, a third-generation retinoid, has physiochemical properties which hinder the...
Retinoids are considered the mainstay treatment for moderate to severe acne. Adapalene, a third-generation retinoid, has physiochemical properties which hinder the effective delivery of the drug to the skin. Therefore, the current study aimed to develop and evaluate adapalene liposomal loaded gel (ADA-LP gel) for the effective management of acne to improve tolerability and delivery to targeted sites as compared to the conventional dosage form of the drug. A novel spontaneous phase transition method (SPT) was used to formulate liposomes. Liposomal formulation (ADA-LP) was prepared and optimized based on particle size, zeta potential, and PDI. Optimized formulation was further characterized by different techniques and loaded into Carbopol gel. In vitro drug release, ex vivo permeation, and in vivo studies were performed using the prepared adapalene-loaded liposomal-based gel. The in vivo study was done employing the testosterone-induced acne model in mice. The optimized formulation had a size of 181 nm, PDI 0.145, and a zeta potential of -35 mV, indicating that the formulation was stable. Encapsulation efficiency was 89.69 ± 0.5%. ADA-LPs were loaded into the gel. Prepared ADA-LP showed a 79 ± 0.02% release of drug in a sustained manner, within 24 h. The ex vivo permeability study showed a total of 43 ± 0.06 µg/cm of drug able to permeate through the skin within 24 h. Moreover, only 28.27 ± 0.04% was retained on the epidermis. The developed ADA-LP gel showed significant improvement in the acne lesions in mice with no visible scars and inflammation on the skin. Therefore, ADA-LP-based gel could be a promising carrier system for the safe and effective delivery of Adapalene.
PubMed: 36826305
DOI: 10.3390/gels9020135 -
Frontiers in Pharmacology 2022Alternate formulation strategies need to be devised for improving the absorption and bioavailability of drug molecules administered through the intravaginal route....
Alternate formulation strategies need to be devised for improving the absorption and bioavailability of drug molecules administered through the intravaginal route. Enhancing the coating of vaginal mucosa can aid the achievement of this goal. The aim of the current study is to develop a mucoadhesive formulation having adequate adhesiveness, spreading, and viscosity profiles that can ensure good tissue absorption of adapalene upon intravaginal application. A combination of mucoadhesive agents has been employed, including Carbopol-934, HPMC K-15M, and xanthan gum, in varying ratios to formulate five different gels. Furthermore, a cost-effective UV-spectroscopic analytical method was developed to quantify the amount of adapalene in tested samples, both of and origin. The analytical method was validated for different parameters, including specificity, linearity, range, accuracy, precision, and ruggedness. The modified USP-II apparatus was used for dissolution studies, while pharmacokinetic validation was performed in a murine model. Of all the tested formulations, on the basis of the rheo-mechanical attributes, ACX3 performed better than the rest, including the commercially available intravaginal reference product. ACX3 had an average adhesion time of 12 min and a spread diameter of 37 mm. It showed 35 mm as average distance travelled by the diluted sample for leakage assessment. The analytical method developed for the adapalene muco-adhesive gel was within the range for all the validation parameters. For further evaluating the performance of the formulation, dissolution studies were conducted in simulated vaginal conditions which showed 94.83% of drug release within 5 minutes, while on completion of 30 min, it was measured to be 92.90%. Moreover, approximately 67% of the administered drug was recovered after 5 min of administration as evaluated through tissue recovery procedures in mice. The study aided in development of a formulation which can enhance the muco-adhesion of the drug molecule, resulting in an improved pharmacokinetic profile. Moreover, it established an efficient assay method which can be employed for and quantification of adapalene in simulated and physiological fluids.
PubMed: 36249754
DOI: 10.3389/fphar.2022.1017549 -
Journal of the American Academy of... Nov 2023A three-pronged acne treatment approach-combining an antibiotic, antibacterial agent, and retinoid-may provide greater efficacy than single/double treatments. Topical...
BACKGROUND
A three-pronged acne treatment approach-combining an antibiotic, antibacterial agent, and retinoid-may provide greater efficacy than single/double treatments. Topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel (IDP-126) is the first fixed-dose triple-combination in development for acne.
OBJECTIVE
To confirm efficacy, safety, and tolerability of IDP-126 gel in acne treatment.
METHODS
Two phase 3, double-blind, 12-week studies randomized participants aged ≥9 years with moderate-to-severe acne (N = 183; N = 180) 2:1 to once-daily IDP-126 or vehicle gel. Co-primary endpoints comprised participants achieving ≥2-grade reduction from baseline in Evaluator's Global Severity Score (EGSS) and clear/almost clear skin (treatment success) and change from baseline in inflammatory/noninflammatory lesion counts. Treatment-emergent adverse events (TEAEs) were assessed.
RESULTS
At week 12, 49.6% and 50.5% of participants achieved treatment success with IDP-126 versus 24.9% and 20.5% with vehicle (P < .01, both). IDP-126 also provided significantly greater reductions in inflammatory/noninflammatory lesions versus vehicle (least-squares mean percent range: 72.7% to 80.1% vs 47.6% to 59.6%; P < .001, all). Most TEAEs were of mild-moderate severity.
LIMITATIONS
Inter-observer bias/variation in acne severity ratings, limited treatment duration, and population differences that may not generalize to real-world populations.
CONCLUSION
The innovative fixed-dose, triple-combination IDP-126 gel was efficacious and well tolerated in 2 clinical studies of participants with moderate-to-severe acne.
PubMed: 37656094
DOI: 10.1016/j.jaad.2022.08.069 -
Thoracic Cancer Mar 2024Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage...
BACKGROUND
Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder.
METHODS
To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1β. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR.
RESULTS
Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene.
CONCLUSION
We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.
Topics: Humans; Animals; Mice; Afatinib; Erlotinib Hydrochloride; Adapalene; ErbB Receptors; Skin Diseases; Inflammation; Protein Kinase Inhibitors; Lung Neoplasms
PubMed: 38379420
DOI: 10.1111/1759-7714.15249 -
Indian Journal of Dermatology Jul 2014A combination of topical retinoid and antibacterial therapy is often advocated for acne to enhance therapeutic efficacy.
Efficacy and tolerability of topical fixed combination of nadifloxacin 1% and adapalene 0.1% in the treatment of mild to moderate acne vulgaris in Indian patients: a multicenter, open-labelled, prospective study.
BACKGROUND
A combination of topical retinoid and antibacterial therapy is often advocated for acne to enhance therapeutic efficacy.
AIMS
A preliminary study to evaluate the efficacy and tolerability of a topical fixed combination of nadifloxacin (1%) and adapalene (0.1%) in the treatment of mild to moderate acne in Indian patients.
MATERIALS AND METHODS
This was an open-labeled, phase 3 non-randomized, non-comparative study conducted at five centers (Ahmedabad, Nagpur, Thane, Bangalore, and Mumbai) across India. Of 119 enrolled patients with mild to moderate acne, 117 patients were evaluated at the end of the study for efficacy parameters. A fixed combination of nadifloxacin (1%) and adapalene (0.1%) topical gel was applied at the affected area once at night for a period of 8 weeks. Reduction in the total, inflammatory and non-inflammatory lesion counts from the baseline, investigator global assessment (IGA) and reduction in the severity of acne as per combined acne severity classification were the primary efficacy variables measured at 2 weeks, 4 weeks, and 8 weeks.
RESULTS
Overall, 98.3% patients showed a statistically significant progressive reduction in non-inflammatory lesion counts, inflammatory lesion counts, and total lesion counts over the study duration. By the end of 8 weeks, 75% of the patients had their global assessment scores approaching to normal healthy skin score. The adverse events were mild to moderate in severity.
CONCLUSION
This preliminary study shows that a fixed combination of 1% nadifloxacin and 0.1% adapalene topical gel could be an effective and well-tolerated option for the treatment of mild to moderate acne vulgaris. However, further well-controlled, randomized and comparative evaluation of this combination is necessary.
PubMed: 25071260
DOI: 10.4103/0019-5154.135492 -
Clinical, Cosmetic and Investigational... 2023We aim to evaluate the effectiveness and tolerability of a sunscreen formulation containing licochalcone A (LicA) and L-carnitine (LC) as an adjuvant to adapalene in the...
Efficacy and Tolerability of a Sunscreen Containing Licochalcone a and L-Carnitine as an Adjunct to Retinoids in the Management of Acne and Post-Acne Pigmentation Among Malaysian Patients.
PURPOSE
We aim to evaluate the effectiveness and tolerability of a sunscreen formulation containing licochalcone A (LicA) and L-carnitine (LC) as an adjuvant to adapalene in the management of acne and post-acne pigmentation (PAH).
PATIENTS AND METHODS
A randomized, double-blind, active comparator-controlled trial of 51 patients aged 18 years or older with a clinical diagnosis of mild-to-moderate acne vulgaris was conducted at the Hospital Sultan Abdul Aziz Shah, Universiti Putra Malaysia. The efficacy and tolerability of once-daily adapalene 1.0% were assessed during the 2-week run-in period. Subsequently, patients were randomized to receive either an add-on investigational LicA-containing sunscreen or niacinamide-containing comparator sunscreen every 4 hourly during daytime for 4 weeks. Patients were followed up at Weeks 2 and 4 to assess for improvement in acne severity, PAH, calorimetric parameters and cutaneous tolerability.
RESULTS
Two weeks of adapalene usage significantly improved acne severity; however, up to 52% of patients experienced dryness, burning and stinging. Adding LicA-containing or comparator sunscreens was associated with further improvement in acne severity, PAH and calorimetric parameters at the study endpoint. No significant differences in the cutaneous tolerability profiles were observed between treatment groups. Notably, significantly fewer patients receiving LicA-containing sunscreen developed scaliness at Week 4 compared with those in the comparator group. In addition, more patients receiving LicA-containing sunscreen reported less dryness, burning and stinging reactions than the comparator group. Importantly, more patients receiving LicA-containing sunscreen agreed that their treatment led to excellent improvement than the comparator group; of note, one patient reported that their condition worsened with the receipt of the comparator product.
CONCLUSION
The concurrent use of LicA-containing sunscreen with adapalene may improve the cutaneous tolerance to adapalene among Malaysian patients.
PubMed: 38152154
DOI: 10.2147/CCID.S422898