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1.
Int J Nanomedicine ; 14: 9275-9284, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819429

RESUMO

Purpose: Thymosin ß-4(Tß-4) is a macromolecular protein drug with potential for drug development in wound repair but is limited by the shortcomings of macromolecular protein, such as large volumes, poor membrane permeability, and unstable physicochemical characteristics. Ethosomes could enhance cell membrane fluidity and reduce epidermal membrane density to make macromolecular drugs through the stratum corneum into the deeper layers of the skin easily. Herein, we developed and characterized a novel transdermal delivery vehicle to load macromolecular protein peptides and use Tß-4 as a model drug wrapped into ethosomes. Methods: We used the orthogonal method to optimize the formulation of the ethosome preparation prepared by the ethonal infusion method. Ethosomal gels were characterized by using different analytical methods. Transdermal release rate in vitro have been demonstrated in Franz diffusion cells and the efficacy of drug-loaded nanocarriers in vivo was investigated in a mouse model. Results: Optimized Tß-4 ethosomal gels have good physicochemical properties. The drug amounts of the cumulative release in the ethosomal gel within 5 hours were 1.67 times that of the T-ß4 gel in vitro release study, and the wound healing time of ethosomal gel group was only half of the T-ß4 gel group in vivo pharmacokinetic study. Compared with the free drug group, the ethosome preparation not only promotes the percutaneous absorption process of the macromolecular protein drugs but also shortened wound recovery time. Conclusion: Hence, we provide a possible good design for ethosomal gel system that can load macromolecular protein peptide drugs to achieve transdermal drug administration, promoting the percutaneous absorption of the drug and improving the effect.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Etanol/química , Géis/química , Timosina/administração & dosagem , Administração Cutânea , Animais , Liberação Controlada de Fármacos , Feminino , Lipossomos , Camundongos , Tamanho da Partícula , Pele/efeitos dos fármacos , Pele/patologia , Absorção Cutânea , Testes de Irritação da Pele , Timosina/farmacocinética , Cicatrização/efeitos dos fármacos
2.
Int J Nanomedicine ; 14: 8509-8520, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749618

RESUMO

Background: 20(S)-Protopanaxadiol (PPD) has a higher anti-wrinkle effect than the other glycone forms of ginsenosides. However, as PPD has low solubility in water and a high molecular weight, it cannot easily penetrate the stratum corneum layer, which is the rate-limiting step of topical skin delivery. Thus, the objective was to enhance the topical skin deposition of PPD using an optimized nanostructured lipid carriers (NLC) formulation. NLC formulations were optimized using a Box-Behnken design. Materials and methods: NLC formulations were optimized using a Box-Behnken design, where the amount of PDD (X1), volume of the liquid lipid (X2), and amount of surfactant (X3) were set as the independent variables, while the particle size (Y1), polydispersity index (PDI) (Y2), and entrapment efficiency (EE) (Y3) were dependent factors. An in vitro deposition study was performed using Strat-M® and human cadaver skin, while in vivo skin irritation effect of the NLC formulation was evaluated in humans. Results: An NLC was successfully prepared based on the optimized formulation determined using the Box-Behnken design. The particle size, PDI, and EE of the NLC showed less than 5% difference from the predicted values. The in vitro deposition of PPD after the application of the NLC formulation on a Strat-M® artificial membrane and human cadaver skin was significantly higher than that of the controls. Moreover, NLC formulations with and without PDD were not skin irritants in a human study. Conclusion: An NLC formulation for the topical delivery of PPD was successfully optimized using the Box-Behnken design, and could be further developed to enhance the topical skin deposition of PPD.


Assuntos
Portadores de Fármacos/química , Lipídeos/química , Nanoestruturas/química , Sapogeninas/farmacologia , Adulto , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Sapogeninas/química , Pele/efeitos dos fármacos , Testes de Irritação da Pele , Solubilidade , Tensoativos/química , Adulto Jovem
3.
Regul Toxicol Pharmacol ; 108: 104473, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494190

RESUMO

In the last 20 years, alternative approaches to the identification of skin sensitisation hazards have been at the forefront of the 3Rs and have helped refine the validation and acceptance processes. However, experience with the local lymph node assay showed that, post-validation, challenges still occurred, particularly when a wider diversity of chemical substances was addressed, a situation which will arise with validated in vitro alternatives. In the present work, a range of substances potentially challenging to assess in current nonanimal OECD test guidelines were evaluated in several of the emerging in vitro alternatives. Twelve such substances (of which just over half were known skin sensitisers) were assessed in 4 assays, all based on reconstructed human epidermis (RHE) models. For hazard identification, the overall predictive accuracy ranged around 70% for three assays, although for one (SensCeeTox), it fell below 50% when human data was used as the benchmark. In most cases, sensitivity was high, such that sensitisation was overpredicted. As the substances were challenging to assess in other nonanimal methods, the results indicate that the 3D RHE models may be a useful tool for assessing skin sensitisation potentials without needing to revert to animal use.


Assuntos
Alternativas aos Testes com Animais , Bioensaio , Epiderme/efeitos dos fármacos , Haptenos/toxicidade , Epiderme/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Interleucina-18/metabolismo , Testes de Irritação da Pele
4.
ScientificWorldJournal ; 2019: 5985207, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485198

RESUMO

Acne vulgaris occurs due to the inflammation of sebaceous follicles in the skin. It is triggered by the activity of some bacterial species like Propionibacterium acnes, Staphylococcus aureus, and Staphylococcus epidermidis. Acquisition of antibiotic resistance by these microorganisms and adverse effects associated with the current treatment regimens necessitate the introduction of novel therapeutic agents for acne vulgaris. Thus, this study was undertaken to develop novel gel formulations from seeds of Nigella sativa L. and to evaluate the antibacterial potential against some acne-causing bacterial species. The antibacterial activity of seed extracts was initially screened against S. aureus and P. acnes by the agar well diffusion method. Thereafter, topical gels were formulated incorporating the ethyl acetate extract of seeds of N. sativa at three different concentrations. These topical formulations were subjected to antimicrobial activity studies while the stability was evaluated over a period of 30 days. All three formulations were capable of inhibiting the growth of S. aureus and P. acnes, with the highest antibacterial activity in the formulation comprising 15% of the seed extract. Interestingly, the antibacterial potency of this formulation against S. aureus surpassed the commercial synthetic product used as the positive control. Moreover, any alteration in color, odor, homogeneity, washability, consistency, and pH was not observed while the antibacterial potency was also retained during the storage period. The potent antibacterial activity in topical gel formulations developed from the ethyl acetate extract of N. sativa signposts their suitability as alternatives to existing antiacne agents in the management of acne vulgaris.


Assuntos
Acne Vulgar/tratamento farmacológico , Acne Vulgar/microbiologia , Antibacterianos/uso terapêutico , Cosmecêuticos/uso terapêutico , Nigella sativa/química , Acetatos , Administração Tópica , Adolescente , Adulto , Misturas Complexas , Cosmecêuticos/administração & dosagem , Composição de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Testes de Irritação da Pele , Adulto Jovem
5.
Toxicol Lett ; 314: 172-180, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31404593

RESUMO

Vesicants cause a multitude of cutaneous reactions like erythema, blisters and ulcerations. After exposure to sulfur mustard (SM) and related compounds, patients present dermal symptoms typically known for chemicals categorized as skin sensitizer (e.g. hypersensitivity and flare-up phenomena). However, although some case reports led to the assumption that SM and other alkylating compounds represent sensitizers, a comprehensive investigation of SM-triggered immunological responses has not been conducted so far. Based on a well-structured system of in chemico and in vitro test methods, the Organization for Economic Co-operation and Development (OECD) established procedures to categorize agents on their skin sensitizing abilities. In this study, the skin sensitizing potential of SM and three related alkylating agents (AAs) was assessed following the OECD test guidelines. Besides SM, investigated AAs were chlorambucil (CHL), nitrogen mustard (HN3) and 2-chloroethyl ethyl sulfide (CEES). The methods are described in detail in the EURL ECVAM DataBase service on ALternative Methods to animal experimentation (DB-ALM). In accordance to OECD recommendations, skin sensitization is a pathophysiological process starting with a molecular initiating step and ending with the in vivo outcome of an allergic contact dermatitis. This concept is called adverse outcome pathway (AOP). An AOP links an adverse outcome to various key events which can be assayed by established in chemico and in vitro test methods. Positive outcome in two out of three key events indicates that the chemical can be categorized as a skin sensitizer. In this study, key event 1 "haptenation" (covalent modification of epidermal proteins), key event 2 "activation of epidermal keratinocytes" and key event 3 "activation of dendritic cells" were investigated. Covalent modification of epidermal proteins measured by using the DPRA-assay provided distinct positive results for all tested substances. Same outcome was seen in the KeratinoSens assay, investigating the activation of epidermal keratinocytes. The h-CLAT assay performed to determine the activation of dendritic cells provided positive results for SM and CEES but not for CHL and HN3. Altogether, following OECD requirements, our results suggest the classification of all investigated substances as skin sensitizers. Finally, a tentative AOP for SM-induced skin sensitization is suggested.


Assuntos
Substâncias para a Guerra Química/toxicidade , Irritantes/toxicidade , Gás de Mostarda/toxicidade , Testes de Irritação da Pele/normas , Pele/efeitos dos fármacos , Biomarcadores/metabolismo , Substâncias para a Guerra Química/classificação , Clorambucila/classificação , Clorambucila/toxicidade , Guias como Assunto , Humanos , Irritantes/classificação , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Células de Langerhans/metabolismo , Mecloretamina/classificação , Mecloretamina/toxicidade , Gás de Mostarda/análogos & derivados , Gás de Mostarda/classificação , Medição de Risco , Pele/imunologia , Pele/metabolismo
6.
Int J Nanomedicine ; 14: 6135-6150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447556

RESUMO

Background: Nanostructured lipid carriers (NLCs) are emerging as attractive drug carriers in transdermal drug delivery. The surface modification of NLCs with cell-penetrating peptides (CPPs) can enhance the skin permeation of drugs. Purpose: The objective of the current study was to evaluate the ability of the cell-penetrating peptide (CPP) polyarginine to translocate NLCs loaded with lornoxicam (LN) into the skin layers and to evaluate its anti-inflammatory effect. Methods: The NLCs were prepared using an emulsion evaporation and low temperature solidification technique using glyceryl monostearates, triglycerides, DOGS-NTA-Ni lipids and surfactants, and then six histidine-tagged polyarginine containing 11 arginine (R11) peptides was modified on the surface of NLCs. Results: The developed NLCs formulated with LN and R11 (LN-NLC-R11) were incorporated into 2% HPMC gels. NLCs were prepared with a particle size of (121.81±3.61)-(145.72±4.78) nm, and the zeta potential decreased from (-30.30±2.07) to (-14.66±0.74) mV after the modification of R11 peptides. The encapsulation efficiency and drug loading were (74.61±1.13) % and (7.92±0.33) %, respectively, regardless of the surface modification. Cellular uptake assays using HaCaT cells suggested that the NLC modified with R11 (0.02%, w/w) significantly enhanced the cell internalization of nanoparticles relative to unmodified NLCs (P<0.05 or P<0.01). An in vitro skin permeation study showed better permeation-enhancing ability of R11 (0.02%, w/w) than that of other content (0.01% or 0.04%). In carrageenan-induced rat paw edema models, LN-NLC-R11 gels inhibited rat paw edema and the production of inflammatory cytokines compared with LN-NLC gels and LN gels (P<0.01). Conclusion: In our investigation, it was strongly demonstrated that the surface modification of NLC with R11 enhanced the translocation of LN across the skin, thereby alleviating inflammation.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Edema/tratamento farmacológico , Lipídeos/química , Nanoestruturas/química , Peptídeos/farmacologia , Piroxicam/análogos & derivados , Administração Cutânea , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/farmacologia , Edema/induzido quimicamente , Edema/metabolismo , Emulsões/química , Endocitose/efeitos dos fármacos , Géis/química , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/ultraestrutura , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Piroxicam/administração & dosagem , Piroxicam/farmacologia , Piroxicam/uso terapêutico , Coelhos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Testes de Irritação da Pele
7.
Toxicol Ind Health ; 35(8): 507-519, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31462197

RESUMO

In commercial products such as household deodorants or biocides, didecyldimethylammonium chloride (DDAC) often serves as an antimicrobial agent, citral serves as a fragrance agent, and the excipient ethylene glycol (EG) is used to dissolve the active ingredients. The skin sensitization (SS) potentials of each of these substances are still being debated. Moreover, mixtures of DDAC or citral with EG have not been evaluated for SS potency. The in vitro alternative assay called human Cell Line Activation Test (h-CLAT) and Direct Peptide Reactivity Assay (DPRA) served to address these issues. On three independent runs of h-CLAT, DDAC and citral were predicted to be sensitizers while EG was predicted to be a non-sensitizer and also by the DPRA. Mixtures of DDAC or citral with EG at ratios of 7:3 and 1:4 w/v were all positive by the h-CLAT in terms of SS potential but SS potency was mitigated as the proportion of EG increased. Citral and its EG mixtures were all positive but DDAC and its EG mixtures were all negative by the DPRA, indicating that the DPRA method is not suitable for chemicals with pro-hapten characteristics. Since humans can be occupationally or environmentally exposed to mixtures of excipients with active ingredients, the present study may give insights into further investigations of the SS potentials of various chemical mixtures.


Assuntos
/efeitos adversos , Etilenoglicol/efeitos adversos , Excipientes/efeitos adversos , Compostos de Amônio Quaternário/efeitos adversos , Testes de Irritação da Pele/métodos , Pele/efeitos dos fármacos , /administração & dosagem , Alternativas aos Testes com Animais/métodos , Antígeno B7-2/metabolismo , Bioensaio/métodos , Linhagem Celular , Etilenoglicol/administração & dosagem , Excipientes/administração & dosagem , Humanos , Molécula 1 de Adesão Intercelular/metabolismo
8.
Toxicol Lett ; 314: 27-36, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295538

RESUMO

Some cosmetic ingredients can act as a chemical hapten to induce an immune response; therefore, evaluating the sensitizing potential of cosmetic ingredients is essential. We previously developed a novel in chemico direct peptide reactivity assay involving a spectrophotometric evaluation (Spectro-DPRA) for animal skin sensitization tests (local lymph node assay; LLNA). Based on previous research, we expanded the test materials to confirm the effectiveness of the Spectro-DPRA method for predicting the animal skin sensitization potential, and further determined the feasibility of the method for estimating the human skin sensitization potential. Spectro-DPRA showed 83.1% or 89.1% accuracy compared to a conventional LLNA or prediction based on human data, respectively, with a combination model using both a cysteine peptide and lysine peptide cut-off. To identify the effect of the lipophilicity of a chemical on predicting the skin sensitization potential, we applied our prediction model to chemicals with a Log Pow range of -1 to 4. Overall predictability was increased, and the accuracy compared to the LLNA and human data was 91.5% and 94.9%, respectively, in the combination cut-off prediction model. In conclusion, Spectro-DPRA serves as an easy, rapid, and high-throughput in chemico screening method with high accuracy to predict the human skin sensitization potential of chemicals.


Assuntos
Alternativas aos Testes com Animais/métodos , Ensaios de Triagem em Larga Escala , Oligopeptídeos/química , Testes de Irritação da Pele/métodos , Pele/efeitos dos fármacos , Animais , Cisteína , Estudos de Viabilidade , Humanos , Ensaio Local de Linfonodo , Lisina , Estrutura Molecular , Reprodutibilidade dos Testes , Medição de Risco , Pele/imunologia , Espectrofotometria , Relação Estrutura-Atividade
9.
Int J Pharm ; 569: 118484, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31260785

RESUMO

Re-activation of the healing process is a major challenge in the field of chronic wound treatment. For that purpose, lipid-nanoparticles, especially nanostructured lipid carriers (NLC), possess extremely useful characteristics such as biodegradability, biocompatibility and long-term stability, besides being suitable for drug delivery. Moreover, they maintain wound moisture due to their occlusive properties, which have been associated with increased healing rates. In the light of above, NLC have been extensively used topically for wound healing; but to date, there are no safety-preclinical studies concerning such type of application. Thus, in this work, biodistribution studies were performed in rats with the NLC previously developed by our research group, using technetium-99 m (99mTc-NLC) as radiomarker, topically administered on a wound. 99mTc-NLC remained on the wound for 24 h and systemic absorption was not observed after administration. In addition, toxicological studies were performed to assess NLC safety after topical administration. The results obtained demonstrated that NLC were non-cytotoxic, non-sensitizing and non-irritant/corrosive. Overall, it might be concluded that developed NLC remained at the administration area, potentially exerting a local effect, and were safe after topical administration on wounds.


Assuntos
Portadores de Fármacos/administração & dosagem , Lipídeos/administração & dosagem , Nanoestruturas/administração & dosagem , Animais , Células 3T3 BALB , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Feminino , Lipídeos/farmacocinética , Lipídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos CBA , Nanoestruturas/toxicidade , Coelhos , Ratos Wistar , Pele/efeitos dos fármacos , Testes de Irritação da Pele , Tecnécio , Distribuição Tecidual , Cicatrização/efeitos dos fármacos
10.
Hum Exp Toxicol ; 38(11): 1314-1326, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31303057

RESUMO

Electrolyzed water (EW) is a widely used disinfectant agent with high oxidation-reduction potential (ORP). Although EW has been used in many areas, such as food hygiene, agriculture, and animal husbandry, the studies presented in the literature are not enough to clarify the toxic effects of EW. The aim of this study is, therefore, to produce EWs at different pH, ORP, and chlorine concentrations and to assess their safety in terms of toxicology. At the beginning of the study, the antimicrobial activity of the EW types with respect to bacteria and fungus was investigated. EWs below pH 7 were all effective in inactivating Enterococcus hirae, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans completely. In vitro studies of cell cultures revealed that different concentrations of EWs were not cytotoxic for the L929 cells under 10- to 80-fold dilutions. In addition, it has been determined that produced EWs did not have irritation potential, according to the in vitro EpiDerm™, reconstituted skin irritation test in the frames of biocompatibility tests. For the mucous membrane irritation test, the hen's egg test-chorioallantoic membrane experiment was performed, and EWs were found to have no eye irritation. In conclusion, it has been shown that produced EWs with antimicrobial efficacy were found to be safe for skin and eye according to in vitro biocompatibility study studies. Thus, the establishment of a technological infrastructure for the EW production and the use of produced EW as an effective disinfectant in the food, medical, and agricultural areas should be encouraged.


Assuntos
Desinfetantes/farmacologia , Eletrólise , Água/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Desinfetantes/química , Olho/efeitos dos fármacos , Humanos , Interleucina-1alfa/metabolismo , Camundongos , Pele/efeitos dos fármacos , Pele/metabolismo , Testes de Irritação da Pele , Água/química
11.
Biomed Pharmacother ; 117: 108993, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228805

RESUMO

The aim of this study was to investigate the release behaviors of sinomenine hydrochloride loaded via in situ hexagonal liquid crystal (ISH), and its potential to improve the local bioavailability in knee joints of sinomenine hydrochloride (SMH) after intra-articular administration. The ISH was prepared by a liquid precursor mixture containing phytantriol (PT), Vitamin E acetate (VEA), ethanol (ET), and water. The in vitro release profiles revealed a sustained release of SMH from the optimized ISH formula (PT/VEA/ET/water, 60.8:3.2:16.0:20.0, w/w/w/w), which was selected for the in vivo pharmacokinetics and preliminary pharmacodynamics studies. In both healthy and adjuvant-induced arthritis (AA) rats, the SMH loaded ISH showed significantly smaller SMH AUC0-∞ in plasma (P < 0.01), and higher SMH concentration in synoviums (2˜168 h) than that of SMH solution, indicating that the ISH significantly reduced the leakage of SMH into systemic circulation. The t1/2α of SMH loaded ISH in the knee joints of AA rats, was longer (13.42 h) than that of healthy rats (1.34 h) (P < 0.05), most likely that in vivo drug release behavior of SMH loaded ISH was affected by the physiological environment of the joint. It was found that the SMH loaded ISH could benefit AA-rats by suppressing the level of IL-1ß in comparison to SMH solutions. The results of the histopathology of knee joints in AA rats displayed that the SMH loaded ISH might be suitable for the development of treatment strategies for rheumatoid arthritis diseases.


Assuntos
Cristais Líquidos/química , Morfinanos/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Liberação Controlada de Fármacos , Álcoois Graxos/química , Injeções Intra-Articulares , Interleucina-1beta/metabolismo , Articulações/patologia , Morfinanos/sangue , Morfinanos/química , Morfinanos/farmacocinética , Ratos , Testes de Irritação da Pele , Membrana Sinovial/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-31192163

RESUMO

Antimicrobial peptides, also known as host defense peptides, have recently emerged as a promising new category of therapeutic agents for the treatment of infectious diseases. This study evaluated the preclinical in vitro, ex vivo, and in vivo antimicrobial activity, as well as the potential to cause skin irritation, of human kininogen-derived antimicrobial peptide DPK-060 in different formulations designed for topical delivery. We found that DPK-060 formulated in acetate buffer or poloxamer gel caused a marked reduction of bacterial counts of Staphylococcus aureus in vitro (minimum microbicidal concentration <5 µg/ml). We also found that DPK-060 in poloxamer gel significantly suppressed microbial survival in an ex vivo wound infection model using pig skin and in an in vivo mouse model of surgical site infection (≥99 or ≥94% reduction in bacterial counts was achieved with 1% DPK-060 at 4 h post-treatment, respectively). Encapsulation of DPK-060 in different types of lipid nanocapsules or cubosomes did not improve the bactericidal potential of the peptide under the applied test conditions. No reduction in cell viability was observed in response to administration of DPK-060 in any of the formulations tested. In conclusion, the present study confirms that DPK-060 has the potential to be an effective and safe drug candidate for the topical treatment of microbial infections; however, adsorption of the peptide to nanocarriers failed to show any additional benefits.


Assuntos
Administração Tópica , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Modelos Animais de Doenças , Feminino , Lipídeos/química , Camundongos , Testes de Sensibilidade Microbiana , Nanocápsulas , Poloxâmero/uso terapêutico , Proteínas Serina-Treonina Quinases/administração & dosagem , Proteínas Serina-Treonina Quinases/farmacologia , Proteínas Serina-Treonina Quinases/uso terapêutico , Testes de Irritação da Pele , Infecções Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Suínos
13.
PLoS One ; 14(5): e0217718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31150479

RESUMO

This study aimed to evaluate the potential adverse effects of the dermal administration of Dillenia indica Linnaeus (D. indica) fruit extract in healthy rodents; the extract was standardized to betulinic acid. In the initial phase, the acute effects were evaluated on the skin application site of a single extract dose. A skin irritation test was performed in male Wistar rats (n = 8/group) receiving the extract (50-150 mg/mL) with betulinic acid (0.5-1.5%, respectively). A photosensitivity test was performed in male BALB/c mice (n = 6/group) receiving the extract (150 mg/mL). Afterwards, other BALB/c mice (n = 20, male:female, 1:1) were used to assess the systemic alterations caused by 14 daily repeated doses (150 mg/mL) by monitoring the effects on mortality, body morphology, behavior, nutrition status, neuromotor reactions, organ morphology and weight, and blood tests. At this time, 0.5 mg/mL clobetasol was used as the positive control. The skin irritation index suggested that negligible skin irritation had occurred, even when the extract was applied to the rat skin at 150 mg/mL. However, the extract acted as a photosensitizer on mouse skin, showing a photosensitizing activity close to that of 10 mg/mL 5-methoxypsoralen. Repeated doses caused no mouse mortality, aggressiveness, piloerection, diarrhea, convulsions, neuromotor alterations or nutrition status changes. The mouse organ weights did not change, and the mice did not have alterations in their blood compositions. Clobetasol caused a reduction in the mononuclear leukocyte numbers. In general, the data suggest that the extract was safe in healthy rodents but indicate that caution should be taken with the photosensitizing activity; in addition, this activity should be further explored as it may be useful for phototherapeutic drug development.


Assuntos
Clobetasol/farmacologia , Dilleniaceae/química , Fármacos Fotossensibilizantes/farmacologia , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Frutas/química , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Camundongos , Fármacos Fotossensibilizantes/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Testes de Irritação da Pele , Triterpenos/química , Triterpenos/farmacologia
14.
J Toxicol Sci ; 44(6): 393-403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31167989

RESUMO

To predict the results of a 24-hr closed human patch test, we previously recommended the use of in vitro test with a reconstructed human epidermis (RhE) model adopted in OECD TG 439, and proposed the margin method, which includes evaluation of twice the concentration to avoid a false positive for surfactants. Therefore, in this study, we used LabCyte EPI-MODEL as a RhE model, and confirmed the reproducibility of this method using five surfactants, including benzalkonium chloride (BC), sodium lauryl sulfate (SLS), and lauryl betaine (LB), for which false negative results have previously been reported, and three different surfactants. For all surfactants, prediction of patch test results using a margin of two revealed that human tests could be performed safely, confirming the utility of the margin method. In addition, we examined the relationship with critical micellar concentration (CMC). The IC50 for cell viability in the RhE model for three types of surfactants (BC, SLS, and LB) was 2.7- to 49.7-times the CMC. Therefore, the range of concentrations in which tests were performed with the present method was within the range of concentrations with high cleansing. Furthermore, we examined the relationship between cell viability and release of the inflammatory mediator interleukin-1α (IL-1α). IL-1α release was associated with cell viability, supporting the results of the human patch test.


Assuntos
Epiderme/efeitos dos fármacos , Testes de Irritação da Pele , Tensoativos/toxicidade , Alternativas aos Testes com Animais , Compostos de Benzalcônio/toxicidade , Betaína/análogos & derivados , Betaína/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Epiderme/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Testes do Emplastro , Reprodutibilidade dos Testes , Dodecilsulfato de Sódio/toxicidade
15.
Int J Nanomedicine ; 14: 2485-2495, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040670

RESUMO

Background: Triamcinolone acetonide (TAA) is an effective and the most commonly used corticosteroid hormone for the treatment of hypertrophic scars (HSs). However, the clinically used dosage has poor tissue permeability and injection safety. By contrast, lipid nanoparticles (LNPs) have the advantage of high affinity for the skin. Materials and methods: This article describes the preparation of TAA-LNPs using poly(lactic-co-glycolic acid) as a carrier material, which have good biocompatibility and biodegradability. Based on a systematic investigation of its physicochemical properties, a rabbit ear HSs model was established to evaluate the percutaneous permeability of TAA-LNPs in scar tissue in vitro as well as to assess its curative effect and skin irritation. Results: The results showed that the TAA-LNPs formed uniform and round particles under fluoroscopy and had a complex structure in which a nanoparticle core was surrounded by multiple vesicles. The particles were 232.2±8.2 nm in size, and the complimentary potential was -42.16 mV. The encapsulation efficiency was 85.24%, which is greater than that of other common liposomes and nanoparticles. A test of in vitro scar tissue permeability showed that penetration into scar tissue was twofold and 40-fold higher for TAA-LNPs than for common liposome and commercial suspensions, respectively. The concentration of the absorbed drug effectively inhibited fibroblast proliferation, achieved a therapeutic effect in HSs, and did not stimulate intact or damaged skin. Conclusion: The preparation of TAA into LNPs for transdermal administration can enhance transdermal permeation performance and the safety of this drug, which is beneficial for the treatment of HSs.


Assuntos
Lipídeos/química , Nanopartículas/química , Triancinolona Acetonida/administração & dosagem , Triancinolona Acetonida/farmacologia , Administração Cutânea , Animais , Cicatriz/patologia , Orelha/patologia , Fluorescência , Lipossomos , Masculino , Nanopartículas/ultraestrutura , Tamanho da Partícula , Permeabilidade , Coelhos , Rodaminas/metabolismo , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Testes de Irritação da Pele
16.
Toxicol In Vitro ; 60: 71-75, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31100379

RESUMO

In Ukraine Globally Harmonized System of classification of chemicals has not been implemented yet. In this article we analyze differences between GHS/CLP classification systems and Hygienic Classification of Pesticides by the Degree of Hazard currently in force in Ukraine in respect of approach and criteria for classification of effects on skin. As a case study, we conducted in silico modelling of herbicide imazamox using skin irritation/corrosion modules of ToxTree. The prediction of ToxTree was "Not Corrosive to skin". Then skin irritation and skin corrosion in vitro tests (OECD TGs 439, 431) were conducted. Classification of this substance based on in vitro and in vivo results according to GHS/CLP was the same, while it was not possible based on in vitro results to assign certain hazard class of Ukrainian classification due to difference in its and GHS/CLP criteria. However, ongoing process of harmonization of Ukrainian legislation with EU will give opportunity not only use alternative methods, but also adopt most recent advances and incorporate data from non-animal methods directly into classification criteria.


Assuntos
Cáusticos/classificação , Imidazóis/classificação , Irritantes/classificação , Praguicidas/classificação , Animais , Cáusticos/toxicidade , Simulação por Computador , União Europeia , Humanos , Imidazóis/toxicidade , Irritantes/toxicidade , Praguicidas/toxicidade , Testes de Irritação da Pele/métodos , Ucrânia
17.
SAR QSAR Environ Res ; 30(4): 279-298, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31012352

RESUMO

We developed a read-across workflow using the OECD QSAR Toolbox for the prediction of skin irritation and corrosion. In the workflow, we gathered analogues using an improved profiler for skin irritation and corrosion to define valid categories. In addition, we refined categories by removing chemicals based on melting points and structural features. Finally, prediction results were obtained using our self-determined rule for read-across. In this rule, we decided the number of analogues from which the read-across is performed, analogue selection criteria (i.e. high similarity vs. near log Pow) and prediction rule (i.e. majority vs. unanimity). We created a program for the optimization of read-across workflows. We applied this program to 313 chemicals in the training set and sought the optimized workflows among >1000 possible choices of profilers and ways of subcategorization and data gap filling. Use of the optimized workflows provided highly accurate, unbiased, user-independent and reproducible read-across predictions. The prediction results obtained from read-across workflows can be used for the selection of in vitro test methods or as part of the weight-of-evidence approaches in the Integrated Approach on Testing and Assessment for skin irritation and corrosion. Moreover, these results can be used for screening purposes and/or preliminary hazard assessment.


Assuntos
Alternativas aos Testes com Animais/métodos , Cáusticos/toxicidade , Técnicas In Vitro/métodos , Irritantes/toxicidade , Relação Quantitativa Estrutura-Atividade , Testes de Irritação da Pele/instrumentação , Humanos , Fluxo de Trabalho
19.
Colloids Surf B Biointerfaces ; 179: 393-404, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30999118

RESUMO

The aim of this study was to prepare a microemulsion based hydrogel containing sesame oil and evaluate its topical application in preventing the harmful effects of UV radiation on the guinea pig's skin using histopathologic and clinical findings. Sesame oil with high antioxidant content and unique chemical and physiological properties is a suitable candidate for the evolution of UV protection on skin. Applying this natural oil in microemulsion formulation containing particles with nanometer size can enhance its efficacy. To prepare a stable microemulsion, it is necessary to select the appropriate surfactants. In this study, first the best combination of hydrophilic surfactant of Tween 80 with various lipophilic surfactants such as Span 20, Span 80 and Span 85 at different surfactant ratios was examined. The microemulsion formulations were assessed for particle size, zeta potential, polydispersity index, refractive index, electrical conductivity, pH value and stability. Results showed that among various samples, microemulsion containing a mixture of Tween 80 and Span 80 with the surfactant ratio of 9:1 was the best sample in terms of stability over time (six months). This sample had a lower particle size of 26.09 nm with a narrow particle size distribution. For topical application, the microemulsion based hydrogel was prepared with 0.6% Carbomer 940 as a gelling agent. The pH value and viscosity of gel formulation were 6.6 and 12.90 Pa.s, respectively, which is appropriate for topical applications. A slight enhancement of particle size inside hydrogel structure was observed after six months of the gel preparation. The clinical evolutions of formulation on guinea pig's skin were included skin scaling, skin irregularity, erythema, skin hyperpigmentation, and edema. Epidermal hyperkeratosis, hyperpigmentation, exocytosis, acanthosis, chromatin discoloration in nucleus of epidermal squamous cells, perifolliculitis, dermal vascular hyperemia, edema and dermal thickness, infiltration of plasma cell lymphocytes and eosinophils into dermis were observed for histopathological investigations. Based on clinical and histopathological examinations, topical application of microemulsion-based hydrogel of sesame oil can effectively prevent skin damage induced by UV radiation and is therefore suitable for skin products.


Assuntos
Composição de Medicamentos , Emulsões/química , Pele/patologia , Pele/efeitos da radiação , Raios Ultravioleta , Animais , Feminino , Cobaias , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Transição de Fase , Coelhos , Reologia , Testes de Irritação da Pele
20.
Int J Pharm ; 562: 96-104, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902706

RESUMO

The present work reports the development, optimization and characterization of novel lipid based nanoformulations viz., Liquid crystalline nanoparticles (LCNP), solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and liposomes loaded with Tacrolimus (Tac) for topical delivery. Different nanoformulations were developed after screening lipids and suitable surfactants depending upon emulsification ability. The various nanoformulations were then optimized (to achieve higher entrapment efficacy, lower particle size, PDI and zeta potential), characterized and loaded into gel. The gels loaded with nanoformulations were also characterized depending upon rheology and viscosity. The gels were analyzed for in vitro drug release, HaCaT cell lines studies and skin permeation studies. The in vivo efficacy studies were carried out using mouse tail model and skin irritation studies using Draize patch test and measurement of TEWL. The developed nanoformulations showed optimum particle size (<200 nm), polydispersity index (PDI < 0.3), zeta potential (≥-10 mV) and higher entrapment efficiency (>85%). The nanoformulations showed higher penetration of Tac into skin. Tac-LCNP, Tac-SLN, Tac-NLC and Tac-liposomes loaded gels showed 14, 11.5, 12.5 and 3.7 folds increment in dermal bioavailability respectively, in comparison to free Tac loaded gel and 2.5, 2 and ∼2 folds augmentation in dermal bioavailability respectively as compared to Tacroz™ Forte. In case of Tac-liposomes, the dermal bioavailability was lower as compared with the marketed formulation, Tacroz™ Forte. Despite, the increased bioavailability into the skin, the developed nanoformulations showed no significant skin irritation. The above mentioned nanoformulations were able to achieve greater penetration of Tac into the skin as compared to marketed ointment of Tac, Tacroz™ Forte.


Assuntos
Portadores de Fármacos/administração & dosagem , Imunossupressores/administração & dosagem , Lipídeos/administração & dosagem , Cristais Líquidos , Nanopartículas/administração & dosagem , Tacrolimo/administração & dosagem , Administração Cutânea , Animais , Linhagem Celular , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Imunossupressores/química , Lipídeos/química , Cristais Líquidos/química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Pele/metabolismo , Testes de Irritação da Pele , Suínos , Tacrolimo/química , Resultado do Tratamento
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