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1.
Anticancer Res ; 39(12): 6701-6709, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810935

RESUMO

BACKGROUND/AIM: Extracellular vesicles (exosomes, EVs) (30-200 nm in diameter) are secreted by various cells in the body. Owing to the pharmaceutical advantages of EVs, an EV-based drug delivery system (DDS) for cancer therapy is expected to be the next-generation therapeutic system. However, preservation methods for functional and therapeutic EVs should be developed. Here, we developed the method of lyophilization of arginine-rich cell penetrating peptide (CPP)-modified EVs and investigated the effects of lyophilization on the characteristics of EVs. MATERIALS AND METHODS: Particle size, structure, zeta-potential, and cellular uptake efficacy of the arginine-rich CPP-modified EVs were analyzed. The model protein saporin (SAP), having anti-cancer effects, was encapsulated inside the EVs to assess the cytosolic release of EV content after cellular uptake. RESULTS: Lyophilization of the EVs did not affect their particle size, structure, zeta-potential, and cellular uptake efficacy; however, the biological activity of the encapsulated SAP was inhibited by lyophilization. CONCLUSION: Lyophilization of EVs may affect SAP structures and/or reduce the cytosolic release efficacy of EV's content after cellular uptake and needs attention in EV-based DDSs.


Assuntos
Arginina , Peptídeos Penetradores de Células/farmacocinética , Vesículas Extracelulares/metabolismo , Veículos Farmacêuticos , Saporinas/farmacocinética , Animais , Células CHO , Sobrevivência Celular , Peptídeos Penetradores de Células/administração & dosagem , Peptídeos Penetradores de Células/química , Cricetulus , Liofilização , Humanos , Tamanho da Partícula , Pinocitose , Preservação Biológica/métodos , Saporinas/administração & dosagem , Tetraspanina 30/metabolismo
2.
Nat Biotechnol ; 37(10): 1174-1185, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570898

RESUMO

Therapeutic messenger RNA vaccines enable delivery of whole antigens, which can be advantageous over peptide vaccines. However, optimal efficacy requires both intracellular delivery, to allow antigen translation, and appropriate immune activation. Here, we developed a combinatorial library of ionizable lipid-like materials to identify mRNA delivery vehicles that facilitate mRNA delivery in vivo and provide potent and specific immune activation. Using a three-dimensional multi-component reaction system, we synthesized and evaluated the vaccine potential of over 1,000 lipid formulations. The top candidate formulations induced a robust immune response, and were able to inhibit tumor growth and prolong survival in melanoma and human papillomavirus E7 in vivo tumor models. The top-performing lipids share a common structure: an unsaturated lipid tail, a dihydroimidazole linker and cyclic amine head groups. These formulations induce antigen-presenting cell maturation via the intracellular stimulator of interferon genes (STING) pathway, rather than through Toll-like receptors, and result in limited systemic cytokine expression and enhanced anti-tumor efficacy.


Assuntos
Antineoplásicos , Vacinas Anticâncer , Lipídeos/farmacocinética , Veículos Farmacêuticos , RNA Mensageiro , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Vacinas Anticâncer/química , Vacinas Anticâncer/genética , Vacinas Anticâncer/farmacocinética , Vacinas Anticâncer/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Células HeLa , Humanos , Interferons/genética , Interferons/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Veículos Farmacêuticos/química , Veículos Farmacêuticos/farmacocinética , RNA Mensageiro/genética , RNA Mensageiro/farmacocinética , RNA Mensageiro/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas
3.
AAPS PharmSciTech ; 20(8): 309, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520191

RESUMO

A synthetic, dispersible magnesium aminoclay (MgAC) was synthesized in the present study. Besides, structural and spectroscopic detections were conducted to investigate the MgAC nanoclay. With a poor aqueous solubility, methotrexate (MTX) has been applied as a valid antitumor agent in recent years. In our research, an unobtrusive sol-gel process was carried out to manufacture the MgAC-MTX nanohybrids through entrapment of MTX over MgAC in situ. The final product was capable of desquamating and thus dispersed in water, equably. In comparison with rough MTX, the MgAC-MTX nanocomposite with a preferable treatment efficacy against MCF-7 cells was mainly attributed to the preeminent enhanced aqueous solubility, controlled release and the increased cellular uptake capacity. Moreover, with excellent anticancer function and hypotoxicity as vindicated in vivo, the MgAC-MTX nanohybrid was supposed to own the potency in the application of malignant tumors cure as a valid nanomedicine. It turned out that, by virtue of its high bioavailability, the MgAC-MTX nanohybrids with high bioavailability is deserving of further study for the treatment of cancers.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Argila/química , Compostos de Magnésio/química , Metotrexato/administração & dosagem , Veículos Farmacêuticos/química , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Feminino , Géis , Humanos , Células MCF-7 , Metotrexato/química , Metotrexato/uso terapêutico , Camundongos , Nanoestruturas , Neoplasias Experimentais/tratamento farmacológico , Tamanho da Partícula
4.
J Drugs Dermatol ; 18(8): 756-770, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424707

RESUMO

BACKGROUND: Topical corticosteroids are efficacious treatment options for multiple dermatoses. However, ointments and cream corticosteroid vehicles can be cumbersome to patients and may act as a barrier to adherence. Foam vehicles may be preferred by some patients. OBJECTIVE: To evaluate the efficacy and safety of topical corticosteroid foams. METHODS: A literature review was conducted using the keywords "clobetasol," "betamethasone," "propionate," "valerate," "topical," "foam," "vehicles," "desonide," and "clinical trial." Thirty-seven articles were chosen. RESULTS: For moderate plaque-type psoriasis, 68% of subjects using clobetasol propionate foam achieved a Physician Static Global Assessment score of 0 or 1 at week 2 compared with 21% in the control group (P<0.0001). For betamethasone valerate (BMV) foam, a 12-week regimen for alopecia areata yielded a mean Investigator Global Assessment score of 2.9 compared with placebo (4.6; P<0.001) and achieved ≥75% hair regrowth in 42.86% of subjects. Furthermore, BMV foam cleared or almost cleared 72% of scalp psoriasis subjects compared with BMV lotion (P≤0.005%). For calcipotriol plus betamethasone dipropionate foam, 38.3% of psoriasis subjects achieved treatment success compared with placebo (22.5%; P<0.001). Desonide 0.05% foam was superior to vehicle foam in pediatric atopic dermatitis subjects. CONCLUSION: Topical corticosteroid foams can be used for a variety of corticosteroid-responsive dermatoses. Topical corticosteroid foams are generally easy to apply and may improve patient adherence and, therefore, clinical outcome in patients who prefer a convenient and less messy topical therapy.


Assuntos
Glucocorticoides/administração & dosagem , Adesão à Medicação , Preferência do Paciente , Veículos Farmacêuticos/efeitos adversos , Dermatopatias/tratamento farmacológico , Administração Cutânea , Ensaios Clínicos como Assunto , Glucocorticoides/efeitos adversos , Veículos Farmacêuticos/administração & dosagem , Resultado do Tratamento
5.
J Drugs Dermatol ; 18(8): 790-796, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424709

RESUMO

BACKGROUND: A novel foam formulation of halobetasol propionate, 0.05% (HBP-Foam) has been developed to treat plaque psoriasis in patients who prefer a thermostable topical foam with low application shear that allows for easier coverage over large and/or hirsute areas than existing formulations. OBJECTIVE: To determine the safety and effectiveness of HBP-Foam in subjects with plaque psoriasis. METHODS: Two randomized, double-blind, vehicle-controlled clinical studies were conducted in 560 adult subjects with moderate to severe plaque psoriasis. Subjects applied the assigned test article to all psoriatic plaques twice daily for 14 days. The key efficacy measures were the proportion of subjects with "treatment success," defined as those subjects that achieved a score of 0 (clear) or 1 (almost clear) and at least a two-grade improvement compared to baseline for the Investigator's Global Assessment (IGA) and for the clinical signs of psoriasis (plaque elevation, scaling, and erythema) as well as pruritus. Safety measurements included adverse events and local skin reactions in the treatment area. RESULTS: HBP-Foam was statistically superior to vehicle in achieving "Treatment Success" in 25.3% and 30.7% vs 3.9% and 7.4% (P<0.001) in Studies 1 and 2, respectively. Pruritus scores statistically improved by over 30% in HBP-Foam treated subjects. In addition, these subjects experienced a significant reduction in the clinical signs of psoriasis (plaque elevation, scaling, and erythema). In contrast, in the vehicle groups the decrease in psoriasis-related signs was generally not observed. Safety outcomes were unremarkable and similar in both the HBP-Foam and vehicle treatment groups. CONCLUSIONS: These results demonstrate the safety and effectiveness of HBP-Foam in the treatment of plaque psoriasis. Furthermore, this novel foam formulation has demonstrable for its ease of application over large and/or hairy treatment areas. ClinicalTrials.gov Registration: NCT02742441 NCT02368210


Assuntos
Clobetasol/análogos & derivados , Fármacos Dermatológicos/administração & dosagem , Veículos Farmacêuticos/administração & dosagem , Prurido/tratamento farmacológico , Psoríase/tratamento farmacológico , Vasoconstritores/administração & dosagem , Adulto , Idoso , Clobetasol/administração & dosagem , Clobetasol/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Veículos Farmacêuticos/efeitos adversos , Prurido/diagnóstico , Prurido/etiologia , Psoríase/complicações , Psoríase/diagnóstico , Índice de Gravidade de Doença , Pele , Resultado do Tratamento , Vasoconstritores/efeitos adversos
6.
Arch Dermatol Res ; 311(9): 653-672, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31321504

RESUMO

Wounds are a common medical infliction. With the increase in microbial resistance and a shift of interest towards complementary medicines, essential oils have been shown to be beneficial in suppressing microbial growth. However, in practice, essential oils are more often diluted into a base due to the risk of topical adverse effects, such as dermatitis. There is a lack of collated evidence-based information on toxicity and efficacy of carrier oils. The current information on the subject matter is restricted to generic, aroma-therapeutic books and pamphlets, based on anecdotal evidence rather than an experimental approach. Therefore, this review aimed at identifying the recommended carrier oils used in dermatology and thereafter collating the scientific evidence to support the use of carrier oils together with essential oils recommended for dermatological use. Aloe vera gel had multiple studies demonstrating the ability to enhance wound healing; however, several other carrier oils have been largely neglected. It was observed that the extracts for certain plant species had been used to justify the use of the carrier oils of the same plant species. This is an inaccurate cross assumption due to the difference in chemical composition and biological activities. Lastly, despite these carrier oils being recommended as a base for essential oils, very little data was found on the interactive profile of the carrier oil with the essential oil. This review provides a platform for further studies, especially if essential oils are to receive credence in the scientific field.


Assuntos
Óleos Voláteis/administração & dosagem , Veículos Farmacêuticos/química , Óleos Vegetais/química , Pele/efeitos dos fármacos , Administração Cutânea , Aloe/química , Humanos , Óleos Voláteis/efeitos adversos , Pomadas , Veículos Farmacêuticos/efeitos adversos , Óleos Vegetais/efeitos adversos , Cicatrização/efeitos dos fármacos
7.
Planta Med ; 85(13): 1114-1123, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31340396

RESUMO

The fruit from various pepper plants has been employed for the seasoning of food, as perfuming agents, and also as traditional medicines. Phytochemicals isolated from different pepper species have been found to modulate the pharmacokinetics of orally administered drugs. This study investigated the possibility to apply capsaicin and piperine (extracted alkaloids) as modulators for drug delivery across the nasal epithelium. Both a nasal epithelial cell line (RPMI 2650) and excised sheep nasal tissue were used as models to investigate the effects of the selected pepper compounds on drug permeation. FITC-dextran 4400 (MW 4400 Da) was used as a large molecular weight marker compound for paracellular transport, while rhodamine 123 was used as a marker compound that is a substrate for P-glycoprotein-mediated efflux. From the permeation results, it was clear that capsaicin inhibited P-glycoprotein efflux to a larger extent, while piperine showed drug permeation enhancement via other mechanisms. The cell cytotoxicity studies indicated that capsaicin was noncytotoxic up to a concentration of 200 µM and piperine up to a concentration of 500 µM as indicated by cell viability above 80%. The histological analysis of the excised nasal tissue and cultured RPMI 2650 cell layers indicated that some damage occurred after treatment with 200 µM capsaicin, but no changes were observed for piperine up to a concentration of 50 µM.


Assuntos
Alcaloides/uso terapêutico , Benzodioxóis/uso terapêutico , Capsaicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Mucosa Nasal/metabolismo , Veículos Farmacêuticos/uso terapêutico , Piperidinas/uso terapêutico , Alcamidas Poli-Insaturadas/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Alcaloides/farmacologia , Animais , Benzodioxóis/farmacologia , Capsaicina/farmacologia , Mucosa Nasal/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Ovinos
8.
J Drugs Dermatol ; 18(6): 557, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251548

RESUMO

Objective: The study was conducted to determine the efficiency of the botanicals combination incorporated in the Kamedis Eczema Therapy Cream (the tested product) for adults and children suffering from mild to moderate Atopic Dermatitis. Design: The study designed as an interventional, multi-center, double-blind, randomized, controlled study. Setting: Subjects were evenly randomly divided into three treatment groups: tested product, vehicle, and comparator. The vehicle used was the identical tested product without the botanical combination while the comparator was a leading OTC brand in the US market. All three above groups used a similar Kamedis wash for the body and face following by one of the three randomized treatment creams for the affected areas on the face and body. Participants: One hundred and eight (108) subjects with uncomplicated, stable, mild to moderate atopic dermatitis recruited and qualified for the study; 71 females and 37 males, age 3 to 73. Measurements: The investigator assessed the severity of each subject using the Investigator Global Assessment (IGA) and affected body surface area (BSA) at each of the visit days 0, 7, 14, and 28. Results: The tested product demonstrated an improvement in IGA and BSA over the vehicle at every visit across treatment time, proving the validation that the botanical product is much more effective and beneficial than the same product without the botanicals. The tested product as well as the comparator reached exactly the same percentage, 34%, of 'clear' IGA subjects of the enrolled subjects, presenting advantage over the vehicle. The BSA improvement comparison analysis of the tested product over the vehicle yielded statistically significant P value of 0.0369. Conclusion: The study results approve and validate that the botanical combination is the key factor for the efficacy and improvement of the AD symptoms within this study population. J Drugs Dermatol. 2019;18(6):557-561.


Assuntos
Dermatite Atópica/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Creme para a Pele/administração & dosagem , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Dermatite Atópica/diagnóstico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Veículos Farmacêuticos/administração & dosagem , Veículos Farmacêuticos/efeitos adversos , Extratos Vegetais/efeitos adversos , Índice de Gravidade de Doença , Creme para a Pele/efeitos adversos , Resultado do Tratamento , Adulto Jovem
9.
J Drugs Dermatol ; 18(6): 570, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251550

RESUMO

Androgens play a key role in acne pathogenesis in both males and females. Clascoterone (CB-03-01, Cortexolone 17α propionate) cream is a topical anti-androgen under investigation for the treatment of acne. The results from a phase 2b dose escalating study are discussed. Methods: Primary objective: to compare the safety and efficacy of topical creams containing clascoterone 0.1% (twice daily [BID]), 0.5% (BID), or 1% (daily [QD] or BID) versus vehicle (QD or BID) in male and female subjects ≥12 years with facial acne vulgaris. Efficacy was assessed by: Investigator's Global Assessment (IGA)--the overall severity of acne using a five-point scale (from 0=clear to 4=severe); inflammatory and non-inflammatory acne lesion counts (ALC); and subject satisfaction with treatment--subjects assessed overall treatment satisfaction using a 4-point scale. Safety assessments: local and systemic adverse events (AEs), physical examination/vital signs, laboratory tests, local skin reactions (LSRs), and electrocardiograms (ECGs). Treatment success required a score of "clear" or "almost clear" (IGA score of 0 or 1) and a two or more-grade improvement from baseline. Results: 363 subjects (N=72, 0.1% BID; N=76, 0.5% BID; N=70, 1% QD; N=70, 1% BID; and N=75, vehicle QD or BID) enrolled. 304 subjects (83.7%) completed the study. Intention to Treat (ITT) population: 196/363 (54.0%) females; 167/363 46.0%) males; (257/363 (70.2%) were white; average age=19.7 years. Demographic and baseline characteristics were similar across all groups. Treatment success at week 12 were highest for the 1% BID (6/70, 8.6%) and 0.1% BID (6/72, 8.3%) groups versus vehicle (2/75, 2.7%). Absolute change in inflammatory (P=0.0431) and non-inflammatory (P=0.0303) lesions was statistically significant among the treatment groups. The median change from baseline at week 12 in inflammatory and non-inflammatory lesions was greatest in the 1% BID group -13.5 and -17.5, respectively. Similar results were observed for the secondary efficacy endpoints whereby the highest success rate and greatest reduction in lesion counts from baseline to week 12 occurred with 1% BID. 93/363 subjects (25.6%) reported ≥1 AEs; total number of AEs=123 with 2 probably/possibly related to treatment (N=1, 1% QD group). Subjects with ≥1AEs: 0.1% BID=25.0%, 0.5% BID=38.2%, 1% QD=22.9%, 1% BID=18.6%, and vehicle=22.7%. AEs were mostly mild in severity and similar across all groups. Most AEs (93/121 76.8%) resolved by the end of the study. Erythema was the most prevalent LSR; 36.8% had at least minimal erythema at some point during the study. Conclusions: All clascoterone cream concentrations were well tolerated with no clinically relevant safety issues noted. Clascoterone 1% BID treatment had the most favorable results and was selected as the best candidate for further clinical study and development. Two Phase 3 investigations of clascoterone topical cream, 1% for the treatment of moderate-to-severe acne vulgaris in individuals ≥9 years recently concluded. J Drugs Dermatol. 2019;18(6):570-575.


Assuntos
Acne Vulgar/tratamento farmacológico , Cortodoxona/análogos & derivados , Propionatos/administração & dosagem , Creme para a Pele/administração & dosagem , Acne Vulgar/diagnóstico , Adolescente , Adulto , Cortodoxona/administração & dosagem , Cortodoxona/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Face , Feminino , Humanos , Masculino , Veículos Farmacêuticos/administração & dosagem , Veículos Farmacêuticos/efeitos adversos , Propionatos/efeitos adversos , Índice de Gravidade de Doença , Creme para a Pele/efeitos adversos , Resultado do Tratamento , Adulto Jovem
10.
J Microencapsul ; 36(6): 523-534, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31190589

RESUMO

Aim: To reduce the toxic effects and achieve efficiency of Tripterygium glycosides, an oral microemulsion was designed. Method: After estimating its stability and characterisation, an animal experiment was held to evaluate its toxicity in vivo, using male and female Sprague Dawley rats. Result: The maximum loading amount of microemulsion to Tripterygium glycosides was 18.87 mg/ml. And comparing to control, the Tripterygium glycoside microemulsion can maintain a normal level of the number of sperms, the weight of testicle, testosterone (∼2.5 ng/mL) and BUN (∼5 mmol/L) to male rats. For female rats, it can prevent the ovary to be atrophy and keep FSH to be stable (>2100 ng/L). The weaker injury induced by drug-loaded microemulsion to rats also could be observed in histological sections to kidney and reproductive organs. Conclusions: Although the blank microemulsion had slight toxicity, it mitigated the toxicity of Tripterygium glycosides to kidney and reproductive system.


Assuntos
Glicosídeos/administração & dosagem , Tripterygium/química , Administração Oral , Animais , Emulsões/efeitos adversos , Emulsões/química , Feminino , Glicosídeos/efeitos adversos , Glicosídeos/química , Glicosídeos/farmacologia , Rim/efeitos dos fármacos , Masculino , Ovário/efeitos dos fármacos , Veículos Farmacêuticos/química , Ratos Sprague-Dawley , Solubilidade , Testículo/efeitos dos fármacos
12.
J Pediatr Nurs ; 47: 36-43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31026679

RESUMO

PROBLEM: To determine the safety and efficacy of topical corticosteroid versus vehicle/moisturizer in children under 2 years old (<2 y). ELIGIBILITY CRITERIA: A systematic review and meta-analysis searching PubMed MEDLINE, Embase, Web of Science, Cochrane Database of Controlled Trials, Cochrane Database of Systematic Reviews, DARE, NHS Economic Evaluation, CINAHL, GREAT, and Clinicaltrials.gov. We selected randomized controlled trials (RCTs) comparing topical corticosteroids to vehicle/moisturizer and included children <2 y. Two authors extracted data. SAMPLE: Only one study limited analyses to children <2 y, so our review included participants older than 2 years. Twelve RCTs were included with 2224 participants. Ten studies were industry-sponsored. RESULTS: The proportion of responders to topical corticosteroid across studies was 0.65 (95% CI, 0.54-0.74), as compared to vehicle/moisturizer 0.32 (95% confidence interval (CI), 0.20-0.48). The proportion of adverse events were similar between groups (topical steroids 0.17 (95% CI, 0.08-0.33) vs. vehicle/moisturizer 0.12 (CI 0.02-0.42)). High heterogeneity in treatment response occurred across studies that could not be explained by potential moderators. Mild adrenal suppression occurred in 4 of 157 measured participants (3%) receiving topical corticosteroids. Limitations include the few RCTs on this topic, the inclusion of participants >2 y and outcome measures and reporting methods rarely met CONSORT guidelines. CONCLUSIONS: Topical corticosteroids trended to being more effective and equally safe to vehicle/moisturizers, but generalizability is limited given the dearth of well-designed studies focused on children <2 y. Adverse events from vehicle/moisturizer may be greater than topical corticosteroid due to under treatment. IMPLICATIONS: Further work is needed in this age group.


Assuntos
Corticosteroides/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Creme para a Pele/administração & dosagem , Administração Tópica , Criança , Humanos , Veículos Farmacêuticos
13.
J Pharm Biomed Anal ; 171: 30-34, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959317

RESUMO

Conjugation of macromolecular drugs to polyethylene glycol (PEG) improves their therapeutic potential by reducing their rate of degradation, thereby extending the drugs half life. As a substantial component of the drug, it is necessary to measure the pharmacokinetic (PK) characteristics of PEG in vivo. A quantitative NMR-based method was developed and successfully applied to measuring double-branched polyethylene glycol 40 kDa (PEG40) in serum samples, enabling determination of PK parameters of PEG40 in preclinical species. NMR is ideal for measuring such polymers because a single, sharp peak is obtained for all the equivalent methylene protons; this amplifies the signal and makes the method insensitive to polymeric heterogeneity. High field NMR (600 MHz) with proton-observe cryoprobe technology allowed for analysis of samples in 300 nM range. Mice received 50 mg/kg of PEG40 intravenously (IV) and serum samples were collected at regular intervals for up to 72 h after dosing. The serum samples were analyzed for PEG40 using the NMR method and PK parameters were calculated using non-compartmental analysis. The volume of distribution was determined to be 0.17 L/kg for IV dosing, indicating limited distribution to interstitial space. A low clearance and observed half life of 18 h is consistent with previous reports on the PK properties of a variety of different PEG molecules ranging from 3 kDa to 190 kDa using 125I-labeled PEG in mice. The current NMR technique is easy to implement and does not require labeling of the PEG. Additionally, this is the first report, to our knowledge, of NMR spectroscopy application to PK profiling in serum.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Veículos Farmacêuticos/farmacocinética , Polietilenoglicóis/farmacocinética , Animais , Meia-Vida , Injeções Intravenosas , Limite de Detecção , Masculino , Camundongos , Veículos Farmacêuticos/administração & dosagem , Polietilenoglicóis/administração & dosagem
14.
Skin Pharmacol Physiol ; 32(3): 132-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909278

RESUMO

BACKGROUND/AIMS: The mechanisms by which permeation enhancers increase human skin permeation of caffeine and naproxen were assessed in vitro. METHODS: Active compound solubility in the vehicles and in the stratum corneum (SC), active compound flux across epidermal membranes and uptake of active and vehicle components into the SC were measured. The effect of vehicle pH on the permeation of caffeine and naproxen was also determined. RESULTS: Oleic acid and eucalyptol significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous controls. Naproxen permeation was increased from vehicles with pH presenting more ionized naproxen. Caffeine maximum flux enhancement was associated with an increase in caffeine SC solubility and skin diffusivity, whereas for naproxen a penetration enhancer/vehicle-induced increase in solubility in the SC correlated with an increase in maximum flux. SC solubility was related to experimentally determined active uptake, which was in turn predicted by vehicle uptake and active compound solubility in the vehicle. CONCLUSION: A permeation enhancer-induced alteration in diffusivity, rather than effects on SC solubility, was the main driving force behind increases in permeation flux of the hydrophilic molecule caffeine. For the more the lipophilic molecule naproxen, increased SC solubility drove the increases in permeation flux.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Cafeína/farmacocinética , Epiderme/efeitos dos fármacos , Naproxeno/farmacocinética , Veículos Farmacêuticos/farmacologia , Absorção Cutânea/efeitos dos fármacos , Epiderme/metabolismo , Etanol/farmacologia , Eucaliptol/farmacologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Ácido Oleico/farmacologia , Permeabilidade , Polietilenoglicóis/farmacologia , Dodecilsulfato de Sódio/farmacologia
15.
J Drugs Dermatol ; 18(2s): s99, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811152

RESUMO

It has been said that the best treatment for a given patient is the one that the patient will actually use. The comment, often spoken with humor, actually underscores several important aspects of dermatology care today. Foremost is the fact that patient adherence (as influenced by their satisfaction with treatment) is a critical driver of clinical success. Additionally, dermatologists now often have a range of vehicle formulations from which to select treatment.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Cooperação do Paciente , Veículos Farmacêuticos , Dermatopatias/tratamento farmacológico , Administração Cutânea , Dermatologia/métodos , Humanos
16.
J Drugs Dermatol ; 18(2s): s100-s107, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811153

RESUMO

Topical delivery of therapeutic agents for skin diseases is a major advantage in dermatology. However, the efficacy and tolerability of topically applied therapies is dependent on several characteristics, including percutaneous penetration and permeation of active ingredient and lack of side effects, especially local tolerability reactions. Importantly, the ultimate performance of a topical product includes collectively the effects of the active ingredient and the impact that specific additives have on vehicle characteristics, such as penetration, permeation, epidermal barrier properties, relative irritancy, allergenicity potential, and patient acceptance/preference of the vehicle formulation used. Foam vehicles have evolved over time with the emergence of a menu of alcohol-based and aqueous-based variations that provide various advantages depending on clinical circumstances and the disease being treated. Aqueous-based foams have gained widespread acceptance and preference, especially due to favorable skin tolerability and the cosmetic elegance of the products. In this manuscript, data are presented supporting the efficacy, tolerability, and safety, of specific aqueous-based foam vehicles for calcipotriene used to treat plaque psoriasis, and for tazarotene used to treat acne vulgaris. Discussions include both vehicle-based properties that are relevant to clinical practice, and outcomes from the large-scale pivotal clinical trials that review efficacy and safety results and patient reported outcomes. The latter also discusses several practical subject assessments about use of the foam vehicle. J Drugs Dermatol. 2019;18(2 Suppl):s100-107.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Veículos Farmacêuticos/farmacologia , Dermatopatias/tratamento farmacológico , Administração Cutânea , Fármacos Dermatológicos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Veículos Farmacêuticos/química , Absorção Cutânea/efeitos dos fármacos , Resultado do Tratamento , Água/química
17.
J Drugs Dermatol ; 18(2s): s111, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811154

RESUMO

Atopic Dermatitis (AD) is estimated to affect 15-20% of children and remains a major health consideration for pediatricians and dermatologists.1 Over the past three decades, studies have shown an increase in the prevalence of AD in industrialized nations, with lower numbers seen in developing countries.2


Assuntos
Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Veículos Farmacêuticos , Administração Cutânea , Adulto , Fatores Etários , Criança , Dermatite Atópica/epidemiologia , Humanos , Prevalência
18.
Food Chem ; 275: 135-142, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30724179

RESUMO

The physiological efficacy of nutraceuticals is dependent on their physicochemical nature and bioavailability across biological barriers. In the present work, effects of nano-sizing of emulsion-based delivery vehicle on the bioavailability of polyunsaturated fatty acids rich fish oil have been investigated via three-step experimental design; ex vivo rat everted intestinal sac model, cellular lipid uptake and the bioactivity in rat PBMCs. Nanoemulsion in comparison to the conventional emulsion has shown significant higher rate of uptake of polyunsaturated fatty acids in three segments of small intestine. The time-kinetics of such uptake was correlated with appearance of short-chain fatty acids in basal side of the everted sac. The bioavailability of the formulated fish oil and its inhibitory response against lipopolysaccharide-induced nitric oxide production in rat PBMCs were positively correlated. This formulation with nano-sized droplets can be utilized as smart delivery vehicles for designing oral therapies in future.


Assuntos
Emulsões/química , Óleos de Peixe/farmacocinética , Nanoestruturas/química , Animais , Disponibilidade Biológica , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacocinética , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/farmacocinética , Emulsões/farmacocinética , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos Insaturados/farmacocinética , Óleos de Peixe/administração & dosagem , Intestino Delgado/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Veículos Farmacêuticos/química , Veículos Farmacêuticos/farmacocinética , Ratos Sprague-Dawley
19.
Pharm Dev Technol ; 24(6): 689-699, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30712434

RESUMO

The purpose of this work was to design and characterize a topical formulation of econazole nitrate (EN) with potential for treating Raynaud's phenomenon (RP). Four topical dosage forms (F1_topical solution, F2_HPMC or hydroxypropyl methylcellulose dispersion, F3_VersaBase® cream, and F4_Lipoderm® Activemax™ Cream) containing 3% w/w EN were prepared and characterized for drug content, pH, viscosity, spreadability, drug crystallinity, stability, and in vitro permeation using Franz cells across pig ear skin, and results were compared to the 1% marketed EN cream. All four formulations had acceptable physical and visual characteristics required for topical application, with 3% w/w EN. The order of amount of drug permeated from highest to lowest was F2 (10.27%) > F4 (2.47%) > F1 (2.28%) > F3 (1.47%) > marketed formulation (0.22%). Formulation F2 showed better penetration of the drug into the stratum corneum, epidermis, and dermis layers. The drug concentration in the stratum corneum and epidermis was approximately 10-20 times higher with F2 compared to the marketed formulation. All formulations were found to be stable for up to 6 months. All four EN formulations were found to be better than the 1% marketed cream. Formulation F2_HPMC dispersion could be further explored as a treatment option for RP.


Assuntos
Inibidores de 14-alfa Desmetilase/administração & dosagem , Antifúngicos/administração & dosagem , Econazol/administração & dosagem , Veículos Farmacêuticos/química , Doença de Raynaud/tratamento farmacológico , Inibidores de 14-alfa Desmetilase/farmacocinética , Administração Tópica , Animais , Antifúngicos/farmacocinética , Cristalização , Composição de Medicamentos/métodos , Econazol/farmacocinética , Humanos , Derivados da Hipromelose/química , Doença de Raynaud/metabolismo , Absorção Cutânea , Suínos
20.
Mol Pharm ; 16(3): 1397-1405, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30753778

RESUMO

Celastrol (CLT)-loaded PEG-PLGA nanoparticles (NPs/CLT) coated with neutrophil membranes (NNPs/CLT) were explored for the management of acute pancreatitis (AP). PEG-PLGA nanoparticles sized around 150 nm were proven to selectively accumulate in the pancreas in rats with AP. NNPs were found to overcome the blood-pancreas barrier and specifically distributed to the pancreatic tissues. Moreover, NNPs showed more selective accumulation in the pancreas than nanoparticles without any membrane coating in AP rats. Compared to CLT solution and the NPs/CLT group, NNPs/CLT significantly downregulated the levels of serum amylase and pancreatic myeloperoxidase in AP rats. Also, using NNPs as the delivery vehicle significantly reduced the systemic toxicity of CLT in AP rats. Together, these results suggest that NNPs/CLT represent a highly promising delivery vehicle for the targeted therapy of AP.


Assuntos
Membrana Celular/química , Inflamação/tratamento farmacológico , Nanopartículas/química , Neutrófilos/citologia , Pancreatite/tratamento farmacológico , Veículos Farmacêuticos/metabolismo , Triterpenos/química , Amilases/sangue , Animais , Membrana Celular/metabolismo , Modelos Animais de Doenças , Interleucina-6/sangue , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Masculino , Terapia de Alvo Molecular/métodos , Nanopartículas/metabolismo , Pancreatite/complicações , Pancreatite/diagnóstico por imagem , Tamanho da Partícula , Veículos Farmacêuticos/química , Poliésteres/química , Poliésteres/metabolismo , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Resultado do Tratamento , Triterpenos/metabolismo , Fator de Necrose Tumoral alfa/sangue
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