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1.
J Dermatol ; 46(6): 457-465, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31106905

RESUMO

The pH of the skin surface increases with age and thus reduces epidermal barrier function. Aged skin needs appropriate skin care to counterbalance age-related pH increase and improve barrier function. This confirmatory randomized study investigated the efficacy of water-in-oil (w/o) emulsions with either pH 4 or pH 5.8 in 20 elderly subjects after 4 weeks of treatment. After the treatment, the skin was challenged with a sodium dodecyl sulphate (SDS) solution in order to analyze barrier protection properties of both formulations. The pH 4 w/o emulsion resulted in a significantly lower skin pH compared with the pH 5.8 w/o emulsion and an improved skin hydration after 4-week treatment. Further, the pH 4 emulsion led to more pronounced improvements in length of intercellular lipid lamellae, lamellar organization as well as lipid levels than the pH 5.8 emulsion. Following SDS-induced barrier damage to the skin, the pH of all test areas increased, but the area treated with the pH 4 emulsion showed the lowest increase compared with baseline. In addition, even after the SDS challenge the skin area treated with the pH 4 emulsion still maintained a significantly increased length of intercellular lipid lamellae compared with the beginning of the study. This study provides evidence that topical application of a w/o emulsion with pH 4 reacidifies the skin in elderly and has beneficial effects on skin moisturization, regeneration of lipid lamellae and lipid content. Application of a pH 4 emulsion can improve the epidermal barrier as well as the stratum corneum organization in aged skin.


Assuntos
Cosméticos/administração & dosagem , Epiderme/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Perda Insensível de Água/efeitos dos fármacos , Administração Cutânea , Idoso , Método Duplo-Cego , Emulsões , Epiderme/efeitos dos fármacos , Epiderme/ultraestrutura , Espaço Extracelular/diagnóstico por imagem , Espaço Extracelular/metabolismo , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Óleos/química , Permeabilidade/efeitos dos fármacos , Envelhecimento da Pele/fisiologia , Dodecilsulfato de Sódio/farmacologia , Resultado do Tratamento , Água/química
2.
Toxicol Appl Pharmacol ; 370: 154-169, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905688

RESUMO

The clinical use of the anticholinergic glycopyrrolate dates back to the early 1960s when it was first approved in the U.S. Since then, oral and inhalation formulations have been developed as therapeutic agents inhibiting the muscarinic acetylcholine receptor in various indications including chronic obstructive pulmonary disease (COPD), excessive salivation, and peptic ulcers. More recently, topical formulations of glycopyrrolate (GPB, also known as glycopyrronium bromide) have gained interest as a treatment option for excessive sweating (hyperhidrosis). The U.S. Food and Drug Administration (FDA) approved the first topical glycopyrronium product for the treatment of hyperhidrosis in 2018. Glycopyrrolate, as a quaternary amine, shows minimal penetration of the blood brain barrier which limits CNS side effects. In addition, lack of phototoxicity, genotoxicity and carcinogenicity makes it suitable for chronic indications. The information on the nonclinical and clinical safety profile of glycopyrronium supporting various therapeutically approved uses has been obtained from published literature, our own data as well as summary documents issued by regulatory bodies. Collectively, these data support the conclusion that the benefits of glycopyrronium generally outweigh the risks in chronic use indications that require muscarinic receptor antagonism to provide therapeutic effects.

3.
PLoS One ; 14(1): e0210967, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30677065

RESUMO

This open, prospective, multicenter, observational study was performed to investigate the efficacy and safety of a non-hormonal cream in women undergoing breast cancer treatment and experiencing vulvovaginal dryness symptoms. Overall, 128 patients from 22 study centers participated. The cream was applied to the vagina and vulva for 28 days. For the efficacy analysis, changes in subjective symptoms (feeling of dryness, itching, burning, pain independent of sexual intercourse, dyspareunia, urinary incontinence) were evaluated. Additionally, the following objective diagnostic findings were assessed by a physician: thinning of vaginal epithelium, redness, petechiae, and discharge. Safety and tolerability were assessed by evaluating type and frequency of adverse events, including adverse medical device-related effects. The frequency and intensity of all subjective symptoms significantly improved from baseline at 28 days (p<0.0001). Additionally, 21.4% of patients were completely free of symptoms (p<0.0001) and urinary incontinence was improved or eliminated in 30.8% of women. The overall sum score for all four objective findings was significantly improved from baseline at 28 days (p<0.0001). The frequency of petechial bleedings was significantly reduced (p<0.0001). Further, significant decreases in the severity of vaginal epithelium thinning, redness and petechiae were observed (p<0.0001). More than 88% of patients and investigators assessed the efficacy and tolerability as being good or very good. No serious adverse events were documented. This study demonstrates that the investigated cream is an effective and safe non-hormonal, topical option in the treatment of vulvovaginal dryness symptoms in patients undergoing breast cancer treatment for. However, the study duration and follow-up time of 4 weeks as well as the non-randomized trial design are limitations of the study.


Assuntos
Cremes, Espumas e Géis Vaginais/uso terapêutico , Doenças Vaginais/tratamento farmacológico , Administração Intravaginal , Administração Tópica , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Atrofia , Emulsões/administração & dosagem , Feminino , Humanos , Lubrificantes/administração & dosagem , Menopausa Precoce/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Vagina/patologia , Cremes, Espumas e Géis Vaginais/administração & dosagem , Doenças Vaginais/patologia , Doenças Vaginais/fisiopatologia , Vulva/patologia
4.
Clin Cosmet Investig Dermatol ; 11: 591-602, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538520

RESUMO

Background: Pruritus reduces quality of life and may occur at different sites of the body. To alleviate pruritus, lipid replenishing and rehydration of the skin is often unsatisfactory. Thus, products with additional antipruritic effects are needed. Objectives: Antipruritic effects and cosmetic properties of two different emulsions, water-in-oil (w/o) or oil-in-water (o/w), and a shampoo containing a lipophilic Echinacea purpurea root extract (Ec.-extract) were assessed in adults suffering from pruritus. Methods: Adults (n = 55) with pruritus of the body applied a w/o emulsion for 2 weeks. In a separate study, adults (n = 33) with a pruritic scalp applied an o/w-emulsion for 4 weeks. In a third study, shampoo (n = 34) was applied for 4 weeks. Objective (erythema, dryness, and papules) and subjective (intensity, duration, and burden of pruritus) parameters were assessed. Results: Treatment with the w/o emulsion significantly reduced erythema and dryness (P < 0.0001) as well as pruritus (in 93% of participants) on the body. Treatment with the o/w-emulsion on the scalp significantly (P < 0.0001) reduced objective (erythema in 61% and dryness in 85% of participants) and subjective (85% of participants had reduced pruritus) parameters. Similar results in reduction of dryness (76% of participants) and pruritus (70 % of participants) were seen after 4 weeks of shampoo use. Conclusion: Independent from the type of emulsion (w/o or o/w), cosmetic products containing a proprietary Ec.-extract significantly reduced objective and subjective parameters in adults suffering from acute or chronic pruritus exhibiting excellent tolerability.

5.
mSphere ; 3(3)2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29875146

RESUMO

Bacterial vaginosis (BV) is a prevalent multifactorial disease of women in their reproductive years characterized by a shift from the Lactobacillus species-dominated microbial community toward a taxonomically diverse anaerobic community. For unknown reasons, some women do not respond to therapy. In our recent clinical study, among 37 women diagnosed with BV, 31 were successfully treated with metronidazole, while 6 still had BV after treatment. To discover possible reasons for the lack of response in those patients, we performed a metatranscriptome analysis of their vaginal microbiota, comparing them to the patients who responded. Seven of 8 clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) genes of Gardnerella vaginalis were highly upregulated in nonresponding patients. Cas genes, in addition to protecting against phages, might be involved in DNA repair, thus mitigating the bactericidal effect of DNA-damaging agents such as metronidazole. In the second part of our study, we analyzed the vaginal metatranscriptomes of four patients over 3 months and showed high in vivo expression of genes for pore-forming toxins in L. iners and of genes encoding enzymes for the production of hydrogen peroxide and d-lactate in L. crispatusIMPORTANCE Bacterial vaginosis is a serious issue for women in their reproductive years. Although it can usually be cured by antibiotics, the recurrence rate is very high, and some women do not respond to antibiotic therapy. The reasons for that are not known. Therefore, we undertook a study to detect the activity of the complete microbiota in the vaginal fluid of women who responded to antibiotic therapy and compared it to the activity of the microbiota in women who did not respond. We found that one of the most important pathogens in bacterial vaginosis, Gardnerella vaginalis, has activated genes that can repair the DNA damage caused by the antibiotic in those women that do not respond to therapy. Suppressing these genes might be a possibility to improve the antibiotic therapy of bacterial vaginosis.


Assuntos
Anti-Infecciosos/farmacologia , Tolerância a Medicamentos , Metronidazol/farmacologia , Microbiota/efeitos dos fármacos , Vagina/microbiologia , Vaginose Bacteriana/tratamento farmacológico , Vaginose Bacteriana/microbiologia , Anti-Infecciosos/administração & dosagem , Reparo do DNA , Endonucleases/genética , Feminino , Gardnerella vaginalis/enzimologia , Gardnerella vaginalis/genética , Perfilação da Expressão Gênica , Humanos , Metronidazol/administração & dosagem
6.
Microbiome ; 5(1): 119, 2017 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-28903767

RESUMO

BACKGROUND: Bacterial vaginosis (BV) is the most common vaginal syndrome among women in their reproductive years. It is associated with an increased risk of acquiring sexually transmitted infections and complications like preterm labor. BV is characterized by a high recurrence rate for which biofilms frequently found on vaginal epithelial cells may be a reason. RESULTS: Here, we report a controlled randomized clinical trial that tested the safety and effectiveness of a newly developed pessary containing an amphoteric tenside (WO3191) to disrupt biofilms after metronidazole treatment of BV. Pessaries containing lactic acid were provided to the control group, and microbial community composition was determined via Illumina sequencing of the V1-V2 region of the 16S rRNA gene. The most common community state type (CST) in healthy women was characterized by Lactobacillus crispatus. In BV, diversity was high with communities dominated by either Lactobacillus iners, Prevotella bivia, Sneathia amnii, or Prevotella amnii. Women with BV and proven biofilms had an increased abundance of Sneathia sanguinegens and a decreased abundance of Gardnerella vaginalis. Following metronidazole treatment, clinical symptoms cleared, Nugent score shifted to Lactobacillus dominance, biofilms disappeared, and diversity (Shannon index) was reduced in most women. Most of the patients responding to therapy exhibited a L. iners CST. Treatment with WO 3191 reduced biofilms but did not prevent recurrence. Women with high diversity after antibiotic treatment were more likely to develop recurrence. CONCLUSIONS: Stabilizing the low diversity healthy flora by promoting growth of health-associated Lactobacillus sp. such as L. crispatus may be beneficial for long-term female health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02687789.


Assuntos
Antibacterianos/administração & dosagem , Biofilmes/efeitos dos fármacos , Microbiota/efeitos dos fármacos , Tensoativos/administração & dosagem , Vagina/microbiologia , Vaginose Bacteriana/tratamento farmacológico , Adulto , Feminino , Gardnerella vaginalis/efeitos dos fármacos , Gardnerella vaginalis/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactobacillus/efeitos dos fármacos , Lactobacillus/genética , Lactobacillus crispatus/efeitos dos fármacos , Lactobacillus crispatus/genética , Lactobacillus crispatus/isolamento & purificação , Metronidazol/uso terapêutico , Microbiota/genética , Pessoa de Meia-Idade , Pessários , Prevotella/efeitos dos fármacos , Prevotella/genética , RNA Ribossômico 16S/genética , Vagina/efeitos dos fármacos , Vaginose Bacteriana/microbiologia , Adulto Jovem
7.
Microbiome ; 5(1): 99, 2017 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-28807017

RESUMO

BACKGROUND: The urinary microbiota is similarly complex as the vaginal and penile microbiota, yet its role as a reservoir for pathogens and for recurrent polymicrobial biofilm diseases like bacterial vaginosis (BV) is not clear. RESULTS: Here, we analysed the urinary microbiota of healthy men and women and compared it with that of women during BV and after antibiotic treatment using next-generation sequencing of the 16S rRNA gene V1-V2 regions. Eight different community types, so called urotypes (UT), were identified in healthy humans, all of which were shared between men and women, except UT 7, dominated in relative abundance by Lactobacillus crispatus, which was found in healthy women only. Orally applied metronidazole significantly reduced Shannon diversity and the mean relative abundance of Gardnerella vaginalis, Atopobium vaginae, and Sneathia amnii, while L. iners increased to levels twofold higher than those found in healthy women. Although individual urine microbial profiles strongly responded to the antibiotic, the healthy community could not be restored. The correlation between urinary and vaginal fluid microbiota was generally weak and depending on UT and BV status. It was highest in UT 1 in acute BV (59% of samples), but after metronidazole treatment, only 3 out of 35 women showed a significant correlation between their urinary and vaginal microbiota composition. CONCLUSIONS: Urethra and bladder thus harbor microbial communities distinct from the vagina. The high abundance of BV related species in the urine of both men and women suggests that urine may act as a reservoir of pathogens and contribute to recurrence. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02687789.


Assuntos
Antibacterianos/uso terapêutico , Microbiota/efeitos dos fármacos , Microbiota/genética , Urina/microbiologia , Vaginose Bacteriana/tratamento farmacológico , Vaginose Bacteriana/microbiologia , Actinobacteria/genética , Actinobacteria/isolamento & purificação , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Feminino , Gardnerella vaginalis/genética , Gardnerella vaginalis/isolamento & purificação , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactobacillus/genética , Lactobacillus/isolamento & purificação , Masculino , Metronidazol/administração & dosagem , Metronidazol/uso terapêutico , Microbiota/fisiologia , Pessoa de Meia-Idade , RNA Ribossômico 16S , Uretra/microbiologia , Bexiga Urinária/microbiologia , Vagina/microbiologia , Adulto Jovem
8.
PLoS One ; 11(4): e0154086, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27111438

RESUMO

Bacterial vaginosis (BV) is a common infection in reproductive age woman and is characterized by dysbiosis of the healthy vaginal flora which is dominated by Lactobacilli, followed by growth of bacteria like Gardnerella vaginalis. The ability of G. vaginalis to form biofilms contributes to the high rates of recurrence that are typical for BV and which unfortunately make repeated antibiotic therapy inevitable. Here we developed a biofilm model for G. vaginalis and screened a large spectrum of compounds for their ability to prevent biofilm formation and to resolve an existing G. vaginalis biofilm. The antibiotics metronidazole and tobramycin were highly effective in preventing biofilm formation, but had no effect on an established biofilm. The application of the amphoteric tenside sodium cocoamphoacetate (SCAA) led to disintegration of existing biofilms, reducing biomass by 51% and viability by 61% and it was able to increase the effect of metronidazole by 40% (biomass) and 61% (viability). Our data show that attacking the biofilm and the bacterial cells by the combination of an amphoteric tenside with the antibiotic metronidazole might be a useful strategy against BV.


Assuntos
Biofilmes , Gardnerella vaginalis/efeitos dos fármacos , Vaginose Bacteriana/tratamento farmacológico , Antibacterianos , Feminino , Humanos , Testes de Sensibilidade Microbiana , Modelos Biológicos , Vaginose Bacteriana/microbiologia
9.
PLoS Pathog ; 5(1): e1000264, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19148278

RESUMO

Lignin is incorporated into plant cell walls to maintain plant architecture and to ensure long-distance water transport. Lignin composition affects the industrial value of plant material for forage, wood and paper production, and biofuel technologies. Industrial demands have resulted in an increase in the use of genetic engineering to modify lignified plant cell wall composition. However, the interaction of the resulting plants with the environment must be analyzed carefully to ensure that there are no undesirable side effects of lignin modification. We show here that Arabidopsis thaliana mutants with impaired 5-hydroxyguaiacyl O-methyltransferase (known as caffeate O-methyltransferase; COMT) function were more susceptible to various bacterial and fungal pathogens. Unexpectedly, asexual sporulation of the downy mildew pathogen, Hyaloperonospora arabidopsidis, was impaired on these mutants. Enhanced resistance to downy mildew was not correlated with increased plant defense responses in comt1 mutants but coincided with a higher frequency of oomycete sexual reproduction within mutant tissues. Comt1 mutants but not wild-type Arabidopsis accumulated soluble 2-O-5-hydroxyferuloyl-L-malate. The compound weakened mycelium vigor and promoted sexual oomycete reproduction when applied to a homothallic oomycete in vitro. These findings suggested that the accumulation of 2-O-5-hydroxyferuloyl-L-malate accounted for the observed comt1 mutant phenotypes during the interaction with H. arabidopsidis. Taken together, our study shows that an artificial downregulation of COMT can drastically alter the interaction of a plant with the biotic environment.


Assuntos
Arabidopsis/enzimologia , Lignina/biossíntese , Metiltransferases/genética , Oomicetos/patogenicidade , Arabidopsis/genética , Metiltransferases/metabolismo , Oomicetos/fisiologia , Doenças das Plantas/genética , Reprodução
10.
Plant J ; 47(4): 629-39, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16856982

RESUMO

Using activation tagging in the Arabidopsis Col-0 rps2-101C background, we identified a mutant (FMO1-3D) that showed virtually no symptoms after inoculation with virulent Pseudomonas syringae pv. tomato DC3000 bacteria. The dominant, gain-of-function phenotype of the FMO1-3D mutant is due to over-expression of a class 3 flavin-containing mono-oxygenase (FMO). We recapitulated the FMO1-3D mutant phenotype in independent transgenic Col-0 lines over-expressing the FMO1 cDNA under the control of the 35S CaMV promoter. The increased basal resistance observed in the FMO1-3D mutant was also effective against the taxonomically unrelated downy mildew-causing pathogen Hyaloperonospora parasitica. By investigating the progeny from crosses of the FMO1-3D mutant with the NahG transgenic line, we showed that the enhanced basal resistance phenotype was dependent on the accumulation of salicylic acid. FMO1-3D plants showed wild-type resistant reactions after inoculation with avirulent bacteria, indicating that the R-gene-mediated defence physiology was not compromised by FMO1 over-expression. Transcripts of the class 3 FMO1 gene accumulated within 6 h after inoculation of wild-type Col-0 plants with avirulent Pst + avrRpt2 cells. Moreover, a T-DNA insertion into the FMO1 gene resulted in enhanced susceptibility to virulent Pseudomonas and Hyaloperonospora parasitica, suggesting that expression of the FMO1 gene is a hitherto undescribed component of the plant's resistance repertoire. We discuss the possibility that the FMO may participate in the detoxification of virulence factors produced by pathogens.


Assuntos
Arabidopsis/enzimologia , Oxigenases/metabolismo , Doenças das Plantas/microbiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Mutação , Oxigenases/química , Folhas de Planta/metabolismo , Folhas de Planta/microbiologia , Plantas Geneticamente Modificadas
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