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1.
Eur J Contracept Reprod Health Care ; 26(4): 334-342, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33821738

RESUMO

BACKGROUND: Spermicides have been identified as a potentially attractive alternative to hormonal contraceptives and/or intrauterine devices. Thus, this study aimed evaluating the efficacy and local tolerance of benzalkonium chloride (BKC) and myristalkonium chloride (MKC) contained in Pharmatex® vaginal formulations and compare them with nonoxynol-9 (N-9), the most common active ingredient in topical vaginal contraceptives. METHODS: Human normozoospermic samples were assessed for motility, viability, acrosome status and penetration ability after exposure to control, N-9 or different BKC and MKC doses for 0 and 10 minutes. Local tolerance on HeLa cells was evaluated by the Trypan-blue and MTT assays. RESULTS: Exposure to BKC and MKC reduced acrosome integrity while promoting total immobilisation and complete loss of sperm viability (p < .001, n = 15). Both compounds also compromised sperm penetration ability upon exposure (p < .001, n = 15). N-9 induced the same outcomes (p < .001, n = 15); nevertheless, it was more toxic to HeLa cells than BKC and MKC (p < .05, n = 14). CONCLUSIONS: BKC and MKC present strong in vitro spermicidal activity at lower doses than N-9 and were better tolerated after immediate exposure than N-9. Available Pharmatex® galenic formulations were as effective as products based on N-9.


Assuntos
Compostos de Benzalcônio/farmacologia , Anticoncepcionais/farmacologia , Nonoxinol/farmacologia , Espermicidas/farmacologia , Espermatozoides/efeitos dos fármacos , Cloretos , Feminino , Células HeLa/efeitos dos fármacos , Humanos , Masculino
2.
Biol Reprod ; 104(2): 317-324, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33300559

RESUMO

High unintended pregnancy rates are partially due to lack of effective nonhormonal contraceptives; development of safe, effective topical vaginal methods will address this need. Preclinical product safety and efficacy assessment requires in vivo testing in appropriate models. The sheep is a good model for the evaluation of vaginally delivered products due to its close similarities to humans. The study objective was to develop an ovine model for efficacy testing of female nonhormonal contraceptives that target human sperm. Fresh human semen was pooled from male volunteers. Nonpregnant female Merino sheep were treated with control or vaginal contraceptive product (IgG antibody with action against sperm or nonoxynol-9 [N9]). Pooled semen was added to the sheep vagina and mixed with product and vaginal secretions. Microscopic assessment of samples was performed immediately and progressive motility (PM) of sperm was compared between treatments. Cytokines CXCL8 and IL1B were assessed in vaginal fluid after instillation of human semen. No adverse reactions or elevations in proinflammatory cytokines occurred in response to human semen. N9 produced signs of acute cellular toxicity while there were no cellular changes after IgG treatment. N9 and IgG had dose-related effects with the highest dose achieving complete sperm immobilization (no sperm with PM). Surrogate post-coital testing of vaginally administered contraceptives that target human semen was developed in an ovine model established for vaginal product preclinical testing. This expanded model can aid the development of much needed nonhormonal topical vaginal contraceptives, providing opportunities for rapid iterative drug development prior to costly, time-intensive human testing.


Assuntos
Anticoncepcionais Pós-Coito/farmacologia , Nonoxinol/farmacologia , Vagina , Animais , Anticoncepcionais Pós-Coito/administração & dosagem , Feminino , Humanos , Masculino , Nonoxinol/administração & dosagem , Ovinos , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos
3.
Nat Commun ; 11(1): 199, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924800

RESUMO

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth.


Assuntos
Colo do Útero/lesões , Inflamação/metabolismo , Complicações Infecciosas na Gravidez , Ureaplasma/metabolismo , Animais , Proliferação de Células , Colo do Útero/microbiologia , Colo do Útero/patologia , Citocinas , Modelos Animais de Doenças , Feminino , Humanos , Recém-Nascido , Camundongos , Camundongos Endogâmicos C57BL , Nonoxinol , Gravidez
5.
Biomed Res Int ; 2019: 8043415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949510

RESUMO

The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).


Assuntos
Derivados da Hipromelose , Lactose/análogos & derivados , Metilcelulose/análogos & derivados , Nonoxinol , Ácidos Polimetacrílicos , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Liberação Controlada de Fármacos , Derivados da Hipromelose/química , Derivados da Hipromelose/farmacocinética , Derivados da Hipromelose/farmacologia , Lactose/química , Lactose/farmacocinética , Lactose/farmacologia , Metilcelulose/química , Metilcelulose/farmacocinética , Metilcelulose/farmacologia , Nonoxinol/química , Nonoxinol/farmacocinética , Nonoxinol/farmacologia , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacocinética , Ácidos Polimetacrílicos/farmacologia
6.
Med Chem ; 14(8): 773-783, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29792148

RESUMO

BACKGROUND: In our previous work, several piperazine derived bis(dialkylaminethiocarbonyl) disulfides and disulfide esters of dithiocarbamic acid have been synthesized and evaluated for their spermicidal and microbicidal efficacy. These studies have provided some promising compounds for developing a dually active vaginal microbicidal contraceptive which is under pre-clinical stage. OBJECTIVE: The main objective of this study was the design synthesis and biological evaluation of bis(dialkylaminethiocarbonyl) disulfides (4-15) and 2,2'-disulfanediylbis (3-(substituted-1-yl) propane-2,1-diyl) disubstituted-1-carbodithioates (19-28) as non-surfactant molecules capable of eliminating Trichomonas vaginalis as well as irreversibly immobilizing 100% human sperm promptly. METHOD: Spermicidal, anti-trichomonas, cytotoxicity and biocompatibility study of the synthesized compounds was done as per the reported methodologies. RESULT: Among bis(dialkylaminethiocarbonyl) disulfides (4-15, Table 1), compound 4 (MEC 0.02 mM) was found to be the most desirable for spermicidal activity as it was 40 times more active than Nonoxynol-9 (N-9), and also active against Trichomonas vaginalis (MIC 0.02 &1.10 mM). 2, 2'-disulfanediylbis (3-(substituted- 1-yl) propane-2, 1-diyl) disubstituted-1-carbodithioates (19-28, Table 2), and compounds (19, 22, 23, and 24 MEC 0.05 mM) were sixteen times more active than N-9 with promising Trichomonacidal activity. CONCLUSION: This study suggested that the disulfide linkage alone and dithiocarbamate along with disulfide group within the same chemical entity impart the desired multiple activities of compounds.


Assuntos
Antitricômonas/farmacologia , Dissulfetos/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Espermicidas/farmacologia , Tiocarbamatos/farmacologia , Antitricômonas/síntese química , Dissulfetos/síntese química , Desenho de Fármacos , Células HeLa , Compostos Heterocíclicos com 1 Anel/síntese química , Humanos , Lactobacillus acidophilus/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Nonoxinol/farmacologia , Espermicidas/síntese química , Espermatozoides/efeitos dos fármacos , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Trichomonas vaginalis/efeitos dos fármacos
7.
J Clin Pharmacol ; 58(1): 97-106, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28783867

RESUMO

A study was performed to investigate the effect of an intravaginally administered antimycotic, an antibiotic, and a spermicide plus the co-usage of tampons on the pharmacokinetics (PK) of levonorgestrel (LNG) and anastrozole (ATZ) administered as an intravaginal ring (IVR) releasing 1050 µg ATZ per day and 40 µg LNG per day. In this parallel-group, randomized, open-label study, healthy premenopausal women received an IVR as the main treatment. Comedications were administered on 3 consecutive evenings during treatment with IVR on days 9-11 (group A, 400 mg miconazole; group B, 100 mg clindamycin; group C, 75 mg nonoxynol-9); tampon co-usage (group D) was performed on days 20-23. The primary PK parameter was the average plasma concentration (Cav,ss ) of ATZ and LNG at defined intervals, mainly prior to, during, and up to 7 days after the start of comedication. Fifty-two subjects were included, and at least 11 subjects per group completed the treatments. Overall, the medications and comedications were safe and well tolerated. Very similar ATZ and LNG plasma levels were observed across all groups. The calculated ratios of Cav,ss confirmed the absence of PK interactions because all relevant point estimates and 90% confidence intervals were within the range of 0.800-1.250, which is typically used in bioequivalence studies. These results demonstrate the absence of PK interactions between ATZ/LNG released from IVR and the tested antibiotic, antimycotic, spermicide, and tampons. Therefore, no restrictions for the use of the IVR are needed to continue the clinical program intended to treat endometriosis symptoms.


Assuntos
Clindamicina/administração & dosagem , Anticoncepcionais Orais Combinados/farmacocinética , Levanogestrel/farmacocinética , Miconazol/administração & dosagem , Nitrilas/farmacocinética , Nonoxinol/administração & dosagem , Triazóis/farmacocinética , Administração Intravaginal , Adulto , Anastrozol , Antibacterianos/administração & dosagem , Antifúngicos/administração & dosagem , Endometriose/tratamento farmacológico , Feminino , Humanos , Produtos de Higiene Menstrual
8.
J Reprod Immunol ; 124: 38-43, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29054075

RESUMO

The presence of genital inflammatory responses and a compromised vaginal epithelial barrier have been linked to an increased risk of HIV acquisition. It is important to assure that application of candidate microbicides designed to limit HIV transmission will not cause these adverse events. We previously developed high resolution in vivo imaging methodologies in sheep to assess epithelial integrity following vaginal application of a model microbicide, however characterization of genital inflammation in sheep has not been previously possible. In this study, we significantly advanced the sheep model by developing approaches to detect and quantify inflammatory responses resulting from application of a nonoxynol-9-containing gel known to elicit vaginal irritation. Vaginal application of this model microbicide resulted in foci of disrupted epithelium detectable by confocal endomicroscopy. Leukocytes also infiltrated the treated mucosa and the number and composition of leukocytes obtained by cervicovaginal lavage (CVL) were determined by differential staining and flow cytometry. By 18h post-treatment, a population comprised predominantly of granulocytes and monocytes infiltrated the vagina and persisted through 44h post-treatment. The concentration of proinflammatory cytokines and chemokines in CVL was determined by quantitative ELISA. Concentrations of IL-8 and IL-1ß were consistently significantly increased after microbicide application suggesting these cytokines are useful biomarkers for epithelial injury in the sheep model. Together, the results of these immunological assessments mirror those obtained in previous animal models and human trials with the same compound and greatly extend the utility of the sheep vaginal model in assessing the vaginal barrier and immune microenvironment.


Assuntos
Anti-Infecciosos/uso terapêutico , Epitélio/patologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Leucócitos/imunologia , Vagina/patologia , Vaginite/imunologia , Animais , Biomarcadores/metabolismo , Bovinos , Microambiente Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Epitélio/diagnóstico por imagem , Feminino , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Nonoxinol , Vagina/diagnóstico por imagem , Vaginite/induzido quimicamente , Vaginite/tratamento farmacológico
9.
Forensic Sci Int ; 280: 87-94, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28965000

RESUMO

In this study we demonstrate the use of Direct Analysis in Real Time Mass Spectrometry (DART) as a powerful tool for detection of nonoxynol in vaginal fluid post contact with a condom, enabling rapid tracing and added evidences in sexual assault crimes. Vaginal fluid was sampled using cotton swabs and glass rods and measured directly with DART. Sample preparation using water, hexane, methanol, and dichloromethane extraction, was explored for comparison and optimization of signals. Nonoxynol was detected up to eight hours after sampling. Optimal sampling conditions and mass spectrometry parameters are reported and discussed.


Assuntos
Muco do Colo Uterino/química , Preservativos , Lubrificantes/química , Nonoxinol/análise , Espermicidas/análise , Feminino , Medicina Legal , Humanos , Masculino , Espectrometria de Massas/métodos , Manejo de Espécimes , Fatores de Tempo
10.
Contraception ; 96(2): 124-130, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28606382

RESUMO

OBJECTIVES: The Caya® Diaphragm is a newly approved single-size, nonlatex diaphragm. Contragel® is a personal lubricant containing lactic acid approved in Europe and other countries for use with vaginal barrier devices. This study assessed the effectiveness in preventing sperm from penetrating midcycle cervical mucus of Caya with Contragel, Caya with 3% nonoxynol-9 (N-9) and Caya alone. STUDY DESIGN: Phase I multicenter, single-blind, randomized, crossover, nonsignificant risk study at two sites: Eastern Virginia Medical School, Norfolk, VA, USA, and Profamilia, Santo Domingo, Dominican Republic. Healthy, sexually active women 18-45years old, not at risk for pregnancy due to tubal occlusion, were eligible. Each participant was seen in nine visits, completing a baseline cycle (without product use) followed by three test cycles (sequence determined by randomization), each consisting of a cervical mucus check visit and a postcoital test visit. To proceed to test cycles, the baseline postcoital test had to show adequate cervical mucus and >5 progressively motile sperm per high power field (PMS/HPF). RESULTS: All women had an average of <5 PMS/HPF during the test cycle of each study arm, the primary endpoint. Caya with ContraGel and Caya with N-9 reduced the average number of PMS/HPF from 22.5 to 0. Caya alone reduced the average number of PMS/HPF from 22.5 to 0.4. There were two possibly product-related mild adverse events. CONCLUSION: This study supports that Caya with ContraGel is safe and functions as well as Caya with N-9 in preventing PMS from reaching midcycle cervical mucus. IMPLICATIONS: A single-size diaphragm used with a personal lubricant gel containing lactic acid appears to be safe and to function as well as the same diaphragm used with N-9 in preventing PMS from reaching midcycle cervical mucus.


Assuntos
Dispositivos Anticoncepcionais Femininos/efeitos adversos , Nonoxinol/efeitos adversos , Espermicidas/efeitos adversos , Adolescente , Feminino , Humanos , Pessoa de Meia-Idade , Método Simples-Cego , Adulto Jovem
11.
Contraception ; 93(4): 331-336, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26772905

RESUMO

OBJECTIVE: To determine the feasibility of using quantitative changes in vaginal permeability to small molecules as a measure of candidate microbicide toxicity. STUDY DESIGN: Controlled, open-labeled, prospective study. Seven healthy women received a single vaginal dose of hydroxyethylcellulose gel (HEC), nonoxynol-9 (N-9) or K-Y Jelly. Each gel was radiolabeled with a small molecule ((99m)Tc-DTPA) followed by 12-h blood and urine collection. Pharmacokinetic (PK) parameters of (99m)Tc-DTPA were calculated to compare the impact of each gel on vaginal permeability. Each woman served as her own control. The Friedman test with post hoc Wilcoxon test was used to detect differences among the gels. RESULTS: Vaginal permeability of (99m)Tc-DTPA was highest for the N-9 radiolabel. N-9 plasma area under the concentration curve was 2.7-fold higher (p=.04), and peak concentration was threefold higher (p=.04) compared to HEC. There were no significant PK parameter differences between HEC and K-Y Jelly or between N-9 and K-Y Jelly. Cumulative dose-adjusted median (interquartile range) 12-h timed urine gamma activity was 66.70 × 10(-4)µCi (27.90-152.00) following HEC dosing, 103.00 × 10(-4)µCi (98.20-684.00) following N-9 gel dosing and 20.30 × 10(-4)µCi (11.10-55.90) following K-Y gel dosing. The differences between urine HEC and K-Y Jelly (p=.047) and between N-9 and K-Y Jelly (p=.016) were statistically significant. CONCLUSIONS: It is feasible to measure differences in vaginal permeability among vaginal gels using a radiolabeled small molecule, though there are permeability differences that require a nuanced understanding of gel composition to interpret the results. IMPLICATIONS: Establishing the safety of both vehicle and active pharmaceutical ingredient is an essential task in microbicide development, to be determined as soon as possible. This study suggests that a combination of microbicide toxicity assessments, that is, cervicovaginal permeability, inspection and histopathology, may need to be studied simultaneously.


Assuntos
Permeabilidade da Membrana Celular , Vagina/metabolismo , Adolescente , Adulto , Anti-Infecciosos , Celulose/administração & dosagem , Celulose/análogos & derivados , Celulose/farmacocinética , Feminino , Géis , Glicerol/administração & dosagem , Glicerol/farmacocinética , Infecções por HIV/prevenção & controle , Humanos , Pessoa de Meia-Idade , Nonoxinol/administração & dosagem , Nonoxinol/farmacocinética , Fosfatos/administração & dosagem , Fosfatos/farmacocinética , Propilenoglicóis/administração & dosagem , Propilenoglicóis/farmacocinética , Estudos Prospectivos , Pentetato de Tecnécio Tc 99m/farmacocinética , Cremes, Espumas e Géis Vaginais/química , Cremes, Espumas e Géis Vaginais/farmacocinética
12.
Korean J Intern Med ; 30(6): 873-83, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26552463

RESUMO

BACKGROUND/AIMS: Most pesticide formulations contain both chief and additive ingredients. But, the additives may not have been tested as thoroughly as the chief ingredients. The surfactant, nonyl phenoxypolyethoxylethanol (NP40), is an additive frequently present in pesticide formulations. We investigated the effects of NP40 and other constituents of a validamycin pesticide formulation on cell viability and on the expression of genes involved in cell damage pathways. METHODS: The effects of validamycin pesticide ingredients on cell viability and of NP40 on the mRNA expression of 80 genes involved in nine key cellular pathways were examined in the human neuroblastoma SK-N-SH cell line. RESULTS: The chemicals present in the validamycin pesticide formulation were cytotoxic to SK-N-SH cells and NP40 showed the greatest cytotoxicity. A range of gene expression changes were identified, with both up- and down-regulation of genes within the same pathway. However, all genes tested in the necrosis signaling pathway were down-regulated and all genes tested in the cell cycle checkpoint/arrest pathway were up-regulated. The median fold-change in gene expression was significantly higher in the cell cycle checkpoint/arrest pathway than in the hypoxia pathway category (p = 0.0064). The 70 kDa heat shock protein 4 gene, within the heat shock protein/unfolded protein response category, showed the highest individual increase in expression (26.1-fold). CONCLUSIONS: NP40 appeared to be particularly harmful, inducing gene expression changes that indicated genotoxicity, activation of the cell death (necrosis signaling) pathway, and induction of the 70 kDa heat shock protein 4 gene.


Assuntos
Inositol/análogos & derivados , Neurônios/efeitos dos fármacos , Nonoxinol/toxicidade , Praguicidas/envenenamento , Tensoativos/toxicidade , Idoso , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genes cdc , Proteínas de Choque Térmico HSP110/genética , Proteínas de Choque Térmico HSP110/metabolismo , Humanos , Inositol/química , Inositol/envenenamento , Necrose , Neurônios/metabolismo , Neurônios/patologia , Nonoxinol/química , Praguicidas/química , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tensoativos/química
13.
PLoS One ; 10(7): e0129769, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26177352

RESUMO

Intravaginal anti-HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract might contribute to the lower-than-expected efficacy of HIV microbicides. Our objective was to study the effects of intravaginal gels on the immune microenvironment of the cervix and uterus. In this randomized crossover study, 27 healthy female volunteers used a nightly application of intravaginal nonoxynol-9 (N9) gel as a "failed" microbicide or the universal placebo gel (UPG) as a "safe" gel (intervention cycles), or nothing (control cycle) from the end of menses to the mid-luteal phase. At a specific time-point following ovulation, all participants underwent sample collection for measurements of T-cell phenotypes, gene expression, and cytokine/chemokine protein concentrations from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention effects, for N9 and UPG relative to control. Exposure to N9 gel and UPG generated a common "harm signal" that included transcriptional up-regulation of inflammatory genes chemokine (C-C motif) ligand 20 (macrophage inflammatory factor-3alpha) and interleukin 8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor, and transcriptional up-regulation of inflammatory mediators glycodelin-A and osteopontin in the endometrium. These results need to be replicated with a larger sample, but underscore the need to consider the effects of microbicide agents and gel excipients on the upper female reproductive tract in studies of vaginal microbicides.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Colo do Útero/efeitos dos fármacos , Colo do Útero/imunologia , Nonoxinol/efeitos adversos , Útero/efeitos dos fármacos , Útero/imunologia , Administração Intravaginal , Adulto , Fármacos Anti-HIV/administração & dosagem , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/imunologia , Colo do Útero/metabolismo , Estudos Cross-Over , Feminino , Géis , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Nonoxinol/administração & dosagem , Fenótipo , Placebos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Transcriptoma/efeitos dos fármacos , Útero/metabolismo , Adulto Jovem
14.
Obstet Gynecol ; 125(4): 895-903, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25751199

RESUMO

OBJECTIVE: To estimate contraceptive efficacy, safety, acceptability, and fit of a single-size diaphragm used with contraceptive gel. METHODS: We conducted a multicenter trial in which 450 couples used the single-size diaphragm, 300 randomized to acid-buffering gel and 150 to nonoxynol-9, for at least 190 days and six menstrual cycles. Visits were at enrollment and after menstrual cycles 1, 3, and 6. Study outcomes included pregnancy probability, safety, acceptability, and fit. Pregnancy and safety were compared with an historical control group who used a standard diaphragm with these gels. RESULTS: Most (439/450 [98%]) women could be fitted with the single-size diaphragm. A total of 421 of 450 (94%) provided follow-up. The 35 study pregnancies yielded 6-month Kaplan-Meier cumulative typical use pregnancy probabilities per 100 women with 95% confidence intervals (CIs) of 10.4 (6.9-14.0) for all users and 9.6 (5.5-13.6) and 12.5 (5.4-19.5) with acid-buffering gel and nonoxynol-9, respectively. Historical control analysis yielded a propensity score-adjusted estimate of this pregnancy probability for the single-size diaphragm of 11.3 compared with 10.7 per 100 women for the standard diaphragm ([rounded] difference 0.7, 95% CI -3.6 to 4.9). Approximately half (51%) reported at least one urogenital event but compared favorably to the standard diaphragm in historical control analysis. Most (282/342 [82%]) liked the diaphragm. Results suggest that if provided by a clinician, 94% (95% CI 92-96%) could insert, correctly position, and remove the diaphragm. CONCLUSION: The single-size diaphragm was safe, as effective as a standard diaphragm, and acceptable when used with contraceptive gel. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00578877.


Assuntos
Dispositivos Anticoncepcionais Femininos , Gravidez/estatística & dados numéricos , Espermicidas , Cremes, Espumas e Géis Vaginais , Resinas Acrílicas/efeitos adversos , Adulto , Dispositivos Anticoncepcionais Femininos/efeitos adversos , Desenho de Equipamento , Feminino , Humanos , Masculino , Nonoxinol/efeitos adversos , Satisfação do Paciente , Pontuação de Propensão , Espermicidas/efeitos adversos , Cremes, Espumas e Géis Vaginais/efeitos adversos , Adulto Jovem
15.
Toxicol Appl Pharmacol ; 285(3): 198-206, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25818602

RESUMO

Any vaginal product that alters the mucosal environment and impairs the immune barrier increases the risk of sexually transmitted infections, especially HIV infection, which thrives on mucosal damage and inflammation. The FDA-recommended rabbit vaginal irritation (RVI) model serves as a first line selection tool for vaginal products; however, for decades it has been limited to histopathology scoring, insufficient to select safe anti-HIV microbicides. In this study we incorporate to the RVI model a novel quantitative nuclease protection assay (qNPA) to quantify mRNA levels of 25 genes representing leukocyte differentiation markers, toll-like receptors (TLR), cytokines, chemokines, epithelial repair, microbicidal and vascular markers, by designing two multiplex arrays. Tissue sections were obtained from 36 rabbits (6 per treatment arm) after 14 daily applications of a placebo gel, saline, 4% nonoxynol-9 (N-9), and three combinations of the anti-HIV microbicides tenofovir (TFV) and UC781 in escalating concentrations (highest: 10% TFV+2.5%UC781). Results showed that increased expression levels of toll-like receptor (TLR)-4, interleukin (IL)-1ß, CXCL8, epithelial membrane protein (EMP)-1 (P<0.05), and decreased levels of TLR2 (P<0.05), TLR3 and bactericidal permeability increasing protein (BPI) (P<0.001) were associated with cervicovaginal mucosal alteration (histopathology). Seven markers showed a significant linear trend predicting epithelial damage (up with CD4, IL-1ß, CXCL8, CCL2, CCL21, EMP1 and down with BPI). Despite the low tissue damage RVI scores, the high-dose microbicide combination gel caused activation of HIV host cells (SLC and CD4) while N-9 caused proinflammatory gene upregulation (IL-8 and TLR4) suggesting a potential for increasing risk of HIV via different mechanisms depending on the chemical nature of the test product.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Ensaios de Proteção de Nucleases/métodos , Transcriptoma , Vagina/efeitos dos fármacos , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Estudos de Avaliação como Assunto , Feminino , Interações Hospedeiro-Patógeno , Imuno-Histoquímica , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Nonoxinol/administração & dosagem , Nonoxinol/efeitos adversos , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Organofosfonatos/administração & dosagem , Organofosfonatos/efeitos adversos , Coelhos , Tenofovir , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Vagina/patologia
16.
Biomacromolecules ; 15(12): 4403-9, 2014 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-25347518

RESUMO

Mucosal drug delivery nanotechnologies are limited by the mucus barrier that protects nearly all epithelial surfaces not covered with skin. Most polymeric nanoparticles, including polystyrene nanoparticles (PS), strongly adhere to mucus, thereby limiting penetration and facilitating rapid clearance from the body. Here, we demonstrate that PS rapidly penetrate human cervicovaginal mucus (CVM), if the CVM has been pretreated with sufficient concentrations of Pluronic F127. Importantly, the diffusion rate of large polyethylene glycol (PEG)-coated, nonmucoadhesive nanoparticles (PS-PEG) did not change in F127-pretreated CVM, implying that F127 did not significantly alter the native pore structure of CVM. Additionally, herpes simplex virus type 1 (HSV-1) remains adherent in F127-pretreated CVM, indicating that the presence of F127 did not reduce adhesive interactions between CVM and the virions. In contrast to treatment with a surfactant that has been approved for vaginal use as a spermicide (nonoxynol-9 or N9), there was no increase in inflammatory cytokine release in the vaginal tract of mice after daily application of 1% F127 for 1 week. Pluronic F127 pretreatment holds potential as a method to safely improve the distribution, retention, and efficacy of nanoparticle formulations without compromising CVM barrier properties to pathogens.


Assuntos
Muco do Colo Uterino/efeitos dos fármacos , Portadores de Fármacos/química , Poloxâmero/farmacologia , Vagina/efeitos dos fármacos , Vagina/virologia , Animais , Muco do Colo Uterino/virologia , Feminino , Humanos , Camundongos , Nanopartículas/química , Nanotecnologia , Nonoxinol/farmacologia , Poloxâmero/química , Simplexvirus/patogenicidade , Tensoativos/farmacologia , Vagina/metabolismo
17.
PLoS One ; 9(10): e110980, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25333937

RESUMO

Vaginal microbicides hold great promise for the prevention of viral diseases like HIV, but the failure of several microbicide candidates in clinical trials has raised important questions regarding the parameters to be evaluated to determine in vivo efficacy in humans. Clinical trials of the candidate microbicides nonoxynol-9 (N9) and cellulose sulfate revealed an increase in HIV infection, vaginal inflammation, and recruitment of HIV susceptible lymphocytes, highlighting the need to identify biomarkers that can accurately predict microbicide toxicity early in preclinical development and in human trials. We used quantitative proteomics and RT-PCR approaches in mice and rabbits to identify protein changes in vaginal fluid and tissue in response to treatment with N9 or benzalkonium chloride (BZK). We compared changes generated with N9 and BZK treatment to the changes generated in response to tenofovir gel, a candidate microbicide that holds promise as a safe and effective microbicide. Both compounds down regulated mucin 5 subtype B, and peptidoglycan recognition protein 1 in vaginal tissue; however, mucosal brush samples also showed upregulation of plasma proteins fibrinogen, plasminogen, apolipoprotein A-1, and apolipoprotein C-1, which may be a response to the erosive nature of N9 and BZK. Additional proteins down-regulated in vaginal tissue by N9 or BZK treatment include CD166 antigen, olfactomedin-4, and anterior gradient protein 2 homolog. We also observed increases in the expression of C-C chemokines CCL3, CCL5, and CCL7 in response to treatment. There was concordance in expression level changes for several of these proteins using both the mouse and rabbit models. Using a human vaginal epithelial cell line, the expression of mucin 5 subtype B and olfactomedin-4 were down-regulated in response to N9, suggesting these markers could apply to humans. These data identifies new proteins that after further validation could become part of a panel of biomarkers to effectively evaluate microbicide toxicity.


Assuntos
Citocinas/biossíntese , Genitália Feminina/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/biossíntese , Infecções por HIV/tratamento farmacológico , Mucina-5B/biossíntese , Administração Intravaginal , Animais , Anti-Infecciosos/efeitos adversos , Compostos de Benzalcônio/efeitos adversos , Biomarcadores/metabolismo , Celulose/efeitos adversos , Celulose/análogos & derivados , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genitália Feminina/metabolismo , Genitália Feminina/patologia , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Camundongos , Nonoxinol/efeitos adversos , Coelhos , Vagina/efeitos dos fármacos , Vagina/metabolismo
18.
PLoS One ; 9(9): e107164, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25243914

RESUMO

Crude decoction of Chenopodium album seed showed spermicidal effect at MIC 2 mg/ml in earlier studies. Systematic isolation, characterization and evaluation revealed that the major metabolite Desgalactotigonin (DGT) is the most effective principle in both in vitro and in vivo studies. The in vitro studies comprises (a) rat and human sperm motility and immobilizing activity by Sander-Cramer assay; (b) sperm membrane integrity was observed by HOS test and electron microscopy; (c) microbial potential was examined in Lactobacillus broth culture, and (d) the hemolytic index was determined by using rat RBCs. The in vivo contraceptive efficacy was evaluated by intra uterine application of DGT in rat. Lipid peroxidation and induction of apoptosis by DGT on human spermatozoa were also studied. The minimum effective concentration (MEC) of DGT that induced instantaneous immobilization in vitro was 24.18 µM for rat and 58.03 µM for human spermatozoa. Microbial study indicated DGT to be friendly to Lactobacillus acidophilus. Implantation was prevented in DGT treated uterine horn while no hindrance occurred in the untreated contra lateral side. At the level of EC50, DGT induced apoptosis in human spermatozoa as determined by increased labeling with Annexin-V and decreased polarization of sperm mitochondria. Desgalactotigonin emerged 80 and 2×10(4) times more potent than the decoction and Nonoxynol-9 respectively. It possesses mechanism based detrimental action on both human and rat spermatozoa and spares lactobacilli and HeLa cells at MEC which proves its potential as a superior ingredient for the formulation of a contraceptive safer/compatible to vaginal microflora.


Assuntos
Chenopodium album , Anticoncepcionais/farmacologia , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Motilidade Espermática/efeitos dos fármacos , Espermicidas/farmacologia , Espermatozoides/efeitos dos fármacos , Esteroides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Nonoxinol/farmacologia , Ratos
19.
Eur J Contracept Reprod Health Care ; 19(6): 465-74, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25160062

RESUMO

OBJECTIVE: To determine the minimum effective concentration (MEC) of an imbibing and soluble nonoxynol-9 (N-9) diaphragm (ISND) required for immobilisation of all spermatozoa in vitro and in vivo. The speed of semen absorbance, time of ISND to dissolution, and the antifertility effects were also investigated in rabbits. METHODS: In vitro spermicidal tests with ISND were conducted using fresh semen from humans and rabbits. Spermicidal and antifertility effects were observed in vivo after the ISND was placed directly into the vagina of rabbits. RESULTS: The MEC of N-9 required in the ISND to totally immobilise sperm within 20 seconds was 0.15 mg/ml for human sperm, and 0.5 mg/ml for rabbit sperm. The human semen was absorbed into the ISND in 45 minutes; the diaphragm dissolved in the vagina 3.5 hours later. In vivo, in rabbits, the MEC of N-9 required to immobilise sperm within five minutes of mating was 1 mg/kg in the ISND, and 10 mg/kg for the nonoxynol-9 film. The median effective dose of N-9 in the ISND was 1.07 mg/kg, whereas for the film it was 3.30 mg/kg. CONCLUSION: The spermicidal and antifertility activities of a low dose N-9 in the ISND were high, with properties of imbibition and solubility confirmed.


Assuntos
Dispositivos Anticoncepcionais Femininos , Nonoxinol/administração & dosagem , Espermicidas/administração & dosagem , Animais , Feminino , Humanos , Masculino , Nonoxinol/farmacologia , Coelhos , Sêmen , Motilidade Espermática/efeitos dos fármacos , Espermicidas/farmacologia , Espermatozoides/efeitos dos fármacos
20.
Afr J Reprod Health ; 18(2): 77-86, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25022144

RESUMO

This health systems assessment evaluated the feasibility of introducing a new contraceptive device, the SILCS single-size diaphragm, into the existing family planning method mix in Uganda. A total of 26 focus group discussions with 201 female and 77 male potential users and 98 key informant interviews with policymakers and providers were conducted between June and August 2010. Potential users, providers, and policymakers recognised that the SILCS Diaphragm could fill a gap in the method mix and expressed eagerness to make the SILCS Diaphragm available, particularly because it is nonhormonal and woman initiated. The diaphragm was viewed by all stakeholders as a method that would increase choice and could improve women's reproductive health in Uganda. Like many countries, Uganda's family planning programme is financially stretched, and clear support for the SILCS Diaphragm by end-users will need to be demonstrated before the product will be considered for public-sector introduction.


Assuntos
Dispositivos Anticoncepcionais Femininos , Serviços de Planejamento Familiar , Adolescente , Adulto , Feminino , Grupos Focais , Infecções por HIV/prevenção & controle , Humanos , Masculino , Nonoxinol/administração & dosagem , Uganda
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