RESUMO
Sepsis is recognized as a major contributor to the global disease burden, but there is a lack of specific and effective therapeutic agents. Utilizing Mendelian randomization (MR) methods alongside evidence of causal genetics presents a chance to discover novel targets for therapeutic intervention. MR approach was employed to investigate potential drug targets for sepsis. Pooled statistics from IEU-B-4980 comprising 11,643 cases and 474,841 controls were initially utilized, and the findings were subsequently replicated in the IEU-B-69 (10,154 cases and 454,764 controls). Causal associations were then validated through colocalization. Furthermore, a range of sensitivity analyses, including MR-Egger intercept tests and Cochran's Q tests, were conducted to evaluate the outcomes of the MR analyses. Three drug targets (PSMA4, IFNAR2, and LY9) exhibited noteworthy MR outcomes in two separate datasets. Notably, PSMA4 demonstrated not only an elevated susceptibility to sepsis (OR 1.32, 95% CI 1.20-1.45, p = 1.66E-08) but also exhibited a robust colocalization with sepsis (PPH4 = 0.74). According to the present MR analysis, PSMA4 emerges as a highly encouraging pharmaceutical target for addressing sepsis. Suppression of PSMA4 could potentially decrease the likelihood of sepsis.
Assuntos
Análise da Randomização Mendeliana , Sepse , Humanos , Sepse/tratamento farmacológico , Sepse/genética , Sistemas de Liberação de Medicamentos , Carga Global da Doença , Nonoxinol , Estudo de Associação Genômica AmplaRESUMO
OBJECTIVES: This study aimed to explore the bidirectional association between frailty and social relationships in older adults while distinguishing between interpersonal and intrapersonal effects. METHODS: A prospective cohort study of community-dwelling older adults was conducted in Japan in three waves spanning six years with follow-ups in every three years. Random intercept cross-lagged panel model was used to explore temporal associations between frailty and social relationships. RESULTS: Data for 520 participants (mean age 73.02 [SD 6.38] years, 56.7% women) were analyzed. Across individuals, frailty was associated with social relationships (ß = -0.514, p < 0.001). At the interpersonal level, frailty was cross-sectionally associated with social relationships separately at T1(ß = -0.389, p < 0.01), T2 (ß = -0.343, p < 0.001) and T3 (ß = -0.273, p < 0.05). Moreover, social relationships were associated with subsequent increases in symptoms of frailty in all measurement waves (ß = -0.332, p < 0.001; ß = -0.169, p < 0.01) and vice versa (ß = -0.149, p < 0.05; ß = -0.292, p < 0.001). CONCLUSIONS: The results suggest that frailty was associated with lower levels of social relationships. Frailty improvement programs can be combined with interventions to enhance social relationships, which will be beneficial in preventing frailty. The results emphasize the importance of combining clinical treatments of frailty with interventions to improve social relationships.
Assuntos
Fragilidade , Humanos , Feminino , Idoso , Masculino , Japão/epidemiologia , Fragilidade/epidemiologia , Estudos Prospectivos , Relações Interpessoais , NonoxinolRESUMO
BACKGROUND: Observational studies have demonstrated that there was a significant correlation between systemic lupus erythematosus (SLE) and anxiety disorder, but the causal relationship between them is not so clearly established. This study aims to reveal the potential causal link between SLE and anxiety disorder. METHODS: Summary statistical data of SLE and anxiety disorder were from two large-scale genome-wide association studies (GWAS) of European ancestry, followed by a bidirectional two-sample Mendelian randomization (MR) analysis. The inverse variance-weighted (IVW) method was used as the main method to evaluate causal effects, while MR-Egger, weighted median, simple mode, and weighted mode were supplementary methods. Outliers were excluded by MR-pleiotropy residual sum and outlier (MR-PRESSO). Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis were used to evaluate the stability of the results. RESULTS: According to the results of IVW, we did not observe that there was a statistically significant causal association between genetically predicted SLE and the risk of anxiety disorder (OR = 1.000, 95%CI = 0.992 to 1.008, p =.997). Conversely, there were no causal effects between anxiety disorder and SLE risk (OR = 1.000, 95%CI = 0.992 to 1.008, p = .997). A similar result was obtained by supplementing the MR method. In addition, sensitivity analysis indicated high stability of the result. CONCLUSION: Bidirectional two-sample MR study does not support the causal relationship between SLE and anxiety disorder.
Assuntos
Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/genética , Análise da Randomização Mendeliana , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Nonoxinol , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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 farmacológicoRESUMO
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 , UgandaRESUMO
BACKGROUND: Microbicide toxicity may reduce the efficacy of topical preexposure prophylaxis for human immunodeficiency virus (HIV) transmission. Noninvasive quantitative measures of microbicide toxicity would usefully inform microbicide development. METHODS: Ten subjects received 3 one-time interventions: 5 mL of Normosol-R fluid alone (negative control), 5 mL of 2% nonoxynol-9 (N-9) gel, and 5 mL of Normosol-R with coital simulation and sigmoidoscopic biopsy (CS + BX). Each dose of N-9 and Normosol-R contained 500 µCi of (99m)technetium-diethylene triamine pentaacetic acid. Plasma and urine radioactivity was assessed over 24 hours. RESULTS: The plasma radioisotope concentration peaked 1 hour after N-9 dosing. The mean maximum radioisotope concentration after N-9 receipt was 12.0 times (95% confidence interval [CI], 6.8-21.0) and 8.4 times (95% CI, 5.2-13.5) the mean concentration after Normosol-R control receipt and CS + BX receipt, respectively; paired differences persisted for 24 hours. After N-9 dosing, the urine isotope level was 3.6 times (95% CI, 1.1-11.4) the level observed 8 hours after Normosol-R control receipt and 4.0 times (95% CI, 1.4-11.4) the level observed 4 hours after CS + BX receipt. Permeability after CS + BX receipt was greater than that after Normosol-R control receipt in 0-2-hour urine specimens only (mean permeability, 2.4; 95% CI, 1.0-5.8) but was not greater in blood. CONCLUSIONS: Plasma sampling after rectal radioisotope administration provided quantitative estimates of altered mucosal permeability after chemical and mechanical stresses. Permeability testing may provide a useful noninvasive adjunct to assess the mucosal effects of candidate microbicides. Clinical Trials Registration. NCT00389311.
Assuntos
Biópsia/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Nonoxinol/efeitos adversos , Permeabilidade/efeitos dos fármacos , Reto/efeitos dos fármacos , Espermicidas/efeitos adversos , Humanos , Mucosa Intestinal/fisiopatologia , Plasma/química , Radioisótopos/administração & dosagem , Radioisótopos/sangue , Reto/fisiopatologia , Tecnécio/administração & dosagem , Tecnécio/sangueRESUMO
A major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens.
Assuntos
Anti-Infecciosos/efeitos adversos , Biomarcadores/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Selectina L/metabolismo , Selectina-P/metabolismo , Adenina/efeitos adversos , Adenina/análogos & derivados , Animais , Compostos de Benzalcônio/efeitos adversos , Carboximetilcelulose Sódica/efeitos adversos , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Quimiocina CCL2 , Feminino , Infecções por HIV/tratamento farmacológico , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mucosa/efeitos dos fármacos , Nonoxinol/efeitos adversos , Nonoxinol/uso terapêutico , Organofosfonatos/efeitos adversos , Dodecilsulfato de Sódio/efeitos adversos , TenofovirRESUMO
OBJECTIVE: Colposcopy has been used to detect epithelial damage with vaginal microbicides. In animal models, optical coherence tomography provided increased sensitivity over colposcopy in detecting epithelial injury. This randomized, double-blinded, clinical study compared optical coherence tomography to colposcopy for the evaluation of epithelial injury in women using placebo or nonoxynol-9. METHODS: Thirty women aged 18-45 were randomized to use hydroxyethyl cellulose placebo or nonoxynol-9 vaginal gel twice daily for 5.5 days. Imaging with colposcopy and optical coherence tomography was performed before product use, after the last dose, and 1 week later. Colposcopy was graded using standard criteria. Optical coherence tomography images were scored for epithelial integrity based on a published scoring system and were measured for epithelial thickness. RESULTS: Colposcopy findings, optical coherence tomography scores, and epithelial thicknesses were similar between treatment groups at baseline. After treatment, there were significant differences between the nonoxynol-9 (1.37) and control group (1.15) optical coherence tomography scores (P<.001), indicating epithelial injury, and there was epithelial thinning in the nonoxynol-9 group (237 micrometers) compared with the control group (292 micrometers; P=.008). There were no significant posttreatment colposcopic differences in epithelial disruption between treatment groups, with only increased erythema noted after nonoxynol-9 use (P=.02). CONCLUSION: Optical coherence tomography detected epithelial disruption and thinning not identified by colposcopy. Vaginal epithelial thickness, a measure previously available only through biopsy, decreased after nonoxynol-9 use, a finding that may contribute to increased susceptibility to human immunodeficiency virus after frequent use. Optical coherence tomography shows promise for the noninvasive clinical assessment of vaginal epithelial damage. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry, www.umin.ac.jp/ctr/index.htm, R000006186. LEVEL OF EVIDENCE: I.
Assuntos
Colposcopia , Nonoxinol/efeitos adversos , Espermicidas/efeitos adversos , Tomografia de Coerência Óptica , Doenças Vaginais/diagnóstico , Adulto , Método Duplo-Cego , Feminino , Humanos , Doenças Vaginais/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: To effectively block the invasion of human immunodeficiency virus (HIV)-1 on mucosal surface, vaginal anti-HIV-1 microbicides should avoid inflammatory responses and disruption of mucosa integrity because these will facilitate transepithelial viral penetration and replication. However, existing models fail to predict and evaluate vaginal mucosal toxicity induced by microbicides, and most importantly, they are unable to identify subtle or subclinical inflammatory reactions. This study was designed to develop a cost-effective in vivo model to evaluate microbicide safety in a preclinical study which can recapitulate the mucosal topical reaction. METHODS: A murine model was employed with nonoxynol-9 (N-9) as the topical stimulant within the vagina. Different concentrations of N-9 (1%, 3%, and 4%) were topically applied to the vagina for five consecutive days. A panel of inflammatory cytokines including interleukine-2 (IL-2), IL-4, IL-6, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and immuno-regulatory IL-10 were assayed in vaginal lavage. Cytokines were quantified by using cytometric bead array (CBA) and reverse transcript (RT) real-time PCR. Histopathological evaluation of vaginal tissues was conducted on hematoxylin-eosin stained slides and scored with a semi-quantitative system according to the severity of epithelial disruption, leucocyte infiltration, edema, and vascular injection. The association between the cytokines and histopathological scores was assessed by linear regression analysis. RESULTS: All three concentrations of N-9 induced inflammatory cytokine production. The 4% N-9 application resulted in a consistent production of cytokines in a time-dependent manner. The cytokines reached peak expression on day three with the exception of IL-4 which reached its peak on day one. Histopathological examination of 4% N-9 treated cervicovaginal tissues on day three showed intensive damage in four mice (sores: 10 - 13) and moderate damage in one mouse (score: 8), which were significantly associated with both inflammatory cytokines IL-17A and IL-6 and anti-inflammatory cytokines IL-4 and IL-10. Interestingly, IL-17A showed significant positive association with inflammatory cytokine TNF-α (r = 0.739; P < 0.05), anti-inflammatory cytokines IL-10 (r = 0.804; P < 0.01) and IL-4 (r = 0.668; P < 0.05). CONCLUSIONS: Our data demonstrate that a panel of cytokines (IL-17A, IL-6, IL-4 and IL-10) could be used as surrogate biomarkers to predict the histopathological damage. Th17 may play a central role in orchestrating inflammatory cytokine responses. This Th17 based mouse model is cost-effective and suitable to assess the toxicity of candidate microbicides in preclinical studies.
Assuntos
Anti-Infecciosos/toxicidade , Nonoxinol/toxicidade , Células Th17/fisiologia , Animais , Análise Custo-Benefício , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Feminino , Modelos Lineares , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Vagina/efeitos dos fármacos , Vagina/patologiaRESUMO
Barrier contraceptives are a safe alternative to hormonal methods of fertility management. Newer barrier method options include the Today Sponge, the FemCap, and the Lea's Shield. Understanding the use, benefits, and limitations of these barrier methods of birth control will assist women's health care providers to better meet the family planning needs of their patients.
Assuntos
Método de Barreira Anticoncepção/tendências , Dispositivos Anticoncepcionais Femininos/tendências , Compostos de Benzalcônio , Comportamento de Escolha , Método de Barreira Anticoncepção/efeitos adversos , Método de Barreira Anticoncepção/métodos , Método de Barreira Anticoncepção/enfermagem , Dispositivos Anticoncepcionais Femininos/efeitos adversos , Desenho de Equipamento , Serviços de Planejamento Familiar/educação , Serviços de Planejamento Familiar/métodos , Serviços de Planejamento Familiar/tendências , Feminino , Previsões , Necessidades e Demandas de Serviços de Saúde , Humanos , Nonoxinol , Papel do Profissional de Enfermagem , Avaliação em Enfermagem , Seleção de Pacientes , Colato de SódioAssuntos
Anti-Infecciosos Locais/uso terapêutico , Infecções por HIV/prevenção & controle , Sexo Seguro , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/etnologia , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Administração Intravaginal , África Subsaariana/etnologia , Anti-Infecciosos Locais/administração & dosagem , Ensaios Clínicos como Assunto , Características Culturais , Feminino , Fundações/economia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/etnologia , Humanos , Nonoxinol/uso terapêutico , Projetos de Pesquisa , Apoio à Pesquisa como Assunto/economia , Falha de TratamentoRESUMO
The efficacy of a microbicide depends on the balance between its specific activity and its safety. The experience with nonoxynol-9, the first microbicide to be tested in clinical trials, provides a good example of a compound with high in-vitro activity and poor clinical performance, possibly because of underestimated local safety issues. In order to identify compounds that may induce epithelial toxicity and inflammation early in drug development, we have established a preclinical evaluation system based on the assessment of cytotoxicity, cytokine secretion, and tissue inflammatory reaction using a human vaginal cell line (VK-2/E6E7) and a refined rabbit vaginal irritation model. Evaluated through this system, nonoxynol-9 displayed high cytotoxicity and proinflammatory activity. VK-2 cells incubated for 6 h with nonoxynol-9 released significant amounts of IL-1, IL-6 and IL-8. Gels containing 2 and 4% nonoxynol-9, administered to female rabbits intravaginally for 3 days, induced a potent inflammatory reaction evidenced by high levels of IL-lb and CD3+ T cells in cervicovaginal lavages and a significant influx of CD4 and nuclear factor kappa B cells into mucosal and submucosal tissues. Interestingly, cervicovaginal epithelium exposed to nonoxynol-9 also showed high levels of active nuclear factor kappa B immunoreactivity. This combined, sequential, preclinical evaluation system based on VK-2 cells in culture and a refined rabbit vaginal irritation model represents a valuable tool to assess the local safety profile of anti-HIV microbicide candidates.
Assuntos
Anti-Infecciosos/efeitos adversos , Inflamação/induzido quimicamente , Animais , Fármacos Anti-HIV/efeitos adversos , Linhagem Celular , Colo do Útero/efeitos dos fármacos , Colo do Útero/imunologia , Colo do Útero/patologia , Citocinas/biossíntese , Avaliação Pré-Clínica de Medicamentos , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Técnicas In Vitro , Inflamação/imunologia , Inflamação/patologia , Masculino , NF-kappa B/metabolismo , Nonoxinol/efeitos adversos , Coelhos , Segurança , Vagina/efeitos dos fármacos , Vagina/imunologia , Vagina/patologiaAssuntos
Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos/uso terapêutico , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , HIV/efeitos dos fármacos , Resinas Acrílicas , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/farmacologia , Pesquisa Biomédica , Ensaios Clínicos como Assunto , Países em Desenvolvimento , Feminino , Géis , Humanos , Cooperação Internacional , Masculino , Naftalenossulfonatos/farmacologia , Naftalenossulfonatos/uso terapêutico , Nonoxinol/farmacologia , Nonoxinol/uso terapêutico , Organizações sem Fins Lucrativos , Polímeros/farmacologia , Polímeros/uso terapêutico , Apoio à Pesquisa como Assunto , Espermicidas/farmacologia , Espermicidas/uso terapêuticoAssuntos
Fármacos Anti-HIV/uso terapêutico , Proteínas de Bactérias , Transmissão de Doença Infecciosa/prevenção & controle , Infecções por HIV/transmissão , Fármacos Anti-HIV/economia , Anticorpos Monoclonais/uso terapêutico , Soluções Tampão , Proteínas de Transporte/uso terapêutico , Sulfato de Dextrana/uso terapêutico , Feminino , Infecções por HIV/prevenção & controle , Humanos , Masculino , Nonoxinol/uso terapêutico , Tensoativos/uso terapêutico , Cremes, Espumas e Géis VaginaisRESUMO
PIP: Current research efforts are addressing the potential use of nonoxynol-9 and other spermicides as an effective female-controlled contraceptive method. In the laboratory, nonoxynol-9 is lethal to organisms that cause gonorrhea, syphilis, trichomoniasis, genital herpes, and HIV, but findings of human studies have been inconsistent. Carrageenan, a compound derived from red seaweed, has been combined with nonoxynol-9 in an effort to develop a spermicide that will protect against HIV and pregnancy. A novel gel formulation that contains low amounts of octoxynol-9 and benzalkonium chloride is scheduled to enter a Phase III trial. The first part of the trial will determine the product's effectiveness in preventing pregnancy and halting the transmission of chlamydia and gonorrhea; the second will focus on HIV. Another Phase III clinical trial is testing a bioadhesive contraceptive gel that contains nonoxynol-9. Also under study is a vaginal sponge that contains low levels of nonoxynol-9 and benzalkonium chloride. Finally, researchers are evaluating the potential for precoating diaphragms and cervical caps with a spermicide.^ieng
Assuntos
Anticoncepção , Nonoxinol , Pesquisa , América , Anticoncepcionais , Países Desenvolvidos , Economia , Serviços de Planejamento Familiar , América do Norte , Espermicidas , Tecnologia , Estados UnidosRESUMO
PIP: More and more women are becoming infected with HIV. While the use of male condoms greatly reduces the transmission of HIV, the condoms must be used correctly and consistently in order to confer protection against contracting an infection, and their use is not controlled by women. Female condoms are a barrier method which women can use, but there use may be objectionable to some men, who can see the condoms' outer ring. However, women can easily control the use of vaginal microbicides. Several such products are being researched. Some use nonoxynol-9 or other surfactants, while others include acid buffering gels; natural products such as lactobacillus crispatus, antimicrobial peptides, magainins, or plant extracts; inhibitors of viral entry; post-binding fusion inhibitors; and reverse transcriptase inhibitors. While in vitro tests have found that spermicides containing nonoxynol-9 (N-9) kill organisms which cause gonorrhea, genital herpes, trichomoniasis, syphilis, and AIDS, the disruptive effect of N-9 upon the vaginal epithelium raises questions upon the merit of their use and their overall effectiveness in preventing disease transmission. The ideal microbicide should be effective against HIV/STDs, nonirritating, long-acting, inexpensive, readily available, and easy to use. It should be available in spermicidal and nonspermicidal formulations.^ieng
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Necessidades e Demandas de Serviços de Saúde , Nonoxinol , Espermicidas , Vaginite , Anticoncepção , Anticoncepcionais , Doença , Economia , Serviços de Planejamento Familiar , Vagina , VirosesRESUMO
Advanced Care Products has been active in the development of vaginal microbicides, with public sector support. Currently, nonoxynol-9 gel is being evaluated in two Phase-III studies. Work has been conducted on polystyrene sulfonate, with the aim of filing an investigational new drug application (IND) in the USA. This paper discusses the challenges in development of an over-the-counter (OTC) product for the USA. Public sector support has been pivotal in the progress shown to date. Further challenges lie ahead, vis-à-vis an OTC approval.
Assuntos
Anti-Infecciosos , Indústria Farmacêutica , Pesquisa , Cremes, Espumas e Géis Vaginais , Anti-Infecciosos/administração & dosagem , Anticoncepcionais Femininos/administração & dosagem , Comportamento Cooperativo , Feminino , Humanos , Nonoxinol/administração & dosagem , Medicamentos sem Prescrição , Espermicidas/administração & dosagemRESUMO
OBJECTIVE: To assess the in vivo efficacy of the tablet drug delivery system containing nonoxynol-9 coprecipitated with polyvinylpyrrolidone by delivering the spermicidal agents vaginally and evaluating their ability to prevent the onset of pregnancy in rabbits. DESIGN: Controlled clinical study. SETTING: Division of Laboratory and Animal Resources, College of Pharmacy, University of Kentucky. ANIMAL(S): Forty-two New Zealand White female rabbits. INTERVENTION(S): The rabbits were artificially inseminated at various intervals after vaginal insertion of the tablet drug delivery system containing either polyvinylpyrrolidone only (0 minutes) or nonoxynol-9 coprecipitated with polyvinylpyrrolidone (polyvinylpyrrolidone/nonoxynol-9; 0, 3, 30, 180, and 360 minutes). The rabbits were induced to ovulate 6 hours before insemination by i.m. injection of hCG (200 IU). MAIN OUTCOME MEASURE(S): The onset of pregnancy in the rabbits was evaluated after insertion of the tablet drug delivery system containing polyvinylpyrrolidone only or polyvinylpyrrolidone/nonoxynol-9 at various intervals, followed by artificial insemination. RESULT(S): The onset of pregnancy was not reduced significantly when the tablet drug delivery system containing polyvinylpyrrolidone or polyvinylpyrrolidone/nonoxynol-9 was used and insemination was performed immediately after tablet insertion (time 0). However, pregnancy rates (PRs) were reduced significantly in the rabbits that received the tablet drug delivery system containing polyvinylpyrrolidone/nonoxynol-9 and were inseminated at 3, 30, 180, and 360 minutes after tablet insertion. The highest PR reduction occurred between 30 and 180 minutes after insertion of the tablet drug delivery system containing polyvinylpyrrolidone/nonoxynol-9. CONCLUSION(S): The tablet drug delivery system is an efficient method of delivering the tested spermicidal agents vaginally. The design and dosage used in preparing the tablet drug delivery system provide short- and long-term release of the spermicidal agents, which results in almost immediate and extended enhancement of their contraceptive properties.
Assuntos
Sistemas de Liberação de Medicamentos , Nonoxinol/administração & dosagem , Excipientes Farmacêuticos/administração & dosagem , Povidona/administração & dosagem , Espermicidas/administração & dosagem , Administração Intravaginal , Animais , Precipitação Química , Estudos de Coortes , Combinação de Medicamentos , Feminino , Inseminação Artificial , Masculino , Nonoxinol/farmacologia , Excipientes Farmacêuticos/farmacologia , Povidona/farmacologia , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Coelhos , Motilidade dos Espermatozoides/efeitos dos fármacos , Motilidade dos Espermatozoides/fisiologia , Espermicidas/farmacologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Comprimidos , Fatores de TempoRESUMO
PIP: Until recently, the only topical microbicide being considered for protection against sexually transmitted HIV infection contains nonoxynol-9 (N-9), a detergent ingredient widely used for more than 30 years in the form of gels, foams, aerosols, creams, sponges, suppositories, films, and foaming tablets. While N-9 has both spermicidal and antibacterial/antiviral properties against pathogens responsible for STDs, including HIV, recent clinical studies have found it to be ineffective in protecting against HIV and other STDs. Moreover, N-9 disrupts cell membranes, damages cervicovaginal epithelia, and causes an acute tissue inflammatory response, thus enhancing the likelihood of HIV infection. There is therefore an urgent need for new, effective, safe, and easy-to-use microbicides with anti-HIV activity lacking detergent-type membrane toxicity. Dr. Osmond D'Cruz et al. of the Hughes Institute in St. Paul, Minnesota, have developed an anti-HIV spermicide with the potential of becoming the active ingredient in many beneficial products. Its lead compound is 400 times more potent than N-9 against HIV and at least 10 times more potent than N-9 as a spermicide. These dual-function compounds are non-inflammatory by their nature. Hughes et al.'s discovery is expected to enter human clinical trials within 12 months. A clinical paper describing their achievement won the prestigious Prize Paper Award for the Plenary Session of the Conjoint 16th World Congress on Fertility and Sterility at the 54th Annual Meeting of the American Society of Reproductive Medicine, held in San Francisco, California, during October 4-9, 1998.^ieng