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1.
Expert Opin Pharmacother ; 21(4): 409-415, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31928093

RESUMO

Introduction: Dyspareunia caused by vulvovaginal atrophy is a primary symptom of genitourinary syndrome of menopause (GSM), a chronic, progressive medical condition that results from estrogen and androgen deficiency at menopause. Dehydroepiandrosterone (DHEA, prasterone) is an endogenous precursor steroid hormone that is metabolized into both androgens and estrogens that has been recently been approved by the FDA for the treatment of moderate to severe dyspareunia caused by vulvovaginal atrophy secondary to menopause.Areas covered: This is a comprehensive drug evaluation describing the chemical composition, pharmacokinetics, metabolism, clinical efficacy and safety of dehydroepiandrosterone (prasterone) in the treatment of dyspareunia and VVA secondary to menopause. Preclinical and clinical data suggesting further potential uses, benefits, and contraindications in the genitourinary health of postmenopausal women are also considered.Expert opinion: Intravaginal dehydroepiandrosterone (prasterone) is effective for the management of dyspareunia secondary to menopause and may be effective in the treatment of other types of sexual dysfunction that are secondary to menopause. Further studies should explore additional dosing regimens and different indications.


Assuntos
Desidroepiandrosterona/uso terapêutico , Doenças Urogenitais Femininas/tratamento farmacológico , Menopausa/metabolismo , Vagina/efeitos dos fármacos , Administração Intravaginal , Androgênios/metabolismo , Atrofia , Desidroepiandrosterona/administração & dosagem , Dispareunia/tratamento farmacológico , Dispareunia/metabolismo , Estrogênios/metabolismo , Feminino , Doenças Urogenitais Femininas/metabolismo , Humanos , Resultado do Tratamento , Vagina/patologia
2.
PLoS One ; 15(1): e0224874, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995557

RESUMO

Antenatal vaginal progesterone (VP) reduces the risk of preterm birth (PTB) in women with shortened cervical length, and we hypothesize that it may also prevent PTB in women with HIV as their primary risk factor. We conducted a pilot feasibility study in Lusaka, Zambia to investigate uptake, adherence, and retention in preparation for a future efficacy trial. This was a double-masked, placebo-controlled, randomized trial of 200mg daily self-administered VP suppository or placebo. Pregnant women with HIV who were initiating or continuing antiretroviral therapy were eligible for participation. Potential participants underwent ultrasound to assess eligibility; we excluded those ≥24 gestational weeks, with non-viable, multiple gestation, or extrauterine pregnancies, with short cervix (<2.0cm), or with prior spontaneous PTB. Participants initiated study product between 20-24 weeks of gestation and continued to 37 weeks (or delivery, if sooner). The primary outcome was adherence (proportion achieving ≥80% study product use), assessed by dye stain assay of returned single-use vaginal applicators. Secondary outcomes with pre-defined feasibility targets were: uptake (≥50% eligible participants enrolled) and retention (≥90% ascertainment of delivery outcomes). We also evaluated preliminary efficacy by comparing the risk of spontaneous PTB <37 weeks between groups. From July 2017 to June 2018, 208 HIV-infected pregnant women were eligible for screening and 140 (uptake = 67%) were randomly allocated to VP (n = 70) or placebo (n = 70). Mean adherence was 94% (SD±9.4); 91% (n = 125/137) achieved overall adherence ≥80%. Delivery outcomes were ascertained from 134 (96%) participants. Spontaneous PTB occurred in 10 participants (15%) receiving placebo and 8 (12%) receiving progesterone (RR 0.82; 95%CI:0.34-1.97). Spontaneous PTB < 34 weeks occurred in 6 (9%) receiving placebo and 4 (6%) receiving progesterone (RR 0.67; 95%CI:0.20-2.67). In contrast to findings from vaginal microbicide studies in HIV-uninfected, non-pregnant women, our trial participants were highly adherent to daily self-administered vaginal progesterone. The study's a priori criteria for uptake, adherence, and retention were met, indicating that a phase III efficacy trial would be feasible.


Assuntos
Infecções por HIV/tratamento farmacológico , Nascimento Prematuro/tratamento farmacológico , Progesterona/administração & dosagem , Vagina/efeitos dos fármacos , Administração Intravaginal , Adulto , Medida do Comprimento Cervical , Colo do Útero/efeitos dos fármacos , Colo do Útero/fisiopatologia , Colo do Útero/virologia , Estudos de Viabilidade , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Recém-Nascido , Gravidez , Gravidez Múltipla , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/fisiopatologia , Vagina/fisiopatologia , Vagina/virologia , Zâmbia/epidemiologia
3.
Biomed Pharmacother ; 118: 109359, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545243

RESUMO

As one of the highly contagious forms, herpes simplex virus type 2 (HSV-2) commonly caused severe genital diseases and closely referred to the HIV infection. The lack of effective vaccines and drug-resistance proclaimed the preoccupation for alternative antiviral agents against HSV-2. Molecules bearing indole nucleus presented diverse biological properties involving antiviral and anti-inflammatory activities. In this study, one of the indole molecules, arbidol derivative (ARD) was designed and synthesized prior to the evaluation of its anti-HSV-2 activity. Our data showed that the ARD effectively suppressed HSV-2-induced cytopathic effects and the generation of progeny virus, with 50% effective concentrations of 3.386 and 1.717 µg/mL, respectively. The results of the time-course assay suggested that the ARD operated in a dual antiviral way by interfering virus entry and impairing the earlier period of viral cycle during viral DNA synthesis. The ARD-mediated HSV-2 inhibition was partially attained by blocking NF-κB pathways and down-regulating the expressions of several inflammatory cytokines. Furthermore, in vivo studies showed that oral administration of ARD protected BALB/c mice from intravaginal HSV-2 challenge by alleviating serious vulval lesions and histopathological changes in the target organs. Besides, the treatment with ARD also made the levels of viral protein, NF-κB protein and inflammatory cytokines lower, in consistent with the in-vitro studies. Collectively, ARD unveiled therapeutic potential for the prevention and treatment of HSV-2 infections.


Assuntos
Colo do Útero/patologia , Colo do Útero/virologia , Células Epiteliais/virologia , Herpesvirus Humano 2/efeitos dos fármacos , Indóis/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Humanos , Indóis/química , Indóis/toxicidade , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Receptores Toll-Like/metabolismo , Vagina/efeitos dos fármacos , Vagina/patologia , Vagina/virologia , Replicação Viral/efeitos dos fármacos
4.
Int J Pharm ; 570: 118691, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31518632

RESUMO

Vaginally delivered tamoxifen is being developed as alternative to estrogen-based therapies for the treatment of vulvar and vaginal atrophy (VVA) symptoms in subjects at high risk for breast cancer, undergoing treatment for breast cancer with aromatase inhibitors or are breast cancer survivors. Tamoxifen (1 or 20 mg) was administered intra-vaginally to female rabbits once-daily over a 28-day period to assess its pharmacokinetics, systemic exposure and local vaginal tolerance. Plasma samples were taken to assess concentrations of tamoxifen and its metabolites 4-hydroxytamoxifen and N-desmethyltamoxifen over the first day of vaginal administration and following the last dose on Day 28. In-life observations included evaluation of the vaginal region for signs of irritation. At necropsy, vaginal irritation was assessed by the method of Eckstein which reflect collective histopathological grading of four parameters within the vagina including epithelial morphology, leukocytic infiltration, congestion, and edema. Uterine effects of vaginal tamoxifen were also assessed. Plasma concentrations of tamoxifen were higher following administration of 20 mg tamoxifen compared to 1 mg tamoxifen at both Day 1 and Day 28. The metabolite 4-hydroxytamoxifen could not be detected on Day 1 and concentrations were low at Day 28 at the 1 mg tamoxifen dose. 4-Hydroxytamoxifen concentrations were low, but detectable at Day 1 and 28 following administration of 20 mg tamoxifen. The metabolite N-desmethyltamoxifen was undetectable at the 1 mg and 20 mg doses on Day 1; it remained undetectable at the 1 mg tamoxifen dose at Day 28. N-desmethyltamoxifen was detected over the first 8 h of Day 28 then fell below the quantitation limits. There was little to no vaginal or systemic accumulation of tamoxifen following once-daily dosing for 28 days. Tamoxifen accounted for more than 85% of the total systemic exposure compared to its metabolites, 4-hydroxytamoxifen, and N-desmethyltamoxifen. There was essentially no detectable vaginal irritation evident over the course of the study. At necropsy the individual Eckstein scores (maximum score of 16) of the proximal, mid, and distal vagina of females in the 1 mg and 20 mg dose groups were generally comparable in both groups and ranged from minimal to mild magnitude (1 mg dose group: ranging from 1 to 3 in the proximal vagina, 4 to 5 in the mid vagina, and 3 to 7 in the distal vagina; 20 mg dose group: ranging from 3 to 5 in the proximal vagina, 4 to 7 in the mid vagina, and 4 to 5 in the distal vagina). Overall, tamoxifen was absorbed and metabolized following vaginal administration and vaginal irritation was minimal to none at both doses.


Assuntos
Atrofia/tratamento farmacológico , Tamoxifeno/administração & dosagem , Vagina/efeitos dos fármacos , Administração Intravaginal , Animais , Neoplasias da Mama/tratamento farmacológico , Feminino , Coelhos , Tamoxifeno/análogos & derivados , Tamoxifeno/metabolismo
5.
Int J Pharm ; 570: 118643, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31446023

RESUMO

Although vaginal films were initially developed for a fast release of the drug, with the adequate formulation they can also be useful for sustained release. The latest strategies for the prevention of the sexual transmission of HIV have moved towards sustained-release dosage forms, so films may be an effective strategy that could also improve the patient's comfort. A hydrophilic polymer (hydroxypropylmethyl cellulose) and an amphiphilic polymer (zein) have been evaluated for the development of Tenofovir sustained-release vaginal films. The modification of the film's properties by the inclusion of polar (glycerol and polyethylene glycol 400 (PEG)) and amphiphilic (tributyl citrate and oleic acid) plasticisers was also evaluated. The films' physicochemical and mechanical properties were determined. The in vitro release of Tenofovir from the films and their bioadhesive capacity and behaviour in simulated vaginal fluid were also assessed. The combination of hydroxypropylmethyl cellulose and zein in films (ratio 1:5), with the inclusion of PEG (40% w/w) proved not only to have excellent mechanical properties, but was also able to release TFV in a sustained manner for 120 h and remain attached to biological tissues throughout this time. This film could be an interesting option for the prevention of sexual transmission of HIV.


Assuntos
Adesivos/química , Fármacos Anti-HIV/química , Infecções por HIV/prevenção & controle , Derivados da Hipromelose/química , Polímeros/química , Vagina/efeitos dos fármacos , Zeína/química , Adesivos/administração & dosagem , Administração Intravaginal , Animais , Fármacos Anti-HIV/administração & dosagem , Linhagem Celular , Química Farmacêutica/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Feminino , Glicerol/química , Humanos , Polietilenoglicóis/química , Doenças Sexualmente Transmissíveis/prevenção & controle , Células THP-1 , Tenofovir/administração & dosagem , Tenofovir/química
6.
Folia Med (Plovdiv) ; 61(2): 266-276, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301667

RESUMO

BACKGROUND: The in-situ gel-forming polymeric formulations offer sustained and prolonged action in comparison to conventional drug delivery systems. AIM: To formulate and evaluate in situ vaginal gel of clotrimazole. MATERIALS AND METHODS: Poloxamer 407 (20%) was slowly added to freezing water (5°C) with constant stirring. The prepared dispersion was refrigerated for 5 h, the different concentrations of polymers were added for preliminary batches. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were performed for clotrimazole-excipients compatibility study. The final batch was prepared and evaluated for physicochemical parameters, in vitro clotrimazole release, in vitro antifungal activity, and in vivo vaginal tissue irritation test. RESULTS: The compatibility study showed no chemical interaction between clotrimazole and excipients used. The evaluation parameters showed that clotrimazole release was in the range of 8 to 10 h, gelling temperature was in the range of 27-35°C, gelling time was in the range of 28-34 sec, pH was in the range of 4.4-4.8, and viscosities were in the range of 16.4-182.6 cP (solution form) and 10,500-20,756 cP (gel form). The zone of inhibitions for clotrimazole pure drug, the marketed vaginal gel of clotrimazole, and optimized gel formulation was 9.15±0.75 mm, 14.35±1.12 mm, and 18.85±1.56 mm, respectively (p < 0.0001, q = 5.98). An optimized gel formulation was not irritant to vaginal tissue. CONCLUSION: It was possible to formulate effective in situ vaginal gel for control release action of clotrimazole. LEVEL OF EVIDENCE: IIC.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Clotrimazol/farmacologia , Excipientes/farmacologia , Poloxâmero/farmacologia , Vagina/efeitos dos fármacos , Administração Intravaginal , Animais , Antifúngicos/química , Varredura Diferencial de Calorimetria , Química Farmacêutica , Clotrimazol/química , Preparações de Ação Retardada/síntese química , Excipientes/química , Feminino , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Poloxâmero/química , Distribuição Aleatória , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Cremes, Espumas e Géis Vaginais , Viscosidade
7.
Drugs Aging ; 36(8): 781-788, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31290076

RESUMO

Vulvovaginal atrophy (VVA) is a progressive condition commonly seen in postmenopausal women. The cessation of ovarian estrogen secretion and a fall in serum levels of dehydroepiandrosterone (DHEA), the remaining source of estrogens and androgens, are thought to promote the development of VVA in this population. Intravaginal prasterone (Intrarosa®) is a synthetic form of DHEA indicated for the treatment of VVA in postmenopausal women presenting with moderate to severe symptoms in the EU; prasterone is also approved in the USA for the treatment of dyspareunia due to menopause. Approval for the treatment of VVA was based on the results of the phase III ERC-231 and -238 trials in which intravaginal prasterone 6.5 mg/day significantly improved the signs and symptoms of VVA (as assessed by the percentage of parabasal and superficial cells, vaginal pH and the severity of dyspareunia) compared with placebo. The beneficial effects of prasterone were also evident during 52 weeks' treatment in the phase III ERC-230 safety trial. Prasterone was generally well tolerated, with the most common treatment-emergent adverse event being application site discharge. During 52 weeks of treatment with prasterone, changes in serum concentrations of estrogenic and androgenic metabolites of DHEA increased from baseline but remained within the normal postmenopausal ranges. Thus, intravaginal prasterone is an effective and generally well-tolerated option for the treatment of VVA in postmenopausal women.


Assuntos
Desidroepiandrosterona/uso terapêutico , Dispareunia/prevenção & controle , Menopausa , Vagina/efeitos dos fármacos , Vagina/patologia , Administração Intravaginal , Atrofia , Ensaios Clínicos Fase III como Assunto , Desidroepiandrosterona/administração & dosagem , Dispareunia/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento
8.
Rev Assoc Med Bras (1992) ; 65(6): 857-863, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31340317

RESUMO

OBJECTIVE: To evaluate endocervical and vaginal environment changes in women using a levonorgestrel-releasing intrauterine system (LNG-IUS). METHODS: A quasi-experimental study included sixty women who had an LNG-IUS inserted in the Family Planning Clinic of UNICAMP between April and November of 2016. Women in reproductive age, non-pregnant, without the use of antibiotics and contraceptives seeking for LNG-IUS insertion were selected for this study. All women were evaluated with regard to vaginal and endocervical pH, vaginal and endocervical Gram-stained bacterioscopy, and Pap-smear before and two months after LNG-IUS insertion. Clinical aspects such as cervical mucus, vaginal discharge, and cervical ectopy were also observed. RESULTS: After LNG-IUS insertion, there was an increase in the following parameters: endocervical pH>4.5 (p=0.02), endocervical neutrophil amount (p<0.0001), vaginal cytolysis (p=0.04). There was a decrease in vaginal discharge (p=0.01). No statistically significant changes were found in vaginal pH, neutrophils amount in the vaginal mucosa, vaginal discharge appearance, vaginal candidiasis, bacterial vaginosis, vaginal coccobacillary microbiota, cervical mucus appearance, or cervical ectopy size. CONCLUSIONS: Short-term LNG-IUS use did not increase vulvovaginal candidiasis or bacterial vaginosis, and led to diminished vaginal discharge. Notwithstanding, this device promoted reactional changes in the vaginal and endocervical environment, without modification on cervical ectopy size.


Assuntos
Colo do Útero/efeitos dos fármacos , Anticoncepcionais Femininos/efeitos adversos , Endométrio/efeitos dos fármacos , Dispositivos Intrauterinos Medicados/efeitos adversos , Levanogestrel/efeitos adversos , Vagina/efeitos dos fármacos , Adolescente , Adulto , Colo do Útero/microbiologia , Endométrio/microbiologia , Feminino , Humanos , Pessoa de Meia-Idade , Teste de Papanicolaou , Estatísticas não Paramétricas , Fatores de Tempo , Vagina/química , Vagina/microbiologia , Esfregaço Vaginal , Adulto Jovem
9.
PLoS One ; 14(5): e0217229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107913

RESUMO

Recent data support that the vaginal microbiota may alter mucosal pharmacokinetics (PK) of topically delivered microbicides. Our team developed an intravaginal ring (IVR) that delivers tenofovir (TFV) (8-10 mg/day) alone or with levonorgestrel (LNG) (20 ug/day). We evaluated the effect of IVRs on the vaginal microbiota, and describe how the vaginal microbiota impacts mucosal PK of TFV. CONRAD A13-128 was a randomized, placebo controlled phase I study. We randomized 51 women to TFV, TFV/LNG or placebo IVR. We assessed the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and after approximately 15 days of use. We measured the concentration of TFV in the cervicovaginal (CV) aspirate, and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue at the end of IVR use. The change in relative or absolute abundance of vaginal bacterial phylotypes was similar among active and placebo IVR users (all q values >0.13). TFV concentrations in CV aspirate and vaginal tissue, and TFV-DP concentrations in vaginal tissue were not significantly different among users with community state type (CST) 4 versus those with Lactobacillus dominated microbiota (all p values >0.07). The proportions of participants with CV aspirate concentrations of TFV >200,000 ng/mL and those with tissue TFV-DP concentrations >1,000 fmol/mg were similar among women with anaerobe versus Lactobacillus dominated microbiota (p = 0.43, 0.95 respectively). There were no significant correlations between the CV aspirate concentration of TFV and the relative abundances of Gardnerella vaginalis or Prevotella species. Tissue concentrations of TFV-DP did not correlate with any the relative abundances of any species, including Gardnerella vaginalis. In conclusion, active IVRs did not differ from the placebo IVR on the effect on the vaginal microbiota. Local TFV and TFV-DP concentrations were high and similar among IVR users with Lactobacillus dominated microbiota versus CST IV vaginal microbiota. Trial registration: ClinicalTrials.gov NCT02235662.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Dispositivos Anticoncepcionais Femininos , Levanogestrel/administração & dosagem , Microbiota/efeitos dos fármacos , Tenofovir/administração & dosagem , Tenofovir/farmacocinética , Vagina/metabolismo , Vagina/microbiologia , Adenina/análogos & derivados , Adenina/farmacocinética , Adulto , Antivirais/administração & dosagem , Antivirais/farmacocinética , Remoção de Dispositivo , Feminino , Infecções por HIV/prevenção & controle , Herpes Genital/prevenção & controle , Humanos , Microbiota/genética , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Organofosfatos/farmacocinética , Vagina/efeitos dos fármacos , Adulto Jovem
10.
Int J Nanomedicine ; 14: 2371-2381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040662

RESUMO

Purpose: HIV-1 and herpes simplex virus type-2 (HSV-2) represent two of the most relevant sexually transmitted diseases (STDs) worldwide. Moreover, each year there are >200 million pregnancies worldwide, and more than half are unintended. Continued high rates of unintended pregnancies and spread of HIV-1 and HSV-2 require new approaches to address these problems. G1-S4 and G2-S16 dendrimers emerge as potential candidates for the development of a topical microbicide due to their safety and effectivity against HIV-1 and HSV-2 infection, both in vitro and in vivo. Our goal is to develop a dual topical microbicide to prevent the transmission of STDs and unintended pregnancies. Platycodin D (PD) was selected for its great spermicidal activity, topical application, and biocompatibility. Materials and methods: Toxicology and inhibitory profile of G1-S4/PD and G2-S16/PD were evaluated in vitro and in vivo. Spermicidal activity was assessed by a computer-assisted sperm analysis system (CASA). Results: G1-S4/PD and G2-S16/PD presented >95% of HIV-1 inhibition in TZM-bl cells and peripheral blood mononuclear cells. CASA assessment determined that 0.25 mM of PD with therapeutic concentrations of G1-S4 or G2-S16 was able to induce 100% immobilization of the sperm in 30 seconds. To evaluate the toxicity in vivo, a vaginal toxicity assay was performed in BALB/c mice. No significant changes or damage to the vaginal epithelium after 7 consecutive days of application were observed. Conclusion: Our data indicate that G1-S4/PD and G2-S16/PD combinations are promising candidates to be developed for vaginal microbicides with contraceptive activity.


Assuntos
Anti-Infecciosos/farmacologia , Anticoncepcionais/farmacologia , Dendrímeros/farmacologia , Saponinas/farmacologia , Silanos/farmacologia , Triterpenos/farmacologia , Vagina/microbiologia , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Capacitação Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testes de Toxicidade , Vagina/efeitos dos fármacos , Células Vero
11.
Gac Med Mex ; 155(2): 199-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31056600

RESUMO

Introduction: Conjugated estrogens, when used by the vaginal route for the relief of vaginal dryness and atrophy, can produce endometrial changes. Objective: To know the effect of vaginal conjugated estrogens application frequency on endometrial thickness in postmenopausal women. Method: Seventy postmenopausal women with vaginal dryness who received conjugated estrogen cream (0.625 mg/1 g) for 12 weeks were studied. The women were divided according to application frequency as follows: group 1, twice-weekly (n = 35), and group 2, thrice-weekly (n = 35). At baseline and at end-of-treatment, vaginal cytology was examined to determine the estrogenic value, and an endovaginal ultrasound was performed to measure endometrial thickness. The comparison between groups was carried out with Mann Whitney's U-test, and the comparison between baseline and post-treatment values, with Wilcoxon's test. Results: Of 70 recruited women, only 38 were studied, 19 in each group, paired by baseline estrogenic value. No difference was found between groups, neither at baseline nor after treatment, in the maturation index, estrogenic value or endometrial thickness. Conclusion: There were no differences in endometrial thickness between the conjugate estrogen cream different application frequencies.


Assuntos
Estrogênios Conjugados (USP)/administração & dosagem , Pós-Menopausa , Vagina/efeitos dos fármacos , Administração Intravaginal , Idoso , Atrofia/tratamento farmacológico , Atrofia/etiologia , Esquema de Medicação , Endométrio/diagnóstico por imagem , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Estudos Prospectivos , Estatísticas não Paramétricas , Resultado do Tratamento , Ultrassonografia , Vagina/diagnóstico por imagem
12.
PLoS Pathog ; 15(5): e1007776, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31083697

RESUMO

VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4ß7 mAb (Rh-α4ß7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4ß7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4ß7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4ß7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4ß7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4ß7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4ß7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4ß7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4ß7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais/farmacologia , Integrinas/antagonistas & inibidores , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vagina/efeitos dos fármacos , Viremia/prevenção & controle , Animais , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Quimioterapia Combinada , Feminino , Anticorpos Anti-HIV , Integrinas/imunologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Vagina/imunologia , Vagina/virologia , Viremia/imunologia , Viremia/virologia
13.
Breast Cancer Res Treat ; 177(1): 185-195, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144152

RESUMO

PURPOSE: Tamoxifen is an important targeted endocrine therapy in breast cancer. However, side effects and early discontinuation of tamoxifen remains a barrier for obtaining the improved outcome benefits of long-term tamoxifen treatment. Biomarkers predictive of tamoxifen side effects remain unidentified. The objective of this prospective population-based study was to investigate the value of tamoxifen metabolite concentrations as biomarkers for side effects. A second objective was to assess the validity of discontinuation rates obtained through pharmacy records with the use of tamoxifen drug monitoring. METHODS: Longitudinal serum samples, patient-reported outcome measures and pharmacy records from 220 breast cancer patients were obtained over a 6-year period. Serum concentrations of tamoxifen metabolites were measured by LC-MS/MS. Associations between metabolite concentrations and side effects were analyzed by logistic regression and cross table analyses. To determine the validity of pharmacy records we compared longitudinal tamoxifen concentrations to discontinuation rates obtained through the Norwegian Prescription database (NorPD). Multivariable Cox regression models were performed to identify predictors of discontinuation. RESULTS: At the 2nd year of follow-up, a significant association between vaginal dryness and high concentrations of tamoxifen, Z-4'-OHtam and tam-NoX was identified. NorPD showed a tamoxifen-discontinuation rate of 17.9% at 5 years and drug monitoring demonstrated similar rates. Nausea, vaginal dryness and chemotherapy-naive status were significant risk factors for tamoxifen discontinuation. CONCLUSIONS: This real-world data study suggests that measurements of tamoxifen metabolite concentrations may be predictive of vaginal dryness in breast cancer patients and verifies NorPD as a reliable source of adherence data.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/complicações , Neoplasias da Mama/epidemiologia , Monitoramento de Medicamentos , Tamoxifeno/efeitos adversos , Tamoxifeno/farmacocinética , Vagina/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Cromatografia Líquida , Feminino , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Prognóstico , Inquéritos e Questionários , Tamoxifeno/uso terapêutico , Espectrometria de Massas em Tandem , Vagina/fisiopatologia , Adulto Jovem
14.
Nanoscale ; 11(19): 9679-9690, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31066407

RESUMO

Acquired immune deficiency syndrome (AIDS) due to human immunodeficiency virus type-1 (HIV-1) represents one of the most important sexually transmitted infections (STI) worldwide. Great international efforts have been made to stop new infections but, to date, several compounds failed as microbicides at different stages of clinical trials. The quest to design new molecules that could prevent these infections is essential. In this work, we synthesized the first, second and third generations of anionic dendrimers having carboxylate and sulfonate terminal groups, respectively named G1C, G2C, G3C and G1S, G2S, and G3S, starting from a family of poly(alkylideneamine) dendrimers with nitrile termini. The anionic terminal groups of these dendrimers were expected to prompt them to act against HIV-1 infection. All dendrimers were fully characterized by 1H- and 13C-NMR, FTIR, MS and zeta potential techniques. Importantly, they were able to remain stable in the solid state and aqueous solutions at least for one and a half years. Screening of these six new dendrimers was then performed to shed light on their potential anti-HIV-1 activity and their mechanism of action. Results showed that the dendrimers were cytocompatible and that G1C and G1S dendrimers had important activity against R5-HIV-1NLAD8 and X4-HIV-1NL4.3 isolates by acting directly on viral particles and blocking their entry in host cells. Additionally, G1C and G1S dendrimers maintained their inhibitory effect at different pH values. Through a vaginal irritation assay carried out in BALB/c mice, the safety of these new dendrimers for topical application was also shown. Taken together, our results clearly show that G1C and G1S dendrimers are strong candidates for developing an effective microbicide to prevent HIV-1 new infections.


Assuntos
Anti-Infecciosos/química , Dendrímeros/química , Animais , Ânions/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Ácidos Carboxílicos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/farmacologia , Dendrímeros/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ácidos Sulfônicos/química , Vagina/efeitos dos fármacos , Vagina/patologia , Internalização do Vírus/efeitos dos fármacos
16.
Pharm Biol ; 57(1): 226-230, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30946631

RESUMO

CONTEXT: We identified an active prenylated derivative of genistein, 8-prenylgenistein (8PG) from Erythrina variegata L. (Leguminosae) and found that 8PG increased osteoprotective effects of genistein in oestrogen-deficient mice. OBJECTIVE: This study investigated and compared the oestrogenic effects of genistein and 8PG on uterus and vagina of immature mice. MATERIALS AND METHODS: Immature female CD-1 mice were orally treated with vehicle (Control, n = 10) or genistein (75 mg/kg, n = 10) or 8PG with low (8PG-L, 75 mg/kg, n = 10) and high dose (8PG-H, 150 mg/kg, n = 10) for 7 consecutive days by intragastric gavage. The uterus and vagina were harvested for histological and molecular measurements. RESULTS: Treatment with genistein and 8PG-H significantly increased uterus index (1.98 ± 0.21 & 1.49 ± 0.16 mg/g) and vagina index (3.83 ± 0.11 & 3.13 ± 0.25 mg/g) as compared to untreated control (uterus, 1.12 ± 0.13 mg/g; vagina, 2.32 ± 0.18 mg/g). Accordingly, both genistein and 8PG-H made vaginal cells keratinized and induced uterine and vaginal hypertrophy associated with the endometrial proliferation. 8PG-L did not affect oestrus cycle and histology of uterus and vagina. Treatment of immature mice with genistein or 8PG-H upregulated protein expression of oestrogen receptor-α (ER-α) and proliferating cell nuclear antigen (PCNA), but 8PG-L did not alter ER-α and PCNA expression in uterus and vagina. CONCLUSION: This study indicated that 8-prenylgenistein exerted oestrogenic effects in immature female mice. The efficacy and safety of 8-prenylgenistein when applied in improving oestrogen deficiency-induced syndrome requires further elucidation.


Assuntos
Estrogênios/farmacologia , Genisteína/análogos & derivados , Genisteína/farmacocinética , Útero/efeitos dos fármacos , Vagina/efeitos dos fármacos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/metabolismo , Estrogênios/administração & dosagem , Estrogênios/toxicidade , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genisteína/administração & dosagem , Genisteína/farmacologia , Genisteína/toxicidade , Camundongos , Regulação para Cima/efeitos dos fármacos , Útero/metabolismo , Vagina/metabolismo
17.
J Pharm Pharmacol ; 71(7): 1044-1054, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30887519

RESUMO

OBJECTIVES: Injured vaginal infection is detrimental to women. A curcumin hydrogel was studied for local treatment of injured vaginal infection. METHODS: Curcumin solid dispersions (CSDs) were prepared from polyvinyl pyrrolidone and characterized by differential scanning calorimetry and an X-ray diffraction method. An in situ hydrogel CSD hydrogel (CSDG) was prepared with CSD/poloxamers and characterized. In vitro curcumin release and antibacterial effects of CSDs, CSDGs and curcumin were compared. The therapeutic effect of the CSDGs and Lincomycin/Lidocaine Gel was explored after intravaginal administration on the injured rat vaginal infection models. KEY FINDINGS: Curcumin was amorphous in CSDs where curcumin rapidly released in simulated vaginal fluids. However, CSDGs showed sustained release. CSDGs quickly formed gels in the vagina. CSDGs showed high in vivo anti-Escherichia coli or Staphylococcus aureus effect though weak in vitro effect. The recovery of vaginal microenvironment and improvement of intravaginal Lactobacillus growth may be the major reason. Furthermore, CSDGs remarkably improved vaginal wound healing by alleviating inflammation and restoring vaginal epidermal tissues compared with the Lincomycin/Lidocaine Gel. CONCLUSION: CSDGs are a promising topical formulation for local treatment of vaginal bacterial infection and improvement of vaginal wound healing.


Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Curcumina/farmacologia , Hidrogéis/farmacologia , Vagina/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Curcumina/administração & dosagem , Escherichia coli/efeitos dos fármacos , Feminino , Hidrogéis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Staphylococcus aureus/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Vagina/patologia
18.
Asian Pac J Cancer Prev ; 20(3): 817-823, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30911301

RESUMO

Sexual dysfunction (SDF) is a common sequel to cancer treatment which affects the quality of life in women treated with pelvic radiotherapy. The aim of this study was to evaluate the safety, symptom resolution and objective improvement the injection of autologous platelet released growth factor (APRGF) for treatment of SDF in cited patients. This prospective pilot study enrolled 10 cancer-free patients with SDF who underwent pelvic radiotherapy at least 5 years ago, randomly. Each patient was received 1-2 cc APRGF within four weeks and all patients were re-evaluated at eight weeks and six months. CD34 immuno histochemistry and Masson's trichrome staining were performed on vaginal biopsy section for angiogenesis and fibrosis assay respectively. Sexual satisfaction after the injection of APRFG was clinically difference and the entire patient had sexual satisfaction. In the patient's follow-up, none of them needs to repeat the treatment. Our results declared that APRGF injection was effective and symptoms were disappeared in the entire patients. Significant objective improvements in vaginal diameter (mean before injection, 6.5 cm vs 7.1 cm after injection) (p-value = 0.001) and vaginal flexibility (mean before treatment, 0.72 cm vs 1.85 cm after injection) (P-value = 0.026) were observed. Characteristics of discharge before the injection in 60% of patients were included dry vagina and 40% had mild discharge but after injection 40% of patients had moderate and also 60% had mild and sufficient discharge (P-value= 0.190). Overally, our patients reported better sexual function and showed better vaginal function indexes, after APRFG injection.


Assuntos
Plaquetas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Neoplasias Pélvicas/radioterapia , Radioterapia/efeitos adversos , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Vagina/efeitos dos fármacos , Adulto , Transfusão de Sangue Autóloga , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Pélvicas/patologia , Projetos Piloto , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Disfunções Sexuais Fisiológicas/etiologia , Disfunções Sexuais Fisiológicas/patologia , Vagina/patologia
19.
Emerg Microbes Infect ; 8(1): 197-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30866773

RESUMO

The use of depot medroxyprogesterone acetate (DMPA), a 3-monthly injectable hormonal contraceptive, is associated with an increased risk of HIV acquisition possibly through alteration of the vaginal microbiome. In this longitudinal interventional study, we investigated the impact of DMPA administration on the vaginal microbiome in Hispanic White and Black women at the baseline (visit 1), 1 month (visit 2), and 3 months (visit 3) following DMPA treatment by using 16S rRNA gene sequencing. No significant changes in the vaginal microbiome were observed after DMPA treatment when Hispanic White and Black women were analysed as a combined group. However, DMPA treatment enriched total vaginosis-associated bacteria (VNAB) and Prevotella at visit 2, and simplified the correlational network in the vaginal microbiome in Black women, while increasing the network size in Hispanic White women. The microbiome in Black women became more diversified and contained more VNAB than Hispanic White women after DMPA treatment. While the Firmicutes to Bacteroidetes (F/B) ratio and Lactobacillus to Prevotella (L/P) ratio were comparable between Black and Hispanic White women at visit 1, both ratios were lower in Black women than in Hispanic White women at visit 2. In conclusion, DMPA treatment altered the community network and enriched VNAB in Black women but not in Hispanic White women. The Lactobacillus deficiency and enrichment of VNAB may contribute to the increased risk of HIV acquisition in Black women. Future studies on the impact of racial differences on the risk of HIV acquisition will offer insights into developing effective strategies for HIV prevention. Abbreviations: DMPA: depot medroxyprogesterone acetate; PCR: polymerase chain reaction; OTU: operational taxonomic unit; STI: sexually transmitted infections; VNAB: vaginosis-associated bacteria.


Assuntos
Bactérias/classificação , Anticoncepcionais Femininos/efeitos adversos , Acetato de Medroxiprogesterona/efeitos adversos , Microbiota/efeitos dos fármacos , Análise de Sequência de DNA/métodos , Vaginose Bacteriana/etnologia , Adulto , Afro-Americanos , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , DNA Bacteriano/genética , DNA Ribossômico/genética , Feminino , Hispano-Americanos , Humanos , Estudos Longitudinais , Filogenia , Prevotella/isolamento & purificação , Estudos Prospectivos , RNA Ribossômico 16S/genética , Estados Unidos/etnologia , Vagina/efeitos dos fármacos , Vagina/microbiologia , Vaginose Bacteriana/epidemiologia , Adulto Jovem
20.
Support Care Cancer ; 27(4): 1325-1334, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729333

RESUMO

PURPOSE: Vaginal atrophy is one of the most common side effects of using tamoxifen in women with breast cancer. Hormone therapy for vaginal atrophy is prohibited in these women. The present study was conducted to investigate the effect of vitamin D and E vaginal suppositories on vaginal atrophy in women with breast cancer receiving tamoxifen. METHODS: Women under breast cancer management receiving tamoxifen and showing symptoms of vaginal atrophy were randomized triple-blind to an 8-week trial on vaginal suppository vitamin E or vitamin D or placebo administered every night before bedtime. The genitourinary atrophy self-assessment tool was administered, and pH was measured in all three groups before the intervention and at the end of weeks 2, 4, and 8 of the intervention. The Vaginal Maturation Index (VMI) was also measured before the intervention and at the end of the eighth week. Data were analyzed with paired t tests, repeated measures analysis of variance, and chi-square test. RESULTS: Thirty-two patients were randomized in each group. The results obtained showed an increase in the VMI by the end of the eighth week of the intervention in the groups receiving the vitamin D and E vaginal suppositories compared with the placebo group (P < 0.001). The vaginal pH also reduced in both groups compared with that in the placebo group (P < 0.001). The symptoms of self-reported genitourinary atrophy also improved in the two intervention groups compared with those in the placebo group by the end of the eighth week (P < 0.001). CONCLUSION: These data support that vitamin D and E vaginal suppositories were beneficial in improving vaginal atrophy in women with breast cancer receiving tamoxifen. Given the prohibition on hormone therapy in these women, the suppositories can be used as an alternative therapy to improve these symptoms.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/efeitos adversos , Vagina/efeitos dos fármacos , Doenças Vaginais/induzido quimicamente , Doenças Vaginais/tratamento farmacológico , Vitamina D/administração & dosagem , Vitamina E/administração & dosagem , Adulto , Atrofia/induzido quimicamente , Atrofia/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Irã (Geográfico) , Pessoa de Meia-Idade , Pós-Menopausa , Supositórios , Tamoxifeno/administração & dosagem , Vagina/patologia , Vitamina D/farmacologia , Vitamina E/farmacologia
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