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AbstractIntramuscular (250 mg once weekly) or subcutaneous (275 mg once weekly) injections of 17-hydroxyprogesterone caproate (17-OHPC) has been utilised to prevent recurent spontaneous preterm birth in pregnant women with a short cervix or those with a prior preterm birth but its efficacy in these conditions has been questioned. It is unclear whether adequate concentrations of 17-OHPC reach the suspected target organs such as the cervix and uterus following either IM or SC administration.The objective of this study was to determine feasibility and safety of vaginal administration of 17-OHPC in adult female Sprague Dawley rats and female New Zealand rabbits.Gels containing 17-OHPC were administered intravaginally to rats and rabbits for 10 consecutive days. After the last dose, serial blood samples and terminal uterine and adipose tissue samples were collected. 17-OHPC concentrations were measured by LC-MS-MS.Tissue histology showed that intravaginal administration of 17-OHPC was safe. There was no renal or hepatic toxicity as measured by liver function and kidney function tests.Intravaginal administration of 17-OHPC resulted in low systemic plasma concentrations but substantially higher uterus and adipose tissue concentrations of 17-OHPC. Composition of the formulation affected the tissue distribution of 17-OHPC.Future studies warrant further evaluation of the effect and safety of daily intravaginal administration of 17-OHPC gel in pregnant animals.Intramuscular (250 mg once weekly) or subcutaneous (275 mg once weekly) injections of 17-hydroxyprogesterone caproate (17-OHPC) has been utilised to prevent recurent spontaneous preterm birth in pregnant women with a short cervix or those with a prior preterm birth but its efficacy in these conditions has been questioned. It is unclear whether adequate concentrations of 17-OHPC reach the suspected target organs such as the cervix and uterus following either IM or SC administration.The objective of this study was to determine feasibility and safety of vaginal administration of 17-OHPC in adult female Sprague Dawley rats and female New Zealand rabbits.Gels containing 17-OHPC were administered intravaginally to rats and rabbits for 10 consecutive days. After the last dose, serial blood samples and terminal uterine and adipose tissue samples were collected. 17-OHPC concentrations were measured by LC-MS-MS.Tissue histology showed that intravaginal administration of 17-OHPC was safe. There was no renal or hepatic toxicity as measured by liver function and kidney function tests.Intravaginal administration of 17-OHPC resulted in low systemic plasma concentrations but substantially higher uterus and adipose tissue concentrations of 17-OHPC. Composition of the formulation affected the tissue distribution of 17-OHPC.Future studies warrant further evaluation of the effect and safety of daily intravaginal administration of 17-OHPC gel in pregnant animals. [ABSTRACT FROM AUTHOR]

Aims: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations. Methods: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation. Results: For lidocaine and tenofovir vaginal gel, the predicted to observed AUC0‐t and Cmax ratios were well within 2‐fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC0‐t and Cmax ratios were well within 2‐fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83). Conclusion: The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future. [ABSTRACT FROM AUTHOR]

Fungal infections are caused by opportunistic pathogens that can be life threatening or debilitating. Candida spp. are becoming increasingly resistant to current clinically approved antifungal therapeutics. Candida infections afflict not only immunosuppressed but also immunocompetent individuals. Recurrent vulvovaginal candidiasis (RVVC) is a disease that afflicts 5–9% of women. Occidiofungin is a novel cyclic peptide that has a broad spectrum of antifungal activity with a novel fungicidal mechanism of action. A gel formulation containing occidiofungin (OCF001) is being developed for use to treat vulvovaginal candidiasis. The formulated gel for intravaginal application used hydroxyethyl cellulose as the primary gelling agent and hydroxypropyl β-cyclodextrin as a solubilizing agent for occidiofungin. Franz cells and LC-MS/MS were used to determine the rate of drug substance diffusion in the gel formulation. The formulation was tested in an ex vivo mouse skin efficacy study, and the safety was tested following repeat intravaginal administration in rabbits. In this study, the gel formulation was shown to reduce the drug substance rate of diffusion across a skin memetic membrane. The study showed that the formulation extends exposure time to inhibitory concentrations of occidiofungin over a 24-h period and supports a single daily application for the treatment of RVVC. [ABSTRACT FROM AUTHOR]

Fungal infections are caused by opportunistic pathogens that can be life threatening or debilitating. Candida spp. are becoming increasingly resistant to current clinically approved antifungal therapeutics. Candida infections afflict not only immunosuppressed but also immunocompetent individuals. Recurrent vulvovaginal candidiasis (RVVC) is a disease that afflicts 5–9% of women. Occidiofungin is a novel cyclic peptide that has a broad spectrum of antifungal activity with a novel fungicidal mechanism of action. A gel formulation containing occidiofungin (OCF001) is being developed for use to treat vulvovaginal candidiasis. The formulated gel for intravaginal application used hydroxyethyl cellulose as the primary gelling agent and hydroxypropyl β-cyclodextrin as a solubilizing agent for occidiofungin. Franz cells and LC-MS/MS were used to determine the rate of drug substance diffusion in the gel formulation. The formulation was tested in an ex vivo mouse skin efficacy study, and the safety was tested following repeat intravaginal administration in rabbits. In this study, the gel formulation was shown to reduce the drug substance rate of diffusion across a skin memetic membrane. The study showed that the formulation extends exposure time to inhibitory concentrations of occidiofungin over a 24-h period and supports a single daily application for the treatment of RVVC.

Abstract Ethnopharmacological relevance Marantodes pumilum (MP) (Kacip Fatimah) is used to maintain the well-being of post-menopausal women. However, its role in ameliorating post menopause-related vaginal atrophy (VA) is unknown. Aims To investigate the ability of intravaginal MP gel treatment to ameliorate VA in sex-steroid deficient condition, mimicking post-menopause. Methods Ovariectomized female Sprague-Dawley rats received MP (100 μg/ml, 250 μg/ml and 500 μg/ml) and estriol (E) gels intravaginally for seven consecutive days. Rats were then euthanized and vagina was harvested and subjected for histological and protein expression and distribution analyses. Vaginal ultrastructure was observed by transmission electron microscopy (TEM). Results Thickness of vaginal epithelium increased with increasing intravaginal MP doses. Additionally, increased in expression and distribution of proliferative protein i.e. PCNA, tight junction protein i.e. occludin, water channel proteins i.e. AQP-1 and AQP-2 and proton extruder protein i.e. V-ATPase A1 were observed in the vagina following intravaginal MP and E gels treatment. Intravaginal MP and E gels also induced desmosome formation and approximation of the intercellular spaces between the vaginal epithelium. Conclusions Intravaginal MP was able to ameliorate features associated with VA; thus, it has potential to be used as an agent to treat this condition. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Recently, a growing number of macromolecules such as peptides and proteins have been formulated into various microbicide formulations for the prevention of sexually transmitted infections. However, a fast and reliable high-throughput method for quantitating peptide/protein in polymer-based microbicide formulations is still lacking. As a result, we developed and validated a reversed-phase high-performance liquid chromatography method for the quantitation of gp120 fragment and LL-37 simultaneously in various microbicide gel formulations. This method was capable of detecting a limit of linearity (regression coefficient of 0.999) for gp120 fragment and LL-37 within a range of 0.625-80 and 1.25-80 µg mL, respectively. The lower limit of quantification for gp120 fragment and LL-37 was 1.14 and 0.31 µg mL, respectively. Method validation demonstrated acceptable intra- and inter-day RSD % (<5 %) and accuracy (95.67-100.5 %). Formulating both peptides into polymeric pharmaceutical gel formulations showed high extraction efficiency (in the range of 95.90 ± 3.03 to 111.45 ± 2.51 %). Using this method, we were able to separate and identify the forced degraded products from both peptides simultaneously without affecting the quantitation of both peptides in the polymeric dosage forms. Furthermore, this method was able to detect and separate degradants that were unable to be revealed using gel eletrophoresis. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To prospectively investigate diagnostic value and tolerability of MRI after intra-vaginal gel opacification for diagnosis and preoperative assessment of deeply infiltrating endometriosis. Methods: Sixty-three women with clinical suspicion of deeply infiltrating endometriosis were previously examined with trans-vaginal ultrasonography and then with MRI pre and post administration of vaginal gel. We evaluated the tolerability of this procedure with a scoring scale from 0 to 3. We also assessed with a score from 1 to 4 the visibility of four regions: Douglas-pouch, utero-sacral-ligaments, posterior-vaginal-fornix and recto-vaginal-septum. All patients underwent laparoscopic surgery after MRI. Results: Five patients considered procedure intolerable. Visibility of utero-sacral-ligaments and posterior-vaginal-fornix showed to be increased with gel (p <0.001). In 57 out of 80 patients the MRI has allowed us to diagnose deeply infiltrating endometriosis. Overall, the percentages of MRI-sensitivity, specificity, positive predictive value and negative predictive value were respectively 67.8%, 95.3%, 89.4 and 83.5% without gel, and 90.8%, 94.6%, 90.8% and 94.6% with gel; trans-vaginal ultrasonography sensitivity, specificity, positive predictive value and negative predictive value were 57.5%, 96.6%, 90.9% and 79.5%. In evaluation of utero-sacral-ligaments trans-vaginal ultrasonography, MRI without gel and with gel sensitivity was respectively 61.9%, 47.6% and 81%; for recto-vaginal-septum these values were 12.5%, 68.7% and 93.7%; for pouch of Douglas 82%, 87% and 97.4%; finally for posterior-vaginal-fornix 27.3%, 36.4% and 81.8%. Conclusions: MRI with gel opacification of vagina should be recommended for suspicion of deep infiltrating endometriosis, in particular for the added value in evaluation of recto-vaginal septum, utero-sacral ligaments and posterior vaginal fornix. [Copyright &y& Elsevier]

The goal of this study was to develop and characterize an intravaginal nanomedicine for the active targeted delivery of saquinavir (SQV) to CD4(+) immune cells as a potential strategy to prevent or reduce HIV infection. The nanomedicine was formulated into a vaginal gel to provide ease in self-administration and to enhance retention within the vaginal tract. SQV-encapsulated nanoparticles (SQV-NPs) were prepared from poly(lactic-co-glycolic acid) (PLGA) and conjugated to antihuman anti-CD4 antibody. Antibody-conjugated SQV-NPs (Ab-SQV-NPs) had an encapsulation efficiency (EE%) of 74.4% + 3.7% and an antibody conjugation efficiency (ACE%) of 80.95% + 1.10%. Over 50% of total loaded SQV was released from NPs over 3 days. NPs were rapidly taken up by Sup-T1 cells, with more than a twofold increase in the intracellular levels of SQV when delivered by Ab-SQV-NPs in comparison to controls 1 hour post-treatment. No cytotoxicity was observed when vaginal epithelial cells were treated for 24 hours with drug-free Ab-NPs (1,000 μg/mL), 1% HEC placebo gel (200 mg/mL), or 1% HEC gel loaded with drug-free Ab-NPs (5 mg NPs/g gel, 200 mg/mL of gel mixture). Overall, we described an intravaginal nanomedicine that is nontoxic and can specifically deliver SQV into CD4(+) immune cells. This platform may demonstrate potential utility in its application as postexposure prophylaxis for the treatment or reduction of HIV infection, but further studies are required.