Search Results (23)

Background/Objectives: Localized provoked vulvodynia (LPV) is characterized by chronic vulvar pain upon light touch to the vestibule, a specialized ring of tissue immediately surrounding the vaginal opening. LPV affects about 14 million people in the US, yet the etiopathology of the disease is unknown. In LPV, the vestibule expresses elevated levels of the pro-nociceptive pro-inflammatory mediators prostaglandin E₂ (PGE2) and interleukin-6 (IL-6), which corresponds to lower pain thresholds. Previous studies have shown reduced amounts of arachidonic acid (AA)-derived pro-resolving lipid mediators in tissue biopsies from LPV patients that might impede the resolution of inflammation. AA is obtained from dietary linoleic acid, pointing to a defect in the metabolism of dietary polyunsaturated fatty acids in LPV. We aimed to further explore the involvement of AA metabolism in LPV, which appears dysregulated in the vestibule of LPV patients and culminates in chronic inflammation and chronic pain. Methods: Vestibular and vulvar tissue biopsies obtained from LPV and non-LPV patients were used to generate fibroblast strains and assessed for COX/LOX expression using qRT-PCR. Fibroblast strains were treated with inflammatory stimuli, and then COX-1 and COX-2 expression was assessed using Western blot analysis. Pro-inflammatory mediator production was assessed using enzyme-linked immunosorbent assays (ELISAs). ALOX5 and ALOX12 expression was assessed using qRT-PCR. Finally, lipidomic analysis was carried out to screen for 143 lipid metabolites following inflammatory challenge. Results: Tissue and fibroblasts from LPV patients exhibited altered expression of COX/LOX enzymes and production of AA-derived lipid mediators compared to non-LPV patients. Conclusions: Lipid profiles of tissue and vestibular fibroblasts from LPV patients differed from non-LPV patients, and this difference was attributed to differential COX/LOX expression and activity, which metabolizes AA derived from dietary linoleic acid. This dysregulation fosters chronic inflammation and reduced resolution capacity in LPV patients, causing chronic pain. While further work is needed, these findings suggest that dietary modifications could impact the LPV mechanism. Full article

Background/Objectives: Using healthcare vouchers mitigates the financial burdens of low-income individuals, therefore enhancing mothers’ satisfaction and encouraging service utilization. In Yemen, reducing financial barriers results in marked improvement in reproductive health services utilization for mothers and their newborns. Such financial strain can be addressed through reproductive health vouchers, which reduce out-of-pocket expenses of family planning, pregnancy, birth, postnatal care and neonatal care. This study compares the Safe Motherhood and Family Planning Voucher Program in the Lahj governorate to the non-voucher program in the Abyan governorate in terms of enhancement of reproductive healthcare accessibility and use. Methods: This facility-based, quantitative, comparative, cross-sectional study was conducted in the Lahj governorate, which supports the Safe Motherhood and Family Planning Voucher Program, and the Abyan governorate, which does not. Results: The voucher-supported program has greatly improved mothers’ satisfaction, access, and use of all reproductive health services by covering transportation, covering lodging during hospitalization, and providing free reproductive treatments. Compared to Abyan mothers, Lahj governorate mothers more frequently used rental vehicles (paid for by the voucher program) and free reproductive health services (p-value < 0.001). Lahj governorate mothers (who used the vouchers) used family planning, prenatal care, facility-based delivery, home delivery by competent birth staff, cesarean section, postnatal care, and neonatal care more frequently than Abyan governorate mothers. A health institution which supported the Safe Motherhood and Family Planning Voucher Program (SMHFPVP) provided prenatal care (98.5%), competent birth services (99.0%), and modern contraceptive use (92.3%)—oral contraceptive pills, implants, injectables, contraceptive patches, vaginal rings, and intrauterine devices—for mothers who were interviewed and attended the targeted HFs in the Lahj governorate, compared with (77.6%), (80.3%), and (67.8%), respectively, for mothers in Abyan governorate who were not supported by the SMHFPVP. This study demonstrates substantially higher satisfaction levels among voucher-using mothers in the Lahj governorate compared to those in the Abyan governorate, across all satisfaction domains and overall satisfaction scores. Conclusions: This study found that women without access to maternal health vouchers experienced worse prenatal, natal, and postnatal care and were less satisfied with healthcare services compared with women who used vouchers. Full article

Tereancistrum is a common genus of Neotropical monopisthocotylans; however, information on its diversity and phylogeny remains limited. In this study, we describe four new species of Tereancistrum parasitizing the gills of Prochilodus brevis (Characiformes: Prochilodontidae) from a weir in the state of Ceará, Brazil. Tereancistrum spiralocirrum n. sp. and Tereancistrum scleritelongatum n. sp. are characterized by a dextro-ventral vaginal pore and a Y-shaped dorsal bar. Notably, Tereancistrum spiralocirrum n. sp. is the first species in the genus to possess a male copulatory organ (MCO) with multiple rings (16 to 18). In contrast, Tereancistrum ancistrum n. sp. and Tereancistrum kritskyi n. sp. are distinguished by a sinistral vaginal pore, a sclerotized MCO in the form of a coiled tube with slightly more than one clockwise ring, and an accessory piece that is non-articulated with the base of the MCO. However, Tereancistrum ancistrum n. sp. is unique in lacking a dorsal bar. Sequences of the LSU rDNA obtained from seven species of Tereancistrum parasitizing P. brevis and Leporinus piau, along with published sequences of other Dactylogyridae members, were included in the molecular analyses. Phylogenetic reconstructions supported the monophyly of Tereancistrum. Full article

Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface production (CLIP™) (referred to as CLIP_LOW for low drug loading and CLIP_HIGH IVRs for high drug loading) and NuvaRing, a commercially available injection molded IVR. We conducted in vitro release studies in simulated vaginal fluid to compare the release of ENG and EE from CLIP_LOW IVRs and NuvaRing. CLIP_LOW IVRs had a similar hormone dose to NuvaRing and exhibited slightly slower ENG release and greater EE release in vitro compared to NuvaRing. When administered to female sheep, NuvaRing demonstrated greater ENG/EE levels in plasma, vaginal tissue and vaginal fluids compared to CLIP_LOW IVR despite similar drug loadings. Leveraging observed hormones levels in sheep from NuvaRing as an effective contraceptive benchmark, we developed a long-acting CLIP_HIGH IVR with increased ENG and EE doses that demonstrated systemic and local hormone levels greater than the NuvaRing for 90 days in sheep. No signs of toxicity were noted regarding general health, colposcopy, or histological analysis in sheep after CLIP_HIGH IVR administration. Our results provided (1) a comparison of ENG and EE release between a 3D-printed IVR and NuvaRing in vitro and in vivo, (2) a preclinical pharmacokinetic benchmark for vaginally delivered ENG and EE and (3) the generation of a 90-day CLIP IVR that will be utilized in future work to support the development of a long-acting ENG/EE IVR combined with an antiretroviral for the prevention of HIV and unplanned pregnancy. Full article

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients’ needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence. Full article

Background: Delivering contraceptive hormones through a transdermal patch or a vaginal ring might have advantages over the traditional oral route. Objectives: To compare the effectiveness, compliance, and side effect profile of oral and parenteral drug administration methods. Methods: We performed a systematic literature search in four medical databases—MEDLINE (via PubMed), Cochrane Library (CENTRAL), Embase, and Scopus—from inception to 20 November 2022. Randomized controlled trials assessing the efficacy, compliance, and adverse event profile of combined parenteral and oral hormonal contraceptives were included. Results: Our systematic search provided 3952 records; after duplicate removal, we screened 2707 duplicate-free records. A total of 13 eligible studies were identified after title, abstract, and full-text selection. We observed no significant difference in contraceptive efficacy (Pearl Index) between oral and parenteral drug administration (MD = −0.06, CI: −0.66–0.53; I² = 0%). We found significant subgroup differences between parenteral methods in terms of compliance (χ² = 4.32, p =0.038, I² = 80%) and certain adverse events: breast discomfort (χ² = 19.04, p =0.001, I² = 80%), nausea (χ² = 8.04, p =0.005, I² = 75%), and vomiting (χ² = 9.30, p =0.002; I² = 72%). Conclusion: Both parenteral and oral contraceptives can be used as an effective contraceptive method, and the route of administration should be tailored to patient needs and adverse event occurrence. Full article

Three-dimensional printing technologies can be implemented for the fabrication of personalized vaginal rings (VRs) as an alternative approach to traditional manufacturing. Although several studies have demonstrated the potential of additive manufacturing, there is a lack of knowledge concerning the opinions of patients and clinicians. This study aimed to investigate the perception of women and gynecologists regarding VRs with personalized shapes. The devices were printed with different designs (traditional, “Y”, “M”, and flat circle) by Fused Deposition Modeling for a cross-sectional survey with 155 participants. Their anticipated opinion was assessed through a questionnaire after a visual/tactile analysis of the VRs. The findings revealed that most women would feel comfortable using some of the 3D-printed VR designs and demonstrated good acceptability for the traditional and two innovative designs. However, women presented multiple preferences when the actual geometry was assessed, which directly related to their age, previous use of the vaginal route, and perception of comfort. In turn, gynecologists favored prescribing traditional and flat circle designs. Overall, although there was a difference in the perception between women and gynecologists, they had a positive opinion of the 3D-printed VRs. Finally, the personalized VRs could lead to an increase in therapeutic adherence, by meeting women’s preferences. Full article

The dapivirine (DPV) vaginal ring was developed by the nonprofit International Partnership for Microbicides (IPM) for reducing the risk of HIV infection. A clinical study (IPM 028) showed that concomitant use of the DPV ring and miconazole (MIC) altered DPV pharmacokinetic profile. In this work, we investigated whether or not DPV transport and permeation contributed to the observed DPV-MIC interaction. Our study evaluated the interaction between DPV and several transporters that are highly expressed in the human female reproductive tract, including MRP1, MRP4, P-gp, BCRP, and ENT1, using vesicular and cellular systems. We also evaluated the impact of DPV/MIC on cellular tight junctions by monitoring transepithelial electrical resistance with the Ussing chamber. Lastly, we evaluated the effect of MIC on DPV permeability across human cervical tissue. Our findings showed that DPV was not a substrate of MRP1, MRP4, P-gp, BCRP, or ENT1 transporters. Additionally, DPV did not inhibit the activity of these transporters. DPV, MIC, and their combination also did not disrupt cellular tight junctions. MIC did not affect DPV tissue permeability but significantly reduced DPV tissue levels. Therefore, our results suggest that the DPV-MIC interaction is not due to these five transporters, altered tight junction integrity, or altered tissue permeability. Full article

MK-2048 is a second-generation integrase inhibitor active against HIV, which has been applied vaginally using ring formulations. In this work, a nanoparticle-in-film technology was developed as a discrete pre-exposure prophylactic product option against HIV for an extended duration of use. A film platform loaded with poly (lactic-co-glycolic acid) nanoparticles (PNP) encapsulating MK-2048 was engineered. MK-2048 PNPs were loaded into films that were manufactured via the solvent casting method. Physicochemical and mechanical properties, in vitro efficacy, Lactobacillus compatibility, in vitro and ex vivo permeability, and in vivo pharmacokinetics in macaques were evaluated. PNPs with a mean diameter of 382.2 nm and −15.2 mV zeta potential were obtained with 95.2% drug encapsulation efficiency. PNP films showed comparable in vitro efficacy to free MK-2048 (IC₅₀ 0.46 vs. 0.54 nM) and were found to have no impact on Lactobacillus. MK-2048 encapsulated in PNPs showed an increase in permeability (>4-fold) compared to the free MK-2048 in MDCKII cell lines. Furthermore, PNPs had higher ectocervical tissue permeability (1.7-fold) compared to free MK-2048. PNP films showed sustained drug levels for at least 3 weeks in the macaque vaginal fluid. This work demonstrates the synergy of integrating nanomedicine and polymeric film technology to achieve sustained vaginal drug delivery. Full article

Dapivirine (DPV) is a potent NNRTI used to prevent the sexual transmission of HIV. In a phase 1 trial (IPM 028), the concomitant use of a DPV vaginal ring and an antifungal miconazole (MIC) vaginal capsule was found to increase the systemic exposure to DPV in women, suggesting a potential for drug-drug interactions. This study’s objective was to investigate the mechanism of DPV-MIC interactions using drug-metabolizing enzymes (DMEs; CYPs and UGTs) that are locally expressed in the female reproductive tract (FRT). In vitro studies were performed to evaluate the metabolism of DPV and its inhibition and induction potential with DMEs. In addition, the impact of MIC on DPV metabolism and the inhibitory potential of DPV with DMEs were studied. Our findings suggest that DPV is a substrate of CYP1A1 and CYP3A4 enzymes and that MIC significantly decreased the DPV metabolism by inhibiting these two enzymes. DPV demonstrated potent inhibition of CYP1A1 and moderate/weak inhibition of the six CYP and eight UGT enzymes evaluated. MIC showed potent/moderate inhibition of seven CYP enzymes and weak/no inhibition of eight UGT enzymes. The combination of DPV and MIC showed potent inhibition of seven CYP enzymes (1A1, 1A2, 1B1, 2B6, 2C8, 2C19, and 3A4) and four UGT enzymes (1A3, 1A6, 1A9, and 2B7). DPV was not an inducer of CYP1A2, CYP2B6, and CYP3A4 enzymes in primary human hepatocytes. Therefore, the increased systemic concentrations of DPV observed in IPM 028 were likely due to the reduced metabolism of DPV because of CYP1A1 and CYP3A4 enzymes inhibition by MIC in the FRT. Full article

Vaginal drug delivery systems can provide a long-term and constant liberation of the active pharmaceutical ingredient even for months. For our experiment, FDM 3D printing was used to manufacture the vaginal ring samples from thermoplastic polyurethane filament, which enables fast manufacturing of complex, personalized medications. 3D printing can be an excellent alternative instead of industrial manufacturing, which is complicated and time-consuming. In our work, the 3D printed vaginal rings were filled manually with jellified metronidazole or chloramphenicol for the treatment of bacterial vaginosis. The need for manual filling was certified by the thermogravimetric and heatflow assay results. The manufactured samples were analyzed by an Erweka USP type II Dissolution Apparatus, and the dissolution profile can be distinguished based on the applied jellifying agents and the API’s. All samples were considered non-similar based on the pairwise comparison. The biocompatibility properties were determined by prolonged MTT assay on HeLa cells, and the polymer could be considered non-toxic. Based on the microbiological assay on E. coli metronidazole and chitosan containing samples had bactericidal effects while just metronidazole or just chitosan containing samples bacteriostatic effect. None of these samples showed a fungistatic or fungicide effect against C. albicans. Based on our results, we successfully manufactured 3D printed vaginal rings filled with jellified metronidazole. Full article

There is a high global prevalence of HIV, sexually transmitted infections (STIs), and unplanned pregnancies. Current preventative daily oral dosing regimens can be ineffective due to low patient adherence. Sustained release delivery systems in conjunction with multipurpose prevention technologies (MPTs) can reduce high rates of HIV/STIs and unplanned pregnancies in an all-in-one efficacious, acceptable, and easily accessible technology to allow for prolonged release of antivirals and contraceptives. The concept and development of MPTs have greatly progressed over the past decade and demonstrate efficacious technologies that are user-accepted with potentially high adherence. This review gives a comprehensive overview of the latest oral, parenteral, and vaginally delivered MPTs in development as well as drug delivery formulations with the potential to advance as an MPT, and implementation studies regarding MPT user acceptability and adherence. Furthermore, there is a focus on MPT intravaginal rings emphasizing injection molding and hot-melt extrusion manufacturing limitations and emerging fabrication advancements. Lastly, formulation development considerations and limitations are discussed, such as nonhormonal contraceptive considerations, challenges with achieving a stable coformulation of multiple drugs, achieving sustained and controlled drug release, limiting drug–drug interactions, and advancing past preclinical development stages. Despite the challenges in the MPT landscape, these technologies demonstrate the potential to bridge gaps in preventative sexual and reproductive health care. Full article

The diversity and dynamics of the microbial species populating the human vagina are increasingly understood to play a pivotal role in vaginal health. However, our knowledge about the potential interactions between the vaginal microbiota and vaginally administered drug delivery systems is still rather limited. Several drug-releasing vaginal ring products are currently marketed for hormonal contraception and estrogen replacement therapy, and many others are in preclinical and clinical development for these and other clinical indications. As with all implantable polymeric devices, drug-releasing vaginal rings are subject to surface bacterial adherence and biofilm formation, mostly associated with endogenous microorganisms present in the vagina. Despite more than 50 years since the vaginal ring concept was first described, there has been only limited study and reporting around bacterial adherence and biofilm formation on rings. With increasing interest in the vaginal microbiome and vaginal ring technology, this timely review article provides an overview of: (i) the vaginal microbiota, (ii) biofilm formation in the human vagina and its potential role in vaginal dysbiosis, (iii) mechanistic aspects of biofilm formation on polymeric surfaces, (iv) polymeric materials used in the manufacture of vaginal rings, (v) surface morphology characteristics of rings, (vi) biomass accumulation and biofilm formation on vaginal rings, and (vii) regulatory considerations. Full article

Vulvovaginal candidiasis (VVC) is a vulvar/vaginal infection that affects approximately 75% of women worldwide. The current treatment consists of antimicrobials with hepatotoxic properties and high drug interaction probabilities. Therefore, this study aimed to develop a new treatment to VVC based on micelles containing curcumin (CUR) dispersed in a ureasil-polyether (U-PEO) hybrid. The physical-chemical characterization was carried out in order to observe size, shape, crystallinity degree and particle dispersion in the formulation and was performed by dynamic light scattering (DLS), scanning electron microscopy (SEM), X-ray diffraction (XRD) and through in vitro release study. The results of DLS and SEM exhibited micelles with 35 nm, and encapsulation efficiency (EE) results demonstrated 100% of EE to CUR dispersed in the U-PEO, which was confirmed by the DRX. The release results showed that CUR loaded in U-PEO is 70% released after 10 days, which demonstrates the potential application of this material in different pharmaceutical forms (ovules and rings), and the possibility of multidose based on a single application, suggesting a higher rate of adherence. Full article

Health authorities carefully evaluate any change in the batch manufacturing process of a drug before and after regulatory approval. In the absence of an adequate in vitro–in vivo correlation (Level A IVIVC), an in vivo bioequivalence (BE) study is frequently required, increasing the cost and time of drug development. This study focused on developing a Level A IVIVC for progesterone vaginal rings (PVRs), a dosage form designed for the continuous delivery in vivo. The pharmacokinetics (PK) of four batches of rings charged with 125, 375, 750 and 1500 mg of progesterone and characterized by different in vitro release rates were evaluated in two clinical studies. In vivo serum concentrations and in vitro release profiles were used to develop a population IVIVC progesterone ring (P-ring) model through a direct differential-equation-based method and a nonlinear-mixed-effect approach. The in vivo release, ${\mathrm{R}}_{\mathrm{vivo}}\left(\mathrm{t}\right)$, was predicted from the in vitro profile through a nonlinear relationship. ${\mathrm{R}}_{\mathrm{vivo}}\left(\mathrm{t}\right)$ was used as the input of a compartmental PK model describing the in vivo serum concentration dynamics of progesterone. The proposed IVIVC P-ring model was able to correctly predict the in vivo concentration–time profiles of progesterone starting from the in vitro PVR release profiles. Its internal and external predictability was carefully evaluated considering the FDA acceptance criteria for IVIVC assessment of extended-release oral drugs. Obtained results justified the use of the in vitro release testing in lieu of clinical studies for the BE assessment of any new PVRs batches. Finally, the possible use of the developed population IVIVC model as a simulator of virtual BE trials was explored through a case study. Full article