Treatment Of Vulvovaginal Candidiasis Research Articles

In vitro photodynamic therapy of Candida albicans, the cause of vulvovaginal candidiasis, is enhanced by Bacillus and Enterococcus probiotics.

Candida albicans is the primary cause of vulvovaginal candidiasis, a worldwide health concern for women. The use of supplemental methods, such as antimicrobial photodynamic therapy (aPDT) and probiotics, was promoted by the ineffectiveness of the existing antifungal drugs. This study examines the combined effects of probiotics (Bacillus and Enterococcus isolated from the fermented pickles) and PDT (using red laser (655 nm, 18 J/cm2) as a light source and methylene blue dye (30 mg/mL) as a photosensitizer) on the in vitro virulence activity of C. albicans including growth, biofilm formation, antifungal resistance, biofilm elimination, and biofilm dispersion. The probiotic strains demonstrated a higher resistance to PDT compared to the fungal cell. Bacillus and Enterococcus enhanced the antifungal effects of PDT on planktonic Candida cells in both pre-PDT and post-PDT interactions. The inhibition of biofilm formation by PDT was improved upon interaction with Bacillus (70%) and Enterococcus (58%). The eradication of Candida biofilm using PDT was increased after a combination with Bacillus (67%) and Enterococcus (46%). The nystatin resistance of the fungal biofilm following PDT treatment was decreased from (µg/ml) 25 to 6.25 due to the interaction with both probiotic strains. Fungal cell dispersion from the biofilm after PDT treatment diminished by 18% and 25% in the presence of Bacillus and Enterococcus strains. Galleria mellonella mortality was significantly changed following the PDT of the fungi/probiotic-injected larvae. This synergistic activity suggests the use of probiotics/PDT as a supplemental treatment for vulvovaginal candidiasis.

Hybrid Nanoparticles Dual‐Loaded With Curcumin and Benzydamine Hydrochloride for the Treatment of Vulvovaginal Candidiasis: From Development to Biological Application In Vitro and In Vivo (Adv. Therap. 1/2025)

Hybrid Nanoparticles Dual‐Loaded With Curcumin and Benzydamine Hydrochloride for the Treatment of Vulvovaginal Candidiasis: From Development to Biological Application In Vitro and In Vivo (Adv. Therap. 1/2025)

Development of amphotericin B inclusion complex formulation in dissolvable microarray patches for intravaginal delivery.

Amphotericin B (AMB) is a drug used to treat vulvovaginal candidiasis (VVC), which is a fungal infection affecting the vagina and vulva. Nevertheless, the substance's limited capacity to dissolve in water leads to poor absorption when taken orally, hence diminishing its therapeutic efficacy. In order to address this limitation, β-cyclodextrin (βCD) was used to create AMB in the form of an inclusion complex. This study aims to enhance the solubility and bioavailability of AMB by formulating it into an inclusion complex with βCD. Subsequently, we developed dissolvable microarray patches (DMP) as a novel drug delivery system, optimizing the formulation for improved retention, penetration, and controlled release of AMB. The stability of the AMB-βCD inclusion complx (IC) structure has been confirmed by employing molecular docking studies. The formulation of DMP involved the incorporation of IC with polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP). The mechanical strength, ability to be inserted, and propensity to irritate Amphotericin B-Inclusion Complex-Dissolvable Microarray Patches (IC-DMP) were evaluated by laboratory experiments utilizing the porcine vaginal mucosal layer. Further investigations, such as Differential Scanning Calorimetry (DSC), were performed to assess the physicochemical characteristics of the IC. The solubility of the pure medication was greatly enhanced up to fourfold by the inclusion complex. The assessment of IC-DMP exhibited exceptional mechanical robustness and insertion abilities, with no indications of discomfort. Among the formulas tested in ex vivo vaginal kinetic experiments, Formula F3 had the most effective retention in the porcine vaginal mucosal layer. It had an AUC value of 208.02 ± 0.33h.µg/cm3 and the highest Cmax value of 20.05 ± 0.06µg/cm3. Therefore, Formula F3 was the most efficient formula in terms of vaginal drug delivery. The integration of IC into the DMP system significantly enhances the solubility and bioavailability of AMB, facilitating its absorption in the circulatory system when applied intravaginally for vulvovaginal candidiasis treatment. These promising initial findings support further clinical evaluation of this novel drug delivery system.

Bioactive Potential of Chitosan-Oleic Acid Nanoparticles Loaded with Lemon Peel Essential Oil for Topical Treatment of Vulvovaginal Candidiasis.

The rising incidence of vulvovaginal candidiasis (VVC) has been leading to the development of alternative antifungal therapies. This study aimed to develop a topical chitosan-oleic acid nanoparticle (CH-OA-NP) cream loaded with lemon peel essential oil (LPEO) for VVC treatment. The characterization of the optimal nanoparticle formulation (F4: 10 g/L CH, 2:1 OA/LPEO ratio) showed high encapsulation efficiency, stability, and controlled release. Moreover, it was characterized regarding its particle size, polydispersity index, zeta potential, and chemical/morphological profile. LPEO-related compounds (e.g., eriodictyol) were identified through LC-ESI-QqTOF-HRMS in the cream matrix, suggesting the preservation of LPEO potential bioactivities after formulation. In silico docking of 12 LPEO metabolites revealed that compounds such as citronellic acid exerted inhibitory effects against several inflammation-associated enzymes (e.g., 14-α-Demethylase). In vitro antimicrobial tests demonstrated remarkable activity against Candida albicans, Gram-negative (e.g., Escherichia coli), and Gram-positive (e.g., Staphylococcus aureus) bacteria. In vivo studies in a rat model of VVC revealed significant antifungal, anti-inflammatory, and immunomodulatory effects of the LPEO-CH-OA-NP cream (5% and 10%), leading to reduced MDA, MPO, and IL-1β levels and increased GSH activity. This novel formulation potentially offers a promising alternative therapy for VVC, addressing the current antifungal therapies' limitations, counteracting drug resistance.

Kushen Gel combined with antifungal drugs for the treatment of vulvovaginal candidiasis: A systematic review and meta-analysis of randomized controlled trials

Ethnopharmacological relevanceVulvovaginal candidiasis (VVC) represents the most prevalent form of candidal infections, imposing a significant societal burden. Kushen gel, a chinese patent medicine, has demonstrated favorable outcomes in the treatment of VVC. In clinical practice, Kushen gel is often used in conjunction with antifungal drugs. However, the clinical evidence supporting the combined use of Kushen gel with antifungal drugs for the treatment of VVC is currently limited. Aim of the studyThis study aimed to evaluate the effectiveness and safety of Kushen gel combined with antifungal drugs in the treatment of vulvovaginal candidiasis (VVC). Materials and methodsDatabases namely CNKI, Wanfang Database, VIP Database, CBM, PubMed, Cochrane Library, and Embase were searched from their inception to January 2024. Randomized controlled trials (RCTs) applying Kushen gel combined with antifungal drugs for the treatment of VVC were included. Methodological quality assessment was performed using the Cochrane risk of bias assessment tool (RoB 1.0). A Meta-analysis was performed using RevMan 5.4 software. The primary outcomes were total efficacy rate, recurrence rate, secondary outcomes included adverse events and time to clinical symptom resolution. ResultsA Meta-analysis of 42 RCTs, encompassing a total of 4259 VVC patients was conducted. The results indicated that compared to antifungal drugs alone, Kushen gel combined with antifungal drugs increased the effectiveness (RR = 1.20, 95%CI [1.17, 1.23], P < 0.00001) and reduced the recurrence rate (RR = 0.21, 95%CI [0.13, 0.34], P < 0.00001), with no significant difference in safety (RR = 0.56, 95%CI [0.30, 1.03], P = 0.11). ConclusionsBased on the available results, it appears that the combination of Kushen gel with antifungal drugs may increase the effectiveness and reduce the recurrence rate. However, due to the poor methodological quality of the included studies, more high-quality evidence from large-sample and well-designed research is needed in the future.

Effects of intravaginal curcumin gels combined with electroporation on vulvovaginal candidiasis

ObjectiveTo provide a curcumin-based vaginal gel combined with electroporation for the treatment of vulvovaginal candidiasis (VVC) caused by Candida albicans. MethodsTemperature-sensitive in situ gels (ISG) were prepared using poloxamers 407 and 188 as matrices. The mass ratio of poloxamer 407 and poloxamer 188 was 7:1 with a gelation temperature of approximately 29°C and gelation time of 2.5 min. ResultsElectroporation increased the transmucosal permeability of the model drug, doxorubicin and improved the antifungal effects of curcumin. In vitro antifungal experiments showed that the number of fungal colonies in curcumin ISG combined with electroporation was lower than that in pure curcumin ISG. In vivo pharmacodynamic experiments showed that, compared to the model group, curcumin ISG with electroporation inhibited the growth of C. albicans, alleviated vaginal mucosal edema, and reduced the inflammatory response. ConclusionCurcumin ISG combined with electroporation has substantial potential for the efficient clinical treatment of VVC.

Hybrid Nanoparticles Dual‐Loaded With Curcumin and Benzydamine Hydrochloride for the Treatment of Vulvovaginal Candidiasis: From Development to Biological Application In Vitro and In Vivo

AbstractVulvovaginal candidiasis represents a public health challenge due to its reports of high incidence and recurrence. These are caused by host‐related factors like compromised immune system, or pathogen‐related factors, such as resistance to antifungal agents, making this medical problem desirable to develop new therapeutic options. In this context, natural origin substances like curcumin, are increasingly treatment alternatives. However, some curcumin properties limit its therapeutic application, such as insolubility in aqueous solvents, which leads to low bioavailability. Nevertheless, nanotechnology association with drugs of plant origin proves to be a promising alternative to overcome the reported drawbacks. Despite being caused by a fungus, patients suffer significantly from the inflammation resulting from this disease, thus this study aimed to develop a hybrid carrier nanoformulation by microfluidics loaded with two drugs, benzydamine hydrochloride (an anti‐inflammatory drug) and curcumin (an antifungal drug). Transmission electron cryomicroscopy combined with energy dispersive X‐ray analysis confirmed that the nanoparticle is properly developed. Through in vitro biological studies, it is possible to observe that, in addition to being safe, the encapsulation of both drugs in the nanocarrier drastically reduced their cytotoxicity. Finally, although the final nanoformulation does not show in vitro activity, the in vivo study indicated therapeutic potential.

Increasing rate of non-Candida albicans yeasts and fluconazole resistance in yeast isolates from women with recurrent vulvovaginal candidiasis in Leeds, United Kingdom

ObjectivesAzoles have been the mainstay of recurrent vulvovaginal candidiasis (RVVC) for many years. Because of a recent anecdotal increase in non-Candida albicans yeasts (NCAY) and azole-resistant C. albicans cases, their...

Effect of blue light emitting diode therapy on recurrent vulvovaginal candidiasis: A randomized assessor-blinded controlled trial.

Vulvovaginal Candidiasis (VVC) is a prevalent genital infection in women of reproductive age and requires effective non-drug therapies. Therefore, this study aimed to investigate the effect of blue light emitting diode (LED) therapy as an alternative treatment for recurrent VVC due to its proven antimicrobial properties. The safety and non-invasiveness of LED therapy make it a promising option for sensitive tissue applications. This randomized controlled trial recruited 60 women with culture-confirmed VVC. Participants were randomly allocated to two groups. Group A (control group) received standard antifungal treatment with Gynoconazol 0.8% vaginal cream for three consecutive nights (n=30). Group B (study group) received the same antifungal treatment plus two 60-min sessions of blue LED therapy directed at the vagina and vulva, with the sessions separated by two days (n=30). Candida count (via CHROMagar™ Candida) and vaginal pH (via AD110-AD111m) were assessed at baseline and one week after initiating treatment. Post-treatment, group (B) demonstrated a significantly greater reduction in Candida count compared to group (A) (mean difference (MD) 8.267; 95% Confidence Interval (CI) 6.723-9.811; p=0.0001). However, there was no statistically significant difference in vaginal pH between the groups (MD -0.03; 95% CI -0.244-0.178; p=0.749). Blue LED therapy effectively reduces Candida count in women with recurrent VVC without adversely affecting the vaginal pH, highlighting its safety and efficacy as a treatment modality.

Development of ROS-sensitive capofungin hydrogel by crosslinking chitosan with four-arm polyethylene glycol derivative for treatment of vulvovaginal candidiasis

Both exogenous and endogenous reactive oxygen species (ROS) in vulvovaginal candidiasis (VVC) play pivotal roles in promoting the hyphal formation of Candida albicans (CA), which suggests that clearing ROS could inhibit CA hyphae formation. A ROS-sensitive hydrogel (CAS@4Arm-PB/CS) was formulated by using a novel four-arm polyethylene glycol (4Arm-PEG) derivative (4Arm-PB) as a crosslinking agent, chitosan (CS) as the hydrogel matrix, and caspofungin (CAS) as the antifungal drug against CA. The ROS-sensitivity, disintegration mechanism, crosslinking action, swelling degree, microstructure, modulus, and rheological properties of 4Arm-PB were characterized. According to the results, 5.0 % 4Arm-PB could quickly and efficiently cross-link 0.5 mg/mL of CS. The ROS-sensitivity of 4Arm-PB was 10–50 μM, indicating a strong ROS sensitivity. The in vitro and in vivo anti-CA results indicated that CAS@4Arm-PB/CS not only cleared endogenous and exogenous ROS and inhibited the formation of CA hyphae and biofilm but also contributed beneficially to the treatment of VVC mice caused by CA infection, implying a certain safety aspect and an in vivo applicability. This research introduces a novel functional crosslinking agent for CS hydrogel formulation, presenting a new avenue for hydrogel-based drug delivery systems and therapeutic strategies for VVC treatment.

Reactive oxygen species sensitive nanomicelles promote the antifungal activity of ketoconazole against Candida albicans in vulvovaginal candidiasis

Excessive local accumulation of reactive oxygen species (ROS) in vulvovaginal candidiasis (VVC) leads to oxidative stress and aggravates inflammation. This study aimed to optimize and synthesize four ROS-sensitive polyethylene glycol (PEG)-boride polymers (PB, PCB, BPB, and BCPCB). A nanomicelle (BCPCB-K) was constructed using BCPCB-encapsulated ketoconazole (KTZ). Finally, the depolymerization principle and ROS-sensitive drug release of BCPCB-K as well as its anti-Candida albicans (CA) and therapeutic effects on mice with VVC were explored through in vitro and in vivo experiments. BCPCB-K exhibited low toxicity to mammalian cells in vitro and good biocompatibility in vivo. It also improved the dispersion and solubility of the hydrophobic drug KTZ. Furthermore, BCPCB-K simultaneously scavenged ROS and released the drug, thus facilitating the antifungal and VVC-treating effects of KTZ. Overall, the findings of this study broadened the application of ROS-sensitive materials in the drug-loading and antifungal fields and provided a strategy for VVC treatment.

Development and Evaluation of Microencapsulated Oregano Essential Oil as an Alternative Treatment for Candida albicans Infections.

Vulvovaginal candidiasis (VVC) is characterized as a very common fungal infection that significantly affects women's health worldwide. Essential oils (EOs) are currently being evaluated as an alternative therapy. The development of efficient techniques such as micro- or nanoencapsulation for protecting and controlling release is essential to overcome the limitations of EO applications. Therefore, the aim of this study was to develop and characterize oregano EO-loaded keratin microparticles (OEO-KMPs) as a potential treatment for VVC. OEO-KMPs were produced using high-intensity ultrasonic cycles and characterized in terms of morphological and physicochemical parameters. In vitro evaluation included assessing the toxicity of the OEO-KMPs and their effect against Candida albicans using microdilution and agar diffusion, while the activity against biofilm was quantified using colony forming units (CFU). The efficacy of the OEO-KMPs in an in vivo VVC mouse model was also studied. Female BALB/c mice were intravaginally infected with C.albicans, 24 h postinfection animals were treated intravaginally with 15 μL of OEO-KMPs and 24 h later vaginal fluid was analyzed for C.albicans and Lactobacillus growth (CFU mL-1). The results showed the stability of the OEO-KMPs over time, with high encapsulation efficiency and controlled release. This nanoparticle size facilitated penetration and completely inhibited the planktonic growth of C.albicans. In addition, an in vitro application of 2.5% of the OEO-KMPs eradicated mature C.albicans biofilms while preserving Lactobacillus species. In in vivo, a single intravaginal application of OEO-KMPs induced a reduction in C.albicans growth, while maintaining Lactobacillus species. In conclusion, this therapeutic approach with OEO-KMPs is promising as a potential alternative or complementary therapy for VVC while preserving vaginal microflora.

Chinese guidelines for diagnosis and treatment of vulvovaginal candidiasis (2024 edition)

Chinese guidelines for diagnosis and treatment of vulvovaginal candidiasis (2024 edition)

Possible adverse events of imidazole antifungal drugs during treatment of vulvovaginal candidiasis: analysis of the FDA Adverse Event Reporting System

Azole antifungal drugs are commonly used to treat vulvovaginal candidiasis (VVC). The nephrotoxicity and developmental toxicity of azole drugs have not been systematically analyzed in the real world. We used the FDA Adverse Event Reporting System (FAERS) to investigate the adverse events (AEs) associated with imidazole therapy for VVC. FAERS data (from quarter 1 2004 to quarter 3 2022) were retrieved using OpenVigil 2.1, and AEs were retrieved and standardized according to the Medical Dictionary for Regulatory Activities (MedDRA). In the top 10 System Organ Class (SOC), all four drugs have been found to have kidney and urinary system diseases and pregnancy. We found significant signals, including clotrimazole [bladder transitional cell carcinoma, (report odds ratio, ROR = 291.66)], [fetal death, (ROR = 10.28)], ketoconazole[nephrogenic anemia (ROR = 22.1)], [premature rupture of membranes (ROR = 22.91 46.45, 11, 3)], Miconazole[hematuria (ROR = 19.03)], [neonatal sepsis (ROR = 123.71)], [spontaneous abortion (ROR = 5.98)], Econazole [acute kidney injury (ROR = 4.41)], [spontaneous abortion (ROR = 19.62)]. We also discovered new adverse reactions that were not reported. Therefore, when using imidazole drugs for treatment, it is necessary to closely monitor the patient's renal function, pay attention to the developmental toxicity of the fetus during pregnancy, and be aware of potential adverse reactions that may occur.

A cost-effectiveness analysis of the use of oral ibrexafungerp versus fluconazole for acute vulvovaginal candidiasis in the UK NHS primary care service.

Vulvovaginal Candidiasis (VVC) is a fungal infection causing inflammation of the vagina and/or the vulva. Symptoms include itching, irritation, and discharge. VVC presents commonly across primary care and, despite its mild symptoms, carries psychological burden and has a significant impact on women's quality of life. UK guidelines support treatment via oral or topical azole antifungal agents. Recent evidence attests to the superiority of novel non-azole antifungals. Thus, rigorous financial assessment of both antifungals is necessary for optimal VVC treatment allocation in UK primary care. To evaluate the cost-effectiveness of ibrexafungerp against the gold standard fluconazole as first-line treatment of VVC within the NHS. A systematic review on the efficacy of ibrexafungerp and fluconazole in acute VVC was conducted. Cost-effectiveness analysis was initiated using health outcome data from the DOVE trial, a Phase 2 RCT. Costs in pound sterling were ascertained in monetary units, and effectiveness determined as reduced need for follow-up medication. An incremental cost-effectiveness ratio of £2185.74 was determined. This suggests oral ibrexafungerp being largely more costly yet slightly more effective than fluconazole, and thus has unfavourable net benefit. Two sensitivity analyses were conducted considering follow-up medication combination and market price, which provided confidence in the calculated cost-effectiveness ratio. This analysis highlights fluconazole's cost-effectiveness in current UK guidelines and favourability.

Transcriptomics Reveals Effect of Pulsatilla Decoction Butanol Extract in Alleviating Vulvovaginal Candidiasis by Inhibiting Neutrophil Chemotaxis and Activation via TLR4 Signaling.

The Pulsatilla decoction is a well-known herbal remedy used in clinical settings for treating vulvovaginal candidiasis (VVC). However, the specific mechanism that makes it effective is still unclear. Recent studies have shown that in cases of VVC, neutrophils recruited to the vagina, influenced by heparan sulfate (HS), do not successfully engulf Candida albicans (C. albicans). Instead, they release many inflammatory factors that cause damage to the vaginal mucosa. This study aims to understand the molecular mechanism by which the n-butanol extract of Pulsatilla decoction (BEPD) treats VVC through transcriptomics. High-performance liquid chromatography was used to identify the primary active components of BEPD. A VVC mouse model was induced using an estrogen-dependent method and the mice were treated daily with BEPD (20 mg/kg, 40 mg/kg, and 80 mg/kg) for seven days. The vaginal lavage fluid of the mice was analyzed for various experimental indices, including fungal morphology, fungal burden, degree of neutrophil infiltration, and cytokines. Various assessments were then performed on mouse vaginal tissues, including pathological assessment, immunohistochemistry, immunofluorescence, Western blot (WB), quantitative real-time PCR, and transcriptome assays. Our results showed that BEPD reduced vaginal redness and swelling, decreased white discharge, inhibited C. albicans hyphae formation, reduced neutrophil infiltration and fungal burden, and attenuated vaginal tissue damage compared with the VVC model group. The high-dose BEPD group even restored the damaged vaginal tissue to normal levels. The medium- and high-dose groups of BEPD also significantly reduced the levels of IL-1β, IL-6, TNF-α, and LDH. Additionally, transcriptomic results showed that BEPD regulated several chemokine (CXCL1, CXCL3, and CXCL5) and S100 alarmin (S100A8 and S100A9) genes, suggesting that BEPD may treat VVC by affecting chemokine- and alarmin-mediated neutrophil chemotaxis. Finally, we verified that BEPD protects the vaginal mucosa of VVC mice by inhibiting neutrophil recruitment and chemotaxis in an animal model of VVC via the TLR4/MyD88/NF-κB pathway. This study provides further evidence to elucidate the mechanism of BEPD treatment of VVC.

Exploring the antifungal potential of Annona muricata leaf extract-loaded hydrogel in treating vulvovaginal candidiasis

Vulvovaginal candidiasis, mostly caused by Candida albicans, remains a prevalent concern in women's health. Annona muricata L. (Annonaceae), a plant native from Brazil, is well-known for its therapeutic potential, including antitumor, anti-inflammatory, and antimicrobial properties. This study presents an innovative hydrogel formulation containing the ethanolic extract from A. muricata leaves designed to control C. albicans in an in vivo model of vulvovaginal candidiasis. Here, we report the development, thermal, physicochemical and rheological characterization of a Carbopol®-based hydrogel containing A. muricata extract. Furthermore, we evaluated its activity in a vulvovaginal candidiasis in vivo model. Thermal analyses indicated that the addition of the extract increased the polymer-polymer and polymer-solvent interactions.Rheological analysis showed a decrease in the viscosity and elasticity of the formulation as the A. muricata extract concentration increased, suggesting a liquid-like behavior. After treatment with the Carbopol®-based hydrogel with A. muricata, our in vivo results showed a significant reduction in vulvovaginal fungal burden and infection, as well as a reduction in mucosal inflammation. The current research opens up possibilities for the application of the Carbopol®-based hydrogel with A. muricata as a natural therapeutic option for the treatment of vulvovaginal candidiasis.

Enhanced Solubility and Bioavailability of Clotrimazole in Aqueous Solutions with Hydrophobized Hyperbranched Polyglycidol for Improved Antifungal Activity.

The poor solubility of clotrimazole in the aqueous medium and the uncontrolled removal of the drug-loaded suppository content limit its effectiveness in the treatment of vulvovaginal candidiasis. We present here the aqueous formulations of clotrimazole in the form of non-Newtonian structured fluids, i.e., Bingham plastic or pseudoplastic fluids constructed of hyperbranched polyglycidol, HbPGL, with a hydrophobized core with aryl groups such as phenyl or biphenyl. The amphiphilic constructs were obtained by the modification of linear units containing monohydroxyl groups with benzoyl chloride, phenyl isocyanate, and biphenyl isocyanate, while the terminal 1,2-diol groups in the shell were protected during the modification step, followed by their deprotection. The encapsulation of clotrimazole within internally hydrophobized HbPGLs using a solvent evaporation method followed by water addition resulted in structured fluids formation. Detailed Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analyses performed for aryl-HbPGLs with clotrimazole revealed the difference in drug compatibility among polymers. Clotrimazole in biphenyl-enriched HbPGL, unlike phenyl derivatives, was molecularly distributed in both the dry and the hydrated states, resulting in transparent formulations. The shear-thinning properties of the obtained fluid formulations make them injectable and thus suitable for the intravaginal application. Permeability tests performed with the usage of the Franz diffusion cell showed a 5-fold increase in the permeability constant of clotrimazole compared to drugs loaded in a commercially available disposable tablet and a 50-fold increase of permeability in comparison to the aqueous suspension of clotrimazole. Furthermore, the biphenyl-modified HbPGL-based drug liquid showed enhanced antifungal activity against both Candida albicans and Candida glabrata that was retained for up to 7 days, in contrast to the phenyl-HbPGL derivatives and the tablet. With their simple formulation, convenient clotrimazole/biphenyl-HbPGL formulation strategy, rheological properties, and enhanced antifungal properties, these systems are potential antifungal therapeutics for gynecological applications. This study points in the synthetic direction of improving the solubility of poorly water-soluble aryl-enriched pharmaceuticals.

Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study

PurposeTo evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC).MethodsA double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4.ResultsIn total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity.ConclusionsAs a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients.Chinadrugtrials.org.cn registry numberCTR20220918.

N-3-Methylbutyl-benzisoselenazol-3(2H)-one Exerts Antifungal Activity In Vitro and in a Mouse Model of Vulvovaginal Candidiasis.

In the present work, we evaluated the antifungal activities of two novel ebselen analogs, N-allyl-benzisoselenazol-3(2H)-one (N-allyl-bs) and N-3-methylbutylbenzisoselenazol-3(2H)-one (N-3mb-bs). Colorimetric and turbidity assays were performed to determine the minimum inhibitory concentration (MIC) of these compounds in S1 (fluconazole-sensitive) and S2 (fluconazole-resistant) strains of C. albicans. N-3mb-bs was more active than the N-allyl-bs compound. It is noteworthy that the concentration of N-3mb-bs observed to inhibit fungal growth by 50% (18.2 µM) was similar to the concentration observed to inhibit the activity of the yeast plasma membrane H+-ATPase (Pma1p) by 50% (19.6 µM). We next implemented a mouse model of vulvovaginal candidiasis (VVC) using the S1 strain and examined the mouse and yeast proteins present in the vaginal lavage fluid using proteomics. The yeast proteins detected were predominately glycolytic enzymes or virulence factors associated with C. albicans while the mouse proteins present in the lavage fluid included eosinophil peroxidase, desmocollin-1, and gasdermin-A. We then utilized the N-3mb-bs compound (12.5 mg/kg) in the mouse VVC model and observed that it significantly reduced the vaginal fungal burden, histopathological changes in vagina tissue, and expression of myeloperoxidase (MPO). All in all, the present work has identified a potentially promising drug candidate for VVC treatment.