Effectiveness of redcore lotion in patients with vulvovaginal candidiasis: a systematic review and Meta-analysis.

OBJECTIVE: To summarize and evaluate the effectiveness and safety of Redcore lotion on treating vulvovaginal candidiasis (VVC) using a systematic review and Meta-analysis of randomized controlled trials. METHODS: A systematic literature search was performed in five English and three Chinese electronic databases up to October 2019. Randomized controlled trials in the treatment for VVC were included; only studies which compared the effectiveness and safety of Redcore lotion plus miconazole with miconazole alone were included. Relative risk (RR) and 95% confidence intervals (CI) were used in the Meta-analysis. RESULTS: Seven studies involving 768 patients suffering from VVC were identified; 468 of the patients were pregnant women (60.9%). Combination group (Redcore lotion plus miconazole) was more effective in reduCIng symptomatic episodes of VVC than miconazole alone, with respect to cure rate (RR, 1.31; 95% CI, 1.09-1.57; P = 0.01), fungal culture negative rate (RR, 1.21; 95% CI, 1.04-1.41; P = 0.01), and effective rate (RR, 1.18; 95% CI, 1.05-1.35; P = 0.01). Subgroup analyses for pregnant women also showed that the combination group had superior outcomes with respect to VVC cure rate (RR, 1.48; 95% CI, 1.16-1.88, P < 0.01), fungal culture negative rate (RR, 1.26; 95% CI; 1.09-1.47; P < 0.01), and effective rate (RR, 1.25; 95% CI, 1.10-1.42; P < 0.01). Additionally, the observed risk of adverse events was lower in the combination medication group (RR, 0.30; 95% CI, 0.14-0.65; P < 0.01). CONCLUSIONS: Though overall quality of individual studies was low, Redcore lotion plus miconazole can significantly improve clinical effectiveness and safety compared with miconazole alone.

Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections.

A series of selenium-containing miconazole derivatives were identified as potent antifungal drugs in our previous study. Representative compound A03 (MIC = 0.01 µg/mL against C.alb. 5314) proved efficacious in inhibiting the growth of fungal pathogens. However, further study showed lead compound A03 exhibited potential hemolysis, significant cytotoxic effect and unfavorable metabolic stability and was therefore modified to overcome these drawbacks. In this article, the further optimization of selenium-containing miconazole derivatives resulted in the discovery of similarly potent compound B17 (MIC = 0.02 µg/mL against C.alb. 5314), exhibiting a superior pharmacological profile with decreased rate of metabolism, cytotoxic effect and hemolysis. Furthermore, compound B17 showed fungicidal activity against Candida albicans and significant effects on the treatment of resistant Candida albicans infections. Meanwhile, compound B17 not only could reduce the ergosterol biosynthesis pathway by inhibiting CYP51, but also inhibited biofilm formation. More importantly, compound B17 also shows promising in vivo efficacy after intraperitoneal injection and the PK study of compound B17 was evaluated. In addition, molecular docking studies provide a model for the interaction between the compound B17 and the CYP51 protein. Overall, we believe that these selenium-containing miconazole compounds can be further developed for the potential treatment of fungal infections.

Preparation, Optimization, and Evaluation of Hyaluronic Acid-Based Hydrogel Loaded with Miconazole Self-Nanoemulsion for the Treatment of Oral Thrush.

Miconazole nitrate (MZ) is a BCS class II antifungal poorly water-soluble drug with limited dissolution properties and gastrointestinal side effects. Self-nanoemulsifying delivery system-based gel of MZ can improve both solubility and oral mucosal absorption with enhanced antifungal activity. The study aims to formulate MZ self-nanoemulsion (MZ-NE) and combine it within hyaluronic acid-based gel. MZ solubility in various oils, surfactants, and cosurfactant used in NE formulations were evaluated. Mixture design was implemented to optimize the levels of NE components as a formulation variable to study their effects on the mean globule size and antifungal inhibition zones. Further, the optimized MZ-NE was loaded into a hyaluronic acid gel base. Rheological behavior of the prepared gel was assessed. Ex vivo permeability of optimized formulation across buccal mucous of sheep and inhibition against Candida albicans were examined. Mixture design was used to optimize the composition of MZ-NE formulation as 22, 67, and 10% for clove oil, Labrasol, and propylene glycol, respectively. The optimized formulation indicated globule size of 113 nm with 29 mm inhibition zone. Pseudoplastic flow with thixotropic behavior was observed, which is desirable for oral gels. The optimized formulation exhibited higher ex vivo skin permeability and enhanced antifungal activity by 1.85 and 2.179, respectively, compared to MZ-SNEDDS, and by 1.52 and 1.72 folds, respectively, compared to marketed gel. Optimized MZ-NE hyaluronic acid-based oral gel demonstrated better antifungal activity, indicating its potential in oral thrush pharmacotherapy.

The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax.

Azole antifungal drugs are used worldwide to treat a variety of fungal infections such as vulvovaginal candidiasis, particularly in pregnant women who are at increased risk. The aim of this study was to mechanistically investigate the endocrine disrupting potential of four commonly used azole antifungal drugs; clotrimazole, miconazole, ketoconazole and fluconazole in vitro using the H295R cell assay and two recombinant, CYP17A1 and CYP19A1 (aromatase), assays. Steroids were quantified using LC-MS/MS. In both recombinant assays, all four azoles inhibited the CYP enzymes investigated, at therapeutically relevant concentrations. However, responses were much more complex in the H295R cell line. Clotrimazole inhibited steroid production in a dose-dependent manner with IC50 values for CYP17A1 and CYP19A1 in the range 0.017-0.184 µM. Miconazole and ketoconazole increased all steroids on the hydroxylase axis (IC50 MIC: 0.042-0.082 µM, KET: 0.041-1.2 µM), leading to accumulation of progestagens and corticosteroids and suppression of androgens and estrogens, indicating inhibition of CYP17A1, in particular lyase activity. However, ketoconazole suppressed all steroids at higher concentrations, resulting in bell-shaped curves for all steroids on the hydroxylase axis. Fluconazole was found to inhibit CYP17A1-lyase activity, causing suppression of androgens (IC50 = 114-209 µM) and estrogens (IC50 = 28 µM). The results indicate that these four azole drugs are highly potent in vitro and, based on plasma Cmax values, may exert endocrine disrupting effects at therapeutically relevant concentrations. This raises concern for endocrine related effects in patients using azole antifungal drugs, particularly when taken during sensitive periods like pregnancy.

Effect of miconazole nitrate on immunological response and its preventive efficacy in Labeo rohita fingerlings against oomycetes Saprolegnia parasitica.

This study evaluated the effect of sublethal doses of antifungal drug miconazole nitrate (MCZ) on immunological responses and its role as a prophylactic drug against S. parasitica in Labeo rohita fingerlings. Fish were fed with sublethal doses of MCZ, that is, T1-6.30 mgMCZ kgBW-1 , T2-12.61 mgMCZ kgBW-1 and T3-25.22 mgMCZ kgBW-1 , and sampling was done at different time intervals for 240 hr. Immunological parameters viz. lysozyme activity, oxygen radical production and plasma antiprotease activity showed significant enhancement (p < 0.05) in fish fed with T2 and T3 doses. Expression of immune-relevant genes such as TLR-22 and ß2-M showed significantly higher expression at 6 hr and 24 hr of sampling in both liver and head kidney. However, these genes showed a downregulation after 120 hr of sampling in both the tissues. Preventive efficacy study showed that single dose of MCZ provides protection against oomycetes up to the fourth day of infection. Significantly higher mortality was observed in control diet-fed fish as compared to fish fed with MCZ medicated diet. Thus, it can be concluded that the MCZ can act as a potent antifungal agent for preventing oomycetes infection as well as to enhance the immune response.

Effects of miconazole/clotrimazole and praziquantel combinations against the liver fluke Opisthorchis felineus in vivo and in vitro.

The liver fluke Opisthorchis felineus (Rivolta, 1884) is the causative agent of opisthorchiasis felinea in Eurasia. Opisthorchiasis is a serious human and fish-eating animal's disease affecting bile ducts and the gall bladder. Currently, the main drug for specific therapy of opisthorchiasis is praziquantel. We have previously shown that azole inhibitors of O. felineus cytochrome P450 significantly reduced survival of the worms in vitro. Here, we studied in vitro anthelmintic effects of drug combinations involving azole substances approved by the US Food and Drug Administration together with praziquantel against adult or juvenile O. felineus liver flukes. A synergistic interaction was shown for praziquantel-clotrimazole (CI = 0.68) combination and for praziquantel-miconazole (CI = 0.68) combination against adult helminths in vitro. Praziquantel-miconazole (CI = 0.30) had a strongly synergistic effect against newly excysted metacercariae. We also tested anthelmintic effects of azole substances and their combinations with praziquantel in vivo in an animal model of chemotherapy. The treatment of juvenile worms (1 day postinfection) with 100 mg/kg miconazole resulted in a worm burden reduction (WBR) of 37.5% (P = 0.049), with 100 mg/kg clotrimazole causing a WBR of 31.25% (P = 0.025). The treatment of adult worms (5-6 weeks postinfection) with 100 mg/kg or 200 mg/kg miconazole yielded a WBR of 23.8% (P = 0.01) and 21.4% (P = 0.006), respectively. When praziquantel was administered together with clotrimazole or with miconazole, a WBR slightly greater than the effect of ED50 praziquantel was observed (WBR of 59.5 and 54.7%, respectively).In conclusion, the synergistic effect of the praziquantel-clotrimazole and praziquantel-miconazole combinations observed in vitro was not confirmed in vivo. Thus, this combination chemotherapy revealed no benefits over praziquantel monotherapy in the treatment of opisthorchiasis felinea.

Vaginal antimycotics and the risk for spontaneous abortions.

BACKGROUND: Spontaneous abortions are the most common complication of pregnancy. Clotrimazole and miconazole are widely used vaginal-antimycotic agents used for the treatment of vulvovaginal candidiasis. A previous study has suggested an increased risk of miscarriage associated with these azoles, which may lead health professionals to refrain from their use even if clinically indicated. OBJECTIVE: The aim of the current study was to assess the risk for spontaneous abortions following first trimester exposure to vaginal antimycotics. STUDY DESIGN: A historical cohort study was conducted including all clinically apparent pregnancies that began from January 2003 through December 2009 and admitted for birth or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Beer-Sheva, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. Time-varying Cox regression models were constructed adjusting for mother's age, diabetes mellitus, hypothyroidism, obesity, hypercoagulable or inflammatory conditions, recurrent miscarriages, intrauterine contraceptive device, ethnicity, tobacco use, and the year of admission. RESULTS: A total of 65,457 pregnancies were included in the study: 58,949 (90.1%) ended with birth and 6508 (9.9%) with a spontaneous abortion. Overall, 3246 (5%) pregnancies were exposed to vaginal antimycotic medications until the 20th gestational week: 2712 (4.2%) were exposed to clotrimazole and 633 (1%) to miconazole. Exposure to vaginal antimycotics was not associated with spontaneous abortions as a group (crude hazard ratio, 1.11; 95% confidence interval, 0.96-1.29; adjusted hazard ratio, 1.11; 95% confidence interval, 0.96-1.29) and specifically for clotrimazole (adjusted hazard ratio, 1.05; 95% confidence interval, 0.89-1.25) and miconazole (adjusted hazard ratio, 1.34; 95% confidence interval, 0.99-1.80). Furthermore, no association was found between categories of dosage of vaginal antimycotics and spontaneous abortions. CONCLUSION: Exposure to vaginal antimycotics was not associated with spontaneous abortions.

Miconazole protects blood vessels from MMP9-dependent rupture and hemorrhage.

Hemorrhagic stroke accounts for 10-15% of all strokes and is strongly associated with mortality and morbidity worldwide, but its prevention and therapeutic interventions remain a major challenge. Here, we report the identification of miconazole as a hemorrhagic suppressor by a small-molecule screen in zebrafish. We found that a hypomorphic mutant fn40a, one of several known ß-pix mutant alleles in zebrafish, had the major symptoms of brain hemorrhage, vessel rupture and inflammation as those in hemorrhagic stroke patients. A small-molecule screen with mutant embryos identified the anti-fungal drug miconazole as a potent hemorrhagic suppressor. Miconazole inhibited both brain hemorrhages in zebrafish and mesenteric hemorrhages in rats by decreasing matrix metalloproteinase 9 (MMP9)-dependent vessel rupture. Mechanistically, miconazole downregulated the levels of pErk and Mmp9 to protect vascular integrity in fn40a mutants. Therefore, our findings demonstrate that miconazole protects blood vessels from hemorrhages by downregulating the pERK-MMP9 axis from zebrafish to mammals and shed light on the potential of phenotype-based screens in zebrafish for the discovery of new drug candidates and chemical probes for hemorrhagic stroke.

Preventive effects of topical washing with miconazole nitrate-containing soap to diaper candidiasis in hospitalized elderly patients: A prospective, double-blind, placebo-controlled study.

The objective of the present randomized, double-blind trial was to evaluate the efficacy and safety of daily washing with miconazole nitrate-containing soap for candidiasis at diaper-covered sites in elderly subjects under long-term inpatient care. To confirm the onset and disappearance of candidiasis, we microscopically evaluated the existence of the pseudohyphae and/or blastoconidia of Candida spp. We enrolled 75 elderly patients who wore diapers all day in the hospital or nursing home. Patients were randomly assigned to receive treatment with either miconazole soap or miconazole-free placebo soap, and 28 patients in the miconazole group and 27 patients in the placebo group were followed for 4 weeks. Although washing with miconazole soap did not affect the frequency of pseudohyphae/blastoconidia-positive patients, it significantly inhibited the positive conversion of pseudohyphae/blastoconidia compared with the placebo group. As a result, the frequency of patients positive for pseudohyphae/blastoconidia was significantly lower in the miconazole group than in the control group at 4 weeks (17.9% vs 44.4%). Clinically apparent diaper candidiasis did not develop in either group. Washing with miconazole soap was a significant independent factor for reducing the cases positive for pseudohyphae/blastoconidia, while diarrhea and heart failure were significant factors associated with an increase in the positive rate at the end-point. Severe adverse effects were not found in any patients. Thus, washing with miconazole soap is well-tolerated and can inhibit the positive conversion of Candida in patients wearing diapers. Therefore, maintenance of genital hygiene using this soap may prophylactically decrease the overall prevalence of patients with diaper candidiasis.

Eficacia, tolerancia y seguridad de una combinación de metronidazol, miconazol, centella asiática, polimixina y neomicina en cápsula blanda para uso vaginal en el tratamiento de la vaginosis bacteriana / Efficacy, tolerability, and safety of a combination including metronidazole, miconazole, Gotu kola, polymixin, and neomycin in soft vaginal capsules for the treatment of bacterial vaginosis

Introducción: La vaginosis bacteriana (VB) es un síndrome polimicrobiano, en la cual la flora dominante de lactobacilos normales es sustituida por una flora polimicrobiana. La prevalencia de VB en Perú varía entre 27 y 43,7%. El Centro de Control y Prevención de Enfermedades (DCD) sugiere el tratamiento de VB en mujeres sintomáticas con metronidazol oral/gel o clindamicina crema. Se planteó en el presente estudio evaluar la eficacia, tolerancia y seguridad de la combinación de metronidazol, miconazol, centella asiática, polimixina y neomicina en cápsula blanda para el tratamiento de VB. Material y Métodos: El presente estudio de tipo abierto, observacional, prospectivo, permitió evaluar la eficacia, tolerancia y seguridad en la aplicación de la combinación de metronidazol, miconazol, centella asiática, polimixina y neomicina en cápsula blanda. Resultados: Se incluyó a 61 pacientes con edad promedio de 29.28 años (rango 18-48) de las cuales 93,4% tenía historia previa de flujo vaginal anormal. Se realizaron dos visitas durante el estudio, la primera para diagnóstico e inicio de tratamiento y la segunda de control post tratamiento. Tres pacientes no tuvieron segunda visita y 8 no tenían registrada toda la información para definir la respuesta terapéutica. La segunda visita se realizó a los 21 días en promedio. Los principales signos y síntomas en la primera visita de diagnóstico fueron flujo vaginal (100,0%), disconfort vaginal (85,2%), dispareunia (70,5%) y dolor abdominal bajo (57,4%), las cuales disminuyeron en forma significativa (p<0,05) a la segunda visita post tratamiento. La prueba de aminas resultó positiva en el 93,4% de los casos en la primera visita y en el 15,5% de los casos en la segunda visita (p<0,05). De la población inicial de estudio, solo 53 mujeres son evaluables para eficacia terapéutica...

Introduction: Bacterial vaginosis (BV) is a polymicrobial syndrome, in which the normal dominant flora consisting in Lactobacillus is replaced by polymicrobial flora. The prevalence of BV in Peru varies between 27 and 43.7%. The Centers for Disease Control and Prevention suggest therapy for BV in symptomatic women should include oral/gel metronidazole or clindamycin cream. We proposed in this study to evaluate the efficacy, tolerability and safety of the combination of metronidazole, miconazole, Gotu kola (Centella asiatica), polymixin, and neomycin in soft capsules, for the treatment of BV. Material and Methods: This investigation was an open, observational, and prospective study, which allowed us to evaluate the efficacy, tolerability and safety of the aforementioned combined therapy administered in soft capsules. Results: The study included 61 patients with a mean age of 29.28 years (range, 18-48) and 93.4% had a history of abnormal vaginal discharge. Two visits took place during the study, the first for making the diagnosis and initiating therapy, and the second was the post-treatment control. Three patients did not have a second visit and 8 did not record all the information required to define the therapeutic response. The second visit took place after 21 days on average. The main signs and symptoms at the first visit were vaginal discharge at diagnosis (100.0%), vaginal discomfort (85.2%), dyspareunia (70.5%) and lower abdominal pain (57.4%), which were significantly reduced (p <0.05) in the second visit after treatment. The amine test was positive in 93.4% of cases in the first visit and in 15.5% of cases in the second visit (p <0.05). From the initial population in the study, only 53 women are evaluable for efficacy. An overall response rate in 44 women (83.02%) was achieved with the soft capsule combination treatment. Adverse events were reported in only one case...

Avaliação clínica e laboratorial do gel da Uncaria tomentosa (Unha de Gato) sobre candidose oral / Clinical and laboratorial evaluation of Uncaria tomentosa (Cat's Claw) gel on oral candidiasis

Na odontologia, a fitoterapia já vem sendo utilizada com sucesso há vários anos. Trata-se de um meio terapêutico que apresenta como vantagem sobre as medicações alopáticas o fato de apresentar reações adversas mínimas. A Uncaria tomentosa é uma planta indígena da floresta Amazônica e de outras áreas tropicais da América do Sul e Central. Tem aplicação no tratamento de diversas patologias, entre elas a candidose. Este trabalho avalia clínico e laboratorialmente a ação do gel da Uncaria tomentosa em pacientes portadores de candidose na cavidade oral. Foram selecionados 20 pacientes que apresentaram clínico e laboratorialmente infecção pelo Candida. Os mesmos foram divididos em 2 grupos. O grupo-teste (Uncaria tomentosa/Imuno-Max Gel), composto por 10 pacientes, foi orientado a utilizar o gel da Uncaria tomentosa, sobre as lesões na cavidade oral, 3x ao dia por um período de 14 dias. O grupo-controle (Miconazol/Daktarin Gel) utilizou a medicação da mesma forma prescrita para o grupo-teste. Após o período de tratamento, os pacientes retornaram para nova avaliação clínica e laboratorial. A Uncaria tomentosa mostrou ser um fitofármaco promissor na odontologia, apresentando vantagem sobre o miconazol de não ter provocado reações adversas nos pacientes, uma vez que, 40 por cento dos pacientes do grupo-controle, apresentaram reações indesejáveis.

In dentistry, the phytotherapy is already being used successfully for some years now. It is about a promising therapeutical way in the pharmaceutical field, having as advantage on pharmacotherapy medications the fact to present minimum adverse reactions. The Uncaria tomentosa is an aboriginal plant of the Amazonian forest and other tropical areas of the South and Central America. It has application in the treatment of several pathologies, including candidiasis. This work evaluates, clinical and laboratorial, the action of the Uncaria tomentosa gel in the oral cavity candidiasis patients. Twenty patients which presented clinical and laboratorial signs of Candida infection were selected. They were divided in 2 groups. The test-group (Uncaria tomentosa/IMUNO-MAX Gel), with 10 patients, was told to use the Uncaria tomentosa gel, on the oral cavity injuries, 3 times a day for a period of 14 days. The control-group (Miconazol/DAKTARIN Gel) used the prescribed medication in the same way of the test-group. After the treatment period, the patients returned for a new clinical and laboratorial evaluation. The Uncaria tomentosa showed to be a promising phytotherapeutical medication in dentistry, in the field of the anti-fungi treatment, presenting as advantage on the Miconazol not causing adverse reactions in the patients, once 40 percent of the control-group patients showed undesirable reactions.