Itraconazole Treatment Research Articles

US database study: burden and healthcare resource utilization in adults with systemic endemic mycoses and aspergillosis.

Aim: This study evaluated burden of illness in immunocompromised patients with systemic mycoses (SM) eligible for itraconazole treatment, specifically, histoplasmosis, blastomycosis and aspergillosis. Methods: A cross-sectional study used an electronic medical record network integrating information from 30 US hospitals, including>34 million patients, to evaluate burden and healthcare resource utilization over 6 months following initiation of antifungal therapy. Results: Symptomatic burden experienced by each of the otherwise healthy or age>65 or immunosuppressed cohorts receiving antifungal therapy for SM was comparable but significantly greater in cancer or HIV patients and transplant recipients. Across groups, there was substantially higher healthcare resource utilization in patients with SM versus matched controls without SM. Conclusion: The total impact of SM is particularly severe in high-risk or vulnerable populations.

Colonic Infection by Histoplasma capsulatum in a Liver Transplant Patient: A Case Report

Histoplasmosis is an infection caused by the dimorphic fungus Histoplasma capsulatum. While the lungs are the most common site of infection, disseminated disease affecting multiple organs can occur, particularly in immunocompromised patients. Gastrointestinal histoplasmosis is usually diagnosed in the context of disseminated disease and can present in any part of the digestive system, the ileum being the most frequently affected. We report the case of a 60-year-old female patient who underwent liver transplant for alcoholic liver cirrhosis. The patient had a 10 mm polypoid lesion in the sigmoid colon diagnosed in a screening colonoscopy performed 8 months prior to the transplant, but biopsy was not done for fear of bleeding due to extensive anorectal varices. There were no other lesions in the rest of the colon at that time. Four months after the transplant, the patient was asymptomatic and was submitted to a control colonoscopy, which showed 8 polypoid lesions in different parts of the colon, all of which were biopsied. Histologic results showed extensive infiltration of the colonic mucosa by Histoplasma capsulatum. Imaging and laboratorial screening for other sites of infection was negative, and the patient was treated with itraconazole for 12 months. A marked reduction in the dose of tacrolimus was necessary to maintain therapeutic levels during itraconazole treatment. Asymptomatic isolated colonic histoplasmosis is an uncommon manifestation of infection by Histoplasma capsulatum, with no previous reports in the literature of this condition affecting liver transplant recipients. This manuscript is compliant with the Helsinki Congress and the Istanbul Declaration.

SUN-338 SUBCUTANEOUS PHAEOHYPHOMYCOSIS IN A RENAL TRANSPLANT RECIPIENT

Subcutaneous Phaeohyphomycosis caused by dematiaceous fungi has rarely been described in a renal transplant recipient. 30 year-old male, deceased renal transplant recipient done in January 2018, Induction with ATG and on triple immunosuppression with normal graft function. November 2018 - Presented with a progressively enlarging swelling of 6.0x3.5cms over the anterior aspect of the left thigh following trauma. I&D done, initiated on IV antibiotics. KOH Stain showed fungal elements(Fig 1A), pus sent for fungal culture and treated with Fluconazole. December 2018:Presented with recurrence of swelling. USG revealed a collection measuring 6.6X3.5cms with loculations. Repeat I&D and punch Biopsy was done. Punch biopsy-Revealed inflammatory cystic lesion lined by palisades of histiocytes along with lymphocytes, plasmacells, neutrophils and giant cells along with fungal hyphae.(Fig 1B, PAS stain) Fungal stain–Darkly pigmented septal hyphal forms consistent with Phaeohyphomycosis. Fungal culture-Phaeohyphomycosis Treated with T.Voriconazole 200 mg BID for 14 days followed by T.Itraconazole 200 mg BID. The lesion healed completely within 2 weeks. January2019: Recurrence of the swelling.USG-subcutaneous abscess measuring 11.5X6cms with loculations. Enbloc Excision was done. Histopathology -Suppurative granulomatous inflammation. Pus swab for fungal culture–Darkly pigmented Septate non-sporulating hyphae s/o Phaeohyphomycosis. Patient was restarted on Tab.Voriconazole, modified the doses of immunosuppressive agents. After one month autologous skin grafting was done. Patient improved and discharged with normal renal function. May 2019 - Patient developed a new swelling in upper part of left thigh proximal to previous swelling, USG showed collection with multiple areas of air foci in subcutaneous plane. Wide local excision was done. Histopathology : Fungal hyphae s/o Phaeohyphomycosis with vascular invasion. Patient restarted on T.Voriconazole again and modified the dose of immunosuppressive agents. Patient have normal graft function and planned for skin grafting of the raw area but deferred in view of repeated culture positive with K.Pneumonia and Acinetobacter. In our case, despite specific antifungal therapy and least immunosuppressive medication, there was persistence of fungal infection with further proximal spread requiring surgical intervention. Sreejith et al, from JIPMER, India reported a series of seven cases of Subcutaneous Phaeohyphomycosis in a Renal Transplant Recipients.1In this series no patient responded to long term Itraconazole treatment, and ultimately requiring surgical excision Surgical management by wide local excision along with Antifungal treatment appears to be a better mode of treatment for Subcutaneous phaeohyphomycosis.

Superficial mycoses in Belgium: Burden, costs and antifungal drugs consumption

Monitoring of superficial mycoses requires more attention due to their important incidence, health costs and antifungal drugs consumption. The objectives were to estimate the burden of superficial mycoses in Belgium and to assess trends in associated antifungal consumption. The burden of dermatophytoses (including onychomycosis), as well as skin and genital candidiasis, was estimated using disability-adjusted life years (DALY). Moreover, trends in systemic and topical antifungal consumption in ambulatory care were examined for the period 2010-2017, together with their associated costs. Due to their high incidence and long treatment duration, dermatophytoses represented the bulk of the burden, accounting for 92.2% of the total DALYs of superficial mycoses. Terbinafine was the most prescribed antifungal in terms of doses (35.4% of the total doses) while fluconazole was the most delivered drug in terms of packages (29.1% of the total packages). More than 70% of the prescriptions were made by general practitioners while consumption varied according to age and gender of the patients. A global 12% decrease in antifungal prescriptions was observed between 2011 and 2017. However, this reduction would result mainly from packaging changes and increased self-medication. A significant decrease in itraconazole treatments was notably compensated by an increased prescription of fluconazole packages. This study emphasises that dermatological presentations of superficial mycoses are the most important in terms of both burden and antifungal consumption in Belgium. Further reduction in antifungals use can be achieved by applying the adequate treatment after identification of the causative agent.

Itraconazole Promotes Macrophage M1 Polarization and Phagocytic Capacity of Macrophage to Candida Albicans

Abstract Objective: The present study was designed to evaluate whether and how itraconazole affects the macrophage polarization and its reactivity to Candida albicans. Methods: Cell toxicity of itraconazole was measured using cell counting kit-8 assay in RAW264.7 cells. The cell models were induced by lipopolysaccharide (LPS), interleukin (IL)-4, or Candida albicans. Levels of cytokines secreted by RAW246.7 treated with itraconazole were detected by Luminex or Cytometric Bead Array compared to the controls without itraconazole treatment, and the expressions of inducible nitric oxide synthase and arginase (Arg) were determined by Western blot. Phagocytosis ability was measured by both flow cytometry and fluorescence microscope. The Student's t test and one-way analysis of variance were used to calculate the differences between groups. Results: In comparison to the control, itraconazole inhibited the growth of the cells in both a time- and a dose-dependent manner. Increased secretion of IL-6 (0.25 μmol/L ITZ [538.03 ± 60.23 pg/mL, P < 0.05], 0.5 μmol/L [550.32 ± 47.87 pg/mL, P < 0.05] and 1 μmol/L [626.95 ± 75.24 pg/mL, P < 0.01] vs. control [370.43 ± 33.98 pg/mL]) and tumor necrosis factor-alpha (TNF-α) (1 μmol/L ITZ vs. control: 2521.51 ± 444.06 pg/mL vs. 1617.85 ± 94.57 pg/mL, P < 0.05) were detected in the LPS-induced cell model with itraconazole treatment. In the cells induced by IL-4, itraconazole increased the secretion of IL-6 (1 μmol/L ITZ vs. control: 528.33 ± 11.60 pg/mL vs. 466.99 ± 28.32 pg/mL, P < 0.05), TNF-α (1 μmol/L ITZ vs. control: 4.85 ± 0.32 pg/mL vs. 4.30 ± 0.19 pg/mL, P < 0.05), and IL-1β (0.25 μmol/L [325.95 ± 13.97 pg/mL, P < 0.05], 0.5 μmol/L [332.38 ± 11.97 pg/mL, P < 0.05] and 1 μmol/L [334.35 ± 16.23 pg/mL, P < 0.05] vs. control [291.62 ± 17.03 pg/mL]), and reduced the secretion of IL-10 (1 μmol/L ITZ vs. control: 7.21 ± 0.68 pg/mL vs. 9.11 ± 0.14 pg/mL, P < 0.05). The secretion of IL-6 (1 μmol/L ITZ vs. control: 38.34 ± 1.36 pg/mL vs. 32.32 ± 0.84 pg/mL, P < 0.05) and TNF-α (1 μmol/L ITZ vs. control: 1060.17 ± 80.16 pg/mL vs. 890.84 ± 52.82 pg/mL, P < 0.01) was improved in Candida albicans-stimulated RAW264.7 cells under the treatment of itraconazole, while the secretion of IL-4 (0.5 μmol/L [2.86 ± 0.20 pg/mL, P < 0.05] and 1 μmol/L [2.24 ± 0.33 pg/mL, P < 0.001] vs. control [3.91 ± 0.23 pg/mL]) and IL-10 (1 μmol/L ITZ vs. control: 19.46 ± 2.05 pg/mL vs. 25.67 ± 1.95pg/mL, P < 0.05) decreased. In all three activated patterns, itraconazole enhanced the expression of inducible nitric oxide synthase (P < 0.01) and slightly inhibited the Arg-1 expression (P < 0.05). Phagocytosis ability of RAW264.7 cells at 1 μmol/L ITZ treatment was increased by 7.53% ± 2.21% (P < 0.01) and 9.73% ± 2.03% (P < 0.01) at the ratio of cells: yeast of 1:4 and 1:8, respectively, in comparison to the control group. Conclusion: Itraconazole improved M1 polarization of RAW264.7 cells and enhanced the phagocytic capacity of RAW264.7 to Candida albicans, indicating a significant immunological enhancement. The study improves the understanding of undergoing mechanisms related to the anti-tumor and anti-infection effects of itraconazole.

2642. Development of Human Intestinal Organoids as an Antiviral Evaluation Platform for Enteroviruses

BackgroundEnteroviruses are non-enveloped, single-stranded positive-sense RNA viruses belonging to the family Picornaviridae. Enterovirus A71 (EV-A71) has caused recurrent outbreaks of hand, foot, and mouth disease especially among children in Asia. Some patients develop severe complications, such as meningitis, encephalitis, myocarditis, and pulmonary edema. A major hurdle for the development of antivirals for EV-A71 infection is the lack of robust antiviral platforms that closely mimic the in vivo setting. Organoids are laboratory-adapted miniaturized organs with preserved three-dimensional micro-anatomical architecture. In recent years, organoid cultures have been increasingly used for studying the pathogenesis of and evaluating antiviral treatment options for viral infections. In this study, we developed human intestinal organoids as a robust platform for evaluating antiviral options for EV-A71.MethodsAn epidemic strain of EV-A71 isolated from a patient with laboratory-confirmed EV-A71 infection was used. We compared the performance of multiple antiviral evaluation assays (virus yield reduction, plaque reduction, and cell protection assays) between human intestinal organoids and Caco-2 cells, using itraconazole (an antifungal previously shown to exhibit potent anti-enteroviral effects) and DMSO as positive and negative controls, respectively.ResultsThe antiviral effect of itraconazole was comparable between human intestinal organoids and Caco-2 cells in the virus yield reduction and plaque reduction assays. In the cell protection assay, Caco-2 cells failed to demonstrate significant differences between the itraconazole-treated and DMSO-treated groups. In contrast, cell protection effects were easily observed and quantified in human intestinal organoids. Moreover, the human intestinal organoids allowed the characterization of the different cell types affected in EV-A71 infection with or without itraconazole treatment.ConclusionHuman intestinal organoids support the replication of EV-A71 and provides a robust platform for antiviral evaluation for EV-A71 infection.Disclosures All authors: No reported disclosures.

In vivo protection of the marjoram (Origanum majorana Linn.) essential oil in the cutaneous sporotrichosis by Sporothrix brasiliensis

Thirty Wistar rats subcutaneously infected by an itraconazole-resistant Sporothrix brasiliensis received the oral daily treatment (n = 10, each) of control (CTL, saline solution), itraconazole (ITZ, 10 mg/kg) and marjoram essential oil (MRJ, 80 mg/kg) for 30 days. Weekly, the clinical evaluation and euthanasia for histopathology and fungal burden were performed. Only animals from MRJ evolved to the remission of the cutaneous lesion with a mild to absent presence of yeasts in footpad, besides decreased the fungal burden in the systemic organs compared to CTL and ITZ (p < 0.05), preventing the fungal spread, mainly in the liver and spleen. The antifungal activity may have been attributed to the majority composition of terpinen-4-ol (34.09%), γ-terpinene (14.28%) and α-terpinene (9.6%), which the mode of action was at the level of ergosterol complexation. These findings highlighted the antifungal and the systemic protective effects of MRJ, supporting the promising use in the treatment of cutaneous sporotrichosis.

CT identifies pulmonary cryptococcosis in a domestic feline.

A domestic cat was presented for lethargy and coughing. Thoracic radiographs identified a mass within the right cranial lung lobe and a nodule in the left cranial lung lobe. Cryptococcus spp. was diagnosed via ultrasound-guided fine needle aspirate cytology. Despite fluconazole and prednisolone treatment, clinical signs progressed and suggested airway obstruction. Computed tomography revealed mass invasion into the trachea and other areas of the lower airway resulting in obstruction. Bronchoscopy was performed to debulk the tracheal mass and obtain biopsies. Histopathology confirmed Cryptococcus spp. At the time of this report, the patient remained clinically stable with daily itraconazole (5mg/kg) treatment.

Characteristics and Prognosis of Talaromyces marneffei Infection in Non-HIV-Infected Children in Southern China

Knowledge about the clinical and laboratory characteristics and prognosis of Talaromyces marneffei infection in children is limited. A retrospective study was conducted on pediatric patients with disseminated T. marneffei infection in a clinical setting. Extracted data included demographic information (age and sex), clinical features, laboratory findings, treatment, and prognosis. Eleven HIV-negative children were enrolled. The male/female ratio was 8:3. The median age of onset was 17.5months (3.5-84months). The mortality rate in these children was 36.36% (4/11). Seven children had underlying diseases. All of the children had multiple immunoglobulin abnormalities and immune cell decline. Ten children received voriconazole treatment, and most of the children (7/10) had a complete response to therapy at primary and long-term follow-up assessment; only three children died of talaromycosis. One patient recovered from talaromycosis but died of leukemia. The child who received itraconazole treatment also showed clinical improvement. No adverse events associated with antifungal therapies were recorded during and after the treatment. Talaromycosis is an indicator disease for undiagnosed severe immunodeficiencies in children. Awareness of mycoses in children by pediatricians may prompt diagnosis and timely treatment. Voriconazole is an effective, well-tolerated therapeutic option for disseminated T. marneffei infection in non-HIV-infected children.

Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett's Esophagus to Invasive Esophageal Adenocarcinoma.

The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma. The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett's Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.

Abstract CT087: Concentration-dependent early anti-vascular and anti-tumor effects of itraconazole in non-small cell lung cancer (NSCLC)

Abstract Introduction: Itraconazole has been repurposed as an anti-cancer therapeutic agent for multiple malignancies, including prostate cancer, and basal cell carcinoma, and lung cancer. In preclinical models, itraconazole has antiangiogenic properties and reduces Hedgehog (Hh) pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients. Methods: Patients who had NSCLC planned for surgical resection were administered 10-14 days of itraconazole 300 mg orally twice daily. Prior to and at the end of therapy, patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic (PK) and pharmacodynamic analyses. Tissue from pre-treatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyl-itraconazole concentration, as well as vascular and Hh pathway biomarkers. Results: A total of 13 patients were enrolled, of whom 8 completed the course of itraconazole and all biomarker studies. Itraconazole was generally well tolerated. Steady state plasma concentrations of itraconazole and hydroxyl-itraconazole demonstrated low intra-patient variability, but there was a six-fold difference in AUC (area under contrast curve) between patients. Itraconazole treatment did not alter transcription of GLI1 (P=0.20) and PTCH1 (P=0.34) mRNA in skin biopsies. There was a significant association between itraconazole PK and (a) tumor volume reduction (Spearman rank correlation -0.71; P=0.05), and (b) tumor perfusion (Ktrans) (correlation -0.71; P=0.01). Changes in IL-1b, G-CSF, and GM-CSF concentrations were significantly correlated with tumor volume reduction. Conclusions: Itraconazole demonstrates exposure-dependent early anti-vascular and anti-tumor effects in patients with NSCLC. However, it appears to have little activity against the Hh pathway. As interest in vascular-directed therapies re-emerges in this disease, itraconazole may offer a relatively inexpensive, convenient, and well-tolerated option. Funding: Department of Defense (DOD) W81XWH-13-LCRP-CEA Lung Cancer Research Program Clinical Exploration Award Citation Format: David E. Gerber, Farjana J. Fattah, Rolf A. Brekken, Rachael Skelton, Jessica Saltarski, Chul Ahn, Kemp H. Kernstine, Chyndhri Padmanabhan, Vaidehi Chemburkar, Sahba Kasiri, Rajareddy Kallem, Indhumathy Subramaniyan, Qing Yuan, Quyen N. Do, Yin Xi, Ivan Pedrosa, William C. Putnam, James Kim. Concentration-dependent early anti-vascular and anti-tumor effects of itraconazole in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT087.

A Case of Deep Cutaneous Purpureocillium lilacinum Fungal Infection in an Immunocompetent Patient

Purpureocillium is a genus of saprophytic fungi that is commonly found in soil or rotting material. Although rarely a pathogen in humans, it can cause serious infections in immunocompromized patients. An 85-year-old woman presented with a 2-week history of pruritic erythematous plaques with yellowish crusts on her right forearm and dorsal hand. Histopathological analysis identified fungal hyphae and spores in the dermis, and Purpureocillium lilacinum was identified through tissue culture, polymerase chain reaction, and DNA sequencing. The skin lesion barely responded to 4 weeks of itraconazole treatment but improved upon the addition of terbinafine. The skin lesion was completely cured after 12 weeks, with no recurrence to date. Here, we report a rare deep cutaneous fungal infection caused by P. lilacinum in an immunocompetent patient and postulate that, in this case, the patient's agricultural lifestyle increased the possibility of P. lilacinum infection.

Comparative evaluation of efficacy of terbinafine and itraconazole in treatment of tinea cruris

Background: In a hot and humid country like India, the prevalence of superficial mycotic infections is on the rise due to contributing environmental and demographic factors. In this study, we sought to assess the efficacies of two oral antifungal drugs, Itraconazole (a traditional azole) and Terbinafine (the only orally available allylamine). The two drugs were analyzed to see whether they differed significantly in their cure rates of tinea cruris. Since data, that compares only systemically administered Itraconazole and Terbinafine in the treatment of tinea cruris, is limited, this study becomes imperative.Methods: 60 patients, all clinically confirmed cases of tinea cruris and belonging to the age group of 18-65 years, were recruited for this prospective study. Patients were then randomly divided into groups A and B and followed-up for a month. Group A received cap. Itraconazole 100 mg, twice a day, for 15 days while group B received tab. Terbinafine 250 mg, once a day, for 4 weeks. Both groups were given topical 2% Sertaconazole that had to be continued for 8 weeks. During the 4 visits, scores for the 3 parameters (erythema, pruritis and scaling) were calculated and recorded for statistical analysis.Results: Authors observed that majority of the patients were exposed to hot and humid environment that contributed to sweating and poor personal hygiene. The changes in scores of erythema, pruritis and scaling from the baseline visit for both, Itraconazole and Terbinafine, were statistically significant at week 4 with P &lt; 0.05 for all parameters. But the difference between the scores of the two drugs was not found to be statistically significant.Conclusions: Although the sample size of this study was small and the data was limited, findings of this study supported that both Itraconazole and Terbinafine were highly effective in the treatment of tinea cruris.

In vitro and in vivo Efficacy of a Synergistic Combination of Itraconazole and Verapamil Against Aspergillus fumigatus.

The incidence of aspergillosis continues to rise sharply, while the progress made in expanding the antifungal drug arsenal remains extremely slow, indicating an urgent need for new strategies. Previous studies have shown that the calcium signaling pathway, which is evolutionarily conserved in mammals and fungi, is involved in regulating the tolerance of azoles in fungi. In this study, we performed a preliminary screening among various combinations of different clinical calcium channel blockers and different antifungal drugs. We found that the combination of itraconazole and verapamil showed the best synergistic effect against Aspergillus fumigatus. Thereafter, using the checkboard assays we observed synergistic effects of the combination treatment against most of the A. fumigatus strains tested, including itraconazole-sensitive and itraconazole-resistant strains, with a fractional inhibitory concentration index (FICI) < 0.5. Furthermore, we showed that verapamil strongly decreased the cytosolic calcium transients following itraconazole stimulation by an aequorin-mediated method. Moreover, verapamil influenced the efflux of rhodamine 6G, an azole mimic substance. An ergosterol assay revealed that verapamil alone had no effect on ergosterol biosynthesis, but the combination of itraconazole and verapamil treatment decreased the ergosterol level. Further murine assays were performed using a luciferase-probed bioluminescence imaging method. Drug combination therapy reduced lung burden and improved survival rate. In conclusion, verapamil is a promising candidate to enhance the antifungal activity of itraconazole against A. fumigatus. In addition, our study suggests the effectiveness of an emerging approach based on bioluminescence imaging in monitoring the efficacy of drug combination therapy for invasive aspergillosis.

428 Itraconazole inhibits the PDGF-D/PI3K/Akt/mTOR pathway in vitro and down-regulates serum PDGF-A of infantile hemangioma via oral administration

The incidence of infantile hemangiomas (IHs) is 8-10% in children. We found that itraconazole, a common anti-fungal agent, can improve or cure IH for the first time. However, the underlying molecular mechanisms are still unclear. Our research showed that itraconazole treatment significantly inhibits the proliferation and promotes apoptosis of the endothelial cells of mouse hemangioma (EOMA) cell line and infantile primary hemangioma endothelial cell (HemEC). Itraconazole also remarkably reduce angiogenesis of HemEC in vitro. We performed transcriptome profiling via mRNA microarrays in HemEC cells upon itraconazole treatment, and identified cytokine-cytokine receptor interaction as the top significantly enriched pathway. Importantly, itraconazole significantly reduced platelet-derived growth factor D (PDGF-D) level, resulting in suppression of PDGFR-β activation and inhibition of its downstream effectors, such as PI3K, Akt, 4E-BP1, p70S6K and mTOR signaling pathway, which are important for cellular growth and survival of IH. Oral itraconazole solution with 5mg/kg/d was administrated in 17 children, aging from 1 to 12 months (average 5.4 months), weighing from 5 to 10.5 kg. The blood samples collected were used to detect the concentration of serum vascular endothelial growth factor (VEGF) and PDGF-A by ELISA kits. The treatment period varied from 13 to 63 days, with total dose of itraconazole 390-2250 mg. Serum PDGF-A concentration was 52879.92 ± 31435.65 pg/mL before treatment and 26289.34 ± 26095.77 pg/mL after treatment (p<0.05), whereas VEGF showed no statistical difference (p>0.05). Both in vitro and in vivo data suggest that PDGF (at least A and D) is a novel target of itraconazole in IH, which need further investigations.

Itraconazole Induces Regression of Infantile Hemangioma via Downregulation of the Platelet-Derived Growth Factor–D/PI3K/Akt/mTOR Pathway

Infantile hemangioma is the most common benign vascular tumor of infancy. We have previously reported that itraconazole, a common antifungal agent, can clinically improve or cure infantile hemangioma; however, the underlying molecular mechanisms are still unclear. Here, we show that itraconazole treatment significantly inhibits proliferation and promotes apoptosis of the endothelial cells of mouse hemangioma cell line and infantile primary hemangioma endothelial cell. Itraconazole also remarkably reduced angiogenesis of hemangioma endothelial cell invitro. We further performed transcriptome profiling via mRNA microarrays in hemangioma endothelial cell upon itraconazole treatment, and identified cytokine-cytokine receptor interaction as the top significantly enriched pathway. Importantly, itraconazole significantly reduced platelet-derived growth factor-D level, resulting in suppression of platelet-derived growth factor-β activation and inhibition of its downstream effectors, such as PI3K, Akt, 4E-BP1, and p70S6K, which are important for cellular growth and survival of infantile hemangioma. In conclusion, our results suggest that platelet-derived growth factor-D is a target of itraconazole in infantile hemangioma.

Benznidazole, itraconazole and their combination in the treatment of acute experimental Chagas disease in dogs

Chagas disease (CD) is a serious public health problem in Latin America and its treatment remains neglected. Benznidazole (BZ) available in Brazil, presents serious side effects and low therapeutic efficacy at chronic phase. This study evaluated the therapeutic efficacy of BZ, itraconazole (ITZ) and BZ + ITZ in dogs infected with VL-10 T. cruzi strain in the acute phase (Ethic protocol number 2013/28). Twenty young mongrel dogs were inoculated with 2.0 × 103 blood trypomastigotes/kg and divided into four groups: treated with BZ, ITZ and BZ + ITZ for 60 days, and control group (INT-infected not treated). The parasitemia of the BZ + ITZ and BZ groups were similar and showed significant reduction compared to the INT group. The ITZ group also showed significant parasitemia reduction compared to the INT group. For cure control the global analysis of hemoculture (HC), blood PCR, conventional serology (CS-ELISA), heart qPCR and histopathology revealed that BZ + ITZ lead to more reduction of parasitemia during the acute phase and heart qPCR positivity, less cardiac damage and total survival than BZ or ITZ. Moreover, two other dogs, one treated with ITZ and other treated with BZ + ITZ, were always negative in all parasitological tests what indicates parasitological cure or that these dogs are in process of cure.•BZ + ITZ lead to more reduction of parasitemia, total survival, less heart qPCR positivity and cardiac damage.•According to the classic cure criterion cure was observed only in one dog submitted to BZ + ITZ treatment.•Two dogs, one treated with ITZ and other treated with BZ + ITZ were always parasitologically negative.

Itraconazole Dosing and Drug Monitoring at a Tertiary Children's Hospital.

Itraconazole is a broad-spectrum antifungal agent used for prophylaxis and treatment of fungal infections in immunocompromised children. Achieving the recommended target serum itraconazole trough concentration of ≥0.5 mg/L is challenging in children because of variation in itraconazole pharmacokinetics with age. We studied itraconazole use and treatment outcomes in a tertiary children's hospital. We did a 10-year retrospective review of medical records of children at the Royal Children's Hospital Melbourne who received oral itraconazole and had therapeutic drug monitoring (TDM). Overall, 81 children received 92 courses of oral itraconazole and had TDM. Of 222 TDM samples, 183 (82.4%) were taken at the appropriate time (trough level at steady state). Patients ≤12 and >12 years of age required median doses of 6.2 and 3.9 mg/kg/d, respectively, to attain target trough levels (P < 0.001). Of children ≤12 years of age, 71.4% required doses above the recommended dose of 5 mg/kg/d to achieve therapeutic levels, compared with 17.4% of those >12 years of age. At least 1 subtherapeutic trough concentration was reported in 63 (76.8%) courses; in only 18 (28.6%) of these was the dose adjusted. Gastrointestinal symptoms [14/92 (15.2%) courses] and hepatotoxicity [6/92 (6.5%)] were the most frequent adverse events. Neither was associated with elevated trough levels. The poor attainment of target levels with current recommended dosing in children <12 years of age suggests that higher empiric doses are needed in this age group. The poor compliance with TDM guidelines highlights the need for better education about appropriate timing of sampling and dose adjustment.

1139. Novel Formulation SUBA-Itraconazole Prophylaxis in Patients With Hematological Malignancy or Undergoing Allogeneic Stem Cell Transplantation: Follow-up Survival Data

BackgroundDespite the advantageous spectrum of activity of itraconazole, it is rarely used as a prophylactic agent due to limited bioavailability and intolerance of the conventional formulation. After the development of a novel formulation SUBA-itraconazole® (SUper BioAvailability), we undertook a study to assess therapeutic levels, safety, tolerability, and IFI rates of this novel formulation when compared with the conventional itraconazole liquid in patients undergoing allogeneic hematopoietic stem cell transplantation or in hematological malignancy patients.MethodsFollowing a single-centre, prospective study of SUBA–itraconazole 200 mg BID vs. conventional liquid itraconazole 200 mg BID, the SUBA–itraconazole group was assessed 1-year postallogeneic stem cell transplant for incidence of IFI and survival.ResultsA total of 57 patients (29 SUBA–itraconazole and 30 liquid-itraconazole) were assessed. Therapeutic concentrations were achieved significantly more quickly in the SUBA–itraconazole group; median of 6 days vs. 14 (P < 0.0001). At day 10, therapeutic concentrations were achieved in 69% of the SUBA–itraconazole group vs. 21% (P < 0.0001). The mean trough serum concentrations at steady state of SUBA–itraconazole were significantly higher, with less interpatient variability (1,577 ng/mL, CV 35%) vs. (1,218 ng/mL, CV 60%) (P < 0.001). There were 2 (7.5%) treatment failures in the SUBA–itraconazole group, both due to cessation of therapy for mucositis, compared with 7 (23.3%) treatment failures in the liquid-itraconazole group, due to subtherapeutic levels (five), mucositis (one), and gastrointestinal intolerance (one) (P = 0.096). There was one confirmed IFI in the SUBA–itraconazole treatment failure group defined by a blood culture that yielded yeast; however, this was after the cessation of SUBA–itraconazole for mucositis. No other probable/possible IFIs were observed. After 1 year postallogeneic stem cell transplant in the SUBA–itraconazole group, there were two deaths (10%) due to disease progression and no further IFIs were reported.ConclusionThe use of the SUBA–itraconazole formulation was a safe and effective prophylactic agent. It was associated with more rapid attainment of therapeutic levels with less interpatient variability when compared with conventional liquid itraconazole.Disclosures J. Lindsay, Mayne Pharma: Consultant, Consulting fee.

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice

Background: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. Methods: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. Results: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-β1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. Conclusion: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.