Efficacy Of Itraconazole Research Articles

S2172 A Unique Case of Disseminated Histoplasmosis Presenting as Colonic Ulcers

Introduction: Histoplasmosis is the most common endemic mycosis in the United States with a disseminated form usually only seen in immunocompromised patients. While localized infections are usually self-limiting and often asymptomatic, some patients present with extra-pulmonary disseminated disease. Although case reports have described colonic and ileal involvement, gastrointestinal manifestations are uncommon. Here we report isolated colonic involvement of disseminated histoplasmosis in an asymptomatic patient. Case Description/Methods: A 62-year-old male with a history of end stage renal disease secondary to IgA nephropathy status post living donor renal transplant on chronic immunosuppressive therapy presented for a routine screening colonoscopy. The patient denied gastrointestinal and pulmonary symptoms to include: cough, shortness of breath, fever, abdominal pain, diarrhea and gastrointestinal bleeding. He grew up in the state of Mississippi and currently resides in Texas working in landscaping. Within the cecum, there were 2 discrete areas of abnormal appearing tissue (Figure A). A 10mm irregular, superficial ulcer with no high-risk stigmata for bleeding was also noted within the distal transverse colon (Figure B). Cold forceps biopsies were obtained at both sites. Surgical pathology with Grocott’s methenamine silver stain demonstrated abundant intra-histiocytic and extracellular organisms morphologically compatible with histoplasmosis. Given a potential for fungal morphological mimicry, the patient was serologically tested for histoplasmosis, coccidioides, and blastomyces. Ultimately, PCR from the tissue sample taken during the biopsy tested positive for Histoplasma capsulatum. The patient was started on itraconazole for 12 months duration which he tolerated without side effects and remained asymptomatic on follow up. Discussion: This case demonstrates an unusual presentation of disseminated histoplasmosis with asymptomatic colonic involvement including the variable endoscopic appearance of this fungal infection. With a mortality rate as high as 31% in the immunocompromised population gastroenterologists need to remain cognizant when encountering colonic ulcerations or abnormal mucosa in high risk patients. In addition, this case highlights the importance of tissue sampling to secure the diagnosis along with the efficacy of itraconazole in treating this potentially deadly infection.Figure 1.: A. Discrete area of anomalous tissue in the cecum B. Area of ulceration along the distal transverse colon.

Abstract 896: An antifungal, Itraconazole, induces cell death by targeting HER2 signaling and stem-like properties in trastuzumab-resistant HER2-positive breast cancer

Abstract Trastuzumab resistance in HER2-positive breast cancer leads to a poorer prognosis and shorter overall survival. Identifying existing drugs for another purpose of use may be considered as a part of new approaches to overcome resistance in cancer biology. Itraconazole is a FDA-approved drug, which is one of anti-fungal drugs. This drug has been reported to exploit as a cancer therapeutic agent in several cancer types. We sought to investigate the anti-cancer effects of itraconazole on cell proliferation, apoptosis, autophagy and breast cancer stem cell-like properties in terms of challenging trastuzumab resistance in HER2-positive breast cancer. The effect of itraconazole on trastuzumab-resistant cell line, JIMT-1, in vitro was examined in aspects of cell viability, apoptosis, autophagy, and impact on cancer stem cells. As in vivo experimental model, trastuzumab-resistant JIMT-1 cells were implanted to generate xenografts to study anti-tumor efficacy of itraconazole. Treatment of itraconazole significantly suppressed the growth of JIMT-1 cells with marked induction of apoptosis. Itraconazole downregulated p185HER2 and truncated-p95HER2, and their phosphorylation levels in JIMT-1 cells. In addition, the outcome of the decrease in the levels of Beclin-1 and p62 and the increase of LC3 I/II after the exposure to itraconazole supported that itraconazole induced autophagy as well. Importantly, itraconazole not only killed proliferating tumor cells but also effectively eradicated cancer stem-like populations. To elucidate eradication of cancer stem-like population by itraconazole, ALDH1 activity assay and FACS analysis of CD44+/CD24- stem-like phenotype in JIMT-1 cells were carried out. As a result, stem-cell like populations were impaired as evidenced by a significant decrease in ALDH1 activity and CD44+/CD24- stem-like populations. Through in vivo mouse model, the physiological relevance of in vitro observations was confirmed. Evident inhibition of tumor burden and growth in trastuzumab-resistant xenografts was shown in consequence of itraconazole administration, accompanying by substantial downregulation of HER2, ALDH1 and microvessel density as well as dramatic decrease of p62 in vivo. No injury to liver or kidneys by itraconazol was found based on no statistically significant difference in serum levels of ALT, AST and BUN between vehicle- and itraconazole-administrated groups. We have demonstrated that itraconazole, which is FDA-approved drug as an anti-fungal drug, exerts anti-tumor activity in trastuzumab-resistant HER2-positive breast cancer by targeting cancer stem-like properties, suppression of the HER2 signaling as well as induction of autophagy. These findings support the notion that itraconazole might be a new strategic approach as a treatment for trastuzumab-resistant HER2-positive breast cancers. Citation Format: Jung Min Park, Soeun Park, Minsu Park, Seongjae Kim, Juyeon Seo, Dongmi Ko, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. An antifungal, Itraconazole, induces cell death by targeting HER2 signaling and stem-like properties in trastuzumab-resistant HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 896.

Neoadjuvant itraconazole (I) in patients (pts) with resectable basal cell carcinoma (BCC): A phase II multistage study.

e22081 Background: Targeting the hedgehog (HH) protein family pathway has consistently shown activity in locally advanced and metastatic BCC. Itraconazole is an affordable agent with known toxicity profile that demonstrates in vitro HH signaling inhibition, suggesting a possible role in BCC treatment. Initial results of a phase 2 study designed to investigate efficacy of Itraconazole as neoadjuvant treatment in patients with resectable BCC are reported. Methods: Eligible pts had biopsy-proven resectable BCC, ECOG PS 0-3, adequate organ function and measurable disease. Dosing of I consisted of 200mg twice daily for 60 days followed by surgery. Simon two-stage design was used to test a null rate of 5% vs. 20% (power = 0.80; α = 0.05, unilateral). If ≥1 of 13 pts in stage 1 have objective response (OR) according to RECIST 1.1 criteria, 14 more pts will be enrolled. If ≥4 of 27 pts have OR, the treatment is worthy of further study. Secondary endpoints include safety and change in Ki-67 and Gli1. Results: Thirteen pts with 14 measurable lesions enrolled from Jan/2018 to Feb/2019; 1 pt was not evaluable, but was included in safety analysis. Demographics and outcomes are summarized in Table. After 60 days of treatment, all patients had R0 resection as primary planned and 1 (8.3%) PR was observed. There were no progressions during the study. OR rate was 8.3%. No grade 3 AE or SAE were reported. 6 pts had grade 1 or 2 AEs at least possibly related to I including depression, headache, GPT elevation, diarrhea, abdominal pain and bilirubin elevation. Conclusions: Itraconazole showed initial anti-tumor activity in pts with resectable BCC, no safety concerns were observed. Study will proceed to Simon’s second stage. Clinical Trial Information: NCT03972748 , 47011715.0.0000.5327 . [Table: see text]

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.

Эффективность итраконазола в преконцепционной профилактике рецидивирующего вульвовагинального кандидоза

Эффективность итраконазола в преконцепционной профилактике рецидивирующего вульвовагинального кандидоза

Abstract 1703: Expression of Hedgehog signals and growth inhibition by itraconazole in endometrial cancer

Abstract Background: There are limited therapeutic opportunities for the treatment of endometrial cancer (EC). Itraconazole, a common antifungal agent and a potent inhibitor of the Hedgehog pathway, has been shown to be clinically effective for various types of cancer, but its clinical efficacy for EC is unknown. Herein, we evaluated the efficacy of itraconazole in treating EC. Patients and Methods: We reviewed cases of patients with serous endometrial intraepithelial carcinoma (SEIC) and patients who were diagnosed with EC with endometrioid adenocarcinoma grade 1 or 2 at FIGO stage IA with myometrial invasion and negative cytology of ascites and who recurred at our institution from January 2005 to December 2013. We also reviewed cases with endometrioid adenocarcinoma grade 1 or 2 at FIGO stage IA with myometrial invasion and negative cytology of ascites without recurrence over 5 years after surgery during 2006 and 2007. Immunohistochemistry was performed on EC tumour samples including SEIC for sonic Hedgehog (sHh), glioma-associated oncogene homolog 1 (GLI1), Progesterone receptor (PR), and chemokine ligand 18 (CCL18). Furthermore, we examined the effects of itraconazole on human EC cell lines (Ishikawa and HEC-1A cells) using a modified methylthiazol tetrazolium (MTT) assay and a migration assay. Results: SHh and GLI1 were expressed in SEIC and endometrioid adenocarcinoma. Immunohistochemical evaluation of sHh and GLI1 did not distinguish between recurrent and non-recurrent low-grade FIGO stage IA EC. The MTT assay revealed that itraconazole significantly inhibited the growth of Ishikawa and HEC-1A cells in a dose-dependent and time-dependent manner. However, migration was not significantly effected for either Ishikawa or HEC-1A cells. HEC-1A cells exhibited dose-dependent migration retardation. Conclusion: Hedgehog signalling plays a role in carcinogenesis and malignant progression in EC. Itraconazole at a physiological dose may suppress progression of EC. Citation Format: Kayo Inoue, Hiroshi Tsubamoto, Hiroaki Shibahara, Kazuo Tamura. Expression of Hedgehog signals and growth inhibition by itraconazole in endometrial cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1703.

Efficacy of combination chemotherapy with itraconazole for treating metastatic pancreatic cancer in the second-line setting.

e15255 Background: The treatment of progressive pancreatic cancer after front-line chemotherapy is under investigation. Pretreated tumors express cancer stem cell markers and P-glycoprotein. Itraconazole, a common antifungal agent, is a potent inhibitor of the Hedgehog pathway, P-glycoprotein, and angiogenesis. We aimed to evaluate the efficacy and feasibility of chemotherapy with itraconazole for treating progressive pancreatic cancer. Methods: We retrospectively reviewed the medical charts of histologically diagnosed pancreatic cancer patients who had received one or more lines of chemotherapy and subsequent chemotherapy with itraconazole. The efficacy of itraconazole was evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1 by considering the survival after chemotherapy with itraconazole. Results: Between 2008 and 2013, we enrolled 38 recurrent patients. All the patients were referred to our institution from tertiary care hospitals; they received docetaxel (35 mg/m2), gem...

A comparative study of itraconazole in various dose schedules in the treatment of pulmonary aspergilloma in treated patients of pulmonary tuberculosis.

Introduction:The optimal dose, duration, and efficacy of itraconazole in Indian patients of pulmonary aspergilloma (PA) are not clearly defined. Therefore, a study was carried out, to resolve these issues in diagnosed cases of PA complicating old treated patients of pulmonary tuberculosis.Materials and Methods:The study patients randomly received itraconazole either in a fixed dose schedule of 200 mg (group I), 200 mg twice daily (group II) or a variable dose schedule (group III), for 12 months. All the patients were followed up for the entire duration of the study for clinical, radiological, and immunological response. The side effects were recorded as and when reported by the patients and managed symptomatically.Results:A total of 60 patients were enrolled, 20, in each group. There were no intergroup differences with regard to age, sex, body weight, smoking status, alcohol intake, symptoms, Potassium hydroxide (KOH) mount, fungal culture, pattern of radiological lesions or anti-aspergillus antibodies (anti-Asp-Ab) titers. The radiological response was poor in group I patients, as compared to the other groups, at two months (P < 0.05). The dose of itraconazole was increased in five of the patients in group I due to poor response. A higher number of group II patients suffered side effects and the dose of itraconazole had to be decreased in three of these patients, but none of the patients on a variable dose schedule required a change in dose schedule.Conclusion:Thus, a weight-based variable dose schedule of itraconazole was found to be a more effective and safer modality in the management of PA than a fixed dose schedule.

Itraconazole for leukemia complicating with invasive fungal infection

Objective To explore the clinical efficacy of itraconazole for leukemia complicating with invasive fungal infection.Methods 149 leukemia patients complicating with fungal infections in our hospital were enrolled from August 2007 to September 2011,and divided them into control group (n =74) and observation group (n=75) according to the antifungal agents they chose.The control group were treated with fluconazole,400 mg/d,and the observation group were treated with itraconazole,200 mg/d.Clinical efficacy and adverse reactions were compared between these two groups.Results The cured rate,effective rate and total effective rate were 48.0％,20.0％,94.6％ in the observation group,respectively,which were significantly higher than that in the control group (32.4％,16.2％,77.0％) (P＜0.05).No serious adverse reactions occurred in both groups during the treatment.The main adverse reaction was liver function abnormality after medication;the occurrence was 16.2％ in the control group patients and 21.3％ in the observation group,without significant difference (P＞ 0.05).Conclusions Itraconazole for leukemia complicating with invasive fungal infection is clinically efficacious,safe,and should be clinically generalized. Key words: Itraconazole; Leukemia; Fungal infection; Clinical efficacy

Abstract LB-223: An open-label, exploratory phase II study of oral itraconazole for the treatment of basal cell carcinoma

Abstract Purpose: Itraconazole is an FDA-approved antifungal drug that has been recently shown to antagonize the Hedgehog (Hh) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis. As oral itraconazole reduced BCC growth in mice, we assessed itraconazole's efficacy in treating human BCC tumors in an open-label, exploratory phase II study. Patients and Methods: Patients with at least one BCC tumor greater than 4 mm in diameter and with no co-morbidities were eligible to enroll. Patients were enrolled in 2 cohorts to receive oral itraconazole 200 mg twice-daily for one month (Cohort A) or 100 mg twice-daily for a longer duration (Cohort B). The primary endpoint was to determine changes in tumor size, proliferation (Ki67 levels), and a target gene of the Hh pathway (GLI1 mRNA). Results: Of the 29 patients that enrolled in the clinical trial, 19 patients were treated with itraconazole. Itraconazole caused 2 treatment-related adverse events (grade 2 fatigue and grade 4 CHF). Tumors treated with itraconazole showed a 23% reduction in clinical tumor area (95% CI: 17.2% to 28.1%), a 45% reduction in cell proliferation (P=0.04), and a 65% reduction in Hedgehog activity (P=0.03). Eight subjects with multiple tumors were assessed for clinical size changes: 4 subjects had partial response and 4 had stable disease. Tumors from control patients and patients previously treated with other Hedgehog inhibitors saw no significant changes in cell proliferation or Hedgehog activity. Conclusion: Itraconazole reduced BCC tumor size, tumor proliferation, and Hedgehog pathway activity in this exploratory study. Additional studies with larger numbers of patients are needed to validate these findings, however this proof-of-concept study demonstrates the possibility of repurposing FDA approved drugs for the treatment of cancers driven by the Hedgehog signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-223. doi:1538-7445.AM2012-LB-223

Abstract 2316: Itraconazole, an antifungal drug with anti-angiogenic activity, inhibits VEGFR2 trafficking, glycosylation, and signaling in endothelial cells

Abstract Itraconazole is a widely used antifungal drug that has been recently shown to inhibit angiogenesis in vivo and to block non-small cell lung cancer growth in animal models. Based on these and other results, itraconazole is currently being evaluated in four clinical trials as a cancer therapeutic. Angiogenesis, one of the hallmarks of cancer, is required for tumor growth and is driven by tumor-secreted growth factors including vascular endothelial growth factor (VEGF). We now report that in endothelial cells, itraconazole inhibits signaling of VEGF through the VEGF receptor 2 (VEGFR2) (80% inhibition; p &amp;lt; 0.05) and subsequently through a downstream substrate, PLCϒ1 (60% inhibition; p &amp;lt; 0.05). Mechanistically, we show that this was due to a nearly complete loss of VEGF binding to VEGR2 that was secondary to a loss of cell surface expression of the receptor. After itraconazole treatment, VEGFR2 was retained in a perinuclear aggregate which partially overlapped with the cis-Golgi marker GM130. Correlated with this loss of VEGFR2 signaling and trafficking, was a dramatic change in VEGFR2 mobility on SDS-PAGE which resulted from incomplete N-glycosylation. Itraconazole globally reduced poly-LacNAc and tetra-antennary glycans in endothelial cells and induced hypoglycosylation of EGFR in a renal cell carcinoma line, suggesting that the effects of itraconazole apply to multiple cell types and receptors. Importantly, small molecule inducers of lysosomal accumulation and mTOR inhibition, two previously known itraconazole-induced effects, did not interfere with VEGFR2 glycosylation. Similarly, glycosylation inhibitors did not affect cholesterol trafficking or inhibit mTOR. However, increasing cellular cholesterol levels, which was known to rescue the effects of itraconazole on mTOR and cholesterol trafficking, restored VEGFR2 glycosylation and signaling. Thus, the newly described properties of itraconazole occur in parallel to inhibition of cholesterol trafficking and mTOR but appear downstream of a single target. Taking these findings together, we propose a model in which itraconazole inhibits intracellular trafficking. This model could explain the loss of VEGFR2 signaling, incomplete VEGFR2 glycosylation, as well as disruption of cholesterol trafficking and mTOR signaling. Importantly, the effects of itraconazole we report here may significantly contribute to the in vivo efficacy of itraconazole and are relevant to ongoing clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2316. doi:1538-7445.AM2012-2316

Treatment of Cutaneous Sporotrichosis With Itraconazole--Study of 645 Patients

Itraconazole has become the first choice for treatment of cutaneous sporotrichosis. However, this recommendation is based on case reports and small series. The safety and efficacy of itraconazole were evaluated in 645 patients who received a diagnosis on the basis of isolation of Sporothrix schenckii in Rio de Janeiro, Brazil. A standard regimen of itraconazole (100 mg/day orally) was used. Clinical and laboratory adverse events were assessed a grades 1-4. A multivariate Cox model was used to analyze the response to treatment. The median age was 43 years. Lymphocutaneous form occurred in 68.1% and fixed form in 23.1%. Six hundred ten patients (94.6%) were cured with itraconazole (50-400 mg/day): 547 with 100 mg/day, 59 with 200-400 mg/day, and 4 children with 50 mg/day. Three patients switched to potassium iodide, 2 to terbinafine, and 4 to thermotherapy. Twenty-six were lost to follow-up. Clinical adverse events occurred in 18.1% of patients using 100 mg/day and 21.9% of those using 200-400 mg/day. The most frequent clinical adverse events were nausea and epigastric pain. Laboratory adverse events occurred in 24.1%; the most common was hypercholesterolemia, followed by hypertriglyceridemia. Four hundred sixty-two patients (71.6%) completed clinical follow-up, and all remained cured. Only 2 variables were significant in explaining the cure: patients with erythema nodosum healed faster, and lymphocutaneous form took longer to cure. In the current series, the therapeutic response was excellent with the minimum dose of itraconazole, and there was a low incidence of adverse events and treatment failure.

Two cases of Schizophyllum asthma: Is this a new clinical entity or a precursor of ABPM?

Background There is a close link between fungal sensitization and asthma severity. Although Schizophyllum commune ( S. commune, “suehirotake” in Japanese), one of the basidiomycetous (BM) fungi, is a fungus that can cause allergic bronchopulmonary mycosis (ABPM) and allergic fungal sinusitis (AFS), whether the fungus causes or sensitizes subjects to asthma is unclear. Methods The bronchial provocation test using S. commune antigen was performed in two asthmatics who had demonstrated positive skin reactions to the S. commune antigen, and low dose of itraconazole (50 mg/day) was prescribed as an adjunctive therapy for 2 weeks. The allergological features and clinical manifestations of these patients are herein evaluated and discussed. Results Case 1 was a 71-year-old female, and case 2 was a 69-year-old male. Both patients demonstrated positive reactions to the inhalation test. A diagnosis of AFS or ABPM was excluded in both patients because of the lack of a history of pulmonary infiltrates, central bronchiectasis, a history of expectoration of brown plugs or flecks, or sinusoidal findings. Although the efficacy of itraconazole in our cases was unclear, the elevated titer of the specific IgG-for S. commune in case 2 gradually decreased during the period of antifungal therapy. Conclusions The two patients described herein were diagnosed to have bronchial asthma caused by S. commune; so-called Schizophyllum asthma. S. commune may also be a causative fungal antigen of bronchial asthma.

Abstract 3271: Inhibition of angiogenesis and tumor growth by itraconazole in primary xenograft models of human non-small cell lung cancer

Abstract Introduction: Lung cancer is the most common cause of cancer-related death in the US. Approximately 85 percent of cases are non-small cell lung cancer (NSCLC). Angiogenesis is a critical component to tumor growth. Bevacizumab is the only anti-angiogenic agent currently approved for NSCLC. Despite aggressive multimodality therapy, 5-year survival in patients with advanced stage NSCLC is exceedingly poor. Novel therapeutic strategies for NSCLC are critically needed. The azole anti-fungal agent, itraconazole (ITRA) has been identified as a potential anti-angiogenic agent. In this study we further characterize the activity of ITRA in human umbilical vascular endothelial cell (HUVEC) based assays. Preclinical efficacy of ITRA is also examined as a single-agent and in combination with cisplatin in xenograft models of NSCLC generated with primary tumor tissue. Methods: HUVECs were cultured in EGM-2 media (Lonza) and assayed in EGM-2 or EBM-2 media supplemented with recombinant growth factors, vascular endothelial growth factor (VEGF; 10 ng/ml), and basic fibroblast growth factor (bFGF; 12 ng/ml). Effects of ITRA on proliferation of HUVECs and three NSCLC cell lines, including H358 (bronchioalveolar carcinoma), H596 (adenosquamous carcinoma) and H1838 (adenocarcinoma) were evaluated by AqueousOne® (Promega). Additionally, HUVEC migration assays were carried out using an 8-micron pore Boyden chamber apparatus and endothelial tube formation assays were conducted using Geltrex® (Invitrogen) coated culture plates. To determine in vivo efficacy, mice bearing established xenografts derived from primary tumor tissue were treated orally with ITRA BID or QD at doses ranging from 75 to 100 mg/kg. In combination experiments, cisplatin (4 mg/kg) administered IP once weekly was given with ITRA. Mice were exposed to intravenous Hoechst 33342 prior to collection of tumors. Vascular area was determined by Hoechst 33342 and anti-CD31 staining. Tumor lysates were analyzed by immunoblot for Hif1α induction. Results: ITRA demonstrates potent dose-dependent inhibition of HUVEC proliferation (IC50 &amp;lt;0.7 μM). ITRA had no effect on proliferation in the panel of NSCLC cell lines tested (IC50 &amp;lt;100 μM). ITRA inhibits HUVEC migration and tube formation with similar potency. In vivo, ITRA inhibits NSCLC tumor xenograft growth with maximum single-agent activity seen with 100 mg/kg BID treatment. Addition of ITRA to a cisplatin regimen significantly enhanced anti-tumor effects compared to either single-agent alone (p &amp;lt;0.01). ITRA therapy resulted in increased tumor expression of HIF1α and significantly decreased tumor vascular area (p &amp;lt;0.01). Conclusion: The anti-angiogenic activity of ITRA and efficacy demonstrated in preclinical models of NSCLC supports development of this agent for the management of NSCLC in combination with standard of care chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3271. doi:10.1158/1538-7445.AM2011-3271

Efficacy of Itraconazole in the Treatment of Patients with Chronic Cough Whose Sputa Yield Basidiomycetous Fungi—Fungus-Associated Chronic Cough (FACC)

Objectives. This controlled study was performed to clarify the therapeutic benefit of itraconazole for the treatment of patients with chronic cough, wherein a sputum culture yielded basidiomycetous (BM) fungi. Methods. Of the 171 patients who visited our hospital for the diagnosis and treatment of chronic cough, BM was detected in the sputum of 39 patients. Informed consents were obtained from 21 patients who were subsequently enrolled in this trial. After the administration of the standard therapy, all the patients were enrolled in a randomized placebo-controlled study with 2 weeks of treatment with a low dose of itraconazole (50 mg/day) (n = 10) in comparison with a corresponding period of treatment with matched placebo (ambroxol hydrochloride 45 mg/day) (n = 11). Coughing was assessed using subjective cough symptom scale and capsaicin cough challenging. Results. The treatment with itraconazole, but not placebo (p = 0.17), was associated with a significant improvement in the cough scale (p = 0.0051); moreover, the improvement achieved with itraconazole was significant (p < 0.001) when compared with that of the placebo. Conclusions. Low-dose itraconazole was shown to be an effective antitussive in patients with chronic cough in which sputum examination yielded BM fungi. The 21 patients described here entailed the following manifestations: (1) chronic cough; (2) the presence of environmental fungi, particularly basidiomycetous (BM) fungi, in the sputum; and (3) good clinical response to antifungal drugs. These clinical features may constitute a unique disease concept called fungus-associated chronic cough (FACC).

The effect of itraconazole on the vaginal candidiasis under different immunity conditions in mice

To study the effect of itraconazole on the vaginal candidiasis caused by Candida under different immunity conditions, the fungal vaginitis model was established in female ICR mice by intravaginal inoculation of suspension of C. albicans after the animal had been pretreated with estradiol or dexamethasone. Mice were divided at random into different groups and then treated with itraconazole or IFN-gamma given by gastrolavage. The burden of the fungus in the vaginal lavage fluids in the mice of the different groups was measured dynamically at different time points after the beginning of the drug treatment. The difference in the effect of itraconazole on the vaginal candidiasis between normal immune system group (group A) and control group (group D) was statistically significant (P<0.01). The difference in the efficacy of itraconazole among immunosuppressed group (group E), immuno-regulated group (group F) and the control group (group G) was statistically significant (P<0.01). But on the 5th, 6th, 7th, 9th, 11th day after the inoculation the average level of colony forming unit (CFU) of groups A, E and F showed no statistically significant difference (P>0.05). It is concluded that the efficacy of itraconazole in the treatment of the vaginal candidiasis under different immunity conditions (groups A, E and F) in mice were all good, but there was no difference in the anti-fungal effect of itraconazole among the three groups.

The Prophylactic Effect of Itraconazole Capsules and Fluconazole Capsules for Systemic Fungal Infections in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes: A Japanese Multicenter Randomized, Controlled Study

We performed a randomized, controlled study comparing the prophylactic effects of capsule forms of fluconazole (n = 110) and itraconazole (n = 108) in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) during and after chemotherapy. There were 4 cases with possible systemic fungal infection in the itraconazole group, and there were 8 possible and 3 probable cases in the fluconazole group. Adverse events did not significantly differ in the 2 groups. In patients with MDS or in the remission-induction phase of chemotherapy, the numbers of cases with probable or possible infections were lower in the itraconazole group than in the fluconazole group, whereas no difference was seen in patients with AML or in the consolidation phase of therapy. In patients with neutrophil counts of >0.1 x 10(9)/L lasting for more than 4 weeks, the frequency of infection in the fluconazole group (5 of 9 patients) was significantly higher than in the itraconazole group (0 of 7 patients; P = .03). Our results suggest that both drugs were well tolerated in patients with AML or MDS who received chemotherapy and that the efficacy of itraconazole for prophylaxis against systemic fungal disease is not inferior to that of fluconazole.

Efficacy of intravenous itraconazole against invasive pulmonary aspergillosis in neutropenic mice

The efficacy of itraconazole (ITZ) solubilized in hydroxypropyl-beta-cyclodextrin (ITZ-IV) was examined in a murine model of invasive pulmonary aspergillosis (IPA). Immunosuppressed mice were infected by the intratracheal inoculation of Aspergillus fumigatus conidia (2 x 10(6) conidia/mouse). Their body weight rapidly decreased and they died within 6 days after infection. Intravenous administration of various doses of ITZ-IV was started 24 h after infection and was continued once a day for 4 days. ITZ-IV at daily doses of 10, 20, or 40 mg/kg was as effective as the intraperitoneal administration of amphotericin B (AMPH) at a dosage of 1 mg/kg daily in improving survival. ITZ-IV (20 mg/kg per day), as well as AMPH (1 mg/kg per day) significantly lowered the fungal burden in the pulmonary tissues. Histological improvement was seen within 2 days after the beginning of administration of ITZ-IV (20 mg/kg per day). In mice intravenously given a single dose of ITZ-IV (20 mg/kg), the blood level and pulmonary tissue level of ITZ plus its active metabolites, mainly hydroxyitraconazole (OH-ITZ), decreased gradually after the injection, but after 4 h their concentration was still between 1.4 microg/ml (ITZ) and 1.9 microg/ml (OH-ITZ), concentrations that were approximately 10 to 20 times greater than the minimum inhibitory concentration (MIC) of ITZ for challenging the strain of A. fumigatus (0.16 microg/ml). These results support the clinical usefulness of ITZ-IV for the treatment of IPA in immunocompromised patients.

Synergism of CAY-1 with Amphotericin B and Itraconazole

Background: CAY-1 is a fungicidal saponin from cayenne pepper whose mode of action differs from amphotericin B (AB) and itraconazole (IT). This work determined CAY-1 synergism with AB or IT. Methods: CAY-1 was purified and used in checkerboard microdilution studies where CAY-1 and AB or IT were mixed with nongerminated (NG) and germinating (G) conidia of three Aspergillus species and Candida albicans. Inhibition was visually determined at 24 and 48 h. Results: CAY-1 had predominantly additive-synergistic interaction with AB or IT against the Aspergillus NG and G conidia. Excellent synergy between CAY-1 and AB occurred at 24 and 48 h against C. albicans. Results suggest CAY-1 enhances AB and IT efficacy.

Cyclophosphamide metabolism is affected by azole antifungals

AbstractWe performed a randomized trial to compare the safety and efficacy of itraconazole with fluconazole in preventing fungal infections in patients undergoing allogeneic stem cell transplantation (SCT). Itraconazole (intravenous 200 mg daily, or oral solution 2.5 mg/kg 3 times daily) and fluconazole (intravenous or oral, 400 mg daily) were administered with the start of conditioning therapy, until at least 120 days after SCT. After enrollment of the first 197 patients, a data and safety monitoring board reviewed potential drug-related toxicities. Patients who received itraconazole developed higher serum bilirubin and creatinine values in the first 20 days after SCT, with highest values in patients who received itraconazole concurrent with cyclophosphamide (CY) conditioning. Analysis of CY metabolism in a subset of patients demonstrated higher exposure to toxic metabolites among recipients of itraconazole compared with fluconazole. These data suggest that azole antifungals, through differential inhibition of hepatic cytochrome P-450 isoenzymes, affect CY metabolism and conditioning-related toxicities.