The effect of topical voriconazole on conjunctiva in rats as revealed by histopathology and immunohistochemistry.

The aim of this study was to evaluate the effects of topical voriconazole with histopathological and immunohistochemical analysis of the conjunctiva in rats. Twenty-eight Sprague Dawley rats were divided into four groups as two study (S1, S2) and two control (C1, C2). Voriconazole was instilled four times daily to S1, S2 rats. Physiologic saline (0.9%) was instilled four times daily in C1 and C2 rats. S1 and C1 were followed in a dark room; S2 and C2 were held in a room with sunlight. Impression cytology was performed at 0, 15, 30, 45 and 60th d after instillations. After 2 months of treatment conjunctival tissue was removed for histological and immunohistochemical analysis. In impression cytology evaluation, there was no difference between S1 and S2. At 60 d the difference between S1 and C1 was significant. In other comparisons, there was no difference between S1 and C1, C2. The scores of S2 was higher than C1 and C2 for all comparisons except 15th day scores of S2 and C2. In study groups, epithelial and gland degeneration were higher in S2, but inflammation scores were similar. The comparison of immunreactivity of ERK, TGFß and E-cadherin were different in the study groups than the control groups for all comparisons. In conclusion, voriconazole has side effects due to phototoxicity including squamous cell carcinoma. Clinicians should particularly be careful with the long-term use of topical voriconazole and should follow-up patients strictly in terms of ocular surface alterations.

Photochemical and Pharmacokinetic Characterization of Orally Administered Chemicals to Evaluate Phototoxic Risk.

This study aimed to verify the applicability of a proposed photosafety screening system based on a reactive oxygen species (ROS) assay and a cassette-dosing pharmacokinetic (PK) study to chemicals with wide structural diversity. The orally taken chemicals, erythromycin, gatifloxacin, 8-methoxypsoralen (MOP), pirfenidone (PFD), trifluoperazine (TFP), and voriconazole (VRZ), were selected as test compounds. The ROS assay was conducted to evaluate their photoreactivity, and all test compounds excluding erythromycin generated significant ROS under simulated sunlight exposure. According to the ROS data, TFP had potent photoreactivity, and the photoreactivity of 4 other compounds was judged to be moderate. Regarding the oral cassette-dosing PK test in rats, the skin deposition of MOP, PFD, and VRZ was relatively high, and gatifloxacin and TFP exhibited moderate skin deposition properties. Based on the ROS and PK data of test compounds, PFD and TFP were judged to be potent phototoxic compounds, and MOP and VRZ were deduced to have phototoxic risk. The predicted phototoxic risk of test compounds by proposed screening was mostly in agreement with observed in vivo phototoxicity in the rat skin. The proposed screening system could provide reliable photosafety information on orally administered compounds with wide structural diversity.

Topically applied 1% voriconazole induces dysplastic changes on the ocular surface: animal study.

PURPOSE: To identify the risk of inducing ocular surface dysplasia following topical administration of 1% voriconazole eye drop. METHODS: Fourteen noninflamed healthy eyes of 14 white adult New Zealand rabbits were included in the study. The rabbits were randomly divided into two groups comprised of 7 rabbits each. Group 1 received topical 1% voriconazole and Group 2 received topical saline as the control group. In all animals, right eye was selected for the study. In Group 1 (Voriconazole Group), single drop of voriconazole was instilled every 10 min consecutively for 17 times a day for 60 days. In Group 2 (Control Group), single drop of saline was instilled every 10 min consecutively for 17 times a day for 60 days. At two months, animals were sacrificed and study eyes were enucleated with the eyelids. The specimens were stained with hematoxylin-eosin and histopathologic changes in cornea, bulbar and palpebral conjunctiva were evaluated under light microscope. RESULTS: There were no macroscopically visible lesions on the ocular surface of any rabbits. Histopathological evaluation showed mild to moderate dysplasia localized mainly in the limbus and extending to the adjacent cornea and bulbar conjunctiva in all rabbits in Voriconazole Group. Severe dysplasia or carcinoma in situ was not observed. In the Control Group, dysplasia was not observed, at all. CONCLUSION: This animal study provides a possible relationship between topically administered 1% voriconazole and ocular surface dysplasia. We recommend ophthalmologists to be aware of the risk of ocular surface dysplasia in patients received voriconazole eye drop.

How common is subsequent central nervous system toxicity in asymptomatic patients with haematologic malignancy and supratherapeutic voriconazole serum levels?

OBJECTIVES: We sought to determine the frequency at which patients with elevated voriconazole (VRC) levels but no clinically evident central nervous system (CNS) toxicity subsequently develop CNS toxicity. METHODS: We retrospectively reviewed the records of adult patients with haematolologic malignancy who had a VRC serum level >5.5 µg/mL at MD Anderson Cancer Center (January 2010 to December 2015). Patients with any documented CNS toxicity at the time the VRC level was obtained or patients whose VRC was discontinued as a response to high VRC level were excluded. Neurologic status was assessed using standard grading scales. Demographic and clinical characteristics, including potentially interacting medications, were correlated with the development of toxicity. RESULTS: We identified 320 such patients (mean age, 57 ± 15 years; 202 male (63%)). Subsequent CNS toxicity was documented in only 16 patients (5%). The most common CNS toxicities were visual disturbances (9/16, 56%), depressed consciousness (5/16, 31%) and cognitive disturbance (4/16, 19%). Patients with CNS toxicity tended to be older than those without (64 ± 8 vs 57 ± 15 y, p 0.08). The use of one or more neurotoxic drugs was common in patients with subsequent CNS toxicity (14/16, 88%). Reduction of VRC dose associated with the high VRC level did not correlate with less subsequent CNS toxicity. CONCLUSIONS: Development of subsequent CNS toxicity is uncommon in haematolologic malignancy patients with elevated VRC levels who had no evidence of toxicity at the time the level was obtained. Automatic reduction of VRC dose out of concern for impending CNS toxicity might not be warranted.

Cytotoxic Effect of Voriconazole on Human Corneal Epithelial Cells.

BACKGROUND: To assess the cytotoxic properties of voriconazole and sulfobutylether-ß-cyclodextrin (SBECD) on cultured primary human corneal epithelial cells. METHODS: Human corneal epithelial cells were cultured and exposed to various concentrations of SBECD (0.016-32 mg/ml) and voriconazole (0.001-2 mg/ml). Cellular cytotoxicity of SBECD and voriconazole on human corneal epithelial cells was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide test and the LIVE/DEAD Viability/Cytotoxicity Assay with fluorescence microscopy analysis. Cell damage was assessed with phase-contrast microscopy after 24 h of exposure to SBECD and voriconazole. RESULTS: The cytotoxicity tests and the morphological characteristic demonstrated the dose-dependent toxic effect of SBECD and voriconazole on human corneal epithelial cells. No corneal epithelial cytotoxicity was observed below the concentration of 0.08 and 0.025 mg/ml after 24-hour exposure to SBECD and voriconazole, respectively. CONCLUSIONS: The results of the study reveal the dose-dependent cytotoxic effect of SBECD and voriconazole on cultured human corneal epithelial cells. Therefore, voriconazole eye drops should be used cautiously in the treatment of fungal corneal ulcers.

In vitro and in vivo study on the effect of antifungal agents on hematopoietic cells in mice.

Liposomal amphotericin B, voriconazole, and caspofungin are currently used for systemic and severe fungal infections. Patients with malignant diseases are treated with granulocyte-colony stimulating factor (G-CSF) for the recovery of granulocytes after chemotherapy or hematopoietic cell (HC) transplantation. Since they have a high incidence of fungal infections, they inevitably receive antifungal drugs for treatment and prophylaxis. Despite their proven less toxicity for various cell types comparatively with amphotericin B and the decrease in the number of leukocytes that has been reported as a possible complication in clinical studies, the effect of liposomal amphotericin B, voriconazole, and caspofungin on HCs has not been clarified. The present study aimed to examine the in vitro and in vivo effect of these three modern antifungals on HCs. Colony-forming unit (CFU) assays of murine bone marrow cells were performed in methylcellulose medium with or without cytokines and in the presence or absence of various concentrations of liposomal amphotericin B, voriconazole, and caspofungin. In the in vivo experiments, the absolute number of granulocytes was determined during leukocyte recovery in sublethally irradiated mice receiving each antifungal agent separately, with or without G-CSF. In vitro, all three antifungal drugs were nontoxic and, interestingly, they significantly increased the number of CFU-granulocyte-macrophage colonies in the presence of cytokines, at all concentrations tested. This was contrary to the concentration-dependent toxicity and the significant decrease caused by conventional amphotericin B. In vivo, the number of granulocytes was significantly higher with caspofungin plus G-CSF treatment, higher and to a lesser extent higher, but not statistically significantly, with voriconazole plus G-CSF and liposomal amphotericin B plus G-CSF treatments, respectively, as compared with G-CSF alone. These data indicate a potential synergistic effect of these antifungals with the cytokines, in vitro and in vivo, with subsequent positive effect on hematopoiesis.