title: Mechanism of voriconazole-induced transient visual disturbance: reversible dysfunction of retinal ON-bipolar cells in monkeys.
abstract: OBJECTIVE
  To investigate the mechanism of voriconazole-induced transient visual disturbance in humans.
  
  
  METHODS
  andard full-field electroretinograms (ERGs) were recorded from monkeys treated intravenously with voriconazole. In addition, photopic ERGs elicited by long-duration stimuli (ON-OFF response) were also recorded from monkeys receiving intravenous voriconazole or intravitreal 2-amino-4-phosphonobutyric acid (APB).
  
  
  RESULTS
  aracteristic changes were observed in the waveform of the standard full-field ERGs obtained immediately after dosing of voriconazole as follows: electronegative combined rod-cone response (markedly attenuated b-wave and oscillatory potentials), undetectable rod response (eliminated b-wave); slightly abnormal single-flash cone response (flattened appearance in the bottom of the a-wave, mildly attenuated b-wave); and slightly abnormal 30 Hz flicker (mildly attenuated b-wave). The above changes fully recovered to baseline 24 hours after each dosing, along with a decrease in plasma voriconazole concentration. In addition, the change in the waveform of the ON-OFF response recorded in voriconazole-treated monkeys was quite similar to that recorded in APB-treated monkeys as follows: the b-wave was eliminated or prominently attenuated; and the a- and d-waves were not apparently attenuated.
  
  
  CONCLUSIONS
  The results strongly suggest that voriconazole induces selective and reversible dysfunction of the retinal ON-bipolar cells in both the rod and cone pathways in monkeys. From the results obtained in monkeys in this study, it is suggested that the function of the retinal ON-bipolar cells was selectively and reversibly affected in voriconazole-treated humans who complained of transient visual disturbances.
authors: Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd., Shizuoka, Japan. kinoshita.junzo.dy@daiichisankyo.co.jp
authors: Junzo
authors: J
authors: Kinoshita
authors: Noriaki
authors: N
authors: Iwata
authors: Mitsuhiro
authors: M
authors: Ohba
authors: Tomofumi
authors: T
authors: Kimotsuki
authors: Mitsuya
authors: M
authors: Yasuda
mesh_terms: D000613:Aminobutyrates / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000633:toxicity*; D004596:Electroretinography / Q000187:drug effects*; D007262:Infusions, Intravenous; D058449:Intravitreal Injections; D008252:Macaca fascicularis; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000502:physiology; D011743:Pyrimidines / Q000097:blood / Q000633:toxicity*; D051245:Retinal Bipolar Cells / Q000187:drug effects* / Q000502:physiology; D014230:Triazoles / Q000097:blood / Q000633:toxicity*; D014786:Vision Disorders / Q000139:chemically induced* / Q000503:physiopathology; D065819:Voriconazole
chemical_list: D000613:Aminobutyrates; D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; C012729:2-amino-4-phosphonobutyric acid; D065819:Voriconazole