https://pubmed.ncbi.nlm.nih.gov/29554829/
Abstract
Voriconazole is a triazole antifungal with activity against a number of yeast and mold species including Candida, Aspergillosis, Fusarium, and Coccidioides. Invasive fungal infections are associated with high morbidity and mortality, prolonged treatment courses, and occasionally lifelong suppressive therapy. Voriconazole therapy can result in a number of acute toxicities that clinicians are frequently aware of including hepatotoxicity, visual disturbances, and hallucinations; however, there is limited experience with extended durations of voriconazole therapy. We describe the case of a 62-year-old man who developed Coccidioides meningitis as a result of prolonged neutropenia from treatment for chronic lymphocytic leukemia. He was initially treated with a number of different antifungal agents including voriconazole, liposomal amphotericin B, fluconazole, and itraconazole; however, he developed acute toxicity due to those agents. He was successfully re-challenged with voriconazole, and maintained therapeutic serum concentrations throughout treatment. As a result of prolonged voriconazole exposure of over 14 years, he has suffered a number of toxicities, most significantly including actinic keratosis, squamous cell carcinoma, and skeletal fluorosis. To our knowledge, this is the longest continuous use of voriconazole therapy currently in the literature.
SEE also:
Skeletal fluorosis after prolonged voriconazole therapy
viewtopic.php?f=4&t=1939&p=1998
Voriconazole induces fluorosis
viewtopic.php?f=4&t=1503&p=1499
More studies:
https://pubmed.ncbi.nlm.nih.gov/?term=F ... &sort=date
Moon WJ, Scheller EL, Suneja A, Livermore JA, Malani AN, Moudgal V, Kerr LE, Ferguson E, Vandenberg DM - "Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain" Clin Infect Dis 59(9):1237-45 (2014) doi: 10.1093/cid/ciu513
https://pmc.ncbi.nlm.nih.gov/articles/PMC4351342/
"The 28 patients shown in Table 1 were prescribed 350–1300 mg of voriconazole, corresponding to 57–211 mg of daily ingested fluoride." --> average plasma amount of fluoride -> 12.78 ± 0.96 µmol of fluoride
NOTE: 400 mg of Voriconazole contains 65mg fluoride.Visual disturbances, skin rash, prolongation of QT interval, and hepatic enzyme elevation have been frequently observed among patients taking voriconazole [11–15]. Periostitis, skeletal fluorosis, and exostoses have also been reported [16–28]. Because of its trifluorinated molecular structure, several studies have suggested a link between excess fluoride intake from voriconazole therapy and the development of periostitis [19, 25, 27]. Patients who are taking the Food and Drug Administration–recommended voriconazole maintenance dose of 200 mg every 12 hours are consuming an average of 65 mg of fluoride per day [19, 27]. This is 15 times greater than what is outlined by the United States Department of Agriculture as an adequate daily intake (3–4 mg) [12, 29, 30]. Most patients who received voriconazole at SJMH during the outbreak required much higher doses to maintain the CDC-recommended therapeutic blood voriconazole trough levels of 2–5 µg/mL (Table 1) [5].
Mohideen H, Dahiya DS, Parsons D, Hussain H, Ahmed RS - "Skeletal Fluorosis: A Case of Inhalant Abuse Leading to a Diagnosis of Colon Cancer" J Investig Med High Impact Case Rep 10:23247096221084919 (2022). doi: 10.1177/23247096221084919
https://pmc.ncbi.nlm.nih.gov/articles/PMC8966097/
Ikeya S, Sakabe JI, Yamada T, Naito T, Tokura Y - "Voriconazole-induced photocarcinogenesis is promoted by aryl hydrocarbon receptor-dependent COX-2 upregulation" Sci Rep 8: 5050 (2018)
https://doi.org/10.1038/s41598-018-23439-7
"Since COX-2 is critical enzyme for UV-induced skin cancer promotion, this signaling pathway possibly leads to skin tumor promotion as in breast cancer cells."
SEE: COX-2 & Fluoride: viewtopic.php?p=5956#p5956
NOTE: It is thought that the periostitis observed in Voriconazole poisoning is not necessarily due to "free" fluoride formation. However, VEGF expression is increased, meaning Gq/11 activity is involved.
Allen KC, Sanchez CJ Jr, Niece KL, Wenke JC, Akers KS - "Voriconazole Enhances the Osteogenic Activity of Human Osteoblasts In Vitro through a Fluoride-Independent Mechanism" Antimicrob Agents Chemother 59(12):7205-13 (2015) doi: 10.1128/AAC.00872-15
"Significant increases in the expression of VEGF and PDGF by osteoblasts were observed following exposure to voriconazole. Our results demonstrate that voriconazole can induce osteoblast proliferation and enhance osteogenic activity in vitro. Importantly, and in contrast to the previously proposed mechanism of fluoride-stimulated osteogenesis, our findings suggest that voriconazole-induced periostitis may also occur through fluoride-independent mechanisms."
Most recently, Menya suggested that moderate/severe dental fluorosis was strongly associated with a 9.4-fold increased risk of esophageal squamous cell carcinoma (ESCC) compared with a no dental fluorosis population in Africa.
Menya D, Maina SK, Kibosia C, Kigen N, Oduor M, Some F, Chumba D, Ayuo P, Middleton DRS, Osano O, Abedi-Ardekani B, Schüz J, McCormack VA - "Dental fluorosis and oral health in the African Esophageal Cancer Corridor: Findings from the Kenya ESCCAPE case-control study and a pan-African perspective" Int J Cancer 145(1):99-109 (2019). doi: 10.1002/ijc.32086
https://pmc.ncbi.nlm.nih.gov/articles/PMC6519293/