Safety of Itraconazole in Diabetic Patients

Verspeelt, J.; Marynissen, G.; Gupta, Aditya K.; Doncker, P. De

doi:10.1159/000018152

Cited by 24 publications

(18 citation statements)

References 13 publications

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“…The present study confirmed that ITCZ was able to activate the AMPK pathway to suppress hepatic gluconeogenesis by repressing the expression of PGC-1α, PEPCK and G-6-Pase and promote glucose uptake by increasing the expression of GLUT4 in HepG2 cells. The present study observed that ITCZ was non-cytotoxic to hepatocytes, which was consistent with the results by Verspeelt et al (17). AMPK is a heterotrimeric serine/threonine kinase ubiquitously expressed in mammalian organs, including the liver, and acts as a major cellular energy sensor and a master regulator of metabolic homeostasis.…”

Section: Discussionsupporting

confidence: 94%

“…Moreover, ITCZ is the only azole anti-fungal that is known to have potent anti-angiogenic and anti-proliferative activities in non-small cell lung cancer and glioblastoma cells (10,11), and has been shown to prolong the overall survival of patients with metastatic pancreatic cancer, ovarian cancer and breast cancer (12)(13)(14)(15). Sano et al (16) reported that ITCZ was capable of reducing the inflammatory degree, mucosal hyperplasia and Candida infection in alloxan-induced diabetic rats (16), while Verspeelt et al (17) reported that ITCZ was safe and efficient against dermatological disorders in diabetic patients. Apart from that, Head et al (18) reported that ITCZ activated the adenosine monosphosphate-activated protein kinase (AMPK) signaling pathway in human umbilical vein cells.…”

Section: Introductionmentioning

confidence: 99%

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Itraconazole attenuates hepatic gluconeogenesis and promotes glucose uptake by regulating AMPK pathway

Liu

et al. 2017

Exp Ther Med

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Abstract. The primarily metabolic abnormality in type 2 diabetes mellitus (T2DM) is the defect in gluconeogenesis and glucose uptake. Itraconazole (ITCZ) is a traditional azole drug with anti-fungal and anticancer properties. However, limited attention has been directed towards the contribution of ITCZ to hepatic gluconeogenesis and glucose uptake in T2DM. The present study aimed to investigate the potential effects of ITCZ on hepatic gluconeogenesis and glucose uptake as well as the underlying mechanisms. No obvious change in cell viability was detected by MTT assay in HepG2 cells with ITCZ treatment at gradually increasing concentrations. Western blot analysis demonstrated that the phosphorylation level of 5' adenosine monophosphate-activated protein kinase (AMPK) was significantly elevated by ITCZ treatment at ≥5 µg/ml (P<0.05). Moreover, ITCZ repressed the gluconeogenesis of HepG2 cells, as evidenced by the dose-dependently increased glycogen synthase kinase 3β phosphorylation level and a notably decreased glucose production rate (P<0.05). Simultaneously, the expression of peroxisome proliferator-activated receptor γ co-activator 1α, phosphoenolpyr uvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in HepG2 cells was reduced by ITCZ in a dose-dependent manner (P<0.001). Furthermore, a 2-deoxyglucose uptake assay revealed that the glucose uptake of HepG2 cells was notably enhanced, accompanied by the ITCZ dose-dependent upregulation of glucose transporter-4 (GLUT-4) (P<0.05). Conversely, silencing of AMPK by small interfering RNA resulted in an increase of ITCZ-reduced gluconeogenesis and inhibition of ITCZ-induced glucose uptake with relative upregulation of PEPCK and G6Pase and downregulation of GLUT4 in the presence of 50 µg/ml ITCZ (P<0.05). Overall, the results indicated that AMPK has an important role in regulating ITCZ-induced glucose uptake by stimulating GLUT4 in HepG2 cells. Therefore, ITCZ may become a promising candidate for T2DM therapy.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Itraconazole attenuates hepatic gluconeogenesis and promotes glucose uptake by regulating AMPK pathway

Liu

et al. 2017

Exp Ther Med

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“…Drug interactions are not expected between itraconazole and antidiabetic therapy, since insulin is not metabolised by CYP enzymes [33]. In addition, there is no evidence to suggest that oral antidiabetic medications are metabolised by the same CYP subfamily as itraconazole.…”

Section: Drug Interactions Involving Oral Antifungal Agentsmentioning

confidence: 99%

“…In addition, there is no evidence to suggest that oral antidiabetic medications are metabolised by the same CYP subfamily as itraconazole. For example, tolbutamide is metabolised via the CYP2C9 subfamily [33]. …”

Section: Drug Interactions Involving Oral Antifungal Agentsmentioning

confidence: 99%

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The Implications and Management of Drug Interactions with Itraconazole, Fluconazole and Terbinafine

et al. 2000

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The efficacy and safety of many pharmacological agents can be adversely affected by drug interactions. However, an appreciation of the mechanisms and incidence of these interactions, together with a knowledge of the patient’s medical history, means that the majority are predictable and can be managed successfully. Drug interactions involving oral antifungal agents such as itraconazole, fluconazole and terbinafine have been studied extensively and are well understood. When problems are known to arise, they can often be overcome or minimised by varying the dosage regimens, or by drug monitoring. Where certain drugs are definitely contraindicated with antifungal agents, suitable alternatives can usually be found. Clinical trials and surveillance monitoring have demonstrated that when viewed in a wider context, drug interactions do not represent a particular safety problem for the newer oral antifungal agents. An improved understanding of the drug interaction processes and appropriate control measures mean that the high benefit-to-risk ratio of these medications can be maintained.

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Antifungal therapy - state of the art at the beginning of the 21st century

Polak¹

2003

Antifungal Agents

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Safety of Itraconazole in Diabetic Patients

Cited by 24 publications

References 13 publications

Itraconazole attenuates hepatic gluconeogenesis and promotes glucose uptake by regulating AMPK pathway

Itraconazole attenuates hepatic gluconeogenesis and promotes glucose uptake by regulating AMPK pathway

The Implications and Management of Drug Interactions with Itraconazole, Fluconazole and Terbinafine

Antifungal therapy - state of the art at the beginning of the 21st century

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