Drug-induced impairment of mitochondrial fatty acid oxidation and steatosis: assessment of causal relationship with 45 pharmaceuticals.

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 nonsteatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl-l-carnitine, palmitoyl-CoA + l-carnitine, or octanoyl- l-carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate, and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, whereas dexamethasone, olanzapine, and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential, and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin, and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition.

Mechanisms of hepatocellular toxicity associated with the components of St. John's Wort extract hypericin and hyperforin in HepG2 and HepaRG cells.

St. John's Wort preparations are used for the treatment of mild to moderate depression. They are usually well tolerated but can cause adverse reactions including liver toxicity in rare cases. To date, the mechanism(s) underlying the hepatotoxicity of St. John's Wort extracts are poorly investigated. We studied the hepatocellular toxicity of hypericin and hyperforin as the two main ingredients of St. John's Wort extracts in HepG2 and HepaRG cells and compared the effects to citalopram (a synthetic serotonin uptake inhibitor) with a special focus on mitochondrial toxicity and oxidative stress. In HepG2 cells, hypericin was membrane-toxic at 100 µM and depleted ATP at 20 µM. In HepaRG cells, ATP depletion started at 5 µM. In comparison, hyperforin and citalopram were not toxic up to 100 µM. In HepG2 cells, hypericin decreased maximal respiration starting at 2 µM and mitochondrial ATP formation starting at 10 µM but did not affect glycolytic ATP production. Hypericin inhibited the activity of complex I, II and IV of the electron transfer system and caused mitochondrial superoxide accumulation in cells. The protein expression of mitochondrial superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2) and total and reduced glutathione decreased in cells exposed to hypericin. Finally, hypericin diminished the mitochondrial DNA copy number and caused cell necrosis but not apoptosis. In conclusion, hypericin, but not hyperforin or citalopram, is a mitochondrial toxicant at low micromolar concentrations. This mechanism may contribute to the hepatotoxicity occasionally observed in susceptible patients treated with St. John's Wort preparations.

Angiographic Evolution of Brain Arteriovenous Malformation Angioarchitecture After Partial Endovascular Treatment.

BACKGROUND AND OBJECTIVES: Endovascular embolization of brain arteriovenous malformations (AVMs) is sometimes intentionally partial, in the case of staged treatment for instance. Residual AVMs may be prone to angioarchitectural modification during follow-up. The objective of this work is to evaluate the nature and extent of these modifications. METHODS: We performed a retrospective monocentric study on a cohort of adult patients treated by incomplete endovascular embolization for ruptured and unruptured AVMs with an available angiographic follow-up, without any intervening confounding event between the 2 angiographic examinations. AVM angioarchitectural modifications (arterial, nidal, and venous) were analyzed. Clinical and radiological data were tested in univariate analyses for association with the occurrence of AVM regression or progression. RESULTS: Eighty-two partial embolization sessions in 57 patients were included in the study. A 40% (33/82) rate of modification was found on follow-up, with 23/82 (28%) controls showing at least one angioarchitectural regression feature and 15/82 (18.3%) showing at least one angioarchitectural progression item. Nidal growth was the most frequent modification occurring after 12/82 (14.6%) embolizations. The only factor associated with nidal volume growth was a longer time interval between embolization and follow-up (median [IQR]: 190 [250] days vs 89.5[133] days in the subgroup without nidal growth; P = .02). Specific modifications of arterial supply, nidal anatomy, and venous drainage were identified and documented. CONCLUSION: Angioarchitectural modifications (both progression and regression) of brain AVMs are frequent findings after partial embolization. Nidal volume growth is associated with longer time intervals between embolization and follow-up.

Increased Multispectral CT Iodine Concentrations in Patients With Transient Neurological Deterioration Following Endovascular Neurointerventional Procedures: an Argument in Favor of the Elusive Contrast-Induced Encephalopathy?

BACKGROUND AND PURPOSE: So-called contrast-induced encephalopathy (CIE) is a rare but worrying condition occurring after cerebral angiography or neuroendovascular interventions using iodine contrast media. This study aimed to compare cerebral iodine concentrations in patients suspected of having CIE after endovascular procedures to those in matched controls. METHODS: This is a retrospective monocentric study of 25 suspected CIE patients in a tertiary care teaching hospital diagnosed from June 2017 to February 2024. Cerebral multispectral computed tomography (CT) iodine mean concentrations were measured and compared with 1:1 matched controls using the CT constructor's workstation in the whole brain and in specific regions of interest (ROIs) corresponding to a vascular territory downstream of the procedure. Concentration values were compared with paired samples t­test. RESULTS: During the study period, 1097 patients underwent aneurysm embolization and 137 arteriovenous malformation (AVM) embolization procedures. So-called CIE was suspected in 25 patients after aneurysm or AVM embolization (2%). Mean iodine concentrations in the procedure vascular territory ROIs were higher in suspected CIE cases (mean 543 ± 147 µg/cm3) compared to matched controls (mean 463 ± 141 µg/cm3; p = 0.01). Whole brain mean iodine concentrations were modestly higher in CIE patients compared to controls across all subgroups, without reaching statistical significance. CONCLUSIONS: CIE may be associated with modest increase in CT iodine concentration in the procedure vascular territory after neurointerventional procedures. The underlying pathophysiology of this condition remains uncertain and merits further investigation. KEY MESSAGES: Contrast-induced encephalopathy (CIE) is known as a rare neurologic condition following iodine contrast media use in neuroendovascular interventions, with unclear pathophysiology. WHAT THIS STUDY ADDS: This study provides evidence that suspected CIE is associated with higher cerebral iodine concentrations in affected vascular territories, a novel quantifiable change. Implications for research, practice, or policy: These findings suggest the potential for iodine concentration monitoring to refine CIE diagnosis and prevention strategies in clinical practice.

Comparison of rescue intracranial stenting versus best medical treatment alone in acute refractory large vessel occlusion: study protocol for the PISTAR multicenter randomized trial.

BACKGROUND: Mechanical thrombectomy (MT) has become a standard treatment for acute ischemic strokes (AIS). However, MT failure occurs in approximately 10-30% of cases, leading to severe repercussions (with mortality rates up to 40% according to observational data). Among the available rescue techniques, rescue intracranial stenting (RIS) appears as a promising option. OBJECTIVE: This trial is poised to demonstrate the superiority of RIS in addition to the best medical treatment (BMT) in comparison with BMT alone, in improving the functional outcomes at 3 months for patients experiencing an AIS due to a large vessel occlusion refractory to MT (rLVO). METHODS: Permanent Intracranial STenting for Acute Refractory large vessel occlusions (PISTAR) is a multicenter prospective randomized open, blinded endpoint trial conducted across 11 French University hospitals. Adult patients (≥18 years) with an acute intracranial occlusion refractory to standard MT techniques will be randomized 1:1 during the procedure to receive either RIS+BMT (intervention arm) or BMT alone (control arm). RESULTS: The primary outcome is the rate of good clinical outcome at 3 months defined as a modified Rankin Scale score ≤2 and evaluated by an independent assessor blinded to the randomization arm. Secondary outcomes include hemorrhagic complications, all adverse events, and death. The number of patients to be included is 346. Two interim analyses are planned with predefined stopping rules. CONCLUSION: The PISTAR trial is the first randomized controlled trial focusing on the benefit of RIS in rLVOs. If positive, this study will open new insights into the management of AIS. TRIAL REGISTRATION NUMBER: NCT06071091.