The patient experienced a marked rise in serum aminotransferase and lactic dehydrogenase levels within a day of starting intravenous amiodarone for ventricular tachyarrhythmias. The major difficulty in making the diagnosis of a drug induced liver injury from high dose amiodarone is that he also had multiple episodes of hypotension just before the abnormalities were identified, and the pattern of serum enzyme elevations with immediate worsening of prothrombin time and mild jaundice is also very typical of ischemic hepatitis. Most reported cases of acute hepatic injury from intravenous amiodarone have occurred in patients with the potential of ischemic liver injury (chronic heart failure and recent acute worsening due to tachyarrhythmias). Furthermore, the few liver biopsy specimens from such patients usually show centrolobular (zone 3) necrosis with minimal inflammation, suggestive of ischemic rather than an inflammatory injury. This patient later tolerated taking oral doses of amiodarone [600 mg daily] without recurrence of liver injury.
Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer's disease.