Does the Time of Drug Administration Alter the Metabolic Risk of Aripiprazole?

Antipsychotic drugs cause metabolic abnormalities through a mechanism that involves antagonism of D2 dopamine receptors (D2R). Under healthy conditions, insulin release follows a circadian rhythm and is low at night, and in pancreatic beta-cells, D2Rs negatively regulate insulin release. Since they are sedating, many antipsychotics are dosed at night. However, the resulting reduction in overnight D2R activity may disrupt 24 h rhythms in insulin release, potentially exacerbating metabolic dysfunction. We examined retrospective clinical data from patients treated over approximately 1 year with the antipsychotic drug aripiprazole (ARPZ), a D2R partial agonist. To identify effects of timing on metabolic risk, we found cases treated with ARPZ either in the morning (n = 90) or at bedtime (n = 53), and compared hemoglobin A1c, and six secondary metabolic parameters across the two groups. After controlling for demographic and clinical factors, patients treated with ARPZ at night had a significant decrease in HDL cholesterol, while in patients who took ARPZ in the morning had no change. There was a non-significant trend toward higher serum triglycerides in the patients treated with ARPZ at night vs. morning. There were no group differences in hemoglobin A1c, BMI, total cholesterol, LDL cholesterol, or blood pressure. Patients taking APPZ at night developed a worse lipid profile, with lower HDL cholesterol and a trend toward higher triglycerides. These changes may pose additional metabolic risk factors compared to those who take ARPZ in the morning. Interventions based on drug timing may reduce some of the adverse metabolic consequences of antipsychotic drugs.

Hydroxamic acids (therapeutics and mechanism): chemistry, acyl nitroso, nitroxyl, reactive oxygen species, and cell signaling.

The hydroxamic acid functionality, a histone deacetylase inhibitor, has received much attention in relation to its physiological properties. This review mainly deals with the chemistry, mechanism, cell signaling, therapeutic properties, clinical trials, and toxicity. The chemistry provides insight concerning the mechanism. Acyl nitroso apparently is an intermediate, based on ease of oxidation of the parent and subsequent formation of nitroxyl (HNO) and nitric oxide. Acyl nitroso bears structural and electrochemical similarity to the phenylhydroxylamine-nitrosobenzene couple and to α-dicarbonyls. Acyl nitroso may be involved in electron transfer, reactive oxygen species formation and oxidative stress. Cell signaling plays a significant role in the biological action. The therapeutic properties are discussed with suberoylanilide hydroxamic acid attracting the most attention as an anticancer agent. Promise as a practical medicine for treatment of cancer is indicated by clinical trials. Toxicity is also included. Acyl nitroso, HNO, nitric oxide, and metal complexes of the parent drug are designated the main actors in the physiological effects.

Integrated approach to the mechanisms of thyroid toxins: electron transfer, reactive oxygen species, oxidative stress, cell signaling, receptors, and antioxidants.

Although considerable numbers of reviews are available on toxicity of major body organs based on electron transfer (ET), reactive oxygen species (ROS), and oxidative stress (OS), the integrated concept has been less applied to glands. This review represents an interdisciplinary approach to thyroid toxicity, involving ET, ROS, OS, cell signaling, receptors, toxicants, and beneficial effects of antioxidants (AOs). The introductory portion includes general function of the thyroid as well as the mechanism of thyroxine synthesis entailing participation of oxidative events, including the role of iodine. Various ROS, both endogenous and exogenous, are importantly involved in the diverse toxic manifestations. Discussion is centered on hydrogen peroxide and lipid peroxides. There is also treatment of receptor-ligand activity. Cell signaling participates in the various biochemical events taking place in the thyroid, both beneficial and adverse. In addition, the mechanism of cell signaling is discussed based on radicals, ET, relays, conduits, and electrochemistry. In addition to endogenous toxins, various exogenous ones are addressed, falling in diverse classes. Data indicate involvement of ET-ROS-OS in the toxic manifestations. Large numbers of reports reveal the beneficial effects of AOs in countering the toxicity, which is in accord with the mechanistic framework.