Orthogonal HPLC methods for quantitating related substances and degradation products of pramlintide.

Pramlintide is a 37-amino acid peptide that is being evaluated as a drug candidate for treating people with type 1 and insulin-using type 2 diabetes. Two high-performance liquid chromatography (HPLC) methods were developed for quantitating related substance impurities in pramlintide drug substance as well as degradation products of pramlintide formulated for parenteral administration. The methods differ with respect to separation mode and therefore provide orthogonal information concerning related substances and degradation products.

Excitotoxic cytopathology, progression, and reversibility of thiamine deficiency-induced diencephalic lesions.

The present study examined the cytopathological changes within diencephalon of a rat model of Wernicke's encephalopathy and determined whether administration of thiamine at various intervals after onset of neurological signs can arrest or reverse the cytopathological process. Electron microscopic examination of the brains from animals sacrificed at four progressively severe stages of pyrithiamine-induced thiamine deficiency (PTD) revealed neurocytopathological changes identical to those that have been described in glutamate-induced excitotoxic lesions. These degenerative changes occurred in gelatinosus (Ge) and anteroventral ventrolateral (AVVL) nuclei at an early symptomatic stage and in the ventroposterolateral (VPL), ventroposteromedial (VPM), and ventrolateral (VL) nuclei at slightly later stages of PTD.

Histamine-mediated neuronal death in a rat model of Wernicke's encephalopathy.

Three experiments were conducted to examine the role of histamine in neuronal degeneration in a rat model of Wernicke's encephalopathy induced by an acute bout of pyrithiamine-induced thiamine deficiency (PTD). In the first experiment, histamine levels in medial thalamus of freely moving PTD rats measured by microdialysis were increased (180% of controls) at a prelesion stage of thiamine deficiency (treatment day 12) and further elevated 48 hr later (380%) in the same animals when necrosis was evident. Histamine levels in dialysates of the hippocampus collected simultaneously from the same animals were unchanged at either stage of thiamine deficiency.