UCN-01 is a protein kinase inhibitor under development as a novel anticancer drug. The initial pharmacologic features in patients were not predicted from preclinical experiments. The distribution volume and the systemic clearance were much lower than those in experimental animals (mice, rats, and dogs), and the elimination half-life was unusually long (>200 hours). The unbound fraction in human plasma was also much smaller than that in dogs, rats and mice, as was the binding of UCN-01 to human alpha-1 acid glycoprotein much stronger than that to human serum albumin or human gamma-globulin. The association constants for alpha-1 acid glycoprotein and human plasma were approximately 8 x 10(8)(mol/L)(-1), indicating extremely high affinity. In this review article, the authors discuss the pharmacologic features of UCN-01 across species and provide a perspective on how this information could be applied prospectively to the future development of this agent.
We used localized 1H-magnetic resonance spectroscopy (MRS) to study the metabolic changes in the brains of patients with migraine during the interictal period. Measurement of metabolite levels in the occipital visual cortex in six normal subjects and six patients disclosed high lactate levels in the five patients who had experienced a migraine attack within the previous 2 months. One patient who had not experienced a migraine attack in the previous 4 years did not show a lactate peak. We speculate that anaerobic glycolysis occurs in the brains of patients with migraine during the interictal period, and a long attack-free period may normalize the subclinical metabolic disturbance.
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