SUMMARY
Previous studies indicated that 36Cl-labelled perchlorate is concentrated by rat and rabbit thyroid gland. However, the extent of concentration of radioactive perchlorate in the gland was much less than that of iodide. Since perchlorate itself has a marked effect on anion transport in the thyroid and the specific activity of available [36C]perchlorate is very low, the stable anion as a carrier present in the injected radioactive perchlorate solution may affect the uptake of this radioactive compound by the gland. In this study, radioactive solutions of perchlorate and iodide containing different amounts of stable perchlorate or iodide (dosages ranged from 0·005 to 5 m-equiv./kg. body weight) were injected into groups of rats and guineapigs, and the thyroid: plasma concentration ratios of radioactive perchlorate and iodide were calculated and compared. These experiments were also repeated in animals pretreated with thyroid-stimulating hormone (TSH), after chronic administration of propylthiouracil (PTU), as well as in hypophysectomized animals. At the same dose levels of perchlorate, there was no difference in thyroid: plasma concentration ratios of radioactive perchlorate and iodide in control rats and guinea-pigs or in treated ones.
There is a growing consensus that the development of novel chemical entities needs to be accelerated. Strategies include the use of biomarkers and surrogate markers in evaluating drug effects, predicting drug metabolism issues, and in the early demonstration of proof of principle and proof of concept designs in Phase 1 studies.
Introduction:We advocate employing an increasingly sophisticated 'Tool Kit' of CNS methodologies early in drug development for therapies to treat psychotic disorders and schizophrenia. Studies combining traditional endpoints, along with biomarkers to demonstrate achievement of critical concentration thresholds and relevant physiological responses indicative of proof of pharmacological effect in schizophrenia are possible in second in human studies or thereafter. These studies and others similar to it have played critical roles in determining doses for Phase II studies for psychiatric and neurological therapies.
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