Intra‐Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first‐in‐human (FIH) testing of new molecular entities (NMEs). ITM combines intra‐target drug delivery and “microdosing,” the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic‐level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18F‐fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well‐tolerated. Results are consistent with ITM proof‐of‐concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach.
SummaryIn this paper, a new possible explanation of the properties of helium II is developed. The basis of the argument is that, due to the internal cohesion of a fluid, potential energy resides within the repulsive field of the atoms. This potential energy will tend to appear as kinetic energy if the fluid expands, but, under its own vapour pressure, the sum of the potential and kinetic energies will be a constant in the system and be intrinsic to it. Arguments based on this conception lead to an understanding of many of the peculiarities of helium II and also to a simple expression for the velocity of the "second sound wave".
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