C. E. Richardson

Current methods for measuring cerebral blood volume (CBV) in newborn infants are unsatisfactory. A new method is described in which the effect of a small change (5-10%) in arterial oxygen saturation (SaO2) on cerebral oxyhemoglobin [HbO2] and deoxyhemoglobin [Hb] concentration is observed by near-infrared (NIR) spectroscopy. Previous experiments in which the NIR absorption characteristics of HbO2 and Hb and the pathlength of NIR light through the brain were defined allowed changes in [HbO2] and [Hb] to be quantified from the Beer-Lambert law. It is shown here that CBV can then be derived from the expression CBV = (delta[HbO2] - delta[Hb])/(2. delta SaO2.H.R.), where H is the large vessel total hemoglobin concentration and R to the cerebral-to-large vessel hematocrit ratio. Observations on 12 newborn infants with normal brains, born at 25-40 wk of gestation and aged 10-240 h, gave a mean value for CBV of 2.22 +/- 0.40 (SD) ml/100 g, whereas mean CBV was significantly higher 3.00 +/- 1.04 ml/100 g in 10 infants with brain injury born at 24 to 42 wk of gestation and aged 4-168 h (P less than 0.05).

A noninvasive method of measuring hemoglobin flow through an organ by near-infrared spectroscopy (NIRS) is described that allows blood flow to be calculated. The method is derived from the Fick principle and uses a small change in arterial oxyhemoglobin concentration (brought about by a change in the fractional inspired O2 concentration) as an intravascular tracer. Changes in deoxyhemoglobin and oxyhemoglobin concentrations are quantified by monitoring variations in the absorption of near-infrared light in the organ, thus providing a measure of tracer accumulation. The tracer input function is calculated from the change in arterial O2 saturation, measured by pulse oximetry. The method was used to determine hemoglobin flow in the forearms of six healthy young adults on 10 occasions. Forearm hemoglobin flow ranged from 22.5 to 82.6 mumol.l-1.min-1. Calculated forearm blood flow ranged from 1.01 to 4.01 ml.100 g-1.min-1. For comparison, forearm blood flow was measured by venous occlusion plethysmography, and the relation between flow calculated by NIRS (y) and plethysmography (x) was y = 0.93x + 0.30 (r2 = 0.95). The mean difference between the methods was 0.14 ml.100 g-1.min-1. The technique may be widely applicable.

We have implemented five drug-like filters, based on 1D and 2D molecular descriptors, and applied them to characterize the drug-like properties of commercially available chemical compounds. In addition to previously published filters (Lipinski and Veber), we implemented a filter for medicinal chemistry tractability based on lists of chemical features drawn up by a panel of medicinal chemists. A filter based on the modeling of aqueous solubility (>1 microM) was derived in-house, as well as another based on the modeling of Caco-2 passive membrane permeability (>10 nm/s). A library of 2.7 million compounds was collated from the 23 compound suppliers and analyzed with these filters, highlighting a tendency toward highly lipophilic compounds. The library contains 1.6 M unique structures, of which 37% (607,223) passed all five drug-like filters. None of the 23 suppliers provides all the members of the drug-like subset, emphasizing the benefit of considering compounds from various compound suppliers as a source of diversity for drug discovery.