The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.
Current systolic time interval techniques have limited clinical applicability since patient co-operation and attention to the carotid pulse and phonocardiogram transducers are required. Therefore only surface electrodes were used to monitor the electrocardiogram and electrical impedance cardiogram first derivative (dZ/dt) in the acquisition of the timing signals. dZ/dt motion artefacts were eliminated by computerised ensemble averaging, thus permitting uninterrupted data acquisition. We studied the continuous response of multistage treadmill exercise on 13 normal volunteers, since maximal distortion of noninvasive measurements occurs in dynamic exercise. The individual response trends were combined for 6 symbolic indices and each mean index had a high statistical significance (P less than 0.001). This new method surveys continuously ventricular performance with surface electrodes and therefore has the potential of monitoring the ventricular performance of critically ill patients.
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