FASEB journal : official publication of the Federation of American Societies for Experimental Biology
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Activation of the complement cascade with the generation of anaphylatoxins accompanies the inflammatory response elicited by acute myocardial ischemia and reperfusion. Although complement is activated in the interstitium during acute myocardial ischemia, we have studied mechanisms whereby complement might exacerbate ischemia by using a model employing intracoronary injection of C5a in nonischemic hearts. Intracoronary injection of complement component C5a induces transient myocardial ischemia, mediated through the production of the coronary vasoconstrictors thromboxane A2 and peptidoleukotrienes (LTC4, LTD4), and causes sequestration of polymorphonuclear leukocytes (PMN) in the coronary vascular bed. ⋯ In separate experiments, the intracoronary injection of LTB4 also resulted in a pronounced myocardial extraction of PMNs (8.6 x 10(3) cells/microliters) greater than during C5a, but did not depress coronary flow or function. Perfusion at constant flow greatly diminished the ischemic response to C5a, indicating that vasoconstriction and resultant ischemia is the main cause of the contractile dysfunction. These data indicate that leukocyte filters inhibit the myocardial ischemia and release of TxB2 induced by C5a via mechanisms not related to PMN depletion.(ABSTRACT TRUNCATED AT 400 WORDS)
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A new strategy for the delivery of cytotoxic agents to solid tumors is described in which monoclonal antibodies are used as carriers for enzymes to tumor cell surfaces. The enzymes are chosen for their abilities to convert relatively noncytotoxic drug precursors (pro-drugs) into active anticancer drugs. The drugs thus formed can then penetrate into nearby tumor cells, resulting in cell death. ⋯ The enzymes have been shown to localize into tumors when linked to monoclonal antibodies that bind to tumor-associated antigens. In vivo studies indicate that MAb-enzyme/prodrug combinations can result in antitumor activities significantly greater than those of the prodrugs or drugs given alone. This is most likely due to the generation of large amounts of active drug at the tumor site.
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The principal metabolite of delta 1-THC, delta 1-THC-7-oic acid exhibits significant analgesic action in the mouse hot plate test. The parent delta 1-THC has a similar effect when measured at later time points; however, 10 min after drug administration, a pronounced hyperalgesia is seen. ⋯ Unlike delta 1-THC, the metabolite does not produce a cataleptic state in the mouse, which eliminates this as a basis for the hot plate response. The evidence presented is consistent with a mechanism in which the metabolite inhibits eicosanoid synthesis whereas the parent drug elevates tissue levels of prostaglandins.