Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upper respiratory and pulmonary complications of cocaine addiction have been increasingly reported in recent years, with most of the patients being intravenous addicts, users of freebase, or smokers of "crack." The toxicity of cocaine is complex and is exerted via multiple central and peripheral pathways. Recurrent snorting of cocaine may result in ischemia, necrosis, and infections of the nasal mucosa, sinuses, and adjacent structures. Pulmonary complications of cocaine toxicity include pulmonary edema, pulmonary hemorrhages, pulmonary barotrauma, foreign body granulomas, cocaine related pulmonary infection, obliterative bronchiolitis, asthma, and persistent gas-exchange abnormalities. Respiratory manifestations are nonspecific and include shortness of breath, cough, wheezing, hemoptysis, and chest pains. Severe respiratory difficulties have been reported in neonates of abusing mothers. In the absence of a cocaine-abuse history, it may be difficult to recognize the etiological role of cocaine, especially in the absence of needle tracks pointing to previous intravenous drug abuse and/or negative toxicology.
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PMID:Respiratory complications of cocaine abuse. 158 7

Cocaine abuse in the United States is widespread, affecting more than 30 million people. Nearly 90% of cocaine-abusing women are of childbearing age. Cardiovascular complications of cocaine intoxication include dysrhythmias, ischemia and/or infarction, and account for most cocaine-related deaths. Pregnancy enhances the cardiovascular toxicity of cocaine. While the epidemiology, pathophysiology, clinical symptomatology and implications on pregnancy of cocaine addiction in pregnancy have received significant attention over the past 25 years, far too little attention has been given to the therapeutic considerations and peripartum care of the cocaine-abusing parturients. The timely treatment of acute cocaine-induced cardiovascular toxicity in pregnancy is by far the best predictor of good maternal and fetal outcome. However, no specific treatment guidelines are currently available for cocaine-induced cardiac dysrhythmias. This article discusses briefly several agents (and considers their mechanism of action) that have been proposed for the treatment of chest pain and other cardiovascular side-effects of cocaine toxicity in pregnancy.
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PMID:Peripartum care of the cocaine-abusing parturient: are we ready? 1568 68

Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.
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PMID:Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. 1707 84

Recently, we described the first small-molecule inhibitor, (E)-ethyl 2-cyano-3-(3,4-dichlorophenyl)acryloylcarbamate (1), of the PDZ domain of protein interacting with Calpha-kinase 1 (PICK1), a potential drug target against brain ischemia, pain and cocaine addiction. Herein, we explore structure-activity relationships of 1 by introducing subtle modifications of the acryloylcarbamate scaffold and variations of the substituents on this scaffold. The configuration around the double bond of 1 and analogues was settled by a combination of X-ray crystallography, NMR and density functional theory calculations. Thereby, docking studies were used to correlate biological affinities with structural considerations for ligand-protein interactions. The most potent analogue obtained in this study showed an improvement in affinity compared to 1 and is currently a lead in further studies of PICK1 inhibition.
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PMID:Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1. 2066 66

Over the past three years we have been involved in high-throughput screening in an effort to discover novel small molecular modulators of aldehyde dehydrogenase (ALDH) activity. In particular, we have been interested in both the activation and inhibition of the three commonly studied isoenzymes, ALDH1A1, ALDH2 and ALDH3A1, as their distinct, yet overlapping substrate specificities, present a particularly difficult challenge for inhibitor discovery and design. Activation of ALDH2 has been shown to benefit cardiovascular outcome following periods of ischemia and renewed interest in specific inhibition of ALDH2 has application for alcohol aversion therapy, and more recently, in cocaine addiction. In contrast, inhibition of either ALDH1A1 or ALDH3A1 has application in cancer treatments where the isoenzymes are commonly over-expressed and serve as markers for cancer stem cells. We are taking two distinct approaches for these screens: in vitro enzyme activity screens using chemical libraries and virtual computational screens using the structures of the target enzymes as filters for identifying potential inhibitors, followed by in vitro testing of their ability to inhibit their intended targets. We have identified selective inhibitors of each of these three isoenzymes with inhibition constants in the high nanomolar to low micromolar range from these screening procedures. Together, these inhibitors provide proof for concept that selective inhibition of these broad specificity general detoxication enzymes through small molecule discovery and design is possible.
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PMID:Discovery of novel regulators of aldehyde dehydrogenase isoenzymes. 2134 55