Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium channel inhibitors have been extensively used to treat arterial hypertension, ischaemic heart disease and supraventricular rhythm irregularities. The poisonings by that category of drugs are extremely dangerous, particularly when accompanied by intoxication with other drugs affecting the circulatory function. This paper reports 3 cases of poisonings with calcium channel inhibitors (verapamil and diltiazem) in combination with angiotensin convertase inhibitors and nonselective beta-adrenolytics. Circulatory insufficiency and cardiac rhythm abnormalities were noted in all reported cases, in one in the form of ventricular bigeminy and two episodes of ventricular fibrillation, while in the two other cases in the form of 1 degree atrioventricular block. The persisting hypotonia combined with heart rhythm disturbances could not be prevented by the typical conservative treatment involving intravenous administration of infusion fluids, calcium formulations, catecholamines and atropin. The application of 4-amino-pyridine (Pymadin) caused that arterial tension and heart rate were higher, and the heart rhythm disturbances disappeared. The reported cases suggest a beneficial effect of 4-aminopyridine used to treat cases of poisonings by calcium channel inhibitors; however, up to the present time, no detailed procedures have been determined for 4-aminopyridine administration in cases like those reported above. 4-aminopyridine has not been included in the list of the antidotes approved by the WHO and, therefore, broader tests and more clinical observations are required to confirm its therapeutic value.
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PMID:[The application of 4-aminopyridine in calcium channel inhibitors acute poisoning]. 1772 89

Peptidases play vital roles in physiology through the biosynthesis, degradation, and regulation of peptides. Prolyl endopeptidase-like (PREPL) is a newly described member of the prolyl peptidase family, with significant homology to mammalian prolyl endopeptidase and the bacterial peptidase oligopeptidase B. The biochemistry and biology of PREPL are of fundamental interest due to this enzyme's homology to the biomedically important prolyl peptidases and its localization in the central nervous system. Furthermore, genetic studies of patients suffering from hypotonia-cystinuria syndrome (HCS) have revealed a deletion of a portion of the genome that includes the PREPL gene. HCS symptoms thought to be caused by lack of PREPL include neuromuscular and mild cognitive deficits. A number of complementary approaches, ranging from biochemistry to genetics, will be required to understand the biochemical, cellular, physiological, and pathological mechanisms regulated by PREPL. We are particularly interested in investigating physiological substrates and pathways controlled by PREPL. Here, we use a fluorescence polarization activity-based protein profiling (fluopol-ABPP) assay to discover selective small-molecule inhibitors of PREPL. Fluopol-ABPP is a substrate-free approach that is ideally suited for studying serine hydrolases for which no substrates are known, such as PREPL. After screening over 300,000 compounds using fluopol-ABPP, we employed a number of secondary assays to confirm assay hits and characterize a group of 3-oxo-1-phenyl-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile and 1-alkyl-3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile PREPL inhibitors that are able to block PREPL activity in cells. Moreover, when administered to mice, 1-isobutyl-3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile distributes to the brain, indicating that it may be useful for in vivo studies. The application of fluopol-ABPP has led to the first reported PREPL inhibitors, and these inhibitors will be of great value in studying the biochemistry of PREPL and in eventually understanding the link between PREPL and HCS.
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PMID:A substrate-free activity-based protein profiling screen for the discovery of selective PREPL inhibitors. 2169 4