Helveticoside and convallatoxin were converted hydrolytically into strophanthidine during perfusion through an isolated rat small intestine segment. Also, the C10-aldehyde group of these compounds was reduced enzymatically to helveticosol, convallatoxol, and strophanthidol. This reduction of strophanthidine cardenolides, beside the hydrolysis reaction, appeared to be the most important biotransformation reaction in the rat small intestine.
IDENTIFICATION AND USE: Convallotoxin is a cardiac glycoside. A phytotoxin from the flowers of Adonis vernalis, Convallaria majalis (Lily of the Valley), Ornthogalum umbellatum and Antiaris toxicaria. The aglycone is convallatoxigenin and the sugar is a rhamnose. Convallatoxin is used in acute and chronic congestive heart-failure and paroxysmal tachycardia. HUMAN STUDIES: Convallotoxin induced cytostatic and cytotoxic effects in human lung A549 cells. Convallotoxin inhibited the Na,K-ATPase in A549 cells at nM concentrations. ANIMAL STUDIES: When administered in a single iv injection at minute to lethal doses to rats or cats, convallatoxin caused vascular disorders in the heart, liver, and kidneys. When injected daily at doses corresponding to 0.2 to 0.4 LD100 for 15 days, it caused dystrophic changes and increased the infiltration and proliferation processes. When injected iv into mice, the LD50 value of convallatoxin was 6.3 mg/kg. The glycoside caused tremor, convulsions, and paralysis of the limbs and affected respiration. The preparation caused disorders in the cardiac activity and a transient coronary insufficiency. The effects of a single or repeated ip injections of convallatoxin on the histology of the heart, liver, kidney, spleen, and lungs was studied in mice, rats, and cats. A single injection dilated blood vessels in the heart, liver, and kidneys, caused hemorrhage in the liver, and caused an infiltrative-proliferative effect in the heart and liver. After chronic injections, the infiltrative-proliferative effect was more pronounced than after the acute administration, and dystrophic changes were observed in the liver. ECOTOXICITY STUDIES: Convallatoxin (20 uM) could significantly prolong the lifespan of wild-type Caenorhabditis elegans up to 16.3% through daf-16, but not sir-2.1 signalling and increased thermotolerance and resistance to paraquat-induced oxidative stress. Convallatoxin also improved pharyngeal pumping, locomotion, reduced lipofuscin accumulation and reactive oxygen species levels in C. elegans, which were attributed to hormesis, free radical-scavenging effects in vivo, and up-regulation of stress resistance-related proteins, such as SOD-3 and HSP-16.1. Furthermore, aging-associated genes daf-16, sod-3, and ctl-2 also appeared to contribute to the stress-resistance effect of convallatoxin.
Convallatoxin (CNT) is classified as a cardiac glycoside. Cardiac glycosides are well known Na+/K+-ATPase inhibitors, and some of them are used to treat congestive heart failure and atrial arrhythmias. Recent studies have reported that cardiac glycosides have potential as anticancer agents. CNT exerts cytotoxic effects on a number of cancer and normal cell lines and induces apoptosis by increasing caspase-3 and poly ADP ribose polymerase (PARP) cleavage. Moreover, dose- and time-dependent autophagic activity was detected in CNT-treated cells, and mammalian target of rapamycin (mTOR)/p70S6K signal pathway inhibition was observed. Notably, CNT inhibits human umbilical vein endothelial cell (HUVEC) growth and exerts anti-angiogenic activity in vitro and in vivo. (A15340)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类无致癌性（未列入国际癌症研究机构IARC清单）。
No indication of carcinogenicity to humans (not listed by IARC).
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
The intestinal absorption of 15 cardenolides was examined after the (3)H-labeled substances were injected intraluminally into ligated duodenal loops of cats. Concentrations of (3)H were followed in the portal circulation and in the bile.
Isolated, everted rat jejunal preparations absorbed convallatoxin by an active transport mechanism. No relation was observed between the amount of cardiotonic glycoside actively transported and the oxygen consumption of the tissue.
Digitalis-like compounds (DLCs), such as digoxin and digitoxin that are derived from digitalis species, are currently used to treat heart failure and atrial fibrillation, but have a narrow therapeutic index. Drug-drug interactions at the transporter level are frequent causes of DLCs toxicity. P-glycoprotein (P-gp, ABCB1) is the primary transporter of digoxin and its inhibitors influence pharmacokinetics and disposition of digoxin in the human body; however, the involvement of P-gp in the disposition of other DLCs is currently unknown. In present study, the transport of fourteen DLCs by human P-gp was studied using membrane vesicles originating from human embryonic kidney (HEK293) cells overexpressing P-gp. DLCs were quantified by liquid chromatography-mass spectrometry (LC-MS). The Lily of the Valley toxin, convallatoxin, was identified as a P-gp substrate (Km: 1.1+/-0.2 mM) in the vesicular assay. Transport of convallatoxin by P-gp was confirmed in rat in vivo, in which co-administration with the P-gp inhibitor elacridar, resulted in increased concentrations in brain and kidney cortex. To address the interaction of convallatoxin with P-gp on a molecular level, the effect of nine alanine mutations was compared with the substrate N-methyl quinidine (NMQ). Phe343 appeared to be more important for transport of NMQ than convallatoxin, while Val982 was particularly relevant for convallatoxin transport. We identified convallatoxin as a new P-gp substrate and recognized Val982 as an important amino acid involved in its transport. ...
Toxicarioside M, a new cytotoxic 10β-hydroxy-19-nor-cardenolide from Antiaris toxicaria
摘要：
A new 10 beta-hydroxy-19-nor-cardenolide, named toxicarioside M (1), was isolated from the trunk bark of Antiaris toxicaria (Pers.) Lesch (Moraceae), along with six known cardenolides (convallatoxin (2), convallatoxol (3), convalloside (4), 3-O-beta-D-xylopyranosylstrophanthidin (5), glucostrophanthidin (6) and strophanthidin (7)). Their structures were elucidated on the basis of HR-MSn analysis, spectroscopic methods (IR, UV, ID and 2D NMR) and by comparison with data reported in the literature. The cardenolides were evaluated for their cytotoxic activity against KB, HCT-116, SF-268. MCF-7, HL-60, PC-3 and MRC-5 cell lines. (C) 2012 Elsevier B.V. All rights reserved.
DOI：
10.1016/j.fitote.2012.02.001
作为产物：
描述：
alkaline earth salt of/the/ methylsulfuric acid 在
enzyme-substance from strophanthus kombe 作用下，
生成 铃兰毒甙
Partialsynthese von Convallatoxin. Glykoside und Aglykone, 61. Mitteilung
作者：K. Reyle、K. Meyer、T. Reichstein
DOI：10.1002/hlca.19500330621
日期：——
Die Teilsynthese von Convallotoxin aus Acetobrom-L-rhamnose und Strophanthidin wird beschrieben.
描述了由乙酰溴-L-鼠李糖和stophanthidin部分合成铃兰辛。
Hydroxylated nebivolol metabolites
申请人：O'Donnell P. John
公开号：US20070014733A1
公开（公告）日：2007-01-18
Hydroxylated nebivolol metabolites increase NO release from human endothelial cell preparations in a concentration dependent fashion following acute administration. In addition, hydroxylated nebivolol metabolites, including but not limited to 4-hydroxy-6,6′difluoro-, 4-hydroxy-5-phenol-6,6′difluoro-, and 4-hydroxy-8-pheno-6,6′difluoro-, have the ability to increase the capacity for NO release in human endothelial cells following chronic administration. This invention provides hydroxylated nebivolol metabolites and compositions comprising nebivolol and/or at least one hydroxylated metabolite of nebivolol and/or at least one additional compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof. In addition, this invention provides methods of treating and/or preventing vascular diseases by administering at least one hydroxylated metabolite of nebivolol that is capable of releasing a therapeutically effective amount of nitric oxide to a targeted site affected by the vascular disease. Also, this invention is directed to the treatment and/or prevention of migraine headaches administering at least one hydroxylated metabolite of nebivolol. This invention may also be used in conjunction with or as a single treatment of metabolic syndrome disorders.
Nitric Oxide Releasing Prodrugs of Therapeutic Agents
申请人：SATYAM Apparao
公开号：US20110263526A1
公开（公告）日：2011-10-27
The present invention relates to nitric oxide releasing prodrugs of known drugs or therapeutic agents which are represented herein as compounds of formula (I) wherein the drugs or therapeutic agents contain one or more functional groups independently selected from a carboxylic acid, an amino, a hydroxyl and a sulfhydryl group. The invention also relates to processes for the preparation of the nitric oxide releasing prodrugs (the compounds of formula (I)), to pharmaceutical compositions containing them and to methods of using the prodrugs.
Topical and oral formulations of cardiac glycosides for treating skin diseases
申请人：Streeper Robert
公开号：US20060205679A1
公开（公告）日：2006-09-14
The present invention provides method, preparation and use of a variety of pharmaceutical compositions containing at least one digitalis glycoside such as oleandrin, odoroside-A, neriifolin, proscillaridin-A, methyl-proscillaridin-A, digitoxin, digoxin alone or at least one digitalis glycoside complexed with cyclodextrins. In another aspect, the present invention provides an effective method to treat diseases in mammals. In yet another aspect, the present invention provides an effective method for treating skin diseases in a human or non-human animal.
[EN] INHIBITORS OF GLUCOSE-6-PHOSPHATE DEHYDROGENASE FOR TREATING CARDIOVASCULAR AND PULMONARY CONDITIONS<br/>[FR] INHIBITEURS DE LA GLUCOSE-6-PHOSPHATE DÉSHYDROGÉNASE PERMETTANT DE TRAITER DES AFFECTIONS CARDIOVASCULAIRES ET PULMONAIRES
申请人：GUPTE SACHIN A
公开号：WO2018093856A1
公开（公告）日：2018-05-24
The present disclosure provides for methods of treating or preventing a cardiovascular disorder and/or a related pulmonary disorder in a subject. In certain embodiments, the method comprises administering a therapeutically effective amount of an inhibitor of Glucose-6-phosphate dehydrogenase (G6PD), or a pharmaceutically acceptable salt, non-salt amorphous form, solvate, poly-morph, tautomer or prodrug thereof.
