Convallatoxin

550.64

550.64

208-086-3

JY264VIR1Y

Prisms from methanol + ether|Crystals or prisms from methanol or ether

163

0.75000

1.41±0.1 g/cm3 (20 ºC 760 Torr)

235-242 °C

757.3ºC at 760 mmHg

247.1ºC

1.622

SOL IN ALCOHOL, ACETONE; SLIGHTLY SOL IN CHLOROFORM, ETHYL ACETATE, & WATER (1:2000); PRACTICALLY INSOL IN ETHER, PETROLEUM ETHER

Keep container tightly closed in a dry and well-ventilated place. Storage class (TRGS 510): 6.1D: Non-combustible, acute toxic Cat.3 / toxic hazardous materials or hazardous materials causing chronic effects

LD50 in mice, rats (mg/kg): 10.0 i.p., 16.0 i.v. (Frster)

D22 -1.7 ± 3° (c = 0.65 in methanol); D25 -9.4 ± 3° (c = 0.72 in dioxane)

238.1 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

/Tests positive for/ Legal's Reaction /SRP: "Legal's test for acetone consists of adding the the liquid a few drops of a solution of sodium nitroprusside, followed by caustic alkali; a red coloration is produced, and gradually diminishes, but deepens to carmine on treatment with excess glacial acetic acid" J Chem Soc (London) 72 Part 2. Analytical Chemistry, page 467. Jan 1, 1897/|Needles from acetone + ether, MP: 215-239 °C. Specific optical rotation: -5.5 deg at 25 °C/D (c = 0.962 in chloroform) /Tri-O-acetyl-convallatoxin/

III

6.1(b)

3249

2

GL4025000

Stable under recommended storage conditions.

P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P311, P312, P321, P322, P330, P361, P363, P403+P233, P405, P501

H301

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong acids, strong bases, strong oxidizing agents.

|Danger|H301: Toxic if swallowed [Danger Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P311, P312, P321, P322, P330, P361, P363, P403+P233, P405, and P501

Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary

ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.|ACCIDENTAL RELEASE MEASURES; Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.|Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

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.

LD50 Mice ip 10 mg/kg|LD50 Rat iv 15 mg/kg|LD50 Mice sc 15 mg/kg|LD50 Mice iv 1 mg/kg|For more Non-Human Toxicity Values (Complete) data for Convallatoxin (6 total), please visit the HSDB record page.

Convallatoxin is found in the blossoms of lily of valley (Convallaria majalis L, Liliaceae), from Ornithogalum umbellatum L, Liliaceae and from Antiaris toxicaria Lesch, Moraceae(1).

Vasodilator Agents|/EXPL THER/ Convallatoxin improved myocardial relaxation and elevated the rate and force of systolic heart contraction in dogs in the initial stages of cor pulmonale (in chronic pneumonia). The positive inotropic effect in experimental cor pulmonale with high pulmonary blood pressures was accompanied by increased overload on the right ventricle and further elevation of pulmonary blood pressures.|/EXPL THER/ Convallotoxin had no effect on left ventricular hemodynamics in intact dogs, but decreased right intraventricular pressure and increased dp/dt max and dp/dt minimum. In animals with surgical stenosis of the pulmonary trunk, an increase in pressure and dp/dt max of the right ventricle, a decrease in left ventricular end-diastolic pressure, and an increase in left dp/dt max were observed. Administration of convallotoxin to dogs 1 month following stenosis did not improve cardiohemodynamics.|/EXPL THER/ Cytomegalovirus (CMV) is a ubiquitous human pathogen that increases the morbidity and mortality of immunocompromised individuals. The current FDA-approved treatments for CMV infection are intended to be virus specific, yet they have significant adverse side effects, including nephrotoxicity and hematological toxicity. Thus, there is a medical need for safer and more effective CMV therapeutics. Using a high-content screen, we identified the cardiac glycoside convallatoxin as an effective compound that inhibits CMV infection. Using a panel of cardiac glycoside variants, we assessed the structural elements critical for anti-CMV activity by both experimental and in silico methods. Analysis of the antiviral effects, toxicities, and pharmacodynamics of different variants of cardiac glycosides identified the mechanism of inhibition as reduction of methionine import, leading to decreased immediate-early gene translation without significant toxicity. Also, convallatoxin was found to dramatically reduce the proliferation of clinical CMV strains, implying that its mechanism of action is an effective strategy to block CMV dissemination. Our study has uncovered the mechanism and structural elements of convallatoxin, which are important for effectively inhibiting CMV infection by targeting the expression of immediate-early genes. IMPORTANCE: Cytomegalovirus is a highly prevalent virus capable of causing severe disease in certain populations. The current FDA-approved therapeutics all target the same stage of the viral life cycle and induce toxicity and viral resistance. We identified convallatoxin, a novel cell-targeting antiviral that inhibits CMV infection by decreasing the synthesis of viral proteins. At doses low enough for cells to tolerate, convallatoxin was able to inhibit primary isolates of CMV, including those resistant to the anti-CMV drug ganciclovir. In addition to identifying convallatoxin as a novel antiviral, limiting mRNA translation has a dramatic impact on CMV infection and proliferation.

Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)

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. ...

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.

The inhibitory activity of glycosides and related compounds toward Na+-K+-ATPase was determined and related to their cardiotonic activity in cats. It appeared that the active site of Na+-K+-ATPase consists of 2 sections; 1 section binds the cardiosteroids to the receptor and orients the molecules relative to the 2nd or catalytic section. The relation of these results to the cardiotonic activity of strophanthidol analogs is discussed.

Convallatoxin batches made in Switzerland, West Germany, and Britain contained periguloside, convallatoxol, aglycons, and noncardenolides. The impurities were removed by column chromatography on neutral aluminum oxide-silica gel (1:1) by elution with CHCl3-ethanol (4:1).

/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/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/ALTERNATIVE and IN VITRO TESTS/ Convallatoxin showed potent cytotoxic activity when assayed against Eagle's KB strain of human epidermoid carcinoma and in a disk-plate assay against kb cells. The results suggested that cytotoxicity is associated with an unsaturated lactone either attached to position 17 by a carbon-carbon bond or fused to ring d across the 16,17-position. Thus, the cardiac principles have either a cardenolide ring or a bufadienolide ring attached to position 17. The data also shows that the glycosides were more active than the corresponding aglycones and that the cardenolide and bufadienolide rings were equally effective in confering activity.|/ALTERNATIVE and IN VITRO TESTS/ Cardiac glycosides consist of a large family of naturally derived compounds that are clinically used to treat congestive heart failure, and also present anticancer properties. In this study, the cytotoxic effects of two cardenolides, digitoxigenin monodigitoxoside (DGX) and convallatoxin (CON) were screened in four human tumor cell lines. Both compounds showed anti-proliferative effects in all tumor cells, at nanomolar concentrations. Since the human lung cancer cell line A549 was the most sensitive, we investigated the anti-proliferative, anti-migratory and anti-invasive effects of these cardenolides. DGX and CON reduced A549 cell migration, being able to reduce more than 90% of cell invasion. Their effects on the expression of key regulators of metastatic mechanism showed decreased levels of MMP-2, MMP-9 and p-FAK. Both compounds also presented low toxicity for healthy cells. Finally, this work provides the first insights into the effects of these cardenolides on key steps of lung cancer metastasis.|/ALTERNATIVE and IN VITRO TESTS/ Autophagy and apoptosis are important processes that control cellular homeostasis and have been highlighted as promising targets for novel cancer therapies. Here, we identified convallatoxin (CNT), isolated from Antiaris toxicaria, as a dual inducer of autophagy and apoptosis. 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. Collectively, these results demonstrate that the naturally occurring compound, CNT, is a novel anti-angiogenic compound via dual inducing of autophagy and apoptosis.|/ALTERNATIVE and IN VITRO TESTS/ Cardenolides are cardiac glycosides, mostly obtained from natural sources. They are well known for their inhibitory action on the Na,K-ATPase, an effect that regulates cardiovascular alterations such as congestive heart failure and atrial arrhythmias. In recent years, they have also sparked new interest in their anticancer potential. In the present study, the cytotoxic effects of the natural cardenolide convallatoxin (CON) were evaluated on non-small cell lung cancer (A549) cells. It was found that CON induced cytostatic and cytotoxic effects in A549 cells, showing essentially apoptotic cell death, as detected by annexin V-propidium iodide double-staining, as well as changes in cell form. In addition, it prompted cell cycle arrest in G2/M and reduced cyclin B1 expression. This compound also increased the number of cells in subG1 in a concentration- and time-dependent manner. At a long term, the reduction of cumulative population doubling was shown along with an increase of beta-galactosidase positive cells and larger nucleus, indicative of senescence. Subsequently, CON inhibited the Na,K-ATPase in A549 cells at nM concentrations. Interestingly, at the same concentrations, CON was unable to directly inhibit the Na,K-ATPase, either in pig kidney or in red blood cells. Additionally, results of docking calculations showed that CON binds with high efficiency to the Na,K-ATPase. Taken together, our data highlight the potent anticancer effects of CON in A549 cells, and their possible link with non-classical inhibition of Na,K-ATPase.|/OTHER TOXICITY INFORMATION/ None of the cardiac glycosides tested affected total blood serum calcium levels in patients with cardiac insufficiency, but all increased ionic Ca2+ levels.

convallatoxin

... Convallaria majalis (Lily of the Valley), yields cardiac glycoside, convallatoxin, which is not employed clinically but which possesses potent characteristic digitalis-like activity.|A phytotoxin from the flowers of Adonis vernalis, convallaria majalis, ornthogalum umbellatum and antiaris toxicaria. The aglycone is convallatoxigenin and the sugar is a rhamnose.

Determination of cardenolides in Convallaria majalis l by high-performance liquid chromatography.

CONTEXT: Cardiac glycosides of plant origin are implicated in toxic ingestions that may result in hospitalization and are potentially lethal. The utility of commonly available digoxin serum assays for detecting foxglove and oleander ingestion has been demonstrated, but no studies have evaluated the structurally similar convallatoxin found in Convallaria majalis (lily of the valley) for rapid laboratory screening, nor has digoxin immune Fab been tested as an antidote for this ingestion. OBJECTIVE: We aimed to (1) evaluate multiple digoxin assays for cross-reactivity to convallatoxin, (2) identify whether convallatoxin could be detected in vivo at clinically significant doses, and (3) determine whether digoxin immune Fab could be an effective antidote to convallatoxin. MATERIALS AND METHODS: Cross-reactivities of purified convallatoxin and oleandrin with five common digoxin immunoassays were determined. Serum from mice challenged with convallatoxin was tested for apparent digoxin levels. Binding of convallatoxin to digoxin immune Fab was determined in vitro. RESULTS: Both convallatoxin and oleandrin were detectable by a panel of commonly used digoxin immunoassays, but cross-reactivity was variable between individual assays. We observed measurable apparent digoxin levels in serum of convallatoxin intoxicated mice at sublethal doses. Convallatoxin demonstrated no binding by digoxin immune Fab. CONCLUSION: Multiple digoxin immunoassays detect botanical cardiac glycosides including convallatoxin and thus may be useful for rapid determination of severe exposures, but neutralization of convallatoxin by digoxin immune Fab is unlikely to provide therapeutic benefit.|Plant poisonings have left their mark on history and still cause many deaths, whether intentional or accidental. The means to show toxicological evidence of such poisonings should be implemented with great care. This article presents a technique for measuring thirty-nine toxic principles of plant origin in the blood, covering a large amount of toxins from local or exotic plants: a-lobeline, a-solanine, aconitine, ajmaline, atropine, brucine, cephalomannine, colchicine, convallatoxin, cymarine, cytisine, digitoxin, digoxin, emetine, gelsemine, ibogaine, jervine, kavain, lanatoside C, lupanine, mitragynine, neriifolin, oleandrin, ouabain, paclitaxel, physostigmine, pilocarpine, podophyllotoxin, proscillaridin A, reserpine, retrorsine, ricinine, scopolamine, senecionine, sparteine, strophanthidin, strychnine, veratridine and yohimbine. Analysis was carried out using an original ultra-high performance liquid chromatography separation coupled with tandem mass spectrometry detection. Extraction was a standard solid phase extraction performed on Oasis() HLB cartridge. Thirty-four of the thirty-nine compounds were put through a validation procedure. The assay was linear in the calibration curve range from 0.5 or 5 ug/L to 1000 ug/L according to the compounds. The method is sensitive (LOD from 0.1 to 1.6 ug/L). The within-day precision of the assay was less than 22.5% at the LLOQ, and the between-day precision was less than 21.5% for 10 ug/L for all the compounds included. The assay accuracy was in the range of 87.4 to 119.8% for the LLOQ. The extraction recovery and matrix effect ranged from 30 to 106% and from -30 to 14%, respectively. It has proven useful and effective in several difficult forensic cases.|OBJECTIVE: Lily of the valley is a poisonous plant due to the presence of the cardiac glycoside convallatoxin. We compared two immunoassays (LOCI digoxin assay and iDigoxin assay) for rapid detection of convallatoxin if present in human serum. MATERIALS AND METHODS: Aliquots of a drug free serum pool and a digoxin serum pool were supplemented with microliter amounts of lily of the valley extract or nanogram to microgram quantities of convallatoxin, followed by measurement of apparent digoxin concentrations using the LOCI and iDigxoin assays. RESULTS: Apparent digoxin concentrations were observed when aliquots of a drug free serum pool were supplemented with convallatoxin or lily of the valley extract using both assays but apparent digoxin concentrations were significantly higher using the iDigoxin assay. In addition, the interference of convallatoxin in serum digoxin measurement was also significantly higher using iDigxoin assay compared to the LOCI digoxin assay. CONCLUSIONS: The iDigxoin assay is more sensitive in detecting convallatoxin in human serum.

Lipids -> Sterol Lipids [ST] -> Sterols [ST01] -> Cardanolides and derivatives [ST0112]