Lily of the valley

LILY OF THE VALLEY Molly Benning Dawn Anderson Alisa Villarreal

INTRODUCTION

WHAT IS A TOXIN?

 A toxin is a substance produced by an organism that has an adverse effect on other organisms.  Any substance can be toxic depending on the dose.  Dose determines effect.  Plants produce secondary metabolites as a defense mechanism.

LILY OF THE VALLEY  We chose to research Lily of the Valley after learning about it from the television show Breaking Bad. The toxicity of Lily of the Valley is featured in Breaking Bad and we wanted to see how common Lily of the Valley poisoning is and if there are any therapeutic benefits associated with this plant.

LILY OF THE VALLEY DESCRIPTION  Convallaria majalis, commonly known as Lily of the Valley, is a perennial plant that forms rhizomes.  It forms white, bell -shaped flowers and red berries.  4”-8” tall  Lily of the Valley contains toxic cardiac glycosides. Every part of the plant is toxic.

LILY OF THE VALLEY DISTRIBUTION  Convallaria majalis is native to Europe and Asia and is an introduced species in North America.  Lily of the Valley grows in wooded areas in rich soil.

 Lily of the Valley is also used in gardening as ground cover. Introduced

Native

HISTORY

CHRISTIAN LEGEND  Lily of the Valley is also known as “Our Lady ’s tears”.  According to Christian legend, when Mary cried at the crucifixion of Jesus, her tears turned into Lily of the Valley.  Other lore states Lily of the Valley was created when Eve cried after she and Adam were banished from the Garden of Eden.

GOLDEN WATER

 In the 17 th century, Germans added Lily of the Valley to old wine as a remedy for palpitation, vertigo, epilepsy, apoplexy as well as a general “cure all”.

 This concoction was stored in gold and silver vessels.  This concoction was known as aqua aurea, or “golden water ”.

MEDICINAL USES  Lily of the Valley has been used traditionally as a diuretic and as a treatment for heart ailment and irregular heartbeat.  Historical medicinal use is similar to that of Foxglove, Digitalis lanata, the plant from which digoxin is produced.  Unlike Digitalis lanata, Convallaria majalis was never pharmaceutically produced.

Convallaria majalis

Digitalis lanata

NARROW SAFETY MARGIN DRUGS  C. majalis was never used as a clinical treatment for irregular heart function due to its narrow margin of safety.  A narrow safety margin drug is a drug whose adverse effect curve and therapeutic effects curve are very close.  Therapeutic index = AE 50 /TE 50  Narrow safety margin drugs have a therapeutic index of 2.

 Narrow safety margin drugs, liked digoxin, are used when there is no other effective treatment.

TOXICITY

CARDIAC GLYCOSIDES  Cardiac glycosides are a class of compounds made up of a steroid nucleus, a lactone ring, and a series of sugars linked to the third carbon of the nucleus.  Cardenolides are a class of cardiac glycosides produced by plants.  Lily of the Valley contains at least 38 known cardiac glycosides.

CONVALLATOXIN

 Convallatoxin is one of the main cardiac glycosides isolated from Lily of the Valley.  Convallatoxin is highly resistant to hydrolysis.  LD50 for orally delivered convallatoxin in mice is >2 g /kg.

CONVALLAMARIN

 Convallamarin is another main cardiac glycoside isolated from Lily of the Valley.

 There is currently little research on this compound and no determined LD50.

LESSER CARDIAC GLYCOSIDES  There are several lesser cardiac glycosides that have been isolated from C. majalis that are not as well researched:        

Strophanthidin-3-O-6'-deoxy-beta-D-allosido-alpha-L-rhamnoside Strophanthidin-3-O-6'-deoxy-beta-D-allosido-alpha-L-arabinoside Strophanthidin-3-O-alpha-L-rhamnosido-2'-beta-D-glucoside Cannogenol-3-O-6'-deoxy-beta-D-allosido-beta-D-glucoside Cannogenol-3-O-6'-deoxy-beta-D-allosido-alpha-L-rhamnoside 19-hydroxy-sarmentogenin-3-O-alpha-L-rhamnoside Sarmentogenin-3-O-6'-deoxy-beta-D-allosido-alpha-L-rhamnoside Sarmentogenin-3-O-6'-deoxy-beta-D-guloside

MECHANISM OF ACTION  The numerous cardiac glycosides found in Lily of the Valley have similar mechanisms.  Cardiac glycosides inhibit the trans membrane Na + /K + -ATPase pump.  This inhibition leads to an increase in concentration of Na + and Ca 2+ within the cell.  The sarcoplasmic reticulum takes up the increase in Ca 2+ resulting in an increase in myocardial contractility, or the force with which the heart contracts.  In addition, there is an increase in vagal activity which slows down the heart.  Excess levels of cardiac glycosides can lead to bradycardia, or an unusually slow heart beat.

ABSORPTION PATHWAYS

 Lily of the Valley toxicity occurs via ingestion.  All parts of the plant are toxic and edible.  Human ingestion is more common in children than adults.

SYMPTOMS

 Nausea

 Arrhythmias

 Vomiting

 Hyperkalemia

 Headache

 Seizures (more common in dog/cat toxicity)

 Sinus bradycardia  Hypotension

 Death from cardiac arrest (rare)

TREATMENT

 Activated charcoal can be used to induce vomiting.  Electrocardiograms are used to monitor heart activity.

 Lidocaine and atropine can be delivered intravenously to reverse bradycardia and hypotension.  Digoxin Immune Fab, an antidote for the overdose of digitalis, may be used in severe cases.  Digoxin Immune Fab binds cardiac glycosides enabling them to be excreted by the kidneys.

TOXICITY PREVALENCE IN HUMANS  Although Lily of the Valley contains at least 30 cardiac glycosides and every part of the plant is toxic, significant human toxicity is rarely reported.  A ten year analysis of TESS exposures to Lily of the Valley found 2,639 reported cases of toxicity with only 3 patients suffering serious outcomes.  93% of these cases occurred in children younger than 6.

 Human toxicity is rare due to the need to ingest the plant and the amount required to produce severe adverse effects.  French poison control centers consider the ingestion of 5 bays or 2 leaves and stems severe.

 There are currently no reported cases of intentional Lily of the Valley poisoning.

TOXICITY PREVALENCE IN PETS  From 2002-2006, the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center reported 11 cases of C. majalis poisoning.  Because Lily of the Valley is commonly planted as garden ground cover, pets may have an increased risk of exposure to the plant.

FUTURE RESEARCH

HOMEOPATHY  Homeopathy is a form of alternative medicine based on the idea that “like cures like”.  Use of homeopathic remedies has been on the rise within the past couple of years.  Homeopathic remedies are not evaluated by the FDA for safety or effectiveness.  Homeopathic use of C. majalis could potentially lead to adverse side effects due to lack of regulation and information regarding the drug ’s safety.

HOMEOPATHIC USE OF LILY OF THE VALLEY

Some homeopathic retailers make bold claims such as “no side effects”.

CARDIAC GLYCOSIDES AND CANCER THERAPY  Cardiac glycosides appear to be antineoplastic, meaning they have the ability to inhibit the maturation and spread of malignant cancer cells.  Although the mechanism is not fully understood, cardiac glycosides are thought to increase the immunogenicity of dying cancer cells by inhibiting the Na + /K + -ATPase pump.  Clinical trials are currently being conducted to evaluate the effectiveness of cardiac glycoside use in conjunction with conventional chemotherapeutic regimens to treat cancer.  Although these current trials are using digoxin as their experimental cardiac glycoside, we believe researchers should include any of the 30+ available cardiac glycosides from Lily of the Valley as they could also have antineoplastic effects.

POTENTIAL THERAPEUTIC USES FOR ALL LILY OF THE VALLEY COMPOUNDS  While the toxic and therapeutic effects have been studied for the major compounds found in Lily of the Valley, convallatoxin and convallamarin, there is currently very little research into the other 30+ cardiac glycosides found in C. majalis.  Some of these cardiac glycosides may prove to be more efficient than current drugs like digoxin in treating heart irregularities.  We propose further studies should be conducted using in vivo animal testing to test the effectiveness of the many cardiac glycosides isolated from C. majalis in treating heart irregularities and possibly cancer.

CONCLUSION

LILY OF THE VALLEY  Lily of the Valley can produce toxic effects if ingested due to the numerous cardiac glycosides present.  Cardiac glycosides inhibit the Na + /K + -ATPase pump affecting heart rate.  The cardiac glycosides found in Lily of the Valley may prove to be effective treatments for cancer.  Further studies should be conducted in order to evaluate the adverse and therapeutic effects of all 30+ cardiac glycosides isolated from C. majalis.

USE OF LILY OF THE VALLEY AS A POISON  Although the show Breaking Bad shows Lily of the Valley being used as a poison, there are currently no reported intentional real life C. majalis poisonings.  Potential copycat cases may arise following the exposure received on Breaking Bad.

 Health professionals should be aware of the signs of C. majalis poisoning.

RESOURCES 1 . A l exa n d r e , J. , F o u c a u l t , A . , C o u ta n c e , G . , S c a n u , P. , a n d M i l l i e z , P. 2 0 1 2 . D i g i ta l i s i n tox i c a t i o n i n d u c e d b y a n a c u te a c c i d e n ta l p o i s o n i n g b y L i l y o f t h e Va l l e y. C i r c u l a t i o n . Vo l . 125: 1053-1055. 2 . At k i n s o n , K . J. , F i n e , D. M . , Eva n s , T. J. , a n d K h a n , S . 2 0 0 8 . S u s p e c t e d l i l y - o f - t h e - v a l l e y ( C o nva l l a r i a m a j a l i s ) tox i c o s i s i n a d o g ) . J o u r n a l o f Ve te r i n a r y E m e r g e n c y a n d C r i t i c a l C a r e . Vo l . 18, No 4: 388-403. 3 . B l a c k , M . R . , a n d J u d z i e w i e z , E . J. 2 0 0 9 . L i l y - o f - t h e - Va l l e y. I n W i l d f l ow e r s o f W i s c o n s i n a n d t h e G r e a t L a ke s Re g i o n , 2 n d e d i t i o n . p p . 3 4 . M a d i s o n : T h e U n i v e rs i t y o f W i s c o n s i n P r e s s . 4 . C o nva l l a r i a m a j a l i s . 2 0 1 3 . Re t r i e v e d o n M a rc h 3 0 , 2 0 1 3 f ro m < h tt p : / / w w w. r x h o m e o . c o m / p h a r m a c y / h o m e o p a t h i c . p h p ? a c t = v i e w P r o d & p ro d u c t I d = 2 5 4 & p N a m e = C o nva l l a r i a + M a j a l i s > . 5 . C o nva l l a r i a m a j a l i s L . 2 0 1 3 . Re t r i e v e d o n M a rc h 3 1 , 2 0 1 3 f ro m < h tt p : / / p l a n t s . u s d a . g o v / j a v a / p r o f i l e ? sy m b o l = C O M A 7 > . 6 . C o nva l l a t ox i n . 2 0 1 3 . Re t r e i v e d o n A p r i l 9 , 2 0 1 3 f ro m < h tt p : / / w w w. l o o kc h e m . c o m / C O N VA L L ATOX I N / > . 7 . D a n i e l , M . 2 0 0 6 . C o nva l l a r i a m a j a l i s L i n n . ( L i l l i a c a a e ) . I n M e d i c i n a l P l a n t s : C h e m i s t r y a n d Properties. pp. 129 Enfield: Science Publishers. 8 . D r u m m o n d , E . 1 8 8 3 . H i sto r i c a l n o te o n c o nva l l a r i a m a j a l i s . B M J . Vo l . 2 , N o 1 1 9 4 : 9 7 0 .

RESOURCES 9 . E d g e r t o n , P. H . 1 9 8 9 . S y m p t o m s o f d i g i t a l i s - l i ke t o x i c i t y i n a f a m i l y a f t e r a c c i d e n t a l i n g e s t i o n o f l i l y o f t h e v a l l e y p l a n t . J o u r n a l o f E m e r g e n c y N u r s i n g . Vo . 1 5 , N o 3 : 2 2 0 - 2 2 3 . 1 0 . F i e s e r, L . F. , a n d J a c o b s e n , R . P. 1 9 3 7 . C o v a l l a t o x i n . J . A m . C h e m . S o c . Vo l . 5 9 , N o 1 1 : 2 3 3 5 - 2 3 3 9 . 1 1 . H o m e o p a t h y : A n i n t ro d u c t i o n . 2 0 1 2 . R e t r i e v e d o n M a r c h 2 8 , 2 0 1 3 f r o m . 1 2 . K o p p , B . , a n d K u b e l k a , W. 1 9 8 2 . N e w c a r d e n o l i d e s f r o m C o n v a l l a r i a m a j a l i s . P l a n t a M e d . Vo l . 4 5 , No 4: 195-202.

1 3 . L i l y o f t h e Va l l e y. 2 0 1 3 . R e t r i e v e d o n M a r c h 2 6 , 2 0 1 3 f r o m < h t t p : / / w w w. a s p c a . o r g / P e t c a r e / p o i s o n - c o n t ro l / P l a n t s / l i l y - o f - t h e - v a l l e y. a s p x > . 1 4 . L i l l y o f t h e Va l l e y. 2 0 1 3 . R e t r i e v e d o n A p r i l 9 , 2 0 1 3 f r o m < h t t p : / / w w w. f l o w e r f o r y o u . o r g / l i l y - o f t h e - va l l e y. h t m l > . 1 5 . M e l e r o , C . P. , M e d a r d e , M . , a n d F e l i c i a n o , A . S . 2 0 0 0 . A s h o r t r e v i e w o n c a r d i o t o n i c s t e r o i d s a n d t h e i r a m i n o g u a n i d i n e a n a l o g u e s . M o l e c u l e s . Vo l . 5 , N o 1 : 5 1 - 8 1 .

1 6 . M e n g e r, L . , Va c c h e l l i , E . , K e p p , O . , E g g e r m o n t , A . , Ta r t o u r, E . , Z i t v o g e l , L . , K r o e m e r, G . , a n d G a l l u z z i , L . 2 0 1 3 . C a r d i a c G l y c o s i d e s a n d C a n c e r T h e r a p y. O n c o i m m u n o l o g y . Vo l . 2 , N o 2 , e 2 3 0 8 2 : 1 - 7 . 1 7 . S m o l i n s ke , S . C . , D a u b e r t , G . P. , a n d S p o e r ke , D . G . 2 0 0 7 . P o i s o n o u s P l a n t s . I n H a d d a d a n d W i n c h e s t e r ' s C l i n i c a l M a n a g e m e n t o f P o i s o n i n g a n d D r u g O v e r d o s e , 4 th e d i t i o n . p p 4 7 3 - 5 0 6 . P h i l a d e l p h i a : S a u n d e r s E l S e v i e r.