Molly Benning Dawn AndersonAlisa Vil larreal

LILY OF THE VALLEY

INTRODUCTION

A toxin is a substance produced by an organism that has an adverse eff ect on other organisms.

Any substance can be toxic depending on the dose. Dose determines effect.

Plants produce secondary metabolites as a defense mechanism.

WHAT IS A TOXIN?

We chose to research Lily of the Valley aft er 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 therapeuti c benefi ts associated with this plant.

LILY OF THE VALLEY

Convallaria majalis , commonly known as Lily of the Valley, is a perennial plant that forms rhizomes.

It forms white, bell-shaped fl owers 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 DESCRIPTION

Convallaria majalis is nati ve 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.

LILY OF THE VALLEY DISTRIBUTION

Introduced Native

HISTORY

Lily of the Valley is also known as “Our Lady ’s tears”.

According to Christi an legend, when Mary cried at the crucifi xion of Jesus, her tears turned into Lily of the Valley.

Other lore states Lily of the Valley was created when Eve cried aft er she and Adam were banished from the Garden of Eden.

CHRISTIAN LEGEND

In the 17 t h century, Germans added Lily of the Valley to old wine as a remedy for palpitati on, verti go, epilepsy, apoplexy as well as a general “cure all”.

This concocti on was stored in gold and silver vessels.

This concocti on was known as aqua aurea, or “golden water ”.

GOLDEN WATER

Lily of the Valley has been used traditi onally as a diureti c 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 pharmaceuti cally produced.

MEDICINAL USES

Convallaria majalis Digitalis lanata

C. majalis was never used as a clinical treatment for irregular heart functi on due to its narrow margin of safety.

A narrow safety margin drug is a drug whose adverse eff ect curve and therapeuti c eff ects curve are very close. Therapeutic index = AE50/TE50

Narrow safety margin drugs have a therapeutic index of 2.

Narrow safety margin drugs, l iked digoxin, are used when there is no other eff ecti ve treatment.

NARROW SAFETY MARGIN DRUGS

TOXICITY

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.

CARDIAC GLYCOSIDES

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.

CONVALLATOXIN

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

There is currently litt le research on this compound and no determined LD50.

CONVALLAMARIN

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-rhamnosideStrophanthidin-3-O-6'-deoxy-beta-D-allosido-alpha-L-arabinosideStrophanthidin-3-O-alpha-L-rhamnosido-2'-beta-D-glucosideCannogenol-3-O-6'-deoxy-beta-D-allosido-beta-D-glucosideCannogenol-3-O-6'-deoxy-beta-D-allosido-alpha-L-rhamnoside19-hydroxy-sarmentogenin-3-O-alpha-L-rhamnosideSarmentogenin-3-O-6'-deoxy-beta-D-allosido-alpha-L-rhamnosideSarmentogenin-3-O-6'-deoxy-beta-D-guloside

LESSER CARDIAC GLYCOSIDES

The numerous cardiac g lycosides found in L i ly of the Val ley have s imi lar mechanisms.

Cardiac g lycosides inhibit the trans membrane Na + /K + -ATPase pump.

This inhibiti on leads to an increase in concentrati on of Na + and Ca 2 + within the cel l .

The sarcoplasmic reti culum takes up the increase in Ca 2 + resulti ng in an increase in myocardial contracti l i ty, or the force with which the heart contracts .

In additi on, there is an increase in vagal acti vity which s lows down the heart .

Excess levels of cardiac g lycosides can lead to bradycardia, or an unusual ly s low heart beat .

MECHANISM OF ACTION

Lily of the Valley toxicity occurs via ingesti on.

All parts of the plant are toxic and edible.

Human ingesti on is more common in children than adults.

ABSORPTION PATHWAYS

Nausea

Vomiti ng

Headache

Sinus bradycardia

Hypotension

Arrhythmias

Hyperkalemia

Seizures (more common in dog/cat toxicity)

Death from cardiac arrest (rare)

SYMPTOMS

Acti vated charcoal can be used to induce vomiti ng.

Electrocardiograms are used to monitor heart acti vity.

Lidocaine and atropine can be delivered intravenously to reverse bradycardia and hypotension.

Digoxin Immune Fab, an anti dote 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.

TREATMENT

Although Lily of the Valley contains at least 30 cardiac glycosides and every part of the plant is toxic, signifi cant 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 pati ents suff ering 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 eff ects. French poison control centers consider the ingesti on of 5 bays or 2 leaves

and stems severe.

There are currently no reported cases of intenti onal Li ly of the Valley poisoning.

TOXICITY PREVALENCE IN HUMANS

From 2002-2006, the American Society for the Preventi on 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.

TOXICITY PREVALENCE IN PETS

FUTURE RESEARCH

Homeopathy is a form of alternati ve 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 eff ecti veness.

Homeopathic use of C. majalis could potenti ally lead to adverse

side eff ects due to lack of regulati on and informati on regarding the drug ’s safety.

HOMEOPATHY

HOMEOPATHIC USE OF LILY OF THE VALLEY

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

Cardiac glycosides appear to be anti neoplasti c, meaning they have the ability to inhibit the maturati on 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 inhibiti ng the Na +/K+-ATPase pump.

Clinical trials are currently being conducted to evaluate the eff ecti veness of cardiac glycoside use in conjuncti on with conventi onal chemotherapeuti c 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 anti neoplasti c eff ects.

CARDIAC GLYCOSIDES AND CANCER THERAPY

While the toxic and therapeuti c eff ects have been studied for the major compounds found in Lily of the Valley, convallatoxin and convallamarin, there is currently very litt le research into the other 30+ cardiac glycosides found in C. majalis .

Some of these cardiac glycosides may prove to be more effi cient than current drugs like digoxin in treati ng heart irregulariti es.

We propose further studies should be conducted using in vivo animal testi ng to test the eff ecti veness of the many cardiac glycosides isolated from C. majalis in treati ng heart irregulariti es and possibly cancer.

POTENTIAL THERAPEUTIC USES FOR ALL LILY OF THE VALLEY COMPOUNDS

CONCLUSION

Lily of the Valley can produce toxic eff ects if ingested due to the numerous cardiac glycosides present.

Cardiac glycosides inhibit the Na +/K+-ATPase pump aff ecti ng heart rate.

The cardiac glycosides found in Lily of the Valley may prove to be eff ecti ve treatments for cancer.

Further studies should be conducted in order to evaluate the adverse and therapeuti c eff ects of all 30+ cardiac glycosides isolated from C. majalis .

LILY OF THE VALLEY

Although the show Breaking Bad shows Lily of the Valley being used as a poison, there are currently no reported intenti onal real l ife C. majalis poisonings.

Potenti al copycat cases may arise following the exposure received on Breaking Bad.

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

USE OF LILY OF THE VALLEY AS A POISON

1 . A l exa n d re , J . , Fo 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 ez , P. 2 0 1 2 . D i g i ta l i s i ntox i c ati o n i n d u c e d b y a n a c u te a c c i d e nta 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 ti o n . Vo l . 1 2 5 : 1 0 5 3 - 1 0 5 5 .

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 te d l i l y- o f- t h e -va l l e y ( C onva 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 Em e r g e n c y a n d C r i ti ca l C a r e . Vo l . 1 8 , N o 4 : 3 8 8 - 4 0 3 .

3 . B l a c k , M . R . , a n d Ju d z i e w i ez , 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 fl ow e r s o f W i s co 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 ti o n . p p . 3 4 . M a d i s o n : T h e U n i ve rs i t y o f W i s c o n s i n P re 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 ve d o n M a rc h 3 0 , 2 0 1 3 f ro m < htt p : / / w w w. r x h o m e o . c o m / p h a r m a c y / h om e o p at h i c . p h p ?a c t = v i e w P ro 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 ve d o n M a rc h 3 1 , 2 0 1 3 f ro m < htt p : / / p l a nt s . u s d a . g o v / j ava / p rofi l e ? sy m b o l = CO M A 7 > .

6 . C o nva l l atox i n . 2 0 1 3 . Re t re i ve d o n A p r i l 9 , 2 0 1 3 f ro m < htt p : / / w w w. l o o kc h e m . c o m / CO 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 nt s : C h e m i s t r y a n d P r o p e r ti e s . p p . 1 2 9 E n fi e l d : S c i e n c e P u b l i s h e rs .

8 . D r u m m o n d , E . 1 8 8 3 . H i s to r i c a l n ote o n c onva 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 fa m i l y a ft e r a c c i d e n t a l i n g e s ti 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 ti o n . 2 0 1 2 . Re t r i e v e d o n M a rc h 2 8 , 2 0 1 3 f ro m < h tt p : / / n c c a m . n i h . g o v / h e a l t h / h o m e o p a t h y > .

1 2 . Ko p p , B . , a n d Ku b e l ka , W. 1 9 8 2 . N e w c a rd e n o l i d e s f ro 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 , N o 4 : 1 9 5 - 2 0 2 .

1 3 . L i l y o f t h e Va l l e y. 2 0 1 3 . Re 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 tt 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 r o 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 . Re t r i e v e d o n A p r i l 9 , 2 0 1 3 f ro m < h tt p : / / w w w.fl o w e r fo r y o u . o r g / l i l y - o f - t h e -v a l l e y. h t m l > .

1 5 . M e l e ro , C . P. , M e d a rd 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 rd i o t o n i c s t e ro 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 . , Ke 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 ro 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 ra 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 t h e d i ti 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 rs E l S e v i e r.

RESOURCES