Mayapple

Scientific Name(s): Podophyllum peltatum L., P. hexandrum Royle, synonym P. emodi Wall. Family: Berberidaceae 1

Common Name(s): Mayapple , mandrake , American podophyllum ( P. peltatum ) , Indian podophyllum ( P. hexandrum ) . Other common names include wild or American mandrake , devil's apple , vegetable mercury , duck's foot , racoonberry , 2 hog apple , 2 bajiaolian , 3 and gwai-kou . 4 The plant should not be confused with the European mandrake ( Mandragora officinarum L), which contains the anticholinergics hyoscamine, scopolamine, and mandragorine.

Uses

Podophyllum has been used topically in the treatment of genital warts and hairy leukoplakia. Semisynthetic derivatives of podophyllotoxin are used to treat RA and various cancers, including refractory testicular tumors and small-cell lung cancer; however, limited information is available. Use as a cathartic is considered unsafe.

Dosing

The risk of toxicity is too high to recommend home use. Classical use of mayapple resin as a purgative used 10 mg doses. As a caustic for papillomas, a 20% suspension in petrolatum has been used. Pure podophyllotoxin was formulated at 0.5% to 2% in a recent clinical trial for treatment of penile warts.

Contraindications

The use of mayapple in pregnancy is contraindicated.

Pregnancy/Lactation

Birth defects, fetal death, and stillbirth have been associated with the use of podophyllum in pregnant patients. Pregnant patients or patients planning to become pregnant should avoid use of this product. Excretion into breast milk is unknown. Avoid use in nursing patients.

Interactions

None well documented.

Adverse Reactions

Chronic use of mayapple as a cathartic has been associated with hypokalemia and metabolic acidosis. Topical application may cause skin irritation and chemical burns. Application to the inside of the mouth may cause transient burning, unpleasant taste, and pain.

Toxicology

Fatalities have occurred following ingestion or topical application of podophyllum. Clinical signs appear within 12 hours and include altered mental states, tachypnea, peripheral neuropathy, nausea, hypotension, vomiting, and fever. Muscle paralysis with respiratory failure, renal failure, hallucinations, and seizures has been reported.

Botany

P. peltatum is an herbaceous perennial found in damp, open woodlands and wet meadows in Canada and the eastern United States. 2 The plant grows to 0.3 to 0.6 m in height with a single stalk and 1 or 2 broad, deeply divided, shiny leaves about the size of a hand. Plants with 2 leaves bear a single, pendulous, small white flower in May (hence, the name Mayapple); the odor has been described as “nauseous”. 2 The fruit, which ripens in midsummer, is about 2.5 to 5 cm in length and is pulpy, lemon-yellow, and berry-like. It is the only edible part of the plant; all other parts are considered poisonous. The root is composed of many thick tubers and is the main source of podophyllotoxin, the active principle. 2 P. hexandrum is found in Tibet, Afghanistan, 5 and northern India. The roots are stouter and knottier than P. peltatum and contain about twice as much podophyllotoxin. 2 The Latin name is derived from podos (a foot) and phyllon (a leaf), alluding to a resemblance in the palmate leaf to the webbed foot of an aquatic bird. One of the popular names for the plant is duck's foot. 2

History

The American Indians and colonists used podophyllum resin as a cathartic and anthelmintic, an antidote for snakebites, and a poison. 6 Podophyllum was included in the 1864 British Pharmacopoeia 2 and was a common ingredient in many proprietary medicines including Carter's Little Liver Pills . 5 Anticancer activity has been associated with podophyllum resin; derivatives have been used successfully in controlled clinical trials. In 1942, a study was published that demonstrated the efficacy of a 25% topical application of podophyllum in mineral oil for the short-term treatment of condylomas. This was regarded as a therapeutic breakthrough at the time. 7

Chemistry

Podophyllum resin contains at least 16 active compounds, including podophyllotoxin, picropodophyllin, podophyllic acid, α- and β-peltatins, and quercetin. 7 , 8 It also contains significant quantities of 2 flavonoids, quercetin and kampherol, which comprise about 3% and 6% of the dry weight of podophyllum, respectively. 7 Resin yield from the rhizomes of P. emodi is greater than from P. peltatum (approximately 12% and 3% to 6%, respectively). Demand for podophyllotoxin for production of semisynthetic derivatives outstrips the supply. As overexploitation of Indian P. emodi Wall ( P. hexandrum Royle) has resulted in the listing of the species as endangered, alternative sources are being sought. Laboratory synthesis is possible, but because of the highly unusual stereochemical features of the molecule, the process is challenging and is not viable economically. 9 An aqueous extraction technique has been developed for use on the leaves of P. peltatum ; podophyllotoxin yields of 5.2% have been achieved. 10 Podophyllotoxin and α-peltatin content in the leaves is inversely proportional, indicating that selection and cultivation of high-yielding podophyllotoxin leaf biomass may be possible. 11 Cell cultures established from species of Podophyllum or Linum may offer another source of podophyllotoxin. 12

Uses and Pharmacology

A variety of pharmacologically active lignans are present in podophyllum. These lignans (podophyllotoxin being the best known) act as antimitotic agents, with the greatest effects in tissues undergoing rapid cell division. 7 Like colchicine and vinblastine, podophyllotoxin binds to tubulin, the protein subunit of the spindle microtubules, blocking cell division in metaphase. Activity of cytochrome oxidase and succinoxidase in the mitochondria also is reduced, and DNA synthesis is blocked. This results in the slow disruption of cells and the destruction of tissue. 3 , 8 Podophyllum is highly lipid soluble and is absorbed readily from the GI tract. Topical administration to large areas also can result in absorption. Little is known about the distribution of the active compounds. A podophyllic acid preparation was eliminated predominantly in the urine with a half-life of 30 minutes; podophyllotoxin is eliminated in the bile with a half-life of 48 hours. 13

Cathartic

Podophyllum resin is a drastic cathartic. It has a marked purging action, is highly irritant to the intestinal mucosa, and produces violent peristalsis. It is suspected that these effects are caused by colonic irritation attributable to the peltatins. 14 Use of podophyllum as a laxative under any circumstances is considered to be unsafe by the FDA; 7 podophyllum has been superseded by less toxic laxatives.

Wart eradication
Animal data

Research reveals no animal data regarding the use of mayapple for warts.

Clinical data

Topical application of 20% to 25% podophyllum resin in ethanol or benzoin tincture is a well-established, affordable, and effective remedy for genital warts. 7 Lesions become blanched within a few hours of application and necrotic within 24 to 48 hours. After approximately 72 hours, the lesions begin to slough and disappear gradually without scarring. 8 However, use carries a high risk of severe adverse effects, including acute toxicity from absorption through the skin and mucous membranes, chemical burns, and painful ulceration. Therefore, preparations should be applied only by trained staff and must be washed off after 1 to 4 hours. Use of podophyllotoxin, the less toxic, biologically active component of podophyllum, is considered to be safer. Compared with crude podophyllum preparations, podophyllotoxin 0.5% has superior rates of cure, lower recurrence rates, and fewer adverse effects. 7 , 15 Podophyllotoxin is regarded as sufficiently safe for unsupervised application by the patient and does not need to be washed off. Although acquisition costs are higher for podophyllotoxin than for crude podophyllum preparations, a large multicenter British trial has demonstrated economic advantages for podophyllotoxin. 15

Hairy leukoplakia
Animal data

Research reveals no animal data regarding the use of podophyllin for hairy leukoplakia.

Clinical data

A single application of 25% podophyllum resin produced significant short-term resolution of HIV-related, oral hairy leukoplakia in a small study. Reported adverse effects included burning sensation, unpleasant or altered taste, and pain. These occurred immediately after application, were of mild to moderate intensity, and disappeared within approximately 1 hour. 16

Antitumor

Several components of podophyllum, including α- and β-peltatins, podophyllotoxin, and its derivatives, have tumor-inhibiting properties. The severe toxicity of podophyllotoxin limits its use as a cytostatic; however, research into semisynthetic podophyllotoxin congeners is ongoing, and numerous highly potent, less toxic analogs have been found. These analogs do not inhibit tubulin microassembly; instead, they arrest cell growth by inhibiting DNA topoisomerase ΙΙ, thus causing double strand breaks in the DNA. 9

Animal data

Research reveals no animal data regarding the use of podophyllin as a cytostatic.

Clinical data

Several semisynthetic analogs have been investigated clinically. 17 Teniposide and etoposide are active orally and parenterally. 18 Etoposide ( VP-16 , VePesid by Bristol-Myers Oncology ) is a first-line treatment for small-cell lung cancer and a treatment for refractory testicular tumors. 19 , 20 A strong disadvantage of etoposide is its insolubility in water. Etoposide phosphate, a prodrug, is water soluble and converts rapidly to etoposide by endogenous phosphatases. 9 Teniposide, another derivative, is used in the management of patients with acute lymphoblastic leukemia; it also has been used for a variety of lymphomas and other neoplastic diseases. 20

Rheumatoid arthritis (RA)

CPH 82 ( Rheumacon by Meda , Sweden), a semisynthetic lignan glycoside derivative of podophyllum, has been used in the treatment of RA.

Animal data

Research reveals no animal data regarding the use of podophyllum in RA.

Clinical data

Superior efficacy to placebo and tolerability advantages over methotrexate have been demonstrated. 21 , 22

Other uses

Podophyllotoxin inhibits replication of measles and herpes simplex type-1 virus and murine cytomegalovirus. 9 It also has an inhibitory effect on the release of iodine from the thyroid gland and catecholamine from the adrenal medulla. 8 A podophyllotoxin-rich dichloromethane extract of P. hexandrum has insecticidal activity against larvae of Drosophila melanogaster Meigen. A diet containing 2 mcmL of extract killed 100% of larvae; the LC 50 was 0.24 mcmL. Insecticidal activity of podophyllotoxins and congeners against Blattella germanica , Epilachna sparsa orientalis, and Plutella xylostella also has been reported. 23

Dosage

Podophyllum is too toxic for home use and products for oral use have been withdrawn from the market for safety reasons. Topical preparations of podophyllum require professional application and must be rinsed off after 1 to 4 hours. The Centers for Disease Control and Prevention (CDC) recommends use of a 10% to 25% solution in benzoin tincture with a maximum exposure of less than 10 cm 2 and a volume of 0.5 mL per treatment session for genital and perianal warts. 7

Classical use of mayapple resin as a purgative used 10 mg doses. As a caustic for papillomas, a 20% suspension in petrolatum has been used. Pure podophyllotoxin was formulated at 0.5% to 2% in a recent clinical trial for treatment of penile warts. 24

Pregnancy/Lactation

The use of podophyllum is contraindicated in pregnancy. 20 Podophyllum is teratogenic in animals and humans and has been used to terminate pregnancy. 7 Limb deformities and septal heart defects have been associated with its ingestion by pregnant women. 25 Preauricular skin tags and a simian crease were noted in an infant born to a woman treated with topical podophyllum resin from the 23rd to 29th week of pregnancy. Total contact with the drug was 4 hours. 26 An intrauterine death has been reported in a woman treated with podophyllum for vulvar warts during week 32 of her pregnancy. 27 In mice, podophyllum produced a high frequency of fetal mortality following single doses of 5 to 15 mg/kg. 7 Excretion into breast milk is unknown. Avoid use in nursing patients. 20

Interactions

None well documented.

Adverse Reactions

Chronic use of podophyllum resin as a cathartic has resulted in hypokalemia sometimes associated with metabolic alkalosis. 28 Topical application may cause skin irritation and chemical burns. Application to the inside of the mouth in the treatment of HIV-related hairy leukoplakia resulted in transient burning, unpleasant taste, and pain. 16

Toxicology

Podophyllum is caustic, with a slow and indirect action resulting from arrest of cell division and impairment of other cellular processes. 8 Human poisoning may result from topical application or ingestion and may be acute or chronic. Rarely does poisoning result from consumption of unripe fruit or other parts of the plant. Several cases of accidental poisoning have occurred following ingestion of Chinese herbal products adulterated with podophyllum 4 or through inadvertent ingestion in place of the anticholinergic and hallucinatory plant M. officinarum , also known as mandrake. 28 At least 3 deaths have been attributed to podophyllum poisoning. 30 , 31

Neurologic manifestations are a hallmark of podophyllum toxicity. Overexposure causes neuronal swelling, disintegration of Nissl bodies of the dorsal root ganglion neurons, and thickening of the axons. 3 Toxic effects on the intestine, liver, pancreas, and testes are also apparent. 32 Serious vomiting and diarrhea are the initial symptoms in patients with mild toxicity (2 to 8 g podophyllum). Neuropathy becomes apparent 1 to 2 days later, and patients may complain of numbness of the limbs and difficulty in walking. Clinical findings include absence of jerks, reduced plantar responses, lack of coordination, ataxic and unsteady gait, poor standing balance, and impaired proprioception and vibration sense. 4 Tachypnea, hypotension, and fever also may be present. Muscle paralysis with respiratory failure, renal failure, hallucinations, and seizures has been reported. Death generally results from the cerebral, cardiovascular, renal, or hematologic complications. 8 Bone marrow suppression has been noted in acute intoxication and in chronic laxative abusers. Sensory responses and motor coordination may return fully or partially over several months. Encephalopathy was present 5 months after ingestion of a high dose of podophyllin (probably greater than 20 g) in 2 patients. 5

No specific antidote is known; emesis may be useful during the initial phases of toxicity. 33 Podophyllum is lipid soluble; hemodialysis is ineffective, but charcoal hemoperfusion has reversed acute symptoms within hours. 34 Topically administered resin should be removed with petroleum jelly. If eye contact occurs, flush with copious amounts of warm water and consult a physician or poison center immediately. 20

Bibliography

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