Mayapple

The American Indians and colonists used podophyllum resin as a cathartic and anthelmintic, an antidote for snake bite, and as a poison.(Kelly 1954) The first report in medical literature was in 1731 by Catesby in the Natural History of Carolina, Florida, and the Bahama Islands. By the mid 19th century, topical use of podophyllin to treat malignant growths was recognized. By the beginning of the 20th century, podophyllum was a common ingredient in many proprietary medicines, including Carter's Little Liver Pills.(Conroy 1942, Schacter 1996) Anticancer activity has been associated with podophyllum resin; derivatives have been used successfully in controlled clinical trials. In 1942, a podophyllum 25% preparation formulated with mineral oil for the short-term topical treatment of condylomas demonstrated efficacy and was regarded as a therapeutic breakthrough at the time.(Longstaff 2001)

Chemistry

Podophyllum resin contains at least 16 active compounds, including podophyllotoxin, picropodophyllin, podophyllic acid, alpha- and beta-peltatins, and quercetin.(Longstaff 2001, Nantel 1997) It also contains significant quantities of the 2 flavonoids quercetin and kampherol, which comprise about 3% and 6% of the dry weight of podophyllum, respectively.(Longstaff 2001) Resin yield from the rhizomes of P. emodi is greater than from P. peltatum (approximately 12% and 3 to 6%, respectively). The podophyllotoxin structure is closely related to the aryltetralin lactone lignans that have antineoplastic and antiviral activity.(Ardalani 2017) The most studied lignan, podophyllotoxin, and its semisynthetic derivatives (etoposide, teniposide, etoposide phosphate), are of particular interest due to their cytotoxic properties. Demand for the natural podophyllotoxin needed for production of semisynthetic derivatives tends to outstrip the supply. As a result, overexploitation of Indian P. emodi Wall (P. hexandrum Royle) has resulted in listing of the species as endangered, with alternative sources being sought. Laboratory synthesis is possible, but because of the highly unusual stereochemical features of the molecule, the process is challenging and not economically viable.(Damayanthi 1998, Lamblin 2008) An aqueous extraction technique has been developed for the leaves of P. peltatum; podophyllotoxin yields of 5.2% have been achieved.(Canel 2001) Podophyllotoxin and alpha-peltatin content in the leaves is inversely proportional, indicating that the selection and cultivation of a high-yielding podophyllotoxin leaf biomass may be possible.(Moraes 2002) Cell cultures established from Podophyllum or Linum species may offer other possible sources of podophyllotoxin.(Peterson 2001)

Uses and Pharmacology

A variety of pharmacologically active lignans are present in podophyllum. These lignans (podophyllotoxin being the most well known) act as antimitotic agents.(Longstaff 2001) Similar to colchicine and vinblastine, podophyllotoxin binds to tubulin, the protein subunit of the spindle microtubules, blocking cell division in metaphase. The activity of cytochrome oxidase and succinoxidase in the mitochondria is also reduced, and DNA synthesis is blocked. This results in the slowing of cell disruption and tissue destruction.(Chang 1992, Nantel 1997) Podophyllotoxin also has an inhibitory effect on the release of iodine from the thyroid gland and catecholamine from the adrenal medulla.(Nantel 1997) A variety of pharmacologically active lignans are present in podophyllum. These lignans (podophyllotoxin being the most well known) act as antimitotic agents.(Longstaff 2001) Similar to colchicine and vinblastine, podophyllotoxin binds to tubulin, the protein subunit of the spindle microtubules, blocking cell division in metaphase. The activity of cytochrome oxidase and succinoxidase in the mitochondria is also reduced, and DNA synthesis is blocked. This results in the slowing of cell disruption and tissue destruction.(Chang 1992, Nantel 1997) Podophyllotoxin also has an inhibitory effect on the release of iodine from the thyroid gland and catecholamine from the adrenal medulla.(Nantel 1997)

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.(Cassidy 1982)

Antiviral activity

In vitro data

In vitro studies show podophyllotoxin inhibits the replication of measles, herpes simplex virus type 1, and murine cytomegalovirus.(Barnard 2004, Damayanthi 1998, Hammonds 1996)

Cancer

The severe toxicity of podophyllotoxin limits its use as a cytostatic; however, research into semisynthetic podophyllotoxin prescription pharmaceutical agents is ongoing.(Damayanthi 1998, Lamblin 2008)

In vitro data

Several components of podophyllum, including alpha- and beta-peltatins, podophyllotoxin, and its derivatives, have tumor-inhibiting properties.(Damayanthi 1998, Lamblin 2008)

Cathartic

The use of podophyllum as a laxative under any circumstances is considered unsafe by the US Food and Drug Administration (FDA)(Longstaff 2001); podophyllum has been superseded by less toxic laxatives. 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 found in mayapple.(Morton 1977)

Hairy leukoplakia

Clinical data

In a small study (N=10), a single application of a topical podophyllum 25% resin produced short-term resolution of HIV-related, hairy leukoplakia of the tongue. The reported adverse effects included burning sensation, unpleasant or altered taste, and pain. These occurred immediately after the application, were of mild to moderate intensity, and disappeared within approximately 1 hour.(Gowdey 1995)

Insecticidal activity

Experimental data

A podophyllotoxin-rich dichloromethane extract of P. hexandrum showed insecticidal activity against larvae of Drosophila melanogaster Meigen. A diet containing 2 mcmol/mL of extract killed 100% of larvae; the LC₅₀ was 0.24 mcmol/mL. Insecticidal activity of podophyllotoxins and congeners against Blattella germanica, Epilachna sparsa orientalis, and Plutella xylostella has also been reported.(Miyazawa 1999) Also a study to explore natural product–based insecticide candidates supported the potential insecticidal activity of mayapple in agriculture.(Zhang 2021)

Psoriasis

Podophyllotoxin may be a candidate for the treatment of psoriasis due to inhibition of the release of cytokines (eg, interleukin 1, tumor necrosis factor alpha); however, the mode of delivery is crucial and requires further studies.(Singh 2018)

Clinical data

A review of toxic plants used in dermatology mentions a 16-week, double-blind study in patients with stable psoriasis vulgaris (N=152), in which podophyllotoxin was applied once daily at 3 different concentrations (0.1%, 0.25%, and 0.5%). All 3 concentration induced a statistically significant improvement of selected lesions (P<0.001). A statistically significant difference from control lesions was observed after 2 weeks of treatment (P>0.001) and continued to increase during the study course.(Singh 2018)

Rheumatoid arthritis

Clinical data

CPH 82 is a semisynthetic lignan glycoside derivative of P. emodi and has been used successfully in the treatment of rheumatoid arthritis (RA), with superior efficacy to placebo as well as tolerability advantages over methotrexate demonstrated.(CPH 2003, Larsen 1989)

Double-blind studies (N=500) have demonstrated that CPH 82 is clinically more effective than placebo, sulfasalazine, azathioprine, and auranofin. CPH-82 appears to be effective in treating RA, but is not superior to methotrexate.(Singh 2018)

Warts

Topical application of podophyllum 20% to 25% resin in ethanol or benzoin tincture is a well-established, affordable, and effective remedy for genital warts.(Longstaff 2001) 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.(Nantel 1997) However, continued 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 require professional application and must be washed off after 1 to 4 hours. The use of podophyllotoxin, the less toxic, biologically active component of podophyllum, is considered safer. Compared with crude podophyllum preparations, podophyllotoxin 0.5% is associated with superior rates of cure, lower recurrence rates, and fewer adverse effects.(Lacey 2003, Longstaff 2001) 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 the economic advantages of podophyllotoxin.(Lacey 2003)

Clinical data

A review of toxic plants used in dermatology mentions a study of patients with Condyloma acuminata lesions (N=200), in which a podophyllin 25% suspension (in mineral oil) eradicated genital warts in all patients, with most lesions disappearing within 4 days after one application. In another study in women with untreated vulvoperineal warts (N=134), 71.8% of women using a podophyllotoxin 0.5% solution reported complete resolution of lesions.(Singh 2018)

In a study in patients with C. acuminata (N=60), a combination of cryotherapy followed by application of a podophyllin 25% solution was more effective than cryotherapy alone in shortening the required treatment regimen.(Sharma 2017) According to a meta-analysis of 9 randomized controlled trials, podophyllotoxin 0.5% caused complete clearance of genital warts in approximately 56% of patients. Burning sensation, pain, pruritus, and inflammation might occur at the site of application.(Maleš 2019)

Dosing

Toxicity precludes home use of podophyllum, a resin derived from P. peltatum and P. hexandrum; products for oral use have been withdrawn from the market for various 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 cm² and a volume of 0.5 mL per treatment session for genital and perianal warts.(Workowski 2021) A meta-analysis evaluated use of podophyllotoxin 0.5% in 9 randomized controlled trials of patients with genital warts.(Maleš 2019)

Pregnancy / Lactation

While data are lacking and some study findings suggest a lack of adverse fetal outcomes with local podophyllotoxin, pregnancy is a contraindication to use of podophyllum.(Andersson 2020, Moher 1979) Podophyllum has shown teratogenicity in animals and humans. In mice, podophyllum produced a high frequency of fetal mortality following single doses of 5 to 15 mg/kg.(Longstaff 2001) Adverse effects reported during pregnancy are largely from isolated case reports and have included fetal anomalies such as limb malformations and septal heart defects. Preauricular skin tags and a simian crease were noted in an infant born to a woman treated with topical podophyllum resin from weeks 23 to 29 of pregnancy; Total contact with the drug was just 4 hours.(Karol 1980, Singh 2022) An intrauterine death has been reported in a woman treated with podophyllum for vulvar warts during week 32 of pregnancy.(Chamberlain 1972) Excretion into breast milk and effects on breastfeeding infants are unknown; use during breastfeeding should be avoided.

Interactions

None well documented.

Adverse Reactions

Chronic use of podophyllum resin as a cathartic has resulted in hypokalemia, sometimes associated with metabolic alkalosis.(Ramirez 1970) 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.(Gowdey 1995)

Toxicology

Podophyllum is caustic, with a slow and indirect action resulting from cell division arrest and impairment of other cellular processes.(Nantel 1997) Human poisoning may result from topical application or ingestion and may be acute or chronic. Rarely does poisoning result from the 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(But 1996) or through inadvertent ingestion in place of the anticholinergic and hallucinatory plant Mandragora officinarum, also known as mandrake.(Ramirez 1970) At least 3 deaths have been attributed to podophyllum poisoning.(Balucani 1964, Ward 1954)

Neurologic manifestations are a hallmark of podophyllum toxicity. In experimental and animal studies, overexposure caused neuronal swelling, disintegration of Nissl bodies of the dorsal root ganglion neurons, and thickening of the axons.(Chang 1992) Toxic effects on the intestine, liver, pancreas, and testes were also apparent.(Chang 1992)

In an investigation of poisonings in a Hong Kong population, ingestion of podophyllum 2 to 8 g resulted in toxicity, with initial symptoms of serious vomiting and diarrhea. Neuropathy occurred 1 to 2 days later, and patients complained of numbness in the limbs and difficulty walking. Clinical findings included the absence of reflex jerks, reduced plantar responses, lack of coordination, ataxic and unsteady gait, poor standing balance, and impaired proprioception and vibration sense.(But 1996) Tachypnea, hypotension, and fever also may be present. Muscle paralysis with respiratory failure, renal failure, hallucinations, and seizures have been reported. Death generally results from cerebral, cardiovascular, renal, or hematologic complications.(Nantel 1997) Two case reports exist of neuropathy and encephalopathy following consumption of gwai-kou (derived from the roots and rhizomes of P. hexandrum) as an adulterant (high dose of podophyllin [probably greater than 20 g]); encephalopathy was present for 5 months after ingestion.(But 1996)

No specific antidote is known; emesis may be useful during the initial phases of toxicity.(McFarland 1981) Podophyllum is lipid soluble; hemodialysis is ineffective but charcoal hemoperfusion has reversed acute symptoms within hours.(Slater 1978)

Mayapple has been implicated in a generalized toxicity marked by nausea, abdominal pain, bone marrow suppression, confusion, and accompanying liver injury. The podophyllum glycosides are directly toxic to cells. However, hepatotoxicity from the plant is usually mild and greatly overshadowed by its GI, bone marrow, and neurologic toxicity.(LiverTox 2017)

Index Terms

• Podophyllum emodi Wall

References

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