Podophyllotoxin

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. 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 soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

IDENTIFICATION: Podophyllum is a dermatological medication. Origin of the substance: Dried resin from the roots and rhizomes of Podophyllum peltatum (Mandrake or May apple plant) the North American variety; active ingredients are lignans including podophyllotoxins (20%), alpha-peltatin (10%) and beta-peltatin (5%). It is a light brown to greenish yellow solid powder soluble in water, alcohol, chloroform, acetone, warm benzene and glacial acetic acid. Indications: Wart or corn removal preparation. Description: Podophyllum resin has an antimitotic action and is used principally as a topical treatment for ano-genital warts (condylomata acuminata). Podophyllum resin has been used on external genital, perianal and intrameatal warts, but should not be used on cervical or urethral warts. Care must be taken to avoid application to healthy tissue. Podophyllum resin is also used in an ointment for plantar warts. Podophyllum resin has been used as a laxative, but when taken by mouth, it has a marked purging action and it is highly irritating to the intestinal mucosa and produces violent peristalsis. It has been superseded by less toxic laxatives. HUMAN EXPOSURE: Main risk and target organs: Podophyllum resin's major active constituent, podophyllotoxin, is a lipid soluble compound that readily crosses cell membranes. Podophyllotoxin and its derivatives are potent cytotoxic agents that inhibit cell mitosis and deoxyribonucleic acid (DNA) synthesis in a manner similar to that of colchicine. Cell division is arrested and other cellular processes are impaired, gradually resulting in the disruption of cells and destruction of the tissue. Topical podophyllum is easily absorbed systemically and can cross the placenta. Either local application or oral ingestion may produce multisystem toxic effects. Summary of clinical effects: Features of systemic toxicity include nausea and vomiting (which may be persistent), tachypnea, fever, stupor, coma, tachycardia, hypotension, paralytic ileus, oliguria, renal failure, leukocytosis, leucopenia, peripheral neuropathy and death. Contraindications: Pregnancy: topical podophyllum is absorbed systemically and crosses the placental barrier. It has been associated with the induction of congenital malformations in humans. Routes of exposure: Oral: Easily absorbed even if it induces nausea and vomiting. Dermal: It is absorbed systemically after topical application especially if the skin surface is not intact. Eye: Very well absorbed through mucous membranes. Absorption by route of exposure: Oral absorption: Podophyllum is very well and rapidly absorbed after ingestion. In a fatal case, the patient ingested between 10 and 11 gm of a 25% podophyllum solution in benzoin tincture in the physician's office. He was immediately given syrup of Ipecac and vomited 45 minutes after ingestion. He was also given activated charcoal and magnesium citrate. He died 39 hours after ingestion despite hemoperfusion. Dermal absorption: There are several cases of systemic poisoning following topical application of podophyllum in the literature. In such cases, the onset of symptoms is delayed between two and 24 hours. Distribution by route of exposure: Since podophyllum toxin is water soluble, a small volume of distribution may be predicted. Furthermore, no rebound effects were observed after hemoperfusion. Metabolism: No data available. In a case report, podophyllum toxin in the patient's plasma before, during and after hemoperfusion was examined. A rapid fall in plasma concentration of podophyllum toxin occurred in the period before hemoperfusion was started suggesting rapid metabolism. The delay of onset of symptoms in several case reports may suggest that the metabolized of podophyllum toxin are more toxic than podophyllum toxin itself. This study measured a metabolite during hemoperfusion but several other possible metabolites were found on analysis and removed by hemoperfusion. Mode of action: Toxicodynamics: Podophyllum resin is a potent spindle poison that blocks mitosis metaphase in a manner similar to colchicine. Human poisoning results from either topical application or ingestion of the commercial extract. Overexposure causes neurological, gastrointestinal and hematological toxicity that occasionally results in fatalities. Rarely, poisoning results from consumption of unripe fruit or plant parts and causes primarily diarrhea. The ripe fruit does not produce toxicity. Podophyllum is a keratolytic agent with caustic and cathartic actions. Podophyllum is an antimitotic agent. It binds to tubulin, the protein subunit of the spindle micro-tubules, at the same site or greatly overlapping the same site as colchicine. The antimitotic action of podophyllum toxin probably results from interference with the movement of the chromosomes. The molecular mechanism of mitosis blockade is the disruption of the micro-tubules of the mitotic spindle via binding of podophyllum toxin to tubulin. Podophyllum is caustic but its action differs from those of most caustics in that its effect is neither direct nor immediate: rather, the disruption of cells and erosion of tissue occur slowly subsequent to arrest of cell division and impairment of other cellular processes. Human toxicity: Adults: Most systemic poisoning cases following topical application of podophyllum involved women and some of these were fatal. Serious systemic toxicity has occurred following topical application of podophyllum to large areas or in excessive amounts, or when the medication was allowed to remain in contact with the skin or mucous membranes for a prolonged period of time. The risk of systemic toxicity may be increased when podophyllum is applied to friable bleeding, or recently biopsied warts, or when the medication is inadvertently applied to normal skin or mucous membranes surrounding the affected area. Renal failure and hepatotoxicity (increased serum concentrations of lactate dehydrogenase (LDH), aspartate aminotransferase (AST; SGOT) and alkaline phosphase have occurred following topical application or ingestion of podophyllum. Podophyllum can cause severe systemic toxicity, which may result from topical application and ingestion. The toxic effects are usually reversible but in some instances, they have been fatal. Children: Fever and convulsions seem to be more frequent in children. Most reported cases followed accidental ingestion. Carcinogenicity: Podophyllum is a suspected human carcinogen. Teratogenicity: Podophyllum may be a teratogenic agent in humans. At least two cases of possible teratogenic effects of podophyllum have been described. Interactions: Other keratolytic agents may stimulate dermal absorption of podophyllum. Main adverse effects: The risk of systemic toxicity may be increased when podophyllum is applied to friable, bleeding or recently biopsied warts, or when the medication is inadvertently applied to normal skin or mucous membranes surrounding the affected area. Adverse effects on the nervous system may occur following topical application of podophyllum; these are usually delayed in onset and prolonged in duration. Cerebral toxicity (manifested by altered sensorium ranging from mild confusion to coma) may occur following topical application of podophyllum and continue for 7 to 10 days during which the electorencephalogram (EEG) may show generalized slowing. The following side/adverse effects have been selected on the basis of their potential clinical significance. Skin rash or itching: allergic reaction to benzoin, which may be present in some preparations. Redness, burning or other irritation of the skin has been noted. Abdominal pain, nausea or vomiting. Diarrhea, sometimes severe and prolonged. Clumsiness or unsteadiness. Confusion and reduced reflexes. Excitement, irritability, nervousness and hallucinations. Muscle weakness, leucopenia (sore throat and fever) and thrombocytopenia Autonomic neuropathy (difficult or painful urination; dizziness or lightheadedness, especially when getting from a lying or sitting position; fast heartbeat). Difficulty in breathing. Drowsiness. Paralytic ileus (constipation, nausea and vomiting; pain in upper abdomen or stomach, mild dull and continuing) Peripheral neuropathy (numbness, tingling, pain or weakness in hands or feet). If peripheral neuropathy occurs, it usually appears about 2 weeks after podophyllum application, may worsen progressively for up to 3 months and may persist for up to 9 months or longer. Seizures have been noted. Clinical effects: Acute poisoning: Ingestion: Ingestion may cause: nausea and vomiting, which may be severe and persistent and occur rapidly after ingestion. Abdominal pain, ileus (paralytic), lethargy, coma, tachypnea, respiratory failure, tachycardia, hypotension, cardiac arrhythmia, cardiovascular collapse, oliguria, renal failure, fever, metabolic acidosis, leukocytosis, leucopenia, thrombocytopenia, pancytopenia, peripheral neuropathy, death. Skin exposure: In contrast to ingestion, there will be a delay of up to 24 hours before appearance of signs. These are similar to those occurring after ingestion. Eye contact: Podophyllum may be absorbed through this route but severe systemic poisoning seldom occurs. Local irritation and lesions of cornea and conjunctiva may occur. Chronic poisoning: Ingestion: This type of poisoning occurred when podophyllum was used as a cathartic or slimming aid. It has not been reported in recent years. In such cases, poisoning was sometimes difficult to diagnose since the clinical picture did not resemble that of acute poisoning. The first clinical signs are either hematological, gastro-intestinal or peripheral neuropathy. Skin exposure: Repeated local treatment of warts or condyloma may produce systemic poisoning or local lesions of the skin (erosion, pain, bleeding, infection). Course, prognosis, cause of death: The precise course following overdose is difficult to predict since we seldom have good indicators of the absorbed dose. It should be noted that some severely intoxicated patients (especially children) have survived while others either died or developed permanent sequelae (peripheral neuropathy) with lower doses. Death generally results from the cerebral; cardiovascular; renal; or hematological complications. Systematic description of clinical effects: Cardiovascular: Tachycardia, cardiac, arrhythmias, hypotension and cardiovascular collapse. Respiratory: Tachypnea and respiratory failure. Pneumonitis (resembling chemical pneumonitis) and pulmonary edema (rarely). Neurological: Central Nervous System (CNS): Confusion, lethargy, coma and convulsions. Peripheral nervous system: Peripheral neuropathy which develops over several days and may take weeks or months to regress. There may be permanent sequelae. Autonomic nervous system: Paralytic ileus. Skeletal and smooth muscle: Rhabdomyolysis may occur with myoglobinuria. This may aggravate the renal failure. Phosphokinase (CPK) should be monitored. Gastrointestinal: Nausea and vomiting which may be persistent and severe; abdominal pain; paralytic ileus and diarrhea which may produce water and electrolyte imbalance. Hepatic: Elevation of hepatic enzymes. Urinary: Renal: Oliguria and renal insufficiency. Other: Cystitis and painful micturition. Endocrine and reproductive system: Fetal death, abortion, premature labor and fetal malformations. Dermatologic: Pruritus around the treated sites especially if the skin has not been protected by petroleum jelly. Irritation, urticaria, skin necrosis and bleeding. Scarring of tissue, especially of anogenital regions, paraphimosis that may require circumcision and pseudo epitheliomatosis hyperplasia. Eye, ear, nose, throat: local effects: Irritation of skin or mucous membrane, necrosis, scarring of tissues, bleeding and corneal erosion. Hematological: Leucocytosis followed by leucopenia, anemia, thrombocytopenia and pancytopenia. Special risks: The use of podophyllum is contraindicated in pregnant or lactating women. ANIMAL STUDIES: Mutagenicity: Podophyllum is mutagenic in Salmonella typhimurium. /Podophyllum/

Etoposide, a semisynthetic derivative of podofilox, induces DNA breakage through its inhibition of topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics. Podofilox derivatives display binding activity to the enzyme topoisomerase II during the late S and early G2 stage. For instance, etoposide binds and stabilizes the temporary break caused by the enzyme, disrupts the reparation of the break through which the double-stranded DNA passes, and consequently stops DNA unwinding and replication. Mutants resistant to either podofilox, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells. The mutually exclusive cross-resistance patterns of these mutants provide a highly specific mean to distinguish the two kinds of podofilox derivatives. Mutant Chinese hamster cells resistant to podofilox are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein. (Wikipedia)

/HUMAN EXPOSURE STUDIES/ Toxicity reported following systemic administration of podofilox in investigational use for cancer treatment included: nausea, vomiting, fever, diarrhea, bone marrow depression, and oral ulcers. Following 5 to 10 daily intravenous doses of 0.5 to 1 mg/kg/day, significant hematologic toxicity occured but was reversible. Other toxicities occurred at lower doses. Toxicity reported following systemic administration of podophyllum resin included : nausea, vomiting, diarrhea, peripheral neuropathy, altered mental status, lethargy, coma , tachypnea, respiratory failure, leukocytosis, pancytosis, hematuria, renal failure, and seizures.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ There are published reports that, in mouse studies, crude podophyllin resin (containing podofilox) applied topically to the cervix produced changes resembling carcinoma in situ. These changes were revisable at five weeks after cessation of treatment. In one reported experiment, epidermal carcinoma of the vagina and cervix was found in 1 out of 18 mice after 120 applications of podophyllin (the drug was applied twice weekly over a 15-month period). /Podophyllin resin/

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Podofilox was embryotoxic in rats that were given daily intraperitoneal doses of 5 mg/kg of body weight (29.5 mg per square meter of body surface area; corresponding to 19 times the maximum human recommended dose). It was not teratogenic in rats that were given daily topical doses of 0.21 mg/kg of body weight (2.95 mg per square meter of body surface area; corresponding to two times the maximum human recommended dose for 13 days.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Podofilox did not impair fertility in two generations of rats given daily topical doses of 0.2 mg/kg of body weight (1.18 mg per square meter of body surface area) (corresponding to the recommended human daily dose) during gametogenesis, mating, gestation, parturition, and lactation.

/GENOTOXICITY/ Podofilox is not mutagenic according to the Ames plate reverse mutation assay (at concentrations up to 5 mg podofilox, with or without metabolic activation) and BALB/3T3 cells (at concentrations up to 0.008 ug/mL without metabolic activation and 12 ug/mL with activation). Chromosome damage occurs at higher doses; 25 mg/kg (75 mg per square meter of body surface area) of podofilox caused disruption and breakage of chromosomes in vivo in the mouse micronucleus assay.

Treatment of systemic toxicity or accidental ingestion is essentially supportive. To decrease absorption: Wash the skin free of any remaining drug. Supportive care: Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.

LD50 Rat iv 8.7 mg/kg

LD50 Rat ip 15 mg/kg

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl podofilox, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Used in the treatment of warts and corns; [INCHEM]

Antiviral

For treatment of external genital warts (<i>Condyloma acuminatum</i>).

Found in the rhizomes of North American Podophyllum peltatum L., Podophyllaceae

Podophyllin is a complex mixture of crystalline compounds derived from the mayapple plant. The active agent derived from this plant product /is/ podophyllotoxin.