1,3,3a,4,9,9a-Hexahydro-9-hydroxy-6,7-(methylendioxy)-4-(3',4',5'-trimethoxyphenyl)benz[f]isobenzofuran-3-on

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 It has been superseded by less toxic laxatives.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

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.