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PODOPHYLLUM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Podophyllum is found in the leaves, rhizomes, and roots of Podophyllum peltatum (American mandrake, May apple). The resin (podophyllin) is the dried mixture of resins extracted from the podophyllum plant, which is a keratolytic agent that can be strongly irritating to the skin, eyes, and mucous membranes.

Specific Substances

    1) American Mandrake
    2) Bajiaolian
    3) Dysosma pleianthum
    4) Dysosma versipelle
    5) Dysosma emodi
    6) Dysosma pelatum
    7) May apple root
    8) Podofillina
    9) Podophyllum
    10) Podophyllum resin
    11) Podophyllum rhizome
    12) CAS 568-53-6 (alpha-peltatin)
    13) CAS 518-29-6 (beta-peltatin)
    14) PODOPHYLLIN
    15) PODOPHYLLOTOXIN

Available Forms Sources

    A) FORMS
    1) Podophyllin is an amorphous caustic powder which is light brown to greenish- yellow or brownish-grey in color and has a characteristic odor (Reynolds, 2000).
    2) Podophyllin is a mixture of at least 16 physiologic compounds divisible into two groups: lignans (wood extracts) and flavonols. It exists in the rhizomes and roots of the Podophyllum peltatum plant or "Mayapple" and contains at least 40% and up to 50% podophyllotoxin according to the USP (Reynolds, 2000).
    3) Commercial preparations consist of 25 percent podophyllin in either tincture of benzoin or in 10 percent benzoin and 72 percent isopropyl alcohol. The powdered form of podophyllin is also available for compounding.
    B) SOURCES
    1) Podophyllum is found in the leaves, rhizomes, and roots of Podophyllum peltatum (American mandrake, May apple). The ripe fruit is edible. Podophyllum resin (podophyllin) is the dried mixture of resins extracted from the podophyllum plant(Briggs et al, 1998).
    2) Adulteration of Chinese herbal products with the plant Podophyllum hexandrum, resulting in neuropathies and encephalopathy, has been reported (But et al, 1996).
    C) USES
    1) Podophyllum resin, also known as podophyllin, is used as keratolytic agent whose caustic action is thought to be caused by the arrest of mitosis in metaphase (Briggs et al, 1998).
    2) Medically, it is commonly used in the topical treatment of condyloma acuminata (venereal warts). Therapeutically it is dispensed as 25% podophyllum resin in tincture of benzoin or alcohol.
    3) Podophyllinhas been used as a homeopathic medicine (Reynolds, 2000).
    4) CHINESE MEDICINE - Bajiaolian (dysosma pleianthum) is a species of the Mayapple family (Podophyllum pelatum) which has been used in Chinese herbal medicine for the treatment of various conditions including post-partum recovery, tumor growth, snake bites and acne. It has also been used in western medicine as a topical preparation in the treatment of various skin lesions, more recently it has been used in the manufacturer of various oncology agents (Chou et al, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Podophyllum resin (podophyllin) is extracted from the May apple rhizomes and roots (mandrake) and is used as a topical keratolytic to treat external genital and perianal warts, papillomas, and fibroids. It is dispensed as 25% podophyllum resin in benzoin tincture or alcohol. Derivatives are used as anticancer agents (etoposide and teniposide).
    B) PHARMACOLOGY: Podophyllotoxin is the active agent in podophyllum. It interferes with epithelial cell mitosis by binding to tubulin, a microtubule protein subunit, thus producing cytoskeletal changes. The podophyllum binding site is either the same as, or overlaps with, the colchicine binding site. In contrast to colchicine, podophyllum binds more rapidly and reversibly.
    C) TOXICOLOGY: Similar to colchicine, podophyllum arrests cell division by inhibiting microtubule formation and polymerization. It inhibits cell division similarly to a chemotherapeutic agent, and causes toxicity in rapidly dividing cells first. It also inhibits axoplasmic transport, protein, RNA, and DNA synthesis, and oxidation enzymes in the tricarboxylic acid cycle.
    D) EPIDEMIOLOGY: Poisoning is very uncommon but may cause significant morbidity and mortality.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: pruritus, nausea, vomiting, diarrhea, and abdominal pain. SEVERE: hepatotoxicity, leucopenia, peripheral neuropathy, renal failure, and thrombocytopenia.
    F) WITH POISONING/EXPOSURE
    1) Toxicity occurs rapidly (within a few hours) after ingestion but is delayed up to 12 to 24 hours following dermal absorption. Nausea, vomiting, diarrhea, and abdominal pain develop first, along with confusion, delirium, coma, tachycardia, orthostatic hypotension, and metabolic acidosis. Hematologic findings (pancytopenia) occur and nadir within 4 to 7 days of exposure. Neurologic findings include cranial nerve palsy, peripheral sensorimotor axonopathy, and loss of reflexes. Autonomic dysfunction, ileus, and urinary retention may persist for several months after recovery from severe poisoning.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Tachycardia, hypotension and tachypnea are frequently reported in severe overdose; fever may occur but is not a common early finding.
    0.2.4) HEENT
    A) WITH POISONING/EXPOSURE
    1) Eye exposure results in pain and irritation.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Tachycardia and hypotension are frequently reported.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Tachypnea and dyspnea occur frequently.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Typical findings include confusion, dizziness, fever, lethargy, stupor, and coma.
    2) Persistent neuropathies have been described.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, abdominal pain, ileus, and severe diarrhea may occur after oral ingestion or dermal application.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Oliguria and renal failure have been rarely reported.
    0.2.11) ACID-BASE
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may occur following ingestions.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Leukocytosis followed by leukopenia and thrombocytopenia has been reported.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Dermal exposures may be very irritating to skin and mucosa and may cause burn.
    2) Cessation of nail growth was observed in adult female following Bajiaolian intoxication (a species in the Mayapple family {Podophyllum pelatum}).
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Visual and auditory hallucinations associated with paranoid ideation have been reported.
    0.2.20) REPRODUCTIVE
    A) Podophyllum, and podophyllum resin (podophyllin) may be teratogenic.

Laboratory Monitoring

    A) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, urinalysis, and ECG.
    B) Monitor vital signs and mental status.
    C) Monitor neurologic function, over several weeks, in patients who develop severe toxicity.
    D) Obtain nerve conduction studies if peripheral neuropathy develops.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Administer IV fluids as needed and remove from skin.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive, and involves immediate resuscitation with IV fluids, activated charcoal (if ingested and vomiting does not preclude its use), and skin decontamination.
    C) DECONTAMINATION
    1) PREHOSPITAL: Give activated charcoal, if not vomiting. Wash exposed skin with soap and water and remove contaminated clothing.
    2) HOSPITAL: Administer activated charcoal, if not vomiting. Wash exposed skin with soap and water and remove contaminated clothing.
    D) AIRWAY MANAGEMENT
    1) Usually not necessary, but intubation may be necessary in patients with altered mental status.
    E) ANTIDOTE
    1) None.
    F) HYPOTENSIVE EPISODE
    1) IV 0.9% NaCl 10-20 mL/kg, dopamine, norepinephrine.
    G) MYELOSUPPRESSION
    1) Pancytopenia: generally nadirs around 4 to 7 days and resolves in 2 to 3 weeks. Patients may require transfusion. Treatment of Neutropenia: Filgrastim 5 mcg/kg/day subcutaneously. Sargramostim 250 mcg/m(2)/day IV infusion over 4 hours. Transfusion for severe thrombocytopenia or bleeding. Admission to a bone marrow transplant unit (or similar measures to prevent infection) should be considered if the patient develops agranulocytosis.
    H) ENHANCED ELIMINATION
    1) Due to the large molecular weight of the compound it is unlikely that hemodialysis would be effective for removal of podophyllin. Hemodialysis may be necessary when acute renal failure develops. The efficacy of charcoal hemoperfusion is unknown. Hemoperfusion is not recommended unless the patient continues to deteriorate despite intensive supportive therapy.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients may be managed at home ONLY if asymptomatic after limited dermal exposure and appropriate skin decontamination.
    2) OBSERVATION CRITERIA: Any symptomatic patient or with an intentional ingestion should be observed in the hospital until asymptomatic. No guidelines indicate how long to observe these patients, but if no GI symptoms develop within 6 hours of ingestion, it is reasonable to discharge the patient. If the exposure was dermal, the patient should have follow-up within 12 to 24 hours; sooner if any symptoms develop.
    3) ADMISSION CRITERIA: Any patient with altered mental status, hemodynamic instability, history of an intentional ingestion, or suspected or known significant overdose should be admitted to the ICU.
    4) CONSULT CRITERIA: Nephrology should be consulted if acute renal failure develops. Consult a medical toxicologist or poison center for any symptomatic exposure.
    J) PITFALLS
    1) Onset of toxicity may be delayed 12 to 24 hours after dermal exposure. In patients with severe toxicity, some manifestations may be delayed; peripheral sensorimotor axonopathies may occur, orthostatic hypotension and tachycardia may last several months, coma may last 7 to 10 days, pancytopenia generally nadirs at 4 to 7 days and usually resolves in about 2 to 3 weeks.
    K) PHARMACOKINETICS
    1) Podophyllotoxin is highly lipid soluble and rapidly absorbed orally and dermally. Peak serum levels usually occur within 1 to 2 hours. No clear data are available for volume of distribution, duration of effect, elimination half-life, or protein binding.
    L) PREDISPOSING CONDITIONS
    1) Application to non-intact skin predisposes to absorption and systemic toxicity.
    M) DIFFERENTIAL DIAGNOSIS
    1) Rule out the possibility of colchicine, etoposide, teniposide, chloroquine, hydroxychloroquine, or arsenic exposure.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Greater than 0.5 mL of solution may be toxic. Severe toxicity with permanent neurologic sequelae has been reported in toddlers who ingested 10 mL of 8% to 25% podophyllum and an adult who ingested 25 mL of a 25% solution. Dermal application of 90 mL of 17.5% podophyllum to the perineum after CO2 laser ablation was fatal in an adult.
    B) THERAPEUTIC DOSES: Topical application of less than 0.5 mL or application to an area of 10 square centimeters or less to each wart, using 10% to 25% podophyllum products; remove within 1 to 4 hours to reduce local irritation.

Clinical Effects

Summary Of Exposure

    A) USES: Podophyllum resin (podophyllin) is extracted from the May apple rhizomes and roots (mandrake) and is used as a topical keratolytic to treat external genital and perianal warts, papillomas, and fibroids. It is dispensed as 25% podophyllum resin in benzoin tincture or alcohol. Derivatives are used as anticancer agents (etoposide and teniposide).
    B) PHARMACOLOGY: Podophyllotoxin is the active agent in podophyllum. It interferes with epithelial cell mitosis by binding to tubulin, a microtubule protein subunit, thus producing cytoskeletal changes. The podophyllum binding site is either the same as, or overlaps with, the colchicine binding site. In contrast to colchicine, podophyllum binds more rapidly and reversibly.
    C) TOXICOLOGY: Similar to colchicine, podophyllum arrests cell division by inhibiting microtubule formation and polymerization. It inhibits cell division similarly to a chemotherapeutic agent, and causes toxicity in rapidly dividing cells first. It also inhibits axoplasmic transport, protein, RNA, and DNA synthesis, and oxidation enzymes in the tricarboxylic acid cycle.
    D) EPIDEMIOLOGY: Poisoning is very uncommon but may cause significant morbidity and mortality.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: pruritus, nausea, vomiting, diarrhea, and abdominal pain. SEVERE: hepatotoxicity, leucopenia, peripheral neuropathy, renal failure, and thrombocytopenia.
    F) WITH POISONING/EXPOSURE
    1) Toxicity occurs rapidly (within a few hours) after ingestion but is delayed up to 12 to 24 hours following dermal absorption. Nausea, vomiting, diarrhea, and abdominal pain develop first, along with confusion, delirium, coma, tachycardia, orthostatic hypotension, and metabolic acidosis. Hematologic findings (pancytopenia) occur and nadir within 4 to 7 days of exposure. Neurologic findings include cranial nerve palsy, peripheral sensorimotor axonopathy, and loss of reflexes. Autonomic dysfunction, ileus, and urinary retention may persist for several months after recovery from severe poisoning.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia, hypotension and tachypnea are frequently reported in severe overdose; fever may occur but is not a common early finding.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever following cutaneous application has been reported (Conard et al, 1990; Slater et al, 1978; Fisher, 1981).

Heent

    3.4.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Eye exposure results in pain and irritation.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Eye and mucosal exposures result in pain and irritation.

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia and hypotension are frequently reported.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension is frequently reported following oral ingestion and topical exposure (Conard et al, 1990; Stoehr et al, 1978; Ward et al, 1954; Balucani & Zellers, 1964). Orthostatic hypotension and sinus tachycardia may persist for several months following poisonings.
    B) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia is frequently reported following oral ingestions and topical exposure (Conard et al, 1990; Stoehr et al, 1978; Ward et al, 1954; Balucani & Zellers, 1964).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachypnea and dyspnea occur frequently.
    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Tachypnea, hyperpnea, dyspnea and cyanosis may occur following oral or topical exposure (Conard et al, 1990; Balucani & Zellers, 1964; Stoehr et al, 1978)

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Typical findings include confusion, dizziness, fever, lethargy, stupor, and coma.
    2) Persistent neuropathies have been described.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) ALTERED MENTAL STATUS, including acute confusional states, ataxia, dizziness, lethargy, progressive stupor, and coma have been reported following oral ingestion and topical application (Conard et al, 1990; Stoehr et al, 1978; Slater et al, 1978; Stoudemire et al, 1981; Juurlink et al, 1999).
    B) NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Other findings include areflexia, peripheral neuropathy (Fisher, 1981; O'Mahony et al, 1990; Juurlink et al, 1999), and paralysis (Slater et al, 1978; Ward et al, 1954). Selective dorsal radiculopathy has been seen following ingestion of 45 mL of a 5 percent solution of podophyllin (Gorin et al, 1989). Neuropathy and encephalopathy have been reported following ingestions of herbal products adulterated with podophyllum. In cases of mild toxicity (2 to 8 grams), neuropathy was evident in one to two days (But et al, 1996).
    b) CASE REPORT - Polyneuropathy secondary to Bajiaolian intoxication (a species in the Mayapple family) was present following acute recovery of intoxication. Symptoms resolved gradually over several months (Chou et al, 2008).
    c) CASE REPORT - Persistent sensorimotor neuropathy developed in a 22-year-old male following an ingestion of 8 mL of a 25% solution of podophyllin (O'Mahony et al, 1990).
    d) CASE REPORT - Following the ingestion of 25 mL of a 25% podophyllin solution, a 38-year-old male developed prolonged paralytic ileus and generalized paresis with areflexia. Severe sensorimotor axonal neuropathy and diffuse myopathy progressed to a maximum by 5 weeks post-ingestion as shown on serial EMG and nerve conduction studies. He remained hospitalized for 5 months prior to transfer to a long-term care facility (Juurlink et al, 1999).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) Other CNS effects which may occur following oral or dermal toxic exposures include acute confusion, lethargy, dizziness, memory impairment, and seizures (Fisher, 1981).
    b) Permanent intellectual impairment has been reported after severe poisoning in a child (Juurlink et al, 1999).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, abdominal pain, ileus, and severe diarrhea may occur after oral ingestion or dermal application.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, and abdominal pain are common following oral ingestion (O'Mahony et al, 1990; Reynolds, 2000; Frasca et al, 1997) or topical exposure (Conard et al, 1990; Slater et al, 1978; Stoehr et al, 1978). Vomiting may be severe (But et al, 1996; Chou et al, 2008).
    B) DRUG-INDUCED ILEUS
    1) WITH POISONING/EXPOSURE
    a) Adynamic ileus is common following oral ingestion or topical exposure (Chou et al, 2008; Slater et al, 1978; Stoehr et al, 1978; Juurlink et al, 1999).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Oral podophyllin has a dramatic purging action and is highly irritating to the intestinal mucosa, producing violent peristalsis. Violent catharsis occurs shortly following oral ingestion (Chou et al, 2008; Montaldi et al, 1974; O'Mahony et al, 1990; Reynolds, 2000; But et al, 1996).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Liver injury associated with elevated AST(220 International Units), LDH (2184 International Units), and alkaline phosphatase (262 International Units) was reported in one patient following local podophyllin therapy (Stoehr et al, 1978).

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Oliguria and renal failure have been rarely reported.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Oliguria (Conard et al, 1990), anuria, and complete renal failure may occur following oral or topical exposure but is rare.
    B) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) Urinary retention, an autonomic dysfunction, may occur and persist for several months following podophyllin toxicity (Ward et al, 1954).

Acid-Base

    3.11.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may occur following ingestions.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis and coma were reported in an 18-month-old male within 26 hours of ingestion of approximately 10 mL of a 25% podophyllum in benzoin solution (Juurlink et al, 1999).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Leukocytosis followed by leukopenia and thrombocytopenia has been reported.
    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Leukocytosis followed by leukopenia and thrombocytopenia may occur in severe cases. Thrombocytopenia generally reaches its nadir within 5 days and returns to normal within about 20 days (Stoehr et al, 1978; Fisher, 1981).
    b) CASE REPORT - Leukocytosis followed by leukopenia and thrombocytopenia developed in a 15-year-old female 4 days after topical podophyllin therapy for condyloma acuminata (Stoehr et al, 1978).
    B) LEUKOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Leukocytosis developed approximately 16 hours after application of podophyllum in a 17-year-old woman (Conard et al, 1990).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dermal exposures may be very irritating to skin and mucosa and may cause burn.
    2) Cessation of nail growth was observed in adult female following Bajiaolian intoxication (a species in the Mayapple family {Podophyllum pelatum}).
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Podophyllum is very irritating to skin and mucous membranes. A purified form, podophyllotoxin, in a 0.5% concentration, has caused burns with excessive application (White & Sparks, 1991). Generally, this form causes fewer adverse effects.
    B) NAIL FINDING
    1) WITH POISONING/EXPOSURE
    a) An adult developed cessation of nail growth following Bajiaolian (a species in the Mayapple family {Ppdophyllum pelatum}) intoxication. Following recovery from acute intoxication the patient showed no evidence of nail growth at 6 months and up to 7 years after ingesting 15 g Bajiaolian root that was purchased at an herbal store (Chou et al, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Podophyllum, and podophyllum resin (podophyllin) may be teratogenic.
    3.20.2) TERATOGENICITY
    A) SKELETAL MALFORMATION
    1) Podophyllum, and podophyllum resin (podophyllin) may be teratogenic. One case of multiple deformities (extra thumb on the left side, malformed right external ear, right thumb and radius missing) following podophyllin ingestion during the first trimester of pregnancy was reported (Cullis, 1962).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1)
    PodophyllumC
    PodofiloxC
    Podophyllum resinX
    PodophyllotoxinX
    Reference: Briggs et al, 1998.

    2) Podophyllin should not be used during pregnancy for the treatment of genital warts (human papillomavirus infections) due to the potential for severe myelotoxicity and neurotoxicity in the mother (Briggs et al, 1998).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) SKIN CARCINOMA
    1) Squamous cell carcinoma-like changes have been reported following the dermal use of podophyllin in humans (Fisher, 1981).
    B) LABORATORY TEST INTERFERENCE
    1) "PAP" smear test results may demonstrate atypical cellular changes for as long as 6 months following the application of podophyllum resin (Fisher, 1981).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, urinalysis, and ECG.
    B) Monitor vital signs and mental status.
    C) Monitor neurologic function, over several weeks, in patients who develop severe toxicity.
    D) Obtain nerve conduction studies if peripheral neuropathy develops.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Follow serial complete blood counts with differential and platelets for at least one week in symptomatic patients to assess bone marrow effects.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, glucose, BUN, creatinine, and urinalysis to assess electrolyte abnormalities due to gastrointestinal losses and development of renal injury.
    2) Monitor liver enzymes and amylase levels to assess organ injury.
    4.1.4) OTHER
    A) OTHER
    1) ELECTROPHYSIOLOGICAL TESTING
    a) Monitor electromyography and nerve conduction velocity in all patients with symptoms of peripheral neuropathy.

Methods

    A) CHROMATOGRAPHY
    1) Frasca et al (1997) described a high-performance liquid chromatography (HPLC) method for the determination of podophyllotoxin concentrations, the active component of Podophyllum peltatum, in plant stems and roots (Frasca et al, 1997).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit any patient with altered mental status, hemodynamic instability, history of an intentional ingestion, or suspected or known significant overdose should be admitted to the ICU.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients may be managed at home ONLY if asymptomatic after limited dermal exposure and appropriate skin decontamination.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Nephrology should be consulted if acute renal failure develops. Consult a medical toxicologist or poison center for any symptomatic exposure.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any symptomatic patient or with an intentional ingestion should be observed in the hospital until asymptomatic. No guidelines indicate how long to observe these patients, but if no GI symptoms develop within 6 hours of ingestion, it is reasonable to discharge the patient. If the exposure was dermal, the patient should have follow-up within 12 to 24 hours; sooner if any symptoms develop.

Monitoring

    A) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, urinalysis, and ECG.
    B) Monitor vital signs and mental status.
    C) Monitor neurologic function, over several weeks, in patients who develop severe toxicity.
    D) Obtain nerve conduction studies if peripheral neuropathy develops.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor serum electrolytes, BUN, creatinine, glucose, CBC, urinalysis, and ECG.
    2) Monitor vital signs and mental status.
    3) Monitor neurologic function, over several weeks, in patients who develop severe toxicity.
    4) Obtain nerve conduction studies if peripheral neuropathy develops.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) MYELOSUPPRESSION
    1) Pancytopenia: generally nadirs around 4 to 7 days and resolves in 2 to 3 weeks. Patients may require transfusion. Patients generally recover from thrombocytopenia and leukocytopenia within 1 month.
    2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) SKIN ABSORPTION
    1) PREVENTION: Since podophyllin is a widely used drug for the treatment of condyloma acuminata, knowing its proper application is the most effective way to prevent catastrophic intoxications.
    2) Podophyllum resin (podophyllin) 25% in tincture of benzoin should be applied to each individual wart with special care not to involve normal mucosa or skin.
    3) The surrounding area of the wart should be covered with petroleum jelly to prevent dissemination of the drug.
    4) It should be emphasized to each patient that the drug should be very meticulously washed off after 4 to 6 hours.
    5) Under NO circumstances should the doctor debride, biopsy, or in any way uncover the roof of the wart prior to the application of podophyllin since this will enhance its absorption.
    B) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) Due to the large molecular weight of the compound it is unlikely that hemodialysis would be effective for removal of podophyllin. Hemodialysis may be necessary when acute renal failure develops. The efficacy of charcoal hemoperfusion is unknown. Hemoperfusion is not recommended unless the patient continues to deteriorate despite intensive supportive therapy.
    2) It is speculated that the physiologic basis of the renal failure is the destruction of the white cells by the drug and ensuing uric acid load which is presented to the kidney precipitating uric acid nephropathy.
    B) HEMODIALYSIS
    1) Due to the large molecular weight of the compound it is unlikely that hemodialysis would be effective for removal of podophyllin (Slater et al, 1978).
    C) HEMOPERFUSION
    1) Early charcoal or resin hemoperfusion may facilitate neurologic recovery in some patients. Hemoperfusion is recommended by some clinicians, however, there is no conclusive evidence regarding its usefulness.
    2) Hemoperfusion was performed 4 days post exposure in a severely intoxicated 16-year-old female because of deepening coma and general clinical deterioration (Slater et al, 1978).
    a) Three hours after charcoal hemoperfusion the patient became more alert and moved all extremities.
    b) However, no neurologic change was noted following charcoal hemoperfusion in a 54-year-old alcoholic male who ingested between 10 to 11 grams of podophyllum (Cassidy et al, 1982). This patient expired 39 hours after ingestion.
    3) Hemoperfusion is not recommended unless the patient continues to deteriorate despite intensive supportive therapy.

Abstracts

Case Reports

    A) A 43-year-old man drank 45 milliliters of 25 percent podophyllin in benzoin tincture (11 grams of podophyllin resin). Within one hour he was vomiting and had diarrhea. Within the next 24 hours, he became lethargic and then stuporous. He presented for treatment 29 hours post-exposure. Despite supportive measures, the patient died on the sixth hospital day.
    1) Postmortem examination revealed partial maturation arrest of granulocytopoesis and a severe decrease in megakaryocytes. There were multiple petechiae on the pleura, the peritoneal surfaces of many organs, and the gastric mucosa.
    2) Severe pulmonary congestion was present, as well as marked vascular congestion of the liver and kidneys. There was a small area of focal acute necrotizing bronchial pneumonia, and the brain was edematous (West et al, 1982).
    B) ADULT
    1) A 20-year-old female took a large number of Triad Herbal Laxative tablets (Podophyllin 15 mg, Aloin 30 mg, Rhei 20 mg, Senna 40 mg). Sixty-five tablets were missing.
    2) Within 12 hours, the patient experienced abdominal pain, watery diarrhea and vomiting, and appeared confused and agitated.
    3) In the following 12 hours, the patient became comatose, exhibited decorticate posturing, absent deep tendon reflexes, and no plantar response. Pupils were normally reactive. Corneal, gag, and cough reflexes were normal. The EKG showed inverted T waves in 1 and AVL, QT prolongation, and U waves.
    4) Coma lasted 5 days; drowsiness and confusion another 10 days. EMG showed diffuse sensorimotor neuropathy. Treatment included tracheostomy, total parenteral nutrition, and vitamin supplements.
    5) The patient was discharged after 3 months. At 5 months, mentation improved, a foot drop remained and there was a decrease in sensitivity to pin prick in the hands and knees to the feet (Dobb & Edis, 1984).

Range Of Toxicity

Summary

    A) TOXICITY: Greater than 0.5 mL of solution may be toxic. Severe toxicity with permanent neurologic sequelae has been reported in toddlers who ingested 10 mL of 8% to 25% podophyllum and an adult who ingested 25 mL of a 25% solution. Dermal application of 90 mL of 17.5% podophyllum to the perineum after CO2 laser ablation was fatal in an adult.
    B) THERAPEUTIC DOSES: Topical application of less than 0.5 mL or application to an area of 10 square centimeters or less to each wart, using 10% to 25% podophyllum products; remove within 1 to 4 hours to reduce local irritation.

Therapeutic Dose

    7.2.1) ADULT
    A) Sparingly apply podophyllin to cleaned, affected area using the applicator. The first application should not last longer than 30 to 40 minutes; subsequent applications should last the least amount of time to produce results (1 to 4 hours). After treatment, remove podophyllin thoroughly using alcohol or soap and water (Prod Info Podocon-25(R) topical solution, 2012).
    B) The CDC recommends limiting the application to less than 0.5 mL or an area of less than 10 square centimeters of warts per session. Allow to air dry and repeat weekly if necessary. No open lesions or wounds should exist near the treatment area. To reduce local irritation, some specialists suggest washing podophyllum resin off within 1 to 4 hours (Centers for Disease Control and Prevention, 2010).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population has not been established (Prod Info Podocon-25(R) topical solution, 2012).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) Death has occurred with as little as 350 mg of podophyllin (Dudley, 1890).
    2) A 17-year-old woman died following topical application of 90 mL of 17.5% podophyllum in tincture of benzoin to remaining condylomata during a CO2 laser ablation procedure for massive vulvovaginal condyloma acuminata (Conard et al, 1990).
    B) ROUTE OF EXPOSURE
    1) Reported LDLo (lowest published lethal dose) (RTECS , 2000):
    1) LDLo - (ORAL) MAN: 157 mg/kg
    2) LDLo - (ORAL) WOMAN: 6 mg/kg

Maximum Tolerated Exposure

    A) ACUTE
    1) Toxicity generally develops 12 to 24 hours following dermal exposure and within 4 to 8 hours or sooner following oral ingestion (Montaldi et al, 1974; Stoehr et al, 1978; Balucani & Zellers, 1964; Slater et al, 1978).
    2) Survival has occurred with as much as 2.8 g of podophyllin (Clark & Parsonabe, 1957).
    3) Following the ingestion of 25 mL of a 25% podophyllin solution, a 38-year-old male developed prolonged paralytic ileus and generalized paresis with areflexia. Severe sensorimotor axonal neuropathy and diffuse myopathy progressed to a maximum by 5 weeks post-ingestion as shown on serial EMG and nerve conduction studies. He remained hospitalized for 5 months prior to transfer to a long-term care facility (Juurlink et al, 1999).
    4) The level of toxicity of parenterally administered dosages appears to be 300 mg/m(2) of podophyllin. In those cases, thrombocytopenia and leukopenia are the main laboratory findings.
    5) Typically, an initial leukocytosis may be followed by a leukopenia. Uric acid may rise. Some cases have exhibited glucosuria in the face of a normal blood sugar, indicating poisoning of the proximal tubules of the kidneys (Montaldi et al, 1974; Slater et al, 1978).
    B) PEDIATRIC
    1) A 2-year-old female developed seizures, loss of deep tendon reflexes, and coma 6 hours following the ingestion of 10 milliliters of an 8 percent podophyllin solution or 0.35 gram of podophyllotoxin (Campbell, 1980).
    2) After ingesting approximately 10 milliliters of 25% podophyllin in benzoin, an 18-month-old child developed metabolic acidosis and coma, followed by bone marrow depression over a 26 hour period. Progressive generalized cerebral atrophy with evidence of demyelination at 30 days and partial recovery at 6 months was evident on serial CT scans. Severe developmental delay was evidenced over the next 2 years (Juurlink et al, 1999).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) Podophyllin
    1) LD50- (ORAL)MOUSE:
    a) 68 mg/kg (RTECS, 2000)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 58 mg/kg (RTECS, 2000)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 15 mg/kg (Budavari, 1996; RTECS, 2000)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 18 mg/kg (RTECS, 2000)
    B) Podophyllotoxin
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 30 mg/kg (Anon, 1961)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 24.6 mg/kg (Anon, 1970)
    3) LD50- (INTRAMUSCULAR)RAT:
    a) 3mg/kg (Anon, 1948)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 15 mg/kg (Budavari, 1996; RTECS, 2000)
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 8 mg/kg (Anon, 1951)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Medically, it is commonly used in the topical treatment of condyloma acuminata (venereal warts). Therapeutically it is dispensed as 25% podophyllum resin (podophyllin) in tincture benzoin or alcohol.
    1) The component principally responsible for the drug's curative effect on condyloma is podophyllotoxin. More recently podophyllotoxin has been used systemically in the treatment of various types of cancer.
    2) Podophyllin is a highly lipophilic compound and is quite soluble in standard lipid solvents.

Toxicologic Mechanism

    A) Podophyllotoxin is highly lipid soluble and rapidly absorbed orally and dermally. Peak serum levels usually occur within 1 to 2 hours. No clear data are available for volume of distribution, duration of effect, elimination half-life, or protein binding. There have been several case reports in the literature of both cutaneous and oral intoxication from this compound. Both podophyllin and podophyllotoxin have a colchicine-like and vinblastine-like effect, resulting in the following chemical effects (Yang et al, 1994):
    1) Antimitosis (arresting cell mitosis in metaphase)
    2) Inhibition of axoplasmic transport
    3) Inhibitory effects on protein, RNA and DNA synthesis
    4) Blocking of oxidation enzymes in tricarboxylic acid cycle
    B) For centuries, the cathartic effect of podophyllin has been known and there are several proprietary compounds which have contained this drug, especially Canthrone & Carter's Pills.
    1) When taken orally, podophyllum resin (podophyllin) has a drastic purgative action, and it is highly irritant to the intestinal mucosa, producing violent peristalsis (But et al, 1996).

Physicochemical

Physical Characteristics

    A) Podophyllin is an amorphous caustic powder which varies in color from light brown to greenish-yellow or brownish-grey and has a characteristic odor. It becomes darker in color after exposure to light or temperatures above 25 degrees Centigrade (Reynolds, 2000).
    B) Podophyllin is partly soluble in hot water, but precipitates on cooling. It is soluble in alcohol with a slight opalescence, and it is partly soluble in chloroform, ether, and dilute ammonia solution. Alcohol solutions of podophyllin are acid to litmus (Reynolds, 2000).

Molecular Weight

    A) PODOPHYLLIN: 414.4 (Budavari, 1996; Reynolds, 2000)

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