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Podophyllum

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identifications numbers:
      1.4.1 CAS number
      1.4.2 Other
   1.5 Main brand names, main trade names
   1.6 Main manufacturers/main importers
2. SUMMARY
   2.1 Main risk and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage Conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human toxicity
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Animal data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning by
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Encodrine and reproductive system
      9.4.8 Dermatologic
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunologic
      9.4.12 Metabolic
         9.4.12.1 Acid base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks:
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from the literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE (S)



    PODOPHYLLUM

    International Programme on Chemical Safety
    Poisons Information Monograph 427
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Podophyllum

        1.2  Group

             Other dermatological preparations (D11)/ Wart
             and anti-corn preparations (D11A F)

        1.3  Synonyms

             Podophyllum resin;  podophylliresina; 
             podophyllin; Podophyllotoxin

        1.4  Identifications numbers:

             1.4.1  CAS number

                    9000-55-9

             1.4.2  Other

                    NIOSH-RTEC: TP 8925000
    
                    CAS Podophyllotoxin: 518-28-5
    
                    NIOSH (Podophyllotoxin) LV 2500000
    
                    CAS Alpha-peltatin: 568-53-6
    
                    CAS Beta-peltatin: 518-29-6

        1.5  Main brand names, main trade names

             Condofil (Italy); Condyline (Den); Pod-Ben-25 (USA);
             Podofilm (Canada); Vericap (UK); Wartec (Sweden); Warticon
             (UK); Podofin (USA).
    
             Multi-ingredients preparations containing podophyllum resin:
    
             Boldolaxine (Australia); Canthacur-PS (Canda); Cantharone-
             Plus (USA, Canada); Opobyl (UK); posalfilin (UK); Salicylin-P
             (Australia); Verban (Canda); Verrex (USA); Verrusol (USA);
             Wartkil (Australia); Wart-off (Australia)

        1.6  Main manufacturers/main importers

             Pharmascience (Canada); C. & M. (USA); Cuxson (UK);
             Conpharm (Sweden); Norgine (UK).

    2.  SUMMARY

        2.1  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 multi-system toxic effects.

        2.2  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, leucocytosis, leucopenia, peripheral
             neuropathy and death.

        2.3  Diagnosis

             There are no specific analyses for podophyllum. 
             Clinical diagnosis is difficult due to multiple organ
             toxicity.  Measurement of HB-Ht-RBC-WBC-platelets.

        2.4  First aid measures and management principles

             Exposed eyes should be irrigated with copious amounts of
             water.  Remove contaminated clothing.  Decontaminate skin
             with soap and copious  amounts of water.  vomiting is
             frequently the first clinical sign to appear and therefore
             induced vomiting is seldom required.  For recent ingestion,
             perform gastric lavage and/or administer activated
             charcoal.
    
             No effective treatment is known and only supportive therapy
             may be offered whether the exposure was through oral
             ingestion or topical application.  Rapid transfer to hospital
             if symptomatic.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  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%).

        3.2  Chemical structure

             Podophyllotoxin:
             [5R-(5.alpha.,5a.beta.,8a.alpha.,9.alpha.)]-5,8,8a,9-
             Tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl) 
             furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one
    
             The Podophyllum resin extract contains at least 16 active
             compounds including podophyllotoxin, picro-podophyllin, alpha
             and beta-peltatins and quercetin.

        3.3  Physical properties

             3.3.1  Colour

                    Light brown to greenish yellow

             3.3.2  State/form

                    Solid-powder

             3.3.3  Description

                    Amorphous powder, varying in colour from light
                    brown to greenish yellow, turning darker when
                    subjected to a temperature exceeding 25°C or when
                    exposed to light.  When dissolved in alcohol, it gives
                    an acid reaction to moistened litmus paper. It is
                    soluble in alcohol with slight opalescence. It is
                    partially soluble in ether and chloroform. It is lipid
                    soluble.
    
                    Podophyllotoxin:
    
                    Melting point: 114-118°C (effervescence).
                    After drying melting point: 183.3-184.0°C
                    Solubility in water at 23 deg:  120 mg/L. 
                    Solubility in alcohol, chloroform, acetone, warm
                    benzene, glacial acetic acid.
                    Budavari (1996).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    Information not found.
    
                    Old, discoloured, dried or gritty preparations of
                    podophyllum should not be used (USPDI, 1990).

             3.4.2  Storage Conditions

                    Commercial podophyllum resin solutions may
                    contain from 5 to 25% podophyllum resin
                    concentrations.  It has to be stored in a cool place,
                    in air-tight containers and protected from
                    light.

    4.  USES

        4.1  Indications

             4.1.1  Indications

                    Wart or corn preparation

             4.1.2  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
                    intra-meatal warts, but should not be used on cervical
                    or urethral warts. Care must be taken to avoid
                    application to health 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 irritant to the intestinal mucosa and
                    produces violent peristalsis.  It has been superseded
                    by less toxic laxatives.

        4.2  Therapeutic dosage

             4.2.1  Adults

                    For the treatment of exophytic genital and anal
                    warts, the US Communicable Disease Center (CDC)
                    recommends that a 10-25% solution of podophyllum resin
                    in compound tincture of benzoin be used.  The CDC
                    recommends that each treatment session be limited to
                    an area less than 10 cm2 for genital or perianal

                    warts.  In addition, CDC recommends that the total
                    volume of 10 to 25% solution be limited to less than
                    0.5 mL per treatment session.  Alternatively, some
                    clinicians recommend that lower concentrations of the
                    drug (e.g. a 5% solution) be used for the treatment of
                    large (i.e. larger than 10 to 20 cm2). genital and
                    anal warts.  The CDC recommends that the solution be
                    applied to the affected area and then washed off
                    within 1 to 4 hours for genital and perianal warts and
                    within 1 to 2 hours for accessible meatal warts.  Some
                    clinicians prefer longer periods of application, but
                    this must be individualized after patient tolerance
                    and compliance have been established.  Most clinicians
                    recommend that the duration of therapy not exceed 4 to
                    6 hours.  Therapy may be repeated at weekly intervals
                    for up to 4 applications; if beneficial effect is not
                    evident (e.g. regression of warts) after 4
                    applications, alternate therapies should be used.  For
                    vaginal warts, CDC recommends that each treatment
                    session be limited to an area less than 2 cm2;
                    therapy may be repeated at weekly intervals.
    
                    Within a few hours after application of the drug, the
                    lesions become blanched, and they become necrotic
                    within 24 to 48 hours.  After about 72 hours, the
                    lesions begin to slough and gradually disappear
                    without scarring.
    
                    When used for the treatment of verruca vulgaris
                    (common warts), one manufacturer suggests that
                    following application of a solution containing 5%
                    podophyllum resin, the area be covered with a non-
                    porous, slightly elastic tape for up to 24 hours.  The
                    wart is then removed with the tape or by curettage
                    after the tape has been removed.  The manufacturer
                    suggests that the area be treated with a mild topical
                    anti-infective agent until completely healed
                    (A.H.F.S., 1990).

             4.2.2  Children

                    See 4.2.1

        4.3  Contraindications

             - Pregnancy: topical podophyllum is absorbed
             systemically and crosses the placental barrier.  It has been
             associated with the induction of congenital malformations in
             humans (Cullis, 1962).
    
             - Breast-feeding
             - Pediatrics: No established indication to date
             - Friable, bleeding or recently biopsied warts
             - Intolerance to podophyllum

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Easily absorbed even if it induces nausea and
             vomiting.

        5.2  Inhalation

             No specific data available but it would be easily
             absorbed through mucous membranes

        5.3  Dermal

             It is absorbed systemically after topical application
             especially if the skin surface is not intact.

        5.4  Eye

             Very well absorbed through mucous membranes

        5.5  Parenteral

             Should not be used for therapeutic purposes.  No such
             case is reported.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Oral absorption
    
             Podophyllum is very well and rapidly absorbed after
             ingestion.
    
             As an example, in the fatal case reported by Cassidy (1982),
             the patient ingested between 10 and 11 g 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.

        6.2  Distribution by route of exposure

             No data available.  Since podophyllumtoxin is water
             soluble, a small volume of distribution may be predicted. 
             Furthermore, no rebound effects were observed after
             hemoperfusion.

        6.3  Biological half-life by route of exposure

             No data available.  The clinical effects in systemic
             poisoning frequently last for several days.

        6.4  Metabolism

             No data available.  In their case report, Heath et al.
             (1982) analyzed podophyllumtoxin in the patient plasma
             before, during and after hemoperfusion.  A rapid fall in
             plasm concentration of podophyllumtoxin 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 podophyllumtoxin
             are more toxic than podophyllumtoxin itself.  These authors
             were able to identify and measure such a metabolite during
             hemoperfusion but several other possible metabolites were
             found on analysis and removed by hemoperfusion.

        6.5  Elimination and excretion

             No data available.

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  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 haematological toxicity that
                    occasionally result in fatalities.  Rarely, poisoning
                    results from consumption of unripe fruit or plant
                    parts and causes primarily diarrhoea.  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
                    podophyllumtoxin 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
                    podophyllumtoxin 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.
    
                    Podophyllumtoxin has an inhibitory effect similar to
                    that of vinblastine on the release of iodine from the
                    thyroid gland and catecholamine from the adrenal
                    medulla (A.H.F.S. 1990).
    
                    It is classified as a cell cycle-specific (CCS) agent
                    (Salmond and Sartorelli, 1987).

             7.1.2  Pharmacodynamics

                    See section 7.1.1

        7.2  Toxicity

             7.2.1  Human toxicity

                    7.2.1.1  Adults

                             Most systemic poisoning cases
                             following topical application of podophyllum
                             involved women and some of these were fatal
                             (Ward, 1954; Fisher, 1981).
    
                             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 phospase 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.  Death can occur with
                             ingestion of podophyllum in amounts as small
                             as 350 mg (Ellenhorn and Barceloux, 1988).

                    7.2.1.2  Children

                             Fever and convulsions seem to be
                             more frequent in children.  Most reported
                             cases followed accidental ingestion.

             7.2.2  Animal data

                    The toxicological properties of
                    podophyllumtoxin were reviewed by Jardine (1980).
    
                        LD50/LC50
    
                    1.  LD50 (IV) Rat: 8.7 mg/kg
                    2.  LD50 (IP) Rat: 15 mg/kg
                    3.  LD50 (SC) Rat: 8 mg/kg
                    4.  LD50 (IM) Rat: 3 mg/kg
                    5.  LD50 (IP) Mouse: 30 mg/kg
                    6.  LD50 (SC) Mouse: 24.6 mg/kg

        7.3  Carcinogenicity

             Podophyllum is a suspected human carcinogen (Dukes and
             Beeley, 1987).

        7.4  Teratogenicity

             Podophyllum may be a teratogenic agent in humans.  At
             least two cases of possible teratogenic effects of
             podophyllum have been described (Karol, 1980; Cullis, 1962;
             Chamberlain et al., 1972).

        7.5  Mutagenicity

             Podophyllum is  mutagenic in Lalmonella typhimurium
             strain of bacteria.

        7.6  Interactions

             Other keratolytic agents may favour dermal absorption of
             podophyllum.

        7.7  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 (presenting
             signs and symptoms in parentheses where appropriate - not
             necessarily inclusive).
    
             Those indicating need for medical attention:
    
             Skin rash or itching - allergic reaction to benzoin, which
             may be present in some preparations.
             Redness, burning or other irritation of affected area or
             skin.
             Abdominal pain
             Nausea or vomiting
             Diarrhoea, sometimes severe and prolonged
             Clumsiness or unsteadiness
             Confusion
             Reduced reflexes
             Excitement, irritability or nervousness
             Hallucinations
             Muscle weakness
             Leucopenia (sore throat and fever)
             Thrombocytopenia (unusual bleeding or bruising)
    
             Delayed symptoms of systemic toxicity
    
             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.
             USPDI (1990).

    8.  TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             Leucocytosis followed by leucopenia
                             and thrombocytopenia are common and therefore
                             should be closely monitored until full
                             recovery.

                    8.3.1.2  Urine

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4 Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

             Renal and hepatic function must be monitored

             Electrolytes and calcium should be monitored especially if
             severe diarrhoea or paralytic ileus occurs.  Creatinine
             phosphokinase and myoglobin should be monitored to detect
             rhabdomyolysis.
    
             Chest X-Ray
             EEG
             EMG and peripheral nerve conduction in late phase of the
             clinical course.
             ECG especially to detect conduction defects and cardiac
             arrhythmias.

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Since there are no specific toxicological analyses
             available and the fact that podophyllumtoxin is a non-
             specific cell poison, it is essential to monitor the various
             biochemical and physiological parameters in order to detect
             early complications and rapidly correct any significant
             disturbances.
    
             Sample collection
             Blood and urine for haematological and biochemical analysis.
             Blood may be collected for later toxicological analysis
             especially for medico-legal reasons.
    
             Other investigations
             EEG, EMG with nerve conduction measurements and psychometric
             testing may be useful in the later phase of poisoning.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Ingestion may cause: nausea and vomiting, which
                    may be severe and persistent and occur rapidly after
                    ingestion.  Abdominal pain, ileus (paralytic),
                    lethargy, coma, tachypnoea, respiratory failure,
                    tachycardia, hypotension, cardiac arrhythmia,
                    cardiovascular collapse, oliguria, renal failure,
                    fever, metabolic acidosis, leucocytosis, leucopenia,
                    thrombocytopenia, pancytopenia, peripheral neuropathy,
                    death.

             9.1.2  Inhalation

                    Not applicable

             9.1.3  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 (see
                    9.1.1).

             9.1.4  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.

             9.1.5  Parenteral exposure

                    Not reported to date.

             9.1.6  Other

                    None

        9.2  Chronic poisoning by

             9.2.1  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 haematological,
                    gastro-intestinal or peripheral neuropathy.

             9.2.2  Inhalation

                    Not applicable

             9.2.3  Skin exposure

                    Repeated local treatment of warts or condyloma
                    may produce systemic poisoning or local lesions of the
                    skin (erosion, pain, bleeding, infection).

             9.2.4  Eye contact

                    Chronic poisoning not reported.

             9.2.5  Parenteral exposure

                    Not reported

             9.2.6  Other

                    Not applicable

        9.3  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 haematological complications.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Tachycardia, cardiac, arrhythmias, hypotension
                    and cardiovascular collapse.

             9.4.2  Respiratory

                    Tachypnoea
                    Respiratory failure
                    Pneumonitis (resembling chemical pneumonitis)
                    Pulmonary oedema (rarely)

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             - Confusion
                             - Lethargy
                             - Coma
                             - Convulsions

                    9.4.3.2  Peripheral nervous system

                             Peripheral neuropathy which develops
                             over several days and may take weeks or
                             months to regress.  There may be permanent
                             sequelae.

                    9.4.3.3  Autonomic nervous system

                             - Paralytic ileus

                    9.4.3.4  Skeletal and smooth muscle

                             Rhabdomyolysis may occur with
                             myoglobinuria.  This may aggravate the renal
                             failure.  Phosphokinase (CPK) should be
                             monitored.

             9.4.4  Gastrointestinal

                    - Nausea and vomiting which may be persistent
                    and severe;
                    - abdominal pain;
                    - paralytic ileus;
                    - diarrhoea which may produce water and electrolyte
                    imbalance.

             9.4.5  Hepatic

                    Elevation of hepatic enzymes: (ast; GOT), (alt;
                    GPT), alkaline phosphatase.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             - Oliguria
                             - Renal insufficiency

                    9.4.6.2  Other

                             - Cystitis
                             - Painful micturition

             9.4.7  Encodrine and reproductive system

                    - Fetal death
                    - Abortion
                    - Premature labour
                    - Fetal malformations

             9.4.8  Dermatologic

                    - Pruritus around the treated sites especially
                    if the skin has not been protected by petroleum jelly
                    - Irritation
                    - Urticaria
                    - Skin necrosis
                    - Bleeding
                    - Scarring of tissue, especially of anogenital regions
                    - Paraphimosis that may require circumcision
                    - Pseudo-epitheliomatosis hyperplasia

             9.4.9  Eye, ear, nose, throat: local effects

                    - Irritation
                    - Skin or mucous membrane
                    - Necrosis
                    - Scarring of tissues
                    - Bleeding
                    - Corneal erosion

             9.4.10 Haematological

                    - Leucocytosis followed by leucopenia
                    - Anaemia
                    - Thrombocytopenia
                    - Pancytopenia

             9.4.11 Immunologic

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid base disturbances

                             Metabolic acidosis

                    9.4.12.2 Fluid and electrolyte disturbances

                             They may occur secondary to
                             vomiting or diarrhoea.

             9.4.13 Allergic reactions

                    Urticaria

             9.4.14 Other clinical effects

             9.4.15 Special risks:

                    The use of podophyllum is contraindicated in
                    pregnant or lactating women.

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Perform gastric lavage if patient is seen early. 
             Administer activated charcoal.
    
             If topical contact: wash with soap and water.  Repeat until
             pain disappears.  Remove any residual solid podophyllum
             material.
    
             No specific treatment is available.  Intensive supportive
             therapy may be required.

        10.2 Life supportive procedures and symptomatic treatment

             Maintain vital signs

        10.3 Decontamination

             Wash with soap and water if skin contact has occurred. 
             Irrigate eyes with water after eye contact.

        10.4 Enhanced elimination

             Haemoperfusion should be used for severe systemic
             poisoning since it has been shown to be effective in reducing
             the plasma fraction of podophyllumtoxin and other active
             metabolites but its real impact on the course of the disease
             has not been sufficiently documented to date.  Haemodialysis
             is unlikely to be effective in removing podophyllumtoxin or
             its metabolites.

        10.5 Antidote treatment

             10.5.1 Adults

                    None available.

             10.5.2 Children

                    None available

        10.6 Management discussion

             Further research is required on toxicokinetics and
             elimination procedures.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from the literature


        Age/   Dose:       Onset of    Nausea/   Peripheral   Lethargy   Tachypnea   Respiratory   Hematologic        Other       Outcome
    sex    topical/    symptoms    vomit     neuropathy   (L)                    failure       findings
           ingested                                       Coma (C)
    
    60 F   325mg       Few           X                       C           X                                        haematuria  Death
           topical     hours                                                                                                  at 31 h
    18 F   ?,          <12 h        X           X           C           X                                         Renal       Death at
           topical                                                                                                failure,    7 d
                                                                                                                  ileus
    25 F   2.8g        <24 h        X           X           C                                                                 Minimal
           ingested                                                                                                           neuropathy
                                                                                                                              at 16 months
    19 F   ?,          4.5 h         X                                   X                                                    No
           topical                                                                                                            sequelae
           and 1 g
           ingested
    2 F    350 mg,     3 h           X                       L                                 Leukocytosis       Fever       Survived
           ingested                                                                            anaemia            seizure
    25 M   160mg,      2 h           X           X                       X                                                    Survived
           ingested
    71 M   ?,          < 24 h       X                                                                                         Survived
           topical
           on tongue
    18 F   1.88g,      Few           X           X                                    X                                       Neuropathy
           topical     hours                                                                                                  resolved at
                                                                                                                              9 months
    20 F   ?,          13.5 h        X           X           C           X                     Leukocytosis       High        Discharged
           topical                                                                                                amylase     at 25 d with
                                                                                                                              neuropathy
    16 F   1 g,        7 h           X           X           C                        X        Leukocytosis       Abdominal   Neuropathy
           topical                                                                                                pain        at 4 months
    15 F   ?,          Few           X                       L           X                     Pancytopenia                   Survived
           topical     hours
    

    Age/   Dose:       Onset of    Nausea/   Peripheral   Lethargy   Tachypnea   Respiratory   Hematologic        Other       Outcome
    sex    topical/    symptoms    vomit     neuropathy   (L)                    failure       findings
           ingested                                       Coma (C)
    
    20 F   150 mg,     <24 h        X           X           L           X                     Pancytopenia                    Minimal
           topical                                                                                                            neuropathy
                                                                                                                              at 4 yr
    17 F   400 mg,     20 h          X           X           C           X            X        Leukocytosis,                  Complete
           topical                                                                             then leukopenia,               recovery at
                                                                                               thrombocytopenia               10 months
    2 F    1 g,        9 h                       X           C                                                    Fever       Neuropathy
           ingested                                                                                               seizure     at discharge
    59 M   10 g,       10 h                      X           C           X            X        Leukocytosis       Renal       Death at
           ingested                                                                            with abnormal      failure     39 h
                                                                                               morphology
    
    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             No data available.

        12.2 Other

             No data available.

    13. REFERENCES

        American Society of Hospital Pharmacists (1990) American
        Hospital Formulary Service, p. 2055-57.
    
        Association Pharmaceutique Canadienne (1990) Compendium des
        produits et spécialités pharmaceutiques (25ième ed.) p. 969-70.
    
        Budavari  S ed. (1996)  The Merck Index: An Encyclopedia of
        Chemicals, Drugs, and Biologicals. 12th ed. Merck & Co., Inc,
        Whitehouse Station, NJ.
    
        Chamberlain MJ, Reynolds AL & Yeoman WB (1972) Toxic effect of
        podophyllum application in pregnancy. Brit Med J, 8549: 391-392.
    
        Cassidy DE, Drewry J & Fanning JP (1982) Podophyllum toxicity: A
        report of a fatal case and a review of the literature. J Toxicol,
        19 (1): 35-44.
    
        Cullis JE (1962) Congenital deformities and herbal "slimming
        tablets". Lancet 2: 511-512.
    
        Dukes MNG & Beeley L (1987) In: Side effects of drugs annual 11.
        Elsevier, Amsterdam, New York, Oxford. p. 516.
    
        Ellenhorn MJ & Barceloux DG (1988) Medical toxicology. Elsevier,
        New York, Amsterdam, London. p. 1268-69.
    
        Fisher AA (1981) Severe systemic and local reactions to topical
        podophyllum resin. CUTIS, 28: 233-248 & 266.
    
        Heath A, Mellstrans T & Alhmen J (1982) Treatment of podophyllum
        poisoning with resin hemoperfusion. Human toxicol, 1: 373-378.
    
        Jardine I (1980) Podophyllumtoxin. In: Anticancer agents based on
        natural product models (Academic Press), 319-351.
    
        Karol MD, Conner CS, Watanabe AS & Murphrey KJ (1980) Podophyllum:
        suspected teratogenicity from topical application. Clin Toxicol
        16(3):283-286.
    
        Salmon SE & Sartorelli AC (1987) Cancer Chemotherapy. In: Basic
        and clinical pharmacology, Katzung BG, ed. Lange 3rd ed., 665-78.
    
        United States Pharmacopoeial Convention, Inc. (1990) USPDI. Drug
        information for the health care professional, p. 2270-72.
    
        Ward JW, Clifford WS, Monaco AR & Bickerstaff HJ (1954) Fatal
        systemic poisoning following podophyllum treatment of condyloma
        acuminatum. Southern Med J, 75(10): 1204-1206.

    14. AUTHOR(S), REVIEWER(S), DATE (S)

        Author: A.J. Nantel
        directeur
        Centre de Toxicologie du Québec
        Le Centre Hospitalier de l'Université Laval
        2705, boul. Laurier, local 800
        Sainte-Foy (Québec)
        GIV 4G2  Canada
    
        Tél. 654-2254
        Fax. 654-2754
    
        Peer review: Newcastle, U.K. (Janvier 15-19, 1991)
        Adelaide, Autralie (Avril 8-12, 1991)
    
        Editor: Dr M. Ruse (August, 1997)