PATIENT-APPLIED PODOFILOX FOR TREATMENT OF GENITAL WARTS

831 TABLE I-DEMOGRAPHIC AND WART CHARACTERISTICS OF STUDY POPULATION

Therapeutics PATIENT-APPLIED PODOFILOX FOR TREATMENT OF GENITAL WARTS MARCUS A. CONANT1 KARL R. BEUTNER1-3 MARK ILLEMAN1 ALVIN E. FRIEDMAN-KIEN4 RONALD A. THISTED5 NITZA N. ARTMAN4 DANNIE H. KING3

Department of Dermatology, University of California, San Francisco;1 Department of Medicine, Sutter Solano Medical Center, Vallejo, California;2 Oclassen Pharmaceuticals, Inc, San Rafael, California;3 New York University Medical Center, New York;4 Department of Statistics, University of Chicago, USA5 In

a double-blind trial, 0·5% podofilox (podophyllotoxin) or placebo was applied by patients to their own genital warts in up to four treatment cycles. At some time during the study, 25 of the 56 podofilox treated patients and none of the 53 placebo group were

Summary

completely wart-free. At the end of the treatment, 73·6% of the original warts in podofilox treated patients were gone compared with only 8·3% of those in the placebo group (mean percentage of total original wart area was reduced by 82·3% compared with 4·2%). 82% of the treated warts in the podofilox group and 13% in the placebo group had resolved at 6 weeks. Recurrence was observed in 34% of the resolved warts. Consistent with this rate of recurrence, new warts developed in a third of the subjects in each group at sites remote from the treatment site. There were no systemic adverse reactions, although transient inflammation, erosion, pain, and burning were common.

previously

*Values

are means (SEM). tPercentage of warts.

evaluate the safety and efficacy of patient-applied podofilox for treatment of genital warts. controlled trial

to

PATIENTS AND METHODS

Patients men (18 years) with a clinical diagnosis of genital warts enrolled. The number of warts to be treated was between two and twenty in an area not exceeding ten cm2. Patients were excluded from the study if they had the following: untreated syphilis, frequent genital herpes, or a history of bowenoid papulosis; they were also excluded if they gave unreliable answers to questions about history, if they had been treated for genital warts within a month of study entry, or if history and physical examination indicated that they might have been immunocompromised. The study was approved by the institutional review board of each investigator’s study centre: patients who met the entry criteria gave written informed consent before entry into the study.

109

were

INTRODUCTION

SINCE the mid 1960s, the incidence of genital warts has increased rapidly.’ Infection with the causal agent-human papillomavirus (HPV)—may be latent2or subclinical 4,5 and may also be a contributory factor for cervical and genital cancers.6,7 Podophyllum resin has been used for genital 1940s.8 This resin, derived from warts since the emodi or Podophyllum Podophylium peltatum, contains many active biologically lignan compounds including podofilox (podophyllotoxin), ot-peltatin, &bgr;-peltatin, and 4-demethylpodophyllotoxin.9,lo Podofilox is the most thoroughly characterised of these compounds and is thought to be the most active against genital warts.1,10 A regimen, developed by von Krogh ’111-12 whereby patients applied 0,5% podofilox to their own warts was safe, well tolerated, and seemed to be at least as effective as traditional office or clinic based therapy. We here report the first multicentre, placebo-

9. Walter SD. On the detection of household aggregation of disease Biometrics 525-38.

The study medication was 05% podofilox in lactate buffered USP alcohol, and the placebo consisted of the vehicle alone. Patients were randomly assigned to either 05% podofilox (56 patients) or placebo (53). The two groups were comparable in baseline characteristics of age, height, weight, initial wart area, initial wart count, and anatomical location of warts (table i). The randomised list was prestratified according to the duration of the patient’s present episode of genital warts-ie, about half (n 55) of the patients had had their current episode of genital warts for 12 months or less and half (54) for more than 12 months. The investigator asked the patient to apply the medication only to intact lesions and to avoid adjacent uninvolved skin or bleeding or inflamed lesions. Medication was applied in treatment cycles: a treatment cycle consisted of twice daily application (morning and evening) to external genital warts for 3 consecutive days followed by a 4 day period without treatment. At the end of each treatment cycle, patients returned to the investigator for evaluation and for =

1974; 30:

10. Kleinbaum

In:

Study Design

DG, Kupper LL, Morgenstem H. Principles and quantitative methods. Epidemiologic research. Belmont, California Lifetime Learning Publications,

1982: 298-99, 319.

15 16.

11. Anon. Documenta

Geigy: Scientific tables, 6th ed. Basel: Geigy, 1962: 85-194, 185. F, Gershy-Damet G, et al Prevalence of human T-lymphotropic

12 Denis F, Barin retroviruses type III (HIV) and type IV in Ivory Coast Lancet 1987; i. 408-11. 13. Varnier OE, Lillo FB, Reina S, De Maria A, Terragna A, Schito G. Whole blood collection on filter paper is an effective means of obtaining samples for human immunodeficiency virus antibody assay. AIDS Res Human Retroviruses 1988, 4: 131-36. 14. Lindhardt BØ, Bygbjerg IC, Ulrich K, Petersen HD, Lausen I, Frederiksen B

17. 18. 19. 20.

Detection of antibodies to human immunodeficiency virus (HIV) in eluates from whole blood impregnated filter paper discs. J Virol Methods 1987; 18: 73-77. Fultz PN, Switzer WM, Schable CA, et al. Seroprevalence of HIV-1 and HIV-2 in Guinea-Bissau in 1980. AIDS 1988; 2: 129-32. Dufoort G, Comroucé AM, Ancelle-Park R, Bletry O. No clinical signs 14 years after HIV-2 transmission via blood transfusion. Lancet 1988; ii: 510. Ancelle R, Bletry O, Baglin AC, Brun-Vézinet F, Rey MA, Godeau P. Long incubation period for HIV-2 infection Lancet 1987, i 688-89. Burin des Roziers N, Bruet A, Leger JP, et al Infection par le virus HIV-2 avec longue periode d’incubation. Presse Médc 1987; 16: 1981. N’Galy B, Ryder RW, Bila K, et al. Human immunodeficiency virus infection among employees in an African hospital N Engl J Med 1988; 319: 1123-27. Kong LI, Lee SW, Kappes JC, et al. West African HIV-2-related human retrovirus with attenuated cytopathicity. Science 1988; 240: 1525-29.

832 instruction about continued application of medication. The maximum number of treatment cycles permitted was four and the minimum number was two. The site, number, and size of warts before study entry (baseline), at the end of weeks 1, 2, 3, 4 (during treatment evaluations), and after weeks 6, 12, and 16 (during post-treatment follow-up evaluations) were recorded. Most patients who had new lesions or who had not responded to therapy at the end of week 2 were withdrawn from the study at that time. Patients classified as clinically "cured" at the end of week 6 returned at weeks 12 and 16 for follow-up examinations. Any recurrence of lesions or formation of new lesions were recorded by the investigator. A new wart was defined as one that arose during the course of the study at a site distinct from that of original warts. A recurrent wart was difficult to define precisely, because it was often difficult to establish whether the "new" or "recurrent" wart was at the exact site or only in the vicinity of an original wart. Our definition of a recurrent wart was one that appeared near the site of an original baseline wart after complete healing. Patients with recurrent or new warts at week 12 were excluded from further evaluation.

Efficacy and Safety Efficacy was measured by three indices: change in wart count; change in wart area; and number and percent of patients completely cleared.

Systemic safety and toxicity were evaluated by patient reports of adverse reactions, by investigator reports of systemic adverse reactions, and by baseline and follow-up laboratory tests. Baseline evaluations, which included a Venereal Disease Reference Laboratory (VDRL) test, routine haematology, serum chemistries, and urinalysis, were done before study entry and at the final visit of each treatment period irrespective of the treatment outcome. Local adverse reactions, which included pain, burning, inflammation, erosion, and others (to be specified by the investigator after examination of the patient), were classified as none, mild, moderate, or severe. These measurements were recorded at each visit during treatment (weeks 1-4) and at the first follow-up visit (week 6). Statistical Analysis We assessed group differences using two-sample t tests for continuous measurements, and x2-tests with continuity correction for discrete measurements.13 Throughout our study we report two-sided p values. We assessed safety by comparing frequency and type of symptoms recorded at each evaluation and by comparing baseline measurements with end of treatment measurements for haematology and serum chemistry test results. RESULTS

Efficacy (Figure) The

number of treatment cycles was 3-3 for the placebo group and 3-2 for the podofilox group. There was a pronounced decrease in the mean percentage of visible wart count and wart area in the podofilox group (fig 1). At the end of treatment (week 4), 73-6% of all podofilox treated warts were gone whereas only 8-3% of placebo-treated warts mean

TABLE II-LOCAL REACTIONS TO

*No of patients with

reaction/total no of patients examined that week.

Comparison of treatment groups. Reduction in percentage of original wart count (top) and wart area (bottom) of warts or wart area at a particular observation point divided by no of warts or area at the time of entry multiplied by 100. is

no

resolved, and the total

wart area was reduced by 82-3% in podofilox group compared with only 4-2% in the placebo group. These differences were significant (p = 0-0001) at each comparative evaluation (weeks 1-6) for both measures. Duration of infection (< 12 months vs > 12 months) did not influence the therapeutic response (data not shown). Comparative evaluations could not be made at weeks 12 and 16 because there were no patients left in the placebo group, generally because they had not responded to therapy. At week 6, 82% (260/317) of podofilox treated warts had completely resolved and in 34% (88/260) of these there was some evidence of recurrence. By contrast, only 13% (20/158) of placebo treated warts had completely

the

resolved with one recurrence. 25 (44-6%) of the 56 patients in the podofilox group and none of 53 patients in the placebo group were completely free of warts at some time during the treatment (p < 0001). 10 (40%) of the 25 podofilox treated patients who completely healed during the study never had a recurrence of wart tissue. The study population was in a very active state of infection: new warts were seen in 17 (32%) of 54 and 0-5%

PODOFILOX AND TO PLACEBO

833

in 17

(33%) of

52 of the

placebo

and

podofilox

groups,

respectively. Adverse Reactions (Table II)

clinically important systemic reactions or abnormalities attributable to podofilox. The laboratory There

were no

adverse reaction in the podofilox group, in 64% of the patients at some recorded inflammation, time during the study but in only 6% of the placebo group. Other adverse reactions included erosion of skin (63% podofilox vs 4% placebo), burning (59% vs 36%), and pain (46% vs 13%). Itching was the most common "other" adverse reactions and was noted by 7 of the podofilox group. There were 4 cases of dyspareunia, 2 of insomnia, and 1 each of "tingling", bleeding, tenderness, chaffing, malodour, scarring, vesiculation, crusting, and xerosis. All local adverse reactions were transient and reversible: with only a few exceptions, reactions were mild or moderate. 2 patients treated with podofilox had severe pain and burning, 1 severe inflammation, and 5 severe erosions.

most common local was

DISCUSSION

Our study shows the efficacy and safety of patient-applied podofilox for the treatment of genital warts. The therapeutic response of the placebo group was lower than expected. However, in other placebo-controlled studies the test medication was given by intralesional injection whereas our patients applied it topically. According to our study protocol, patients who showed no change or progression at week 2 were regarded as treatment failures and were dropped from the study. Hence, nearly half of the placebo patients were not followed after week 2 of the study. Podofilox therapy was tolerated well with no systemic or laboratory evidence of toxicity. Local reactions were predictable for a drug which destroys wart tissue and which is given in an alcoholic vehicle. Our results are comparable with those of von Kroghll who reported cure rates with self-administered 0-5% podofilox (54%) vs office administered 8% podofilox (48%). In a subsequent study, the cure rates with twice daily application of 0-5% podofilox for 4 and 5 days were 63% and 70%, respectively, and for daily application 35% and 42%, respectively;12 von Krogh concluded that treatment was best given twice daily in 3-day cycles. Others14 reported 68% (17/25) and 65% (17/26) cure rates with patient-applied podofilox solution and cream, respectively, compared with a 33% (8/24) rate with physician-applied podophyllum resin. Thin and co-workers15 reported resolution of warts in 88% (28/32) of patients using 0-5% podofilox compared with 53% (12/19) of patients having podophyllum resin. The major differences between the present study and that of von Krogh are the placebo control used in our study, the use of multiple treatment cycles, and the site of the warts. In von Krogh’s studies, 80-90% of the treated warts were within the urinary meatus or preputial cavity. In these moist occluded sites, warts respond well to topical treatment. In our study, 88% of the treated warts were on the shaft of the penis. Such lesions are often partly keratinised and relatively dry, and are unresponsive to therapy. Interferon is the only other substance which has been thoroughly evaluated in controlled trials for the treatment of genital warts., In these studies, 20-30% of the treated warts recurred.18,19 In our study, up to 82% of podofilox treated warts completely resolved and recurrence rates were comparable with those seen for interferon. 36-62% of warts resolve after intralesional injection of natural and recombinant cx-interferons and natural

05%

(3-interferon 2 or 3 times per week for 3-8 weeks. 16--19 As well pain at the injection site, interferon often leads to systemic reactions characterised by fever, chills, myalgia, and

as

malaise.16--19 None of the existing regimens for treatment of warts prevents recurrence. Most therapies, including podofilox, destroy visible wart tissue. Many patients also have subclinical HPV infection which may be detected by the application of acetic acid and by colposcopy.4,5 The presence of HPV DNA in apparently normal tissue from patients with warts points to latent infection; recurrence may thus represent the natural history of latent or subclinical HPV infection rather than a failure of therapy. Podofilox and its use in wart therapy has been recently reviewed.2O The biological activity of podofilox may be due primarily to its antimitotic effect: it binds reversibly to tubulin at a site close to, but not identical to, the binding site of colchicine.21 The application of the drug to genital warts results in necrosis.22 When 0-5% podofilox is applied to the skin of mice there is damage to dermal circulation as evidenced by leaks in the microcirculation.23 Podofilox also inhibits nucleoside transport,21 and, at non-lethal concentrations, inhibits mitogen response of human lymphocytes, induces production of interleukin-1 by human monocytes and of interleukin-2 by human lymphocytes in the presence of mitogen, and enhances macrophage proliferation.24 Thus, the efficacy of podofilox in the treatment of warts may be attributable to interference with microtubular function of the keratinocytes that constitute the warts as well as the vascular structures which provide blood to the tissue, and to local immunoregulatory effects. The concentration and volume of drug used in this study were such that both the daily and the total doses of podofilox were low. Volumes of between 5 ul and 100 ul are adequate to cover genital warts of 4 cmz or less.25 Each treatment with a 100 ul volume of 0-5% podofilox solution per application would represent a dose of 0-58 mg of podofilox. At these concentrations there is little systemic absorption of drug.25 By contrast, a single 100 III application of podophyllum resin provides 2-5-10-0 mg of podofilox as well as 0-5-2-5 mg of other biologically active lignans. A treatment cycle (twice daily for 3 days) of 0-5% podophyllotoxin would be equivalent to a dose of 600 ul or 3,55 mg of the drug given over three days. Podofilox has been given intravenously to patients with neoplastic disease at daily doses of 0°5-1 °0 mg/kg per day: a mean cumulative dose of 6-0 mg/kg led to some bone marrow or gastrointestinal toxicity.26.27 Excessive ingestion or application of podophyllum resin had led to severe toxic reactions.28 There have been no reported systemic reactions to podofilox which is commercially available in some countries in Scandinavia and Europe. Although recent therapeutic advances such as interferon and laser surgery offer great promise for patients with genital warts, the expense, manner of administration, and materials may limit the number of patients who might benefit from these treatments. Patient-applied podofilox offers promise as a safe and effective first line therapy for patients with genital warts. We thank Steve Hutcherson of Project Management Consultants, Richmond, Virginia, and Pharmaquest Corporation, Corte Madera,

California for technical assistance. This work

was

supported by Oclassen Pharmaceuticals,

Correspondence should be addressed Vallelo, California 94590, USA.

to

Inc.

K. R. B., 1516

Napa Street,

834

development since the US trade embargo has blocked the importation of all medical supplies and equipment. Cuba has also developed an integrated mental health system, which puts emphasis on prevention and community care. Treatment approaches are based in part on social systems models, which focus on current problems and disLurbances.2

Round the World From

our

Correspondents

Cuba CUBAN HEALTH RECORD CHALLENGED

75 Cuban doctors practising in the USA and calling themselves Physicians for Honor and Peace for the Cuban People, have sent an open letter addressed to Dr Fidel Castro, President of Cuba, whom they challenge about the welfare of the Cuban people, and especially about health issues. Since one of the first promises of the

revolutionaries who overthrew the dictator Batista 30 years ago was a striking improvement in health care, it seems worth reviewing this record in the light of the allegations now made. Before the revolution most Cubans had little access to medical care. 60% of all hospital beds in the country, and most of the doctors, were in the capital Havana. Medical treatment needed to be paid for privately. There was an exodus of at least half of these doctors shortly after the revolution, something noted in other countries in the region when right wing or even frankly authoritarian governments have been toppled. Though a basically poor country, an ambitious and comprehensive programme in public health and education was launched, so far unmatched by any other Latin American nation. Based on regional models, the service aimed to provide integration of preventive with curative, social with medical, and environmental with personal health services.’ Priority was given to rural and poor areas to eliminate the substantial inequalities in provision which previously existed. Cuba did not choose to go down the "barefoot doctor" route, taking instead the far more costly course of traming Western style doctors. Expenditure on health is 15 % of GNP (U SA’s is 10%). Treatment is free. Cuba has one doctor for every four hundred of its 10 million people (USA 1 for 540, Brazil 1 for 1740) and at present there are 28 000 medical students enrolled m 21 medical schools. Several thousand Cuban doctors serve abroad-especially in Vietnam, Ethiopia, Angola, and Nicaragua-without cost to the host countries. The number of hospital beds increased from 26 000 in 1958 to 66 000 in 1988. Hospital services extend to advanced treatment such as organ transplantation. Medical care in the community is centred on poly clinics, each serving 20 000-30 000 people. 83% of all drugs are rnanufactured by Cuba’s own pharmaceutical industry, a crucial

1.

Anonymous. Condyloma acuminatum—United States, 1966-1981.

MMWR 1983;

32: 306-08. 2.

Steinberg BM, Topp WC, Schneider PS, Abramson AL. Laryngeal papillomavirus infection dunng clinical remission N Engl J Med 1983; 308: 1261-64 3. Ferenczy A, Mitao M, Nagai N, Siverstein SJ, Crum CP. Latent papillomavirus and recurring genital warts. N Engl J Med 1985, 313: 784-88. 4. Sedlacek TV, Cunnane M, Carpinella V Colposcopy in the diagnosis of penile condyloma. Am J Obstet Gynecol 1986; 154: 494-96 5. Barrasso R, DeBrux J, Croissant O, Orth G. High prevalence of papillomavirus associated penile intraepithelial neoplasia in sexual partners of women with cervical intraepithelial neoplasia. N Engl J Med 1987, 317: 916-23. 6. Durst M, Gissman L, Ikenberg H, Zur Hausen H A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA 1983; 80: 3812-15. 7. Cancer cells. In: Steinberg BM, Brandsma JL, Taichman LB, eds Papillomaviruses. Cold Spring Harbor, NY: Coldspring Harbor Laboratory, 1987. 8. Kaplan IW. Condylomata acuminata. New Orleans Med Surg J 1941 1942, 94: 388-90. 9. von Krogh G, Maibach HI Cutaneous cytodestructive potency of lignans. II. A comparative evaluation of macroscopic-toxic influence on rabbit skin subsequent to repeated 10-day applications. Dermatologica 1983; 167: 70-77. 10. von Krogh G. Topical treatment of penile condylomata acuminata with podophyllin, podophyllotoxin and colchicine. Acta Derm Venereol (Stockh) 1978; 58: 163-68. 11. von Krogh G Penile condylomata acuminata. an experimental model for evaluation of topical self-treatment with 0 5%-1·% ethanoic preparations of podophyllotoxin for three days. Sex Transm Dis 1981, 8: 179-86. 12 von Krogh G. Topical self-treatment of penile warts with 0 5% podophyllotoxin in ethanol for four or five days Sex Transm Dis 1987; 14: 135-40 13 Snedecor GE, Cochran WG. Statistical methods, 6th ed Iowa: Iowa State University Press, 1967. 14. Mazurkiewicz W,

Jablonska S Comparison between the therapeutic efficacy of 0 5% podophyllotoxin preparations and 20% podophyllin ethanol solution in condylomata acuminata. Z Hautkr 1986; 61: 1387-95 15. Edwards A, Aima-Ram A, Thin RN Podophyllotoxin 0 5% versus podophyllin 20%

Cuba’s health statistics rival those of the industralised world and indeed it is ironical that the health profile has begun to shift towards that of "developed" nations: cancer, ischaemic heart disease, and stroke are the leading causes of death. Life expectancy has climbed from 57 years in 1958 to 74 now. Infant mortality was 60/1000 live births in 1958, down to 27 by 1975 and to 133 now.3 By comparison the USA figure is 112 overall, though as high as 21 amongst blacks and those of Hispanic origin. There has been a marked fall in deaths from malaria gastroenteritis, measles, and neonatal tetanus, and polio has been eradicated. In the 1950s there were 5000 new cases of TB a year, but now less than 100.4 These advances have been confirmed in independent work published in international journals. The 75 doctors offer no evidence for their assertion that Cuba conceals the true incidence of infectious diseases, including AIDS. They also allege that Cuba has failed to develop plans to counter the AIDS threat. The facts are that Cuba has been deploying measures which are vigorous to the point of controversy. With the aim of early detention and containment, Cuban Ministry of Health figures indicate that, by early 1988, over 1,1million people-15% of the sexually active population-had been screened and 147 HIV positive individuals detected. Only a handful have died of AIDS so far. Routine testing of pregnant women had produced no cases out of 23 000 screened. All HIV positive cases are being intemed-on full salary-in a sanatorium. This controversial measure is being defended on the grounds that the virus appears to be in only the early stages of spread (unlike thaI of some other countries) and thus isolation of carriers may make a considerable difference. The letter also alleges that Cuba has the highest rate of violent death in the hemisphere. In fact it is El Salvador, Guatemala, and Nicaragua who must compete for this chilly statistic. The political fluxes which underpin the continuing violence in Central America are influenced by US policies in the region, a fact which the signatories, having adopted the USA as their home, must surely know. Alterations in the organisation and delivery of health care have been paralleled by broader political, economic, and social change within the country. That these health gains have been founded on this restructuring—and not just the size of the health budget-may be relevant to the problems facing the world’s poorest nations.

to treat penile warts Genitourin Med 1988; 64: 263-65 16. Vance JC, Bart BJ, Hansen RC, et al. Intralesional recombinant alpha-2 interferon for the treatment of patients with condyloma acuminatum or verruca plantaris. Arch Dermatol 1986, 122: 272-77 17. Eron LJ, Judson F, Tucker S, et al. Interferon therapy for condylomata acuminata.

N Engl J Med 1986; 315: 1059-64. M, et al. Natural interferon alfa for treatment of condylomata acuminata JAMA 1988; 259: 533-38 Reichman RC, Oakes D, Bonnez W, et al Treatment of condyloma acuminatum with three different interferons administered intralesionally. Ann Intern Med 1988; 108:

18 Fiiedman-Kien AE, Eron L], Conant 19

675-79 20. Beutner KR.

Podophyllotoxin in the treatment of genital human papillomavirus infection: a review. Semin Dermatol 1987, 6: 10-18. 21. Loike JD, Horowitz SB. Effects of podophyllotoxin and VP-16-213 on microtubule assembly in vitro and nucleoside transport in HeLa cells. Biochemistry 1976; 15: 5435-42. 22 Wade TR, Ackerman AB. The effects of resin of podophyllin on condyloma acuminatum. Am J Dermatol 1984; 6: 109-22 23. von Krogh G, Maibach HI. Cutaneous cytodestructive potency of lignans. I. A comparative evaluation of epidermal and dermal DNA synthesis and on dermal microcirculation in the hairless mouse Arch Dermatol Res 1982; 274: 9-20. 24 Zheng Q-Y, Wiranowska M, Sadlik JR, Hadden JW. Purified podophyllotoxin (CPH-86) inhibits lymphocyte proliferation but augments macrophage proliferation. Int J Immunopharmacal 1987, 9: 539-49. 25. von Krogh G Podophyllotoxin in serum: absorption subsequent to three-day repeated application of 0 5% ethanoic preparation on condylomata acuminata. Sex Transm Dis 1982, 9: 26-33 26 Savel H. Clinical experience with intravenous podophyllotoxin. Proc Am Assoc Cancer Res 1964; 5: 56. 27. Savel H The metaphase-arresting plant alkaloids and cancer chemotherapy Prog Exp Tumor Res 1966, 8: 189-224. 28 Cassidy DE, Drewry J, Fanning JP Podophyllum toxicity a report of a fatal case and a review of the literature J Toxicol Clin Toxicol 1982; 19: 35-44