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   Chemical Nature ...
   Mode of Action
   Clinical Uses
   Side Effects
   Precautions
   Preparations
   Conclusion
   References

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CONTINUING MEDICAL EDUCATION
Year : 1990  |  Volume : 56  |  Issue : 1  |  Page : 10-14

Podophyllin and its use in the treatment of condylomata acuminata


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Correspondence Address:
J A Sundharam


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How to cite this article:
Sundharam J A. Podophyllin and its use in the treatment of condylomata acuminata. Indian J Dermatol Venereol Leprol 1990;56:10-4

How to cite this URL:
Sundharam J A. Podophyllin and its use in the treatment of condylomata acuminata. Indian J Dermatol Venereol Leprol [serial online] 1990 [cited 2014 Apr 24];56:10-4. Available from: http://www.ijdvl.com/text.asp?1990/56/1/10/3469


After the discovery of podophyllum resin it 1835 by John King,[1] it was put to numerou innovative therapeutic uses over the next century ranging from as a laxative and liver tonic, cancers. However, it was only in 1942 tha Kaplan[2] put it to the use for which it is popu larly used now, viz, the treatment of venerea warts.

Podophyllin is a resinous mixture extractec from the dried rhizome and roots of Podoplryllui emodi (found in the Himalayan regions of northern India), and Podophylluin peltatun (May apple or American Mandrake found it north America).[3],[4] The resin content of P emodi (6-12%) is approximately twice that of P. peltatum(2-8%).[5]


  Chemical Nature of Podophyllin Top


The active components of podophyllin arc a class of compounds-the lignans, which arc characterized by a dibenzyl-butane skeleton.[4] The commercially available resin is not standar­dized for lignan content and thus different batches may vary markedly in their content of these substances. [6] Podophyllotoxin is the major lignan in both the resins. However, small quantities of 4'-demethyl podophyllo­toxin, alpha and beta peitanin are also present. The maximum lignan content in P. ,peltatum is about 20%, while in P. cinodi, it may approach 40%.[3]

sub Sullivan[7] has described in detail, a method by which crystalline podophyllotoxin may be extracted front podophyllin. Using modern methods such as liquid chromatography however, chemically pure podophyllotoxin and other lignans can be isolated.[8] The empirical formula of podophyllotoxin has been calculated to be C 22 H 22 ,O 8 .


  Mode of Action Top


Lignans destabilize the polymerization of tubulins into helical microtubular structures that are involved in chromosome movement during cell division.[9] They also suppress cellular nucleoside transport. These effects produce a metaphase mitotic arrest with sub­sequent cellular necrosis. In addition, an antiviral effect has also been demonstrated.[3]

Its anti-mitotic effect is partly responsible for the systemic toxicity. Tissues with a high rate of proliferation (bone marrow, lymph follicles, intestinal mucosa) are most susceptible to the toxicity of podopl yllin. Microtubules also contribute to the cytoskeleton which is involved in the maintenance of asymmetrical cell shapes, including those of axons and neurons. This may explain the susceptibility of the non­proliferative nerve cells to damage by the lignans.[10]


  Clinical Uses Top


Miller[4] has documented the use of topical podophyllir in over 25 different conditions. These range from infective diseases such as tinea capitis and molluscum contagiosum, to various benign and malignant tumours such as solar keratosis and basal cell carcinoma. Currently however, the use of podophyllin is almost entirely restricted to the treatment of venereal warts. A single topical application of podophyllin cures less than one third of patients with genital warts.[11],[12] Most authors have emphasized the need for multiple appli­cations of podophyllin[13],[14],[15],[16] sometimes supple­mented by other drugs such as di- or trichloro­acetic acid.[12]

It has been observed that patients with fewer, and small warts, limited to the preputial cavity or the transitional area of the prepuce and of less than six months duration responded the best.[11] A larger number of lesions (more than five), especially of the plaque type, involve­ment of the urinary meatus or skin, and longer duration of the lesions were associated with a poor response.

In an attempt to reduce expensive, time­consunling physician consultations without at the same time exposing the patient to systemic toxicity, von Krogh[11] experimented with a three-day self treatment regimen using low concentrations of podophyllotoxin in ethanol. The response was, surprisingly, even better than podophyllin in the usual concentrations applied topically. This questions the entire concept of weekly applications of podophyllin for the treatment of genital warts. Further, the incidence of side effects was not significantly different from the traditional, physician-applied treatments.


  Side Effects Top


Topical application of podophyllin produces an acute inflammatory reaction with necrosis of the treated area. Some degree of irritation of the surrounding area ranging from a peripheral erythematous halo, to extensive erythema, edema and ulceration is almost universal. Inflammation is more common in men with long redundant foreskins. In such cases, balanitis and phimosis have sometimes necessitated circumcision.[5] Severe chemical burns with extensive scarring of the ano-genital area leading to fistula formation has been reported.[5]

True allergic hypersensitivity to podophyllin resin is also known. More often, however, the hypersensitivity is due to the vehicle (benzoin)[5] in which podophyllin is compounded, or to the other contaminants and adulterants (guaicium wood).[17]

An infiltrative, hyperplastic reaction simulat­ing epithelioma has been seen on occasions after the application of podophyllin.[18] Cases are on record where biopsies of penile warts taken after the application of podophyllin were interpreted as squamous cell carcinoma, with subsequent amputation of the penis.[5] The use of podophyllin for cervical warts has led to false positive  Pap smear More Detailss for as long as six months after the topical application.[5]

Sullivan and King" described the appearance of bizarre, enlarged epithelial cells with either a clumped pyknotic nucleus, or with the nuclear chromatin disintegrated and dispersed as small granules throughout the cytoplasm of the cell, after the application of podophyllin to normal skin, verruca vulgaris and condyloma acuminata. These 'podophyllin cells' resemble carcinoma cells, but may be distinguished from malignancy by the absence of cytologic atypia and multi­nucleate giant cells.[5]

Oral administration of podophyllin has long been known to produce systemic toxicityl[20] and it has, if fact, been used for suicidal purposes[3].

The risk of systemic absorption of toxic quantities of podophyllin lignans after topical application of podophyllin is well docu­mented[10],[21],[22],[23] The increased surface area pre­sented by the papillomatous, hypertrophic, genital warts in combination with other factors such as the extreme vascularity of the tumours, thin epidermis which at places may be dis­continuous owing to inflammation or trauma, and occlusion by the covering prepuce may all facilitate percutaneous absorption.[24]

Acute toxicity may manifest within a few hours of exposure. The symptoms[21] include dizziness, generalized weakness, lethargy, nausea, vomiting and diarrhoea. Features of halluci­natory psychosis and in more advanced cases, stupor, depressed respiration, urinary retention and paralytic ileus indicate a poorer prognosis.[3],[4] Transient hepatic dysfunction and pancytopenia may follow within one week.

Repeated exposures to lower doses, however, are usually well tolerated and merely influence the highly proliferative tissues-the bone marrow and intestinal mucosa. Non-lethal damage is clinically fully reversible within days or weeks except peripheral neuropathy[20],[22],[23] which may persist for several months.[10]

Other systemic side effects include urticaria and hyperpyrexia.[25]

Experimental studies in animals have clearly demonstrated that podophyllin is embryotoxic and has a strong growth retarding effect on pregnancy.[26],[27] Foetal anomalies suspected to have been induced by podophyllin include preauricular skin tags, limb malformations, simian crease, septal heart defects and polyne­uritis.[28],[29] Intra-uterine death has also followed the application of podophyllin on vulvar warts.[30]

Bargman[31] has recently reviewed the whole subject of systemic toxicity to podophyllinn including its reported teratogenicity. He noted that in almost all cases there were factors (such as alcohol or drug abuse, recent surgical pro­cedures, general anaesthesia) which may have potentiated the toxicity of podophyllin. Since nearly all reported cases have been blacks, he also considered the possibility of an unsuspected racial susceptibility. He concluded that the dangers of podophyllin toxicity have been over­played, and that it is an extremely safe drug when used properly.


  Precautions Top


Based on the recommendations of Fisher,[5] Miller[4] and others,[25],[28],[29],[30] sub the follow ing precau­

tions are considered obligatory :

1. Podophyllin should be applied only by the physician.

2. The drug should be applied only to small areas of intact skin. Biopsies if taken, should be allowed to heal completely before the application of podophyllin.

3. Alcohol should be avoided before and for several hours after the application. General anaesthesia and central nervous system depressant drugs should be avoided.

4. The drug should be avoided in the oral cavity.

5. It should not be used in pregnant women.

6. Initially, a test application should be left on for a period of one hour. If there is no irritation, subsequent applications should be allowed to remain for 4-6 hours.

7. The volume of liquid applied should be kept to the minimum (von Krogh[3] recommends a volume not exceeding 0.4-0.5 ml for P emodi based podophyllin and 0.9 -1.2 nil for P peltatum based podophyllin).

8. The drug should be stored in narrow-mouthed bottles, otherwise undue evaporation might lead to an increased concentration of podo­phyllin. Preparations containing a sludge or precipitate and old, dried, gritty prepara­tions should be discarded.


  Preparations Top


Compound podophyllin paint (BPC)

Podophyllum resin 15 g, compound tincture benzoin to 100 ml. Store in a cool place in air-tight containers.

Caution : This paint is very irritant to the eyes and tender parts of the skin.

Podophyllum paint

Podophyllum resin 25% w/v in liquid paraffin. This preparation was included in the BPC of 1954 but has since been deleted. It has a tendency to spread from the sites of application and produce irritant dermatitis.

Podophyllin paint (St John's Hospital)

Podophyllum resin 25% in industrial methy­lated spirit.

Podophyllum resin topical solution (USP,

A solution containing about 25% of the alcohol soluble extract of podophyllum resin and about 10 gm of alcohol soluble extract of benzoin in 100 ml of alcohol. Store at tempera­ture not exceeding 40°C in an air-tight container. Protect from light.

Proprietary Preparations Podowart (Shalak Chemicals)

Podophyllum resin 20%; compound tincture benzoin to make 100%.


  Conclusion Top


There is a need for further studies reviewing the necessity of using such high concentrations of podophyllin as are used now. The efficacy of lower concentrations applied more frequently should be evaluated. There is also an urgent need for making available standardized pre­parations of podophyllin, and of chemically pure podophyllotoxin in our country.

 
  References Top

1.Zakon S : Discovery of podophyllum resin, Arch Dermatol Syphilol, 1952; 65 : 620-622.  Back to cited text no. 1    
2.Kaplan IW : Condylomata acuminata, New Orl Med Surg J, 1942; 94 : 388-395 (Quoted in 4).  Back to cited text no. 2    
3.Von Krogh G : Condylomata acuminata 1983 an updated review, Semin Dermatol, 1983; 2 109-1.29.  Back to cited text no. 3    
4.Miller RA : Podophyllin, Internat J Dermatol, 1985; 24 : 491-498.  Back to cited text no. 4    
5.Fisher A : Severe systemic and local reactions to topical podophyllin resin, Cutis, 1981; 28 233-236.  Back to cited text no. 5    
6.Von Krogh G : Podophyllotoxin for condylomata acuminata eradication. Clinical and experimental comparative studies on podophyllum lignans, colchicine and 5-fluoro-uracil, Acta Dermato­Venereol (Stockh), 1982; (Suppl 98) : 1-48.  Back to cited text no. 6    
7.Sullivan M : Podophyllotoxin, Arch Dermatol Syphilol, 1949; 60 : 1-13.  Back to cited text no. 7    
8.Cairnes DA, Kingston GI and Rao MM : High performance liquid chromatography of podo­phyllotoxin and related lignans, J Nat Prod, 1981; 44 : 34.  Back to cited text no. 8    
9.Loike JD and Horwitz SB : Effects of podophyllo­toxin and VP-16-213 on microtubule assembly in vitro and nucleoside transport in HeLa cells, Biochemistry, 1976; 15 : 5435-5437.  Back to cited text no. 9    
10.Filley CM, Graff-Radford NR, Lacy JR et al Neurologic manifestations of rodophyllin toxicity, Neurology, 1982; 32 : 308-311.  Back to cited text no. 10    
11.Von Krogh G : Penile condylomata acuminata An experimental model for evaluation of topical self-treatment with 0.5%-1.0% ethanolic prepara­tions of podophyllotoxin for three days, Sex Trans Dis, 1981 ; 8 : 179-186.  Back to cited text no. 11    
12.Gabriel G and Thin RNT : Treatment of anogeri­tal warts : comparison of trichloroacetic acid and podophyllin vs podophyllin alone, Brit J Vener Dis, 1983; 59 : 124-126.  Back to cited text no. 12    
13.Emanuel S and Varming TK : The podophyllin treatment of venereal warts, Acta Dermato­Venereol, 1948; 28 : 488-496.  Back to cited text no. 13    
14.Finkle TI-I and Frishwasser EJ : Treatment of penile condylomata acuminata with podophyllin, J Invest Dermatol, 1947; 8 : 199-201.  Back to cited text no. 14    
15.Simmons PD : Podophyllin 10% and 25% in the treatment of ano-genital warts : A comparative double blind study, Brit J Vener Dis, 1981 ; 57 208-209.  Back to cited text no. 15    
16.Wallin J : 5 Fluoro-uracil in the treatment of penile and urethral condylomata acuminata, Brit J Vener Dis, 1977; 53 : 240-243.  Back to cited text no. 16    
17.Mitchell J and Rook A : Botanical Dermatology Plants and Plant Products Injurious to the Skin, Greengrass, Vancouver, 1979; p 720 (Quoted in 3).  Back to cited text no. 17    
18.Maxwell T and Lamb J : Unusual reaction to application of podophyllum resin, Arch Dermatol Syphilol, 1954; 70 : 510-511.  Back to cited text no. 18    
19.Sullivan M and King I.: Effects of resin of podo­phyllum on normal skin, condylomata acuminata and verrucae vulgares, Arch Dermatol Syphilol. 1947; 56 : 30-47.  Back to cited text no. 19    
20.McFarland MF and McFarland J : Accidental ingestion of podophyllum, Clin Toxicol, 1981; 18 : 973-975.  Back to cited text no. 20    
21.Stoehr GP, Peterson AL and Taylor WJ : Systemic complications of local podophyllin therapy, Ann Int Med, 1978; 89 : 362-363.  Back to cited text no. 21    
22.Leslie KO and Shitamoto B : The bone marrow in systemic podophyllin toxicity, Amer J Clin Pathol, 1982; 77 : 478-480.  Back to cited text no. 22    
23.Cassidy DE, Drewry J and Fanning JP : Podo­phyllum toxicity : A report of a fatal case and a review of literature, Clin Toxicol, 1982 ; 19 :35.  Back to cited text no. 23    
24.Von Krogh G : Podophyllotoxin in serum Absorption subsequent to three-day repeated applications of a 0.5% ethanolic preparation on condvlomata acuminata, Sex. Trans Dis, 1982; 9 : 26-30.  Back to cited text no. 24    
25.Larsson LG : Podophyllin treatment of hairy tongue A warning, Acta Dermato-Venereol, 1952; 32 : 56-61.  Back to cited text no. 25    
26.Thiersch JB : Effect of podophyllin and podo­phyllotoxin on the rat litter in utero, Proc Soc Exp Med, 1963; 113 : 124-127.  Back to cited text no. 26    
27.Joneja MG and LeLiever WC : Effects of vinbla­stine and podophyllin on DBA mouse fetuses, Toxicol Appl Pharmacol, 1974; 27 : 408-414.  Back to cited text no. 27    
28.Cullis JE : Congenital deformities and herbal "slimming tablets", Lancet, 1962; 2 : 511-512.  Back to cited text no. 28    
29.Karol M, Conner C and Murphrey K : Podo­phyllum : Suspected teratogenicity from topical application, Clin Toxicol, 1980; 16 : 283-286.  Back to cited text no. 29    
30.Chamberlein MJ, Reynolds AL and Yeoman MB Toxic effect of podophyllum application in pre­gnancy, Brit Med J, 1972; 3 : 391-392.  Back to cited text no. 30    
31.Bargman H : Is podophyllin a safe drug to use and can it be used in pregnancy? Arch Dermatol, 1988; 124 : 1718-1729.  Back to cited text no. 31    




 

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