Pharmacology and Therapeutics
Verrucae Treated by Levamisole M. Amer, M.D., Z. Tosson, M.D., A. Soliman, M.D., A. G. Selim, M.D., A. Salem, M.D., and A. A. Al-Gendy, M.B., B.Ch.
Abstract: To assess the role of levamisole in treatment of different types of warts, a double-blind study was conducted on 40 patients with different types of warts. Patients were divided into two equal groups, A and B. Group A received levamisole 5 mg/kg body weight on 3 consecutive days every 2 weeks for a period up to 5 months, while patients of group B received placebo for the same period. In group A, 12 patients showed complete cure (60%), two showed partial cure (10%), and the remaining six patients showed no response (30%). In group B, complete cure was achieved only in one case. The higher cure rate was observed in plane and common warts, while plantar warts showed no improvement with levamisole treatment.
Verrucae are an extremely common viral skin disease caused by human papilloma virus. The host response against the viral wart infection depends on intact immune mechanisms, particularly those involving cellmediated immunity.' Recalcitrant and recurrent warts are more common in patients with cell-mediated immune deficiency states such as Hodgkin disease, chronic lymphatic leukemia, and malignant lymphomas, than in those with purely humoral immune deficiency, as in myeloma.^ Levamisole is a broad-spectrum antiparasitic drug introduced in 1966, and has been shown to increase cellular immunity in vitro and in vivo.^ It has been used as adjunctive therapy for certain chronic infections, rheumatoid arthritis, and immunosuppressive states, including those associated with malignancy.'' Levamisole has been used in the treatment of different varieties of wart, using different schedules with variable results. The aim of our work is to assess the role of levamisole in treatment of different types of warts. Materials and Methods • Forty patients with different types of warts who attended the dermatology elinic of Zagazig University Medical From the Department of Dermatology and Venereology, Zagazig University, Faculty of Medicine, Zagazig, Egypt. Address correspondence to: Mohamed Amer, M.D., 9 Gabalyia Street, Gezeira, Zamalek, Cairo, Egypt.
738
Center were divided into two equal groups: group A (levamisole group) and group B (plaeebo group). The first group included 11 patients with eommon warts, five with plane warts, and four with plantar warts. Ages of patients ranged from 7 to 52 years, and the duration of warts ranged from 1 to 24 months. The second group included ten patients with common warts, three with plane warts, and seven with plantar warts. Their ages ranged from 6 to 50 years, and the duration of warts ranged from 2 to 36 months. A complete history was taken for all patients, and clinical examinations and due investigations were conducted to detect any immunologic disturbance. Patients in group A received levamisole 5 mg/kg body weight for 3 consecutive days every 2 weeks for a period of up to 5 months. Group B patients received starch tablets similar to levamisole tablets in size, shape, color, and taste; these were given in a dose similar to the levamisole dose for equally weighted patients.
Results Table 1 shows that of levamisole-treated patients, 12 (60%) showed complete resolution, two (10%) showed partial resolution, while the remaining six (30%) were completely resistant to treatment. In the second group (placebo-treated patients), only one patient showed complete cure. Table 2 shows that the response of different types of warts to levamisole differs. Of five patients with plane warts, four showed complete resolution. Eight out of 11 patients with common warts showed complete resolution, and two showed partial resolution. Patients with plantar warts showed complete resistance to treatment. Of five patients younger than age 10 yearsj four showed complete resolution (80%). Patients older than age 30 years showed complete resistance to treatment. The shorter the duration of warts, the better the response to levamisole therapy. Of patients whose warts lasted less than 6 months, there was complete resolution in seven and partial resolution in one. Of October 1991, Vol. 30, No. 10
Verrucae Treated by Levamisole • Amer et al.
No. 10
Table 1. Number of Cured and Noncured Patients with Warts in Levamisole- and Placebo-Treated Groups
Levamisole Group Response
No.
%
Complete resolution Partial resolution No response Total
12 2 6 20
60 10 30 100
Placebo Group No. %
T
P
1
5 2.12 0.05
19 20
95 3.36 0.01 100
patients whose warts lasted more than 12 months, only one showed complete resolution. Discussion The immune system seems to play an important role in controlling wart infection. Although the exact mechanisms are unclear, most evidence suggests that both humoral and cell-mediated immunity participate in the host defense against viral warts, with the latter taking the dominant role.^ Levamisole appears to act as an immunostimulant through several mechanisms. It may have a thymosin-like action in states of depressed Tlymphocyte function that result from faulty differentiation of the lymphocytes caused by lack of circulating hormone.* It may also act as a weak mitogen, and hence it may lead to increased proliferation and differentiation of lymphocytes.^ Hadden et al.^ reported that it may raise cyclic GMP, leading to improvement of lymphocyte functions, and it may also stimulate macrophage proliferation and their phagocytic effects. Treatment of warts using the traditional locally destructive methods may result in scarring, and is associated with recurrence in many instances.' Different regimens were used to assess levamisole therapy in treatment of warts. In this study we used levamisole in a dose of 5 mg/kg body weight on 3 consecutive days every 2 weeks for a period of up to 5
739
months. Of 20 patients, 12 (60%) showed complete resolution, two (10%) showed partial resolution, and six (30%) showed complete resistance to treatment, whereas of 20 patients treated with placebo, only one showed complete resolution. This difference in cure rate between levamisole- and placebo-treated patients was significant (p < 0.05). Very good results were obtained in Denmark, where ten patients between the ages of 7 and 16 years with multiple warts were treated with levamisole for 3 months, using the same therapeutic regimen we used in our work. Nine patients (90%) were completely cured.'° In Mexico, similar results were obtained when the same schedule was used in treating patients with multiple warts for a period of up to 4 months. Of 22 patients, 17 were completely cured (77.2%). The higher cure rate using the same therapeutic dose may be attributed to different environmental or constitutional factors reflected in the immune response.' Elsewhere in Egypt, 20 patients with multiple warts were treated with levamisole using 2.5 mg/kg body weight on 2 consecutive days every week for a period of up to 4 months. This resulted in lower cure rates: seven patients (35%) were completely cured, two (10%) showed partial cure, and 11 showed complete resistance to treatment.'' In Denmark, levamisole was used in the treatment of common warts and condyloma accuminata in a double-blind study, with a dose of 150 mg daily for 3 successive days every week for a period of up to 6 to 8 weeks. There was a significant difference in clinical improvement between those who received levamisole and those on placebo. This may be due to the short period of the study and the low dose of drug used.'^ In the cuirent study, a higher cure rate was obtained in patients with plane warts (80%), followed by common warts (72.7%), whereas plantar warts were completely resistant to levamisole treatment. The same results were obtained in other studies.
Table 2. Response of Different Types of Warts to Levamisole Therapy
Types of Warts Common Response
Complete resolution Partial resolution No response Total
Plantar
No.
%
8
72.7 18.2
2 1 11
9.1
100.0
No. — 4 4
Total
Plane %
100 100
No.
%
No,
%
4
80 — 20
12 2
60
1 5
100
6 20
10 30 100
740
International Journal of Dermatology • October 1991
Conciusions The cure rate of warts was higher in younger rather than older patients. Young adults have a more competent immune response to viral infection than do older people, and hence they can produce larger amounts of interferons.'^ Warts of shorter duration respond better to levamisole therapy. The longer the duration of warts, the greater the number of natural killer cells, which exerts a suppressor effect on helper and effector T cells, leading to more immunosuppression.''*
References Moncada B, Rodriguez ML. Levamisole therapy for multiple warts. BrJ Dermatol. 1979;101:327-330. Rogozinski TT, Jublonska S, Chorzelsk JM. Role of cell mediated immunity in spontaneous regression of plane warts. Int J Dennatol. 1988;27:322-326. Ramot B, Biniaminov M, Shoham GH, et al. The effect of levamisole on E. rossette forming cells in vivo and vitro in Hodgkin's disease. N Engl J Med. 1976;294:809.
Vol. 30
4. Brugman I. Levamisole in infectious diseases: Review of literature. J Rheumatol. 1978;5 (suppl 4): 115-121. 5. Bunney MH. Viral Warts: Their Biology and Treatment. Oxford: Oxford Medical Publication, 1982. 6. Merluzzi VJ, Badger AM, Kaiser GW, et al. In vitro stimulation of murine lymphoid cell culture by levamisole. Clin Exp Immunol. 1975;22:486. 7. Pabst HF, Crawford J. Tetramisole enhancement of human lymphocyte response to antigen. Clin Exp Immunol. 1975;21:468. 8. Hadden JW, Coffey RE, Hadden EM, et al. Effects of levamisole on E-rossettes. N Engl J Med. I975;295:230. 9. Vance JC, Burt BJ, Hansen RC, et al. Intralesional recombinant alpha-2 interferon for the treatment of patients with condyloma accuminata or verruca plantaris. Arch Dermatol. 1986; 122:272277. 10. Helin P, Berg M. Levamisole for warts. N Engl J Med. 1979;291:1811. 11. Abdel-All MA, El Saaie L, Mahfouz K, et al. Levamisole therapy and cell mediated immunity in multiple warts. Egypt J Dermatol Venereol. 1987;7:53-61. 12. Schau M, Helin P. Levamisole in a double blind study: No effects on warts. Acta Derm Venereol (Stockh). 1977;57:449-454. 13. El-Batawi YA. The nature of viruses. In: El-Batawi YA, ed. Manual of Microbial Infections of Man. 5th. ed. Part 1. El Nasar Modern Book Shop, 1987:67-68. 14. Tilden AB, Aub T, Blak CM. Suppressor cell function of human granular lymphocyte identified by the HNK-1 (leu-7) monoclonal antibody. J Immunol. 1983;13O:l 171-1175.
"Altheas." Carolyn N. Ter Poorten, Richardson, TX, Oil painting—third place. American Academy of Dermatology Art Exhibit, Atlanta, GA, 1990. Photograph courtesy of Dermik Laboratories, Inc.
Verrucae Treated by Levamisole M. Amer, M.D., Z. Tosson, M.D., A. Soliman, M.D., A. G. Selim, M.D., A. Salem, M.D., and A. A. Al-Gendy, M.B., B.Ch.
Abstract: To assess the role of levamisole in treatment of different types of warts, a double-blind study was conducted on 40 patients with different types of warts. Patients were divided into two equal groups, A and B. Group A received levamisole 5 mg/kg body weight on 3 consecutive days every 2 weeks for a period up to 5 months, while patients of group B received placebo for the same period. In group A, 12 patients showed complete cure (60%), two showed partial cure (10%), and the remaining six patients showed no response (30%). In group B, complete cure was achieved only in one case. The higher cure rate was observed in plane and common warts, while plantar warts showed no improvement with levamisole treatment.
Verrucae are an extremely common viral skin disease caused by human papilloma virus. The host response against the viral wart infection depends on intact immune mechanisms, particularly those involving cellmediated immunity.' Recalcitrant and recurrent warts are more common in patients with cell-mediated immune deficiency states such as Hodgkin disease, chronic lymphatic leukemia, and malignant lymphomas, than in those with purely humoral immune deficiency, as in myeloma.^ Levamisole is a broad-spectrum antiparasitic drug introduced in 1966, and has been shown to increase cellular immunity in vitro and in vivo.^ It has been used as adjunctive therapy for certain chronic infections, rheumatoid arthritis, and immunosuppressive states, including those associated with malignancy.'' Levamisole has been used in the treatment of different varieties of wart, using different schedules with variable results. The aim of our work is to assess the role of levamisole in treatment of different types of warts. Materials and Methods • Forty patients with different types of warts who attended the dermatology elinic of Zagazig University Medical From the Department of Dermatology and Venereology, Zagazig University, Faculty of Medicine, Zagazig, Egypt. Address correspondence to: Mohamed Amer, M.D., 9 Gabalyia Street, Gezeira, Zamalek, Cairo, Egypt.
738
Center were divided into two equal groups: group A (levamisole group) and group B (plaeebo group). The first group included 11 patients with eommon warts, five with plane warts, and four with plantar warts. Ages of patients ranged from 7 to 52 years, and the duration of warts ranged from 1 to 24 months. The second group included ten patients with common warts, three with plane warts, and seven with plantar warts. Their ages ranged from 6 to 50 years, and the duration of warts ranged from 2 to 36 months. A complete history was taken for all patients, and clinical examinations and due investigations were conducted to detect any immunologic disturbance. Patients in group A received levamisole 5 mg/kg body weight for 3 consecutive days every 2 weeks for a period of up to 5 months. Group B patients received starch tablets similar to levamisole tablets in size, shape, color, and taste; these were given in a dose similar to the levamisole dose for equally weighted patients.
Results Table 1 shows that of levamisole-treated patients, 12 (60%) showed complete resolution, two (10%) showed partial resolution, while the remaining six (30%) were completely resistant to treatment. In the second group (placebo-treated patients), only one patient showed complete cure. Table 2 shows that the response of different types of warts to levamisole differs. Of five patients with plane warts, four showed complete resolution. Eight out of 11 patients with common warts showed complete resolution, and two showed partial resolution. Patients with plantar warts showed complete resistance to treatment. Of five patients younger than age 10 yearsj four showed complete resolution (80%). Patients older than age 30 years showed complete resistance to treatment. The shorter the duration of warts, the better the response to levamisole therapy. Of patients whose warts lasted less than 6 months, there was complete resolution in seven and partial resolution in one. Of October 1991, Vol. 30, No. 10
Verrucae Treated by Levamisole • Amer et al.
No. 10
Table 1. Number of Cured and Noncured Patients with Warts in Levamisole- and Placebo-Treated Groups
Levamisole Group Response
No.
%
Complete resolution Partial resolution No response Total
12 2 6 20
60 10 30 100
Placebo Group No. %
T
P
1
5 2.12 0.05
19 20
95 3.36 0.01 100
patients whose warts lasted more than 12 months, only one showed complete resolution. Discussion The immune system seems to play an important role in controlling wart infection. Although the exact mechanisms are unclear, most evidence suggests that both humoral and cell-mediated immunity participate in the host defense against viral warts, with the latter taking the dominant role.^ Levamisole appears to act as an immunostimulant through several mechanisms. It may have a thymosin-like action in states of depressed Tlymphocyte function that result from faulty differentiation of the lymphocytes caused by lack of circulating hormone.* It may also act as a weak mitogen, and hence it may lead to increased proliferation and differentiation of lymphocytes.^ Hadden et al.^ reported that it may raise cyclic GMP, leading to improvement of lymphocyte functions, and it may also stimulate macrophage proliferation and their phagocytic effects. Treatment of warts using the traditional locally destructive methods may result in scarring, and is associated with recurrence in many instances.' Different regimens were used to assess levamisole therapy in treatment of warts. In this study we used levamisole in a dose of 5 mg/kg body weight on 3 consecutive days every 2 weeks for a period of up to 5
739
months. Of 20 patients, 12 (60%) showed complete resolution, two (10%) showed partial resolution, and six (30%) showed complete resistance to treatment, whereas of 20 patients treated with placebo, only one showed complete resolution. This difference in cure rate between levamisole- and placebo-treated patients was significant (p < 0.05). Very good results were obtained in Denmark, where ten patients between the ages of 7 and 16 years with multiple warts were treated with levamisole for 3 months, using the same therapeutic regimen we used in our work. Nine patients (90%) were completely cured.'° In Mexico, similar results were obtained when the same schedule was used in treating patients with multiple warts for a period of up to 4 months. Of 22 patients, 17 were completely cured (77.2%). The higher cure rate using the same therapeutic dose may be attributed to different environmental or constitutional factors reflected in the immune response.' Elsewhere in Egypt, 20 patients with multiple warts were treated with levamisole using 2.5 mg/kg body weight on 2 consecutive days every week for a period of up to 4 months. This resulted in lower cure rates: seven patients (35%) were completely cured, two (10%) showed partial cure, and 11 showed complete resistance to treatment.'' In Denmark, levamisole was used in the treatment of common warts and condyloma accuminata in a double-blind study, with a dose of 150 mg daily for 3 successive days every week for a period of up to 6 to 8 weeks. There was a significant difference in clinical improvement between those who received levamisole and those on placebo. This may be due to the short period of the study and the low dose of drug used.'^ In the cuirent study, a higher cure rate was obtained in patients with plane warts (80%), followed by common warts (72.7%), whereas plantar warts were completely resistant to levamisole treatment. The same results were obtained in other studies.
Table 2. Response of Different Types of Warts to Levamisole Therapy
Types of Warts Common Response
Complete resolution Partial resolution No response Total
Plantar
No.
%
8
72.7 18.2
2 1 11
9.1
100.0
No. — 4 4
Total
Plane %
100 100
No.
%
No,
%
4
80 — 20
12 2
60
1 5
100
6 20
10 30 100
740
International Journal of Dermatology • October 1991
Conciusions The cure rate of warts was higher in younger rather than older patients. Young adults have a more competent immune response to viral infection than do older people, and hence they can produce larger amounts of interferons.'^ Warts of shorter duration respond better to levamisole therapy. The longer the duration of warts, the greater the number of natural killer cells, which exerts a suppressor effect on helper and effector T cells, leading to more immunosuppression.''*
References Moncada B, Rodriguez ML. Levamisole therapy for multiple warts. BrJ Dermatol. 1979;101:327-330. Rogozinski TT, Jublonska S, Chorzelsk JM. Role of cell mediated immunity in spontaneous regression of plane warts. Int J Dennatol. 1988;27:322-326. Ramot B, Biniaminov M, Shoham GH, et al. The effect of levamisole on E. rossette forming cells in vivo and vitro in Hodgkin's disease. N Engl J Med. 1976;294:809.
Vol. 30
4. Brugman I. Levamisole in infectious diseases: Review of literature. J Rheumatol. 1978;5 (suppl 4): 115-121. 5. Bunney MH. Viral Warts: Their Biology and Treatment. Oxford: Oxford Medical Publication, 1982. 6. Merluzzi VJ, Badger AM, Kaiser GW, et al. In vitro stimulation of murine lymphoid cell culture by levamisole. Clin Exp Immunol. 1975;22:486. 7. Pabst HF, Crawford J. Tetramisole enhancement of human lymphocyte response to antigen. Clin Exp Immunol. 1975;21:468. 8. Hadden JW, Coffey RE, Hadden EM, et al. Effects of levamisole on E-rossettes. N Engl J Med. I975;295:230. 9. Vance JC, Burt BJ, Hansen RC, et al. Intralesional recombinant alpha-2 interferon for the treatment of patients with condyloma accuminata or verruca plantaris. Arch Dermatol. 1986; 122:272277. 10. Helin P, Berg M. Levamisole for warts. N Engl J Med. 1979;291:1811. 11. Abdel-All MA, El Saaie L, Mahfouz K, et al. Levamisole therapy and cell mediated immunity in multiple warts. Egypt J Dermatol Venereol. 1987;7:53-61. 12. Schau M, Helin P. Levamisole in a double blind study: No effects on warts. Acta Derm Venereol (Stockh). 1977;57:449-454. 13. El-Batawi YA. The nature of viruses. In: El-Batawi YA, ed. Manual of Microbial Infections of Man. 5th. ed. Part 1. El Nasar Modern Book Shop, 1987:67-68. 14. Tilden AB, Aub T, Blak CM. Suppressor cell function of human granular lymphocyte identified by the HNK-1 (leu-7) monoclonal antibody. J Immunol. 1983;13O:l 171-1175.
"Altheas." Carolyn N. Ter Poorten, Richardson, TX, Oil painting—third place. American Academy of Dermatology Art Exhibit, Atlanta, GA, 1990. Photograph courtesy of Dermik Laboratories, Inc.
