Successful treatment of non-healing cases of cutaneous leishmaniasis, using a combination of meglumine antimoniate plus allopurinol

ARTICLE

Cutaneous leishmaniasis (CL) is endemic in the Middle East, Africa, South and Central America and the eastern Mediterranean countries. It has been recognized as a major public health problem in Iran, to the extent that in some areas of the country about 70 % of the inhabitants show scarring from past leishmaniasis infection [1]. The causative organisms in this area are Leishmania tropica and Leishmania major [2].

The optimal treatment for CL is not known. The pentavalent antimonials, sodium stibogluconate (Pentostam) and meglumine antimoniate (MA) (Glucantime) have been the recommended as first line drugs for the treatment of leishmaniasis for fifty years [3]. They are normally effective (70 %-85 %) when given in adequate doses and for adequate duration [4]. Recently reports of a strain resistant to these drugs have been published [5]. Allopurinol (AL) has been used in treatment of CL [6, 7]. In this study we used combination of AL and MA in treatment of non-healing cases of CL.

Case reports

Case 1

A 24-year-old male worker presented with a red, mildly crusted lesion of 6 years duration on his left arm. He complained of mild itching. The lesion started as a red papule at the site of previous leishmanization (vaccination with live leishmania [8]) and spread gradually to involve the arm. Examination showed an extensive (12 cm x 10 cm) indurated, erythematous, warm, nontender plaque with interspersed red papules over the upper site of the right arm. General physical examination was normal and there was no adenopathy.

Routine investigations were normal except for an elevated erythrocyte sedimentation rate of 30 mm in the first hour. A direct smear was prepared from the exudate of fluid obtained by puncture of the lesion and stained using the Giemsa method for leishman bodies. The border of the lesion was scraped and a punch biopsy was performed for histological study. A part of the tissue obtained by biopsy was used for culture on Nevy-Nicolle-MacNeal (NNN) medium. The smear was positive for leishmania parasites and promastigotes grew on NNN medium. The histological examination was compatible with CL and showed granulomatous structure and macrophages filled with leishmania parasite. During the past 6 years, the patient has been treated for his disease with MA, dapsone, intralesional emetine and methylprednisolone, paromomycine ointment and cryotherapy, but none of them was effective. The patient was known as a case of chronic leishmaniasis due to leishmanization and was treated with combination of AL 20 mg/kg per day for 30 days, and MA 60 mg/kg per day for 20 days. The lesion responded well to treatment within 4 weeks. Healing was obvious with no scar formation. Two years follow up showed no relapse of the lesion.

Case 2

A 14-year-old male student presented with asymptomatic erythematous papules of 8 years duration over the right side of the face. The lesion had started as red papule over the right cheek 8 years previously and the diagnosis of cutaneous leishmaniasis had been confirmed. The lesion eventually formed an ulcer. He was treated with MA 60 mg/kg per day for 15 days. The lesion apparently healed, leaving a depressed scar. After 3 months red papules appeared over and in the periphery of the previous lesion.

The lesion was diagnosed as a case of lupoid leishmaniasis and was treated with dapsone 100 mg/day for 30 days. A few of the papules regressed, but few months later new papules appeared and the lesion gradually extended. The response to cryotherapy, intralesional MA, intralesional emetine hydrochloride and dapsone was unsatisfactory. Later he was treated again with MA 60 mg/kg per day for 20 days. With this treatment papules regressed but a few months later the lesion re-activated. At the time of admission physical examination showed multiple red papules around the periphery of the 3 x 3 cm scar of the previous lesion (Fig. 1). The histopathologic examination of the biopsy was compatible with lupoid leishmaniasis and it showed infiltration by macrophages, lymphoid cells and, tuberculoid granulomas in the dermis with few plasma cells. The patient was treated with a combination of AL 20 mg/kg per day for 30 days and MA 60 mg/kg per day for 20 days. The lesion healed completely in 4 weeks (Fig. 2). Two years follow up showed no relapse of the lesion.

Case 3

A 35-year-old male farmer referred to our clinic with an erythematous lesion on the upper lip. The lesion started as a red papule 16 months previously and a few weeks later an asymptomatic swelling appeared at the site and gradually extended. On examination the erythematous infiltrative lesion involved the upper lip and left cheek. The lesion was covered with fine scales and red papules. No adenopathy was observed and other physical examinations were within normal limits. The Giemsa stained smear of the lesion showed leishman bodies. Routine investigations were normal except for mild leukocytosis and elevated erythrocyte sedimentation rate of 40 mm in the first hour. The patient was known as a case of chronic leishmaniasis and was treated with MA at a dose of 60 mg/kg per day for 20 days but no response was observed. One month later a combination of AL 20 mg/kg per day and MA 60 mg/kg per day was started for him. The lesion regressed completely in 4 weeks. He was followed up for two years and no relapse was observed.

During the past 10 years we had 37 cases of non-healing leishmaniasis that did not respond to many routine treatments (Table I): 26 lupoid leishmaniasis, 6 chronic leishmaniasis cases and 5 patients who had chronic leishmaniasis due to previous leishmanization (to prevent the spread of the disease during the Iran-Iraq conflict [1980-1988], leishmanization was carried out on soldiers and some of the civilians of the hyperendemic area of the country. In this method, a total number of 1,500,000 weakened L. tropica major is injected intradermally [8]). All of the patients were treated with a combination of AL (20 mg/kg for 30 days) and meglumine antimoniate (60 mg/kg per day for 20 days) and were followed up for 2 years. Cure was defined as the complete clinical healing of the lesions and no relapse after two years follow up. The treatment was highly effective. All the patients except 2 responded well to treatment. They tolerated this combination well and none of them experienced any side effects from the medication (Table I). Unfortunately the parasite was not identified in these cases, but on the basis of previous studies [2, 3], it is most probable that the patients in our study were infected with L. major.

Discussion

CL is self-healing disease and about 90 % of primary lesions heal spontaneously [9] and that recovery is supposed to confer lifelong immunity [10]. In the Old World CL, because the healed scars and areas of depigmentation are ugly, treatment is desired, where there are lesions on exposed parts of the body, especially the face. Another reason to treat is to prevent secondary bacterial infection of the lesions. Obviously, one would also want to treat in order to prevent the 10 % of cases that do not heal and progress to chronic forms [11].

The pentavalent antimonials have been the recommended first line drugs for the treatment of leishmaniasis [3]. The mechanism of action of the antimonials is unclear. Phosphofructokinase is an enzyme, which is usually suggested to be inhibited by the drug and production of adenosine triphosphate in the parasite is blocked [12]. The recommended dosage is 15 to 20 mg Sb5/Kg per day for 20 days (equal to 60 mg/kg/day of MA [Glucantime]). They are normally effective (70 %-85 %) when given in this dosage [4]. Increasing resistance of CL to antimonials has been reported in many countries [5, 13]. Antileshmanial effects of AL have been observed in vitro [15]. It also increases the antileshmanial effect of sodium stibogluconate in vitro [14]. It is thought to inhibit parasite adenylosuccinate synthetase or adenine phosphoribosyltransferase. AL was effective in curing six out of 10 patients with visceral leishmaniasis [15], who had not previously responded to sodium stibogluconate. In this group one patient received stibogluconate plus AL. In another study, five patients with kala-azar, who had not responded to stibogluconate, were reported to have been treated with a combination of these two drugs [16]. Allopurinol ribonucleoside was used in American CL [17]. Four of nine patients showed clinical improvement and 2 had a negative culture at the end of therapy. AL was used to treat mucocutaneous leishmaniasis and two out of five patients were clinically cured [17]. A combination of AL and MA has been reported in treatment of leishmaniasis recidivans and it was effective [6]. In this trial we used a combination of AL and MA to treat 26 lupoid leishmaniasis, 6 chronic leishmaniasis and 5 patients who had chronic leishmaniasis due to previous leishmanization. All of these patients did not respond to previous routine treatment. The treatment was highly effective. They tolerated this combination well and none of them experienced any side effects from the medications.

CONCLUSION

A combination of AL and antimonials increases the antileishmanial effect of antimoniate. In those cases which are resistant to antimonials, and in chronic non-healing cases of cutaneous leishmaniasis this combination may prove to be effective.

REFERENCES

1
Azmoudeh M. Report on leishmaniasis in Iran. Islamic Republic of Iran, Ministry of Health. Treatment and Medication Education, 1990.

2
Nadim A, Mesghali A, Amini H. Epidemiology of cutaneous leishmaniasis in Isfahan. Iran. III. The Vector. Trans R Soc Trop Med Hyg 1971; 62: 543-8.

3
Nadim A, Seyedi rashti MA. Brief review of the epidemiology of various type of leishmaniasis in Iran. Acta Med Iran 1971; 99: 106-10.

4
Grevelink SA, Lcrner EA. Leishmaniasis. J Am Acad Dermatol 1996; 34: 257-62.

5
Weinrauch L. EL-on J. Current therapy of cutaneous leishmaniasis. Int J Dermatol 1987; 9: 564-70.

6
Momeni AZ, Yotsumoto S, Mehregan D, Mehregan AH, et al. Chronic lupoid leishmaniasis. Arch Dermatol 1996; 132: 198-220.

7
Martinez S, Marr JJ. Allopurinol in the treatment of american cutaneous leishmaniasis. NEJM 1992; 326: 741-4.

8
Nadim A, Javadian E. Leishmanization in the Islamic Republic of Iran. In: Walton BC, Wijeyaratne PM, Modabber F, eds. Research on control strategies for leishmaniasis. Ottawa: IDRC, 1988: 338-39.

9
Heung-Chong BA. Oriental sore; a look at trends in and approach to the treatment of leishmaniasis. Int J Dermatol 1986; 25: 615-22.

10
Bryeeson A. Immunological aspects of clinical leishmaniasis. Proc R Soc Med 1970; 63: 1056-60.

11
Momeni AZ, Aminjavaheri M. Clinical picture of cutaneous leishmaniasis in Isfahan Iran. Int J Dermatol 1994; 33: 260-5.

12
Roberts WL, Berman JD, Rainey PM. In vitro antileshmanial properties of tri-and pentavalent antimonial preparations. Ant Mic Agen Chemo 1995; 39: 1234-9.

13
Olliaro PL, Bryceson ADM. Practical progress and new drugs for changing patterns of leishmaniasis. Parasit Today 1993; 9: 323-8.

14
Chunge CN, Gachihi G, Muigai R, et al. Visceral leishmaniasis unresponsive to antimonial drugs. III. Successful treatment using a combination of sodium stibogluconate plus allopurinol. Trans P Soc Trop Med Hyg 1985; 79: 715-8.

15
Kager PA, Rees PH, Wellde BT, et al. Allopurinol in the treatment of visceral leishmaniasis. Trans F Soc Trop Med Hyg 1981; 75: 556-9.

16
Jha TK. Evaluation of allopurinol in the treatment of kala-azar occurring in north Bihar, India. Trans R Soc Trop Med Hyg 1983; 77: 204-7.

17
Senz RE, Paz HM, Johnson CM. Treatment of American cutaneous leishmaniasis with orally administered allopurinol riboside. J Inf Dis 1989; 160: 153-8.