- Email: [email protected]
The use of itraconazole in the treatment of leishmaniasis caused by Leishmania aethiopica
532
TRANSA~ICJNS OFTHEROYALSOCIETY OFTROPICAL MEDICINE ANDHYGIENE
1 Short Report ( The use of itraconazole in the treatment of leishmaniasis caused by Leishmania aethiopica H. Akuffo’, M. Dietz’, S. Teldemariam’, T. and T. Yemane Tadesse’, G. Amare’ Be&an’ ‘Department of Infectious Diseases, Karolinska Institute, P.O. Box 5651, S-11489 Stockholm, Sweden; ‘All Africa Leprosy Rehabilitation and Training Centre (ALERT), P.O. Box 169, Addis Ababa, Ethiopia; 3Armauer Hansen Research Institute (AHRZ), Addis Ababa, Ethiopia Introduction
Infection with Leiskmania aetkiopica manifests itself as self-healing lesions in local cutaneous leishmaniasis (LCL) or as non-ulcerative lesions in diffuse cutaneous leishmaniasis (DCL) (BRYCESON, 1969a). DCL, with its refractoriness to presently available treatment, is the more debilitating form (BRYCESON, 1969b). However. even the local. self-healing. form in which cellular hyperactivity at ‘the site of-infection results in tissue destruction and ulceration can take a long time to heal and may cause disfigurement. Several drugs have been used in the treatment of infection caused by Leiskmunia species (BERMAN, 1988) but many are not effective with infections 1969b; VAN DER causedby L. aetkiopica (BRYCESON, MEULEN et al., 1981). Pentamidine is recommended for treatment of this infection, but the associatedhigh toxicity (BRYCESON,1968) 1s a limiting factor for svstemic use in LCL. Both forms of L. aetkioDica mfeciton, however, warrant treatment and new, effective, non-toxic drugs are needed. Itraconazole, a lipophilic triazole drug with high anti-fungal activity (VAN CUSTEMet al., 1987), has been reported to be effective in the treatment of L. braziliensis and L. mexicana pifanoi infection (BORELLI,1987). The sister drug ketoconazole has been used extensively in the Middle East for the treatment of L. major infection. Itraconazole, with its high affinity for tissue and low toxicity, might be expected to be superior to the hepatotoxic ketoconazolein the treatment of dermatological disorders, including those caused by L. aetkiopica.
A ulacebo-controlled double-blind study was used to assessthe effect of itraconaxole in patients with DCL and LCL, taking into account the tendency for self-healing in LCL patients. Patients
and Methods
Parasitologically confirmed DCL and LCL patients, aged between 12 and 48 years, who consented, were entered into the trial regardless of sex. The packets containing itraconazole and those with Correspondenceto Dr Hannah Akuffo, Department of Infectious Diseases,Karolinska Institute, P.O. Box 5651, S-11489Stockholm, Sweden.
(1990) 84, 532-534
placebo were identical and had been numbered by an independent person not involved in the trial. All 4 DCL patients were male. Ten LCL patients were consecutively entered into the trial. Thus there were 3 females in the itraconazole group and one in the placebo group. The female patients were informed about the remote but possible teiatogenic effects of high doses of itraconazole reported from animal experiments (VAN CAUTERENet al., 1987). Medication did not commence at the same time in all patients. Patients received four 50 mg capsules of itraconazole or placebo per day for 4 weeks (200 mgl day). The placebo was the base of the itraconazole capsules without itraconazole and appeared identical to the itraconazole capsule. Clinical examination, photography and parasitological examinations were performed before, and weekly during, the 4 weeks of treatment. One month after the end of therapy, patients came for follow-up assessment.The criteria for clinical assessmentincluded basic dermatological examination of lesions noting the presence of, or changes in, ulceration, exudation, crust formatron, epithelixation, peripheral healing, or shrinkage. Laboratory tests included blood counts, the determination of erythrocyte sedimentation rate, serum glutamic oxalic transaminase (GOT), serum glutamic pyruvic transaminase(GPT), alkaline phosphatase, bilirubin and urine analysis. Patients were weighed’ regularly and interviewed about their general state of health. A semi-quantitative method was devised for assessingparasite growth in culture, which will be described in a subsequent paper (seeTable). Smearswere also made. The same general area of the chosen lesion (within 5 mm) was used each time for obtaining culture and smear samples. All the isolates were isoenzyme typed at the London School of Hvgiene and Tropical Medicine as L. aetkiopica.
The abilitv of itraconazole to kill or inhibit deoxyribonucleic acid (DNA) synthesis of Leiskmania parasites was tested in vitro using tritiated thymidine ([3H]TdR), drug effectiveness being assessedby the diminished ability of promastigotes to incorporate [3H]TdR. Six isolates of L. aetkiopica derived from LCL cases, 3 isolates derived from DCL cases,and one isolate eachof L. tropica and L. major were tested. Results
The duration of diseasevaried from one to 17 years in the DCL patients and from 2 months to 2 years in the LCL paGents.All patients had active lesions at the time of entering the trial. After 4 weeks of treatment all the patients receiving itraconazole still had clinically-assessedactive lesions (Table). Improvement was, however, noted in the lesions of 2 of the placebotreated group. When the patients were asked about their lesions, 5 of 7 in each group thought they had noticed an improvement. At the one month followup, the 3 DCL patients who presented still had active lesions. There was clinical improvement in 2 of the 4 LCL patients receiving itraconaxole and in 4 of the 5 placebo-treated LCL patients. All but one of the LCL patients receiving itraconazole showed a tendency to reduction in number of parasites both by culture (Table) and smear. Three of the 5 placebo-treated LCL patients showed a similar tendency.
533 Table.
Evaluation
Trial no. Itraconazole :z 02 :i 69 76 Placebo 05 11
of treatment
Clinical
by clinical
criteria
Start
Active Active Active Active Active Active/infiltrated Active
Culture” ii: 1
230 NPD
54+0
and
culture
Clinical Active Active’ Activeh Active’ Active” Active Active”
4 weeks Culture” 5.2 6.4 0.4 240 NPD NPD NPD
Clinical
One month follow-up
Culture”
Active ND“
Some improvement Active Active Improved NDd
‘2 NNPDD NP; NIS
Active/infiltrated Activeb 0.8 Active/infiltrated 1.6 07 Active’ Active Active 100 0.4 NP8:: Active Active’ Improved NPD 2: Active 1.6 Improvedh NPD Improved NPD Active Improved” NPD Improved NI’D 8’: NPlS Activeb NPD Improved Active NPD Active 0.8 Active‘ Active 88 102 110 “Number of promastigotes counted in 20 ml of RPM1 medium plus 20% foetal calf serum 7 d after transfer from NNN medium; NPD=no parasites detected after 7 d; + =parasites present but not within counting chamber. bPatient thought that lesion had improved. ‘Patient did not notice improvement. dPatient did not report for follow-up.
There was no evidence of hepatotoxicity from the measurementsof serum transaminases,alkaline phosphatase and bilirubin. Itraconazole had an inhibitorv effect (>lO%) on DNA synthesis in 3 isolates IZ,. rrop& and L. aethiopica derived from LCL) of the 11 tested. There was a small degree of inhibition (~10%) in one DCL isolate. The degree of incorporation of thymidine varied amongst the isolates tested. The ability of itraconazole to inhibit DNA synthesis in someisolates was not related to the degree of promastigote prolif-
gotes to evaluate what effect, if any, itraconazole had on different isolates of L. uerhiopicu. Isolates differed in their response, and it might be interesting to correlate the effect of itraconazole in vitro and in vivo in the same individual. Use of a large number of patients might have permitted more clear-cut conclusions. Even so, this study clearly underlines the need for placebo-controlled trials whenever a self-healing disease is under study, and in a setting where strong positive beliefs may be attached to medical interference.
eration.
Discussion Many studies on both ketoconazole and itraconazole in leishmaniasis have not been performed in a double-blind manner and the intense placebo effect or self-healing observed in the present trial has not been considered as a possible causeof the enhanced clinical healing observed. One patient receiving itraconazole had somewhat elevated levels of serum GOT and GPT during the period that the drug was taken. Otherwise no increase
in serum enzymes or bilirubin was observed that could be attributed to itraconazole. However, the more sensitive bromsulphthalein test could not be done due to its invasive nature. The culture results indicated a tendency towards diminishing numbers of L. aerhio~ica amastigotes, canable of transforming into promastigotes, 6 the lesions of a majority 07 oatients in both ~OUDS. These findines. combined with the clinical gbse&ations, indicate that itraconazole in the regime used here was no more effective than a placebo for treating L. aethiopica leishmaniasis; however, it may be useful as a combination drug after excluding the possibility of adversedrug interactions. Drug testing using promastigotes is inferior as a prediction of in vivo efficacy due to the relatively Y
protected
intracellular
habitat
,
of atnastigotes.
L.
aethtipica, however, does not grow well in vitro in human or mouse macrophages. We used promasti-
Acknowledgements
Itraconazole and placebo were kindly provided by Janssen Pharmaceuticals. Sweden. We thank Dr Paul Converse for his help in coding the drugs. Special thanks go to Sven Britton for helpful discussions. The work was performed at the Armauer Hansen Research Institute and the All Africa Rehabilitation and Training Centre in Addis Ababa, and received financial support (through the funding of H.A.) from the UNDPi World Bar&WI-IO Special Programme for Research and Training in Tropical Diseasesand the Swedish Agency for Research Co-operation with Developing Countries (SAREC). References
Berman, J. D. (1988). Chemotherapy for leishmaniasis: biochemical mechanisms, clinical efficacy, and future strategies. Review of Infectious Diseases, 10, 56&586. Bore& D. A. (1987). Clinical trial of itraconazole in the treatment of deep mycosesand leishmaniasis. Review 0-f Infectious Diseases, 9, supplement 1, S57-S63. Bryceson, A. D. M. (1968). Penn&dine-induced diabetes mellitus. East African Medical Journal, 45, 110-117. Bryceson, A. D. M. (1969a). Diffuse cutaneousleishmaniasis in Ethiopia. I. The clinical and histological features of the disease.Transackms of the Royal Society of Tropical Medicine and Hygiene, 63, 708-737. Bryceson, A. D. M. (1969b). Diffuse cutaneous leishmaniasis. II. Treatment. Transactions of rhe Royal Sociew of Tropical Medicine and Hygiene, 64, 369-379.
Van Cauteren, H., Heykants, J., De Coster, R. & Cauwenbergh, G. (1987). Itraconazole: pharmacological studies
534
in animalsand humans.Reuiew of InfectiousDiseases,9, supplement1, S4U46. Van Cutsem, J., Van Gerven, F. & Jenssen,P. A. J. (1987). Activity of orally, topically, and parenterallyadministereditraconazolein the treatmentof superlicialanddeep mycoses:animalmodels.Review of InfectiousDiseases,9, supplement1, S15-S32.
Van Der Meulen,J., Mock, B., Fekete,E. & Serojini,P. A. (1981). Limited therapeuticaction of rifampicin/isonizide againstLeishmania aethiopica. Lancet, i, 197-198. Received 31 January 1990; revised 6 March 1990; accepted for publication 14 March 1990
TRANSACTIONSOF THE ROYAL SOCIETYOF TROPICALMEDICINE AND HYGIENE(1990) 84, 534-535
1 Shot-&Report 1 Low dosage combination of meglumine antimoniate plus allopurinol as first choice treatment of infantile visceral leishmaniasisin Italy ~,a~oMi~lh Guandahi”
M. Pettoepo .Myttovani’, k. and Gramlccla ‘Dipartimento di Pediatria, IJ Facolta di ’
Medicina e Chirurgia, Universita di Napoli,, Via Sergio Pansini 5,80131 Napoli, Italy; 2Laboratotw di Parassitologia, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Roma, Itat)
The areassurrounding mount Vesuvius &mpania, south Italy) are a well recognized focus of visceral leishmaniasis (VL) caused by Leishmania infantum (PAMPIGLIONE & BETTINI, 1981; GRAMICCJA et al.,
1986). An increased number of paediatric easesof VL+, someshowing resistance to conventional dosesof anumonials, has been recently reported for the above-mentioned areas which belong to Naples Province (BERNI CANANI et al., 1988), and a new..L. infantum enzymatic variant was isolated from one of the cases unresponsive to conventional antimonial therapy (GRAD~NI et al., 1987). CHUNCE et al. 11985)successfullv used a combination of sodium ‘stibogluconate (Pentostam@) plus allopurinol for treating 5 patients with VL who were unresponsive to, or had relapsed after treatment with, Pentostamo alone. However, these authors stressed the need of obtaining more reports from endemic areas to establish the optimum dosage and we have used a combination of meglumine antimoniate (Glucantime~, which shows a pharmacokinetic profile remarkably snnilar to that of sodium stibogluconate (CHULAY et al., 1988)) plus allopurinol (Zylorlco) as first choice treatment for infantile VL. This combination was given at a dosagelower than that previously reported (CHUNGE et al., 1985) to treat 4 children (2 males and 2 females, 410 years old) living in villages surrounding Vesuvius. Thev showed all the tvpical signs of i&mile VL, including hepatosplenomegaly, pancytopenia, hypergammaglobulinaemia and hypoalbuminaemia. Diagnosis of disease was confirmed by the demonstration of amastigotesin smears of bone marrow aspirate.
All children were treated with the following therapeutic regimen: meghunine antimoniate 15 mg Sbl kg body weight given once daily by intramuscular injection plus oral administration of allopurinol, 15 mg/kg body weight in 3 divided dosesdaily. Both drugs were given together for 3 weeks, when bone marrow aspiration was performed. If this test had been positive, the treatment would have been continued for 2 further weeks. Response to treatment and drug toxicity were evaluated according to the previous plan of management of VL patients (CHULAY et al., 1983). All children were then followed-up for at least 12 months after treatment. Patients were re-assessedat 2, 3, 6 and 12 months after discharae. Each check consisted of physical examination, liter and kidney function tests, haemoglobin determination, white blood cell count, and measurement of the spleen axis. Bone marrow aspvate from all the children was negative after 3 weeks of treatment. At the periodical re-examinations following treatment, none of the 4 children had evidence of active VL, and the spleen showed a significant size reduction from that at the start of treatment. In order to avoid repeated bone marrow aspiration, serological evaluation was performed at the end of the follow-up using the indirect immunofluorescent antibody test. Children recovered from VL due to L. infantum give a negative result in this test 12 months after treatment (MOKRANI et al., 1988). All the sera of our patients were negative, and the patients have now been without therapy for 12 months with no sign of relapse. The results suggest that the antimony/allopurinol combination is elective, even at lower doses than those oreviouslv used bv CHUNGE et al. (1985). in previously untreated children with VL in an endemic area where casesunresponsive to conventional doses of antimonials alone are frequently observed. The effectivenessof this combination probably dependson a synergistic or additive effect of the 2 drugs (CHUNGE et al., 1985), and its use could possibly prevent the emergence of drug resistance, with its attendant complications. The therapeutic regimen evaluated seemsto be well tolerated, since clinical, biochemical or haematological signs of toxicity were not observed. It is important that this regimen be tested in adult patients with VL, in whom side effects are usually more severe. We thank Dr A. D. M. Bryceson,of the Hospital for Tropical Diseases,London, for his interestin this studyand his useful advice.
References Berni Canani, M., Bemi Canani, R., Esposito, L., Ferrara, M., Cimaglia, M. L., Del Vasto, F., di Martino, L.,
TRANSA~ICJNS OFTHEROYALSOCIETY OFTROPICAL MEDICINE ANDHYGIENE
1 Short Report ( The use of itraconazole in the treatment of leishmaniasis caused by Leishmania aethiopica H. Akuffo’, M. Dietz’, S. Teldemariam’, T. and T. Yemane Tadesse’, G. Amare’ Be&an’ ‘Department of Infectious Diseases, Karolinska Institute, P.O. Box 5651, S-11489 Stockholm, Sweden; ‘All Africa Leprosy Rehabilitation and Training Centre (ALERT), P.O. Box 169, Addis Ababa, Ethiopia; 3Armauer Hansen Research Institute (AHRZ), Addis Ababa, Ethiopia Introduction
Infection with Leiskmania aetkiopica manifests itself as self-healing lesions in local cutaneous leishmaniasis (LCL) or as non-ulcerative lesions in diffuse cutaneous leishmaniasis (DCL) (BRYCESON, 1969a). DCL, with its refractoriness to presently available treatment, is the more debilitating form (BRYCESON, 1969b). However. even the local. self-healing. form in which cellular hyperactivity at ‘the site of-infection results in tissue destruction and ulceration can take a long time to heal and may cause disfigurement. Several drugs have been used in the treatment of infection caused by Leiskmunia species (BERMAN, 1988) but many are not effective with infections 1969b; VAN DER causedby L. aetkiopica (BRYCESON, MEULEN et al., 1981). Pentamidine is recommended for treatment of this infection, but the associatedhigh toxicity (BRYCESON,1968) 1s a limiting factor for svstemic use in LCL. Both forms of L. aetkioDica mfeciton, however, warrant treatment and new, effective, non-toxic drugs are needed. Itraconazole, a lipophilic triazole drug with high anti-fungal activity (VAN CUSTEMet al., 1987), has been reported to be effective in the treatment of L. braziliensis and L. mexicana pifanoi infection (BORELLI,1987). The sister drug ketoconazole has been used extensively in the Middle East for the treatment of L. major infection. Itraconazole, with its high affinity for tissue and low toxicity, might be expected to be superior to the hepatotoxic ketoconazolein the treatment of dermatological disorders, including those caused by L. aetkiopica.
A ulacebo-controlled double-blind study was used to assessthe effect of itraconaxole in patients with DCL and LCL, taking into account the tendency for self-healing in LCL patients. Patients
and Methods
Parasitologically confirmed DCL and LCL patients, aged between 12 and 48 years, who consented, were entered into the trial regardless of sex. The packets containing itraconazole and those with Correspondenceto Dr Hannah Akuffo, Department of Infectious Diseases,Karolinska Institute, P.O. Box 5651, S-11489Stockholm, Sweden.
(1990) 84, 532-534
placebo were identical and had been numbered by an independent person not involved in the trial. All 4 DCL patients were male. Ten LCL patients were consecutively entered into the trial. Thus there were 3 females in the itraconazole group and one in the placebo group. The female patients were informed about the remote but possible teiatogenic effects of high doses of itraconazole reported from animal experiments (VAN CAUTERENet al., 1987). Medication did not commence at the same time in all patients. Patients received four 50 mg capsules of itraconazole or placebo per day for 4 weeks (200 mgl day). The placebo was the base of the itraconazole capsules without itraconazole and appeared identical to the itraconazole capsule. Clinical examination, photography and parasitological examinations were performed before, and weekly during, the 4 weeks of treatment. One month after the end of therapy, patients came for follow-up assessment.The criteria for clinical assessmentincluded basic dermatological examination of lesions noting the presence of, or changes in, ulceration, exudation, crust formatron, epithelixation, peripheral healing, or shrinkage. Laboratory tests included blood counts, the determination of erythrocyte sedimentation rate, serum glutamic oxalic transaminase (GOT), serum glutamic pyruvic transaminase(GPT), alkaline phosphatase, bilirubin and urine analysis. Patients were weighed’ regularly and interviewed about their general state of health. A semi-quantitative method was devised for assessingparasite growth in culture, which will be described in a subsequent paper (seeTable). Smearswere also made. The same general area of the chosen lesion (within 5 mm) was used each time for obtaining culture and smear samples. All the isolates were isoenzyme typed at the London School of Hvgiene and Tropical Medicine as L. aetkiopica.
The abilitv of itraconazole to kill or inhibit deoxyribonucleic acid (DNA) synthesis of Leiskmania parasites was tested in vitro using tritiated thymidine ([3H]TdR), drug effectiveness being assessedby the diminished ability of promastigotes to incorporate [3H]TdR. Six isolates of L. aetkiopica derived from LCL cases, 3 isolates derived from DCL cases,and one isolate eachof L. tropica and L. major were tested. Results
The duration of diseasevaried from one to 17 years in the DCL patients and from 2 months to 2 years in the LCL paGents.All patients had active lesions at the time of entering the trial. After 4 weeks of treatment all the patients receiving itraconazole still had clinically-assessedactive lesions (Table). Improvement was, however, noted in the lesions of 2 of the placebotreated group. When the patients were asked about their lesions, 5 of 7 in each group thought they had noticed an improvement. At the one month followup, the 3 DCL patients who presented still had active lesions. There was clinical improvement in 2 of the 4 LCL patients receiving itraconaxole and in 4 of the 5 placebo-treated LCL patients. All but one of the LCL patients receiving itraconazole showed a tendency to reduction in number of parasites both by culture (Table) and smear. Three of the 5 placebo-treated LCL patients showed a similar tendency.
533 Table.
Evaluation
Trial no. Itraconazole :z 02 :i 69 76 Placebo 05 11
of treatment
Clinical
by clinical
criteria
Start
Active Active Active Active Active Active/infiltrated Active
Culture” ii: 1
230 NPD
54+0
and
culture
Clinical Active Active’ Activeh Active’ Active” Active Active”
4 weeks Culture” 5.2 6.4 0.4 240 NPD NPD NPD
Clinical
One month follow-up
Culture”
Active ND“
Some improvement Active Active Improved NDd
‘2 NNPDD NP; NIS
Active/infiltrated Activeb 0.8 Active/infiltrated 1.6 07 Active’ Active Active 100 0.4 NP8:: Active Active’ Improved NPD 2: Active 1.6 Improvedh NPD Improved NPD Active Improved” NPD Improved NI’D 8’: NPlS Activeb NPD Improved Active NPD Active 0.8 Active‘ Active 88 102 110 “Number of promastigotes counted in 20 ml of RPM1 medium plus 20% foetal calf serum 7 d after transfer from NNN medium; NPD=no parasites detected after 7 d; + =parasites present but not within counting chamber. bPatient thought that lesion had improved. ‘Patient did not notice improvement. dPatient did not report for follow-up.
There was no evidence of hepatotoxicity from the measurementsof serum transaminases,alkaline phosphatase and bilirubin. Itraconazole had an inhibitorv effect (>lO%) on DNA synthesis in 3 isolates IZ,. rrop& and L. aethiopica derived from LCL) of the 11 tested. There was a small degree of inhibition (~10%) in one DCL isolate. The degree of incorporation of thymidine varied amongst the isolates tested. The ability of itraconazole to inhibit DNA synthesis in someisolates was not related to the degree of promastigote prolif-
gotes to evaluate what effect, if any, itraconazole had on different isolates of L. uerhiopicu. Isolates differed in their response, and it might be interesting to correlate the effect of itraconazole in vitro and in vivo in the same individual. Use of a large number of patients might have permitted more clear-cut conclusions. Even so, this study clearly underlines the need for placebo-controlled trials whenever a self-healing disease is under study, and in a setting where strong positive beliefs may be attached to medical interference.
eration.
Discussion Many studies on both ketoconazole and itraconazole in leishmaniasis have not been performed in a double-blind manner and the intense placebo effect or self-healing observed in the present trial has not been considered as a possible causeof the enhanced clinical healing observed. One patient receiving itraconazole had somewhat elevated levels of serum GOT and GPT during the period that the drug was taken. Otherwise no increase
in serum enzymes or bilirubin was observed that could be attributed to itraconazole. However, the more sensitive bromsulphthalein test could not be done due to its invasive nature. The culture results indicated a tendency towards diminishing numbers of L. aerhio~ica amastigotes, canable of transforming into promastigotes, 6 the lesions of a majority 07 oatients in both ~OUDS. These findines. combined with the clinical gbse&ations, indicate that itraconazole in the regime used here was no more effective than a placebo for treating L. aethiopica leishmaniasis; however, it may be useful as a combination drug after excluding the possibility of adversedrug interactions. Drug testing using promastigotes is inferior as a prediction of in vivo efficacy due to the relatively Y
protected
intracellular
habitat
,
of atnastigotes.
L.
aethtipica, however, does not grow well in vitro in human or mouse macrophages. We used promasti-
Acknowledgements
Itraconazole and placebo were kindly provided by Janssen Pharmaceuticals. Sweden. We thank Dr Paul Converse for his help in coding the drugs. Special thanks go to Sven Britton for helpful discussions. The work was performed at the Armauer Hansen Research Institute and the All Africa Rehabilitation and Training Centre in Addis Ababa, and received financial support (through the funding of H.A.) from the UNDPi World Bar&WI-IO Special Programme for Research and Training in Tropical Diseasesand the Swedish Agency for Research Co-operation with Developing Countries (SAREC). References
Berman, J. D. (1988). Chemotherapy for leishmaniasis: biochemical mechanisms, clinical efficacy, and future strategies. Review of Infectious Diseases, 10, 56&586. Bore& D. A. (1987). Clinical trial of itraconazole in the treatment of deep mycosesand leishmaniasis. Review 0-f Infectious Diseases, 9, supplement 1, S57-S63. Bryceson, A. D. M. (1968). Penn&dine-induced diabetes mellitus. East African Medical Journal, 45, 110-117. Bryceson, A. D. M. (1969a). Diffuse cutaneousleishmaniasis in Ethiopia. I. The clinical and histological features of the disease.Transackms of the Royal Society of Tropical Medicine and Hygiene, 63, 708-737. Bryceson, A. D. M. (1969b). Diffuse cutaneous leishmaniasis. II. Treatment. Transactions of rhe Royal Sociew of Tropical Medicine and Hygiene, 64, 369-379.
Van Cauteren, H., Heykants, J., De Coster, R. & Cauwenbergh, G. (1987). Itraconazole: pharmacological studies
534
in animalsand humans.Reuiew of InfectiousDiseases,9, supplement1, S4U46. Van Cutsem, J., Van Gerven, F. & Jenssen,P. A. J. (1987). Activity of orally, topically, and parenterallyadministereditraconazolein the treatmentof superlicialanddeep mycoses:animalmodels.Review of InfectiousDiseases,9, supplement1, S15-S32.
Van Der Meulen,J., Mock, B., Fekete,E. & Serojini,P. A. (1981). Limited therapeuticaction of rifampicin/isonizide againstLeishmania aethiopica. Lancet, i, 197-198. Received 31 January 1990; revised 6 March 1990; accepted for publication 14 March 1990
TRANSACTIONSOF THE ROYAL SOCIETYOF TROPICALMEDICINE AND HYGIENE(1990) 84, 534-535
1 Shot-&Report 1 Low dosage combination of meglumine antimoniate plus allopurinol as first choice treatment of infantile visceral leishmaniasisin Italy ~,a~oMi~lh Guandahi”
M. Pettoepo .Myttovani’, k. and Gramlccla ‘Dipartimento di Pediatria, IJ Facolta di ’
Medicina e Chirurgia, Universita di Napoli,, Via Sergio Pansini 5,80131 Napoli, Italy; 2Laboratotw di Parassitologia, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Roma, Itat)
The areassurrounding mount Vesuvius &mpania, south Italy) are a well recognized focus of visceral leishmaniasis (VL) caused by Leishmania infantum (PAMPIGLIONE & BETTINI, 1981; GRAMICCJA et al.,
1986). An increased number of paediatric easesof VL+, someshowing resistance to conventional dosesof anumonials, has been recently reported for the above-mentioned areas which belong to Naples Province (BERNI CANANI et al., 1988), and a new..L. infantum enzymatic variant was isolated from one of the cases unresponsive to conventional antimonial therapy (GRAD~NI et al., 1987). CHUNCE et al. 11985)successfullv used a combination of sodium ‘stibogluconate (Pentostam@) plus allopurinol for treating 5 patients with VL who were unresponsive to, or had relapsed after treatment with, Pentostamo alone. However, these authors stressed the need of obtaining more reports from endemic areas to establish the optimum dosage and we have used a combination of meglumine antimoniate (Glucantime~, which shows a pharmacokinetic profile remarkably snnilar to that of sodium stibogluconate (CHULAY et al., 1988)) plus allopurinol (Zylorlco) as first choice treatment for infantile VL. This combination was given at a dosagelower than that previously reported (CHUNGE et al., 1985) to treat 4 children (2 males and 2 females, 410 years old) living in villages surrounding Vesuvius. Thev showed all the tvpical signs of i&mile VL, including hepatosplenomegaly, pancytopenia, hypergammaglobulinaemia and hypoalbuminaemia. Diagnosis of disease was confirmed by the demonstration of amastigotesin smears of bone marrow aspirate.
All children were treated with the following therapeutic regimen: meghunine antimoniate 15 mg Sbl kg body weight given once daily by intramuscular injection plus oral administration of allopurinol, 15 mg/kg body weight in 3 divided dosesdaily. Both drugs were given together for 3 weeks, when bone marrow aspiration was performed. If this test had been positive, the treatment would have been continued for 2 further weeks. Response to treatment and drug toxicity were evaluated according to the previous plan of management of VL patients (CHULAY et al., 1983). All children were then followed-up for at least 12 months after treatment. Patients were re-assessedat 2, 3, 6 and 12 months after discharae. Each check consisted of physical examination, liter and kidney function tests, haemoglobin determination, white blood cell count, and measurement of the spleen axis. Bone marrow aspvate from all the children was negative after 3 weeks of treatment. At the periodical re-examinations following treatment, none of the 4 children had evidence of active VL, and the spleen showed a significant size reduction from that at the start of treatment. In order to avoid repeated bone marrow aspiration, serological evaluation was performed at the end of the follow-up using the indirect immunofluorescent antibody test. Children recovered from VL due to L. infantum give a negative result in this test 12 months after treatment (MOKRANI et al., 1988). All the sera of our patients were negative, and the patients have now been without therapy for 12 months with no sign of relapse. The results suggest that the antimony/allopurinol combination is elective, even at lower doses than those oreviouslv used bv CHUNGE et al. (1985). in previously untreated children with VL in an endemic area where casesunresponsive to conventional doses of antimonials alone are frequently observed. The effectivenessof this combination probably dependson a synergistic or additive effect of the 2 drugs (CHUNGE et al., 1985), and its use could possibly prevent the emergence of drug resistance, with its attendant complications. The therapeutic regimen evaluated seemsto be well tolerated, since clinical, biochemical or haematological signs of toxicity were not observed. It is important that this regimen be tested in adult patients with VL, in whom side effects are usually more severe. We thank Dr A. D. M. Bryceson,of the Hospital for Tropical Diseases,London, for his interestin this studyand his useful advice.
References Berni Canani, M., Bemi Canani, R., Esposito, L., Ferrara, M., Cimaglia, M. L., Del Vasto, F., di Martino, L.,