Miltefosine in children with visceral leishmaniasis: A prospective, multicentric, cross-sectional study
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《美国医学杂志》
1 Department of Pediatrics, Nalanda Medical College, Patna, India
2 Institute of Medical Sciences, B.H.U., Varanasi, Uttar Pradesh, India
Objective. Miltefosine, an alkyl phospholipid has been found effective against visceral leishmaniasis (VL) in adults in various studies. The authors safety, tolerance and efficacy of Miltefosine and compared with available gold standard anti-Ieishmanial drug, Amphotericin B, a parenteral formulation in children with VL. Methods. All consecutive children aged 1 yr to 14 yr, presented with fever, splenomegaly and positive LD body in splenic smear examination, admitted in pediatric ward of Nalanda Medical college and Child care center between 1st July 03 to 30th June 05 were taken for study. Patients were randomized into four groups. Group-l and 2 patients were given Miltefosine in dose of 2.5 mg/Kg day o.d. or b.i.d. per orally to a maxiIpum of 100 mg and group 3 and 4 Amphotericin B at a dose of 1 mg/Kg/day (total: 15 mg/Kg). All patients were followed at completion of therapy, 3 months and 6 months for clinical response, splenic size and parasitologically. Results. Out of 125 children, 44 were in group-I, 20 in group-2, 38 in group-3 and 23 in group4, 124 patients had parasitological cure with relapse in one patient of group 1 during follow up. One patient in-group II had no response with first course but became parasitologically negative with 2nd course of Miltefosine. In-group I, one patient had persistent splenomegaly and found to have associated portal hypertension. Final cure rate with Miltefosine and Amphotericin B was 93.2%, 95%, 92.1% and 91.3% in-group 1, 2, 3 and 4 respectively, which are statistically insignificant. Majority of patients had pancytopenia. Eievated". AL T (>3 times of normal) were seen in 28, 11, 19 and 13 patients of group 1, 2, 3 and group 4 respectively which returned to normal in subsequent follow up. Raised BUN was observed more in patients who got Amphotericin B i.e. 65.42% and 73.91 % in-group 3 and 4 respectively. GI side effects i.e. diarrhea and vomiting were observed in 26 and 23 patients in-group 1 and 2 respectively. Conclusion. Miltefosine is safe, well tolerable, and highly effective and has same efficacy as Amphotericin B in newly diagnosed and SAG resistant children with visceral leishmaniasis.
Keywords: Miltefosine; Amphotericin B; Visceral leishmaniasis (VL); LD Body; SAG (Sodium antimony gluconate)
Visceral leishmaniasis (VL) or kala-azar is a human disease caused by hemoflagellate protozoan parasites of leishmania species and transmitted to human by the sand fly bites. VL is characterized by fever and splenomegaly and is fatal if left untreated. Leishmaniasis is distributed worldwide and 12 million people are estimated to be infected with about 500,0000 new cases each year. Approximately 50% of these patients are children.[1] In India, Bihar is highly infected state and complicated form of VL are referred to authors centers but disease has spread to eastern Uttarpradesh, West Bengal, adjoining areas of Nepal and sporadic cases have been reported from different parts of the country . Furthermore, leishmania has emerged as an opportunistic pathogen of HIV infected children. In recent years, the treatment of VL is far from satisfactory. All anti-leishmanial drugs are toxic and most have to be used parenterally for prolonged period. The therapy has been further complicated by large number of infected children and declining effectiveness of pentavalent antimonial compounds (SAG). Although the lipid formulations of Amphotericin B are an important advancement in therapy, their high cost precludes their use.
Miltefosine is a phosphocholine analogue, originally developed as anti-malignant drug. Although it proved to be ineffective as antimalignant drug, it has been found to be highly active against leishmanial donovani in vitro and animal model.[2],[3] It primarily interferes with cellular membranes without interacting with DNA and modulates membrane permeability and fluidity, membrane lipid composition, metabolism of phospholipids and proliferation signal transduction. It also induces apoptotic cell death. Unlike other chemotherapeutic agents, miltefosine lack pone marrow toxicity and exert growth-stimulating effects on hemopoitic progenitor cells.[4] Very few study have been done with miltefosine in children suffering from VL.[6] Authors studied the efficacy; tolerance, safety and drug related adverse reactions of miltefosine and compared with Amphotericin B in children with visceral leishmaniasis.
Materials and Methods
The authors undertook a prospective, multicentric observational study of miltefosine therapy in children with visceral leishmaniasis. The study was conducted in parallel at children ward of Nalanda Medical College and Child Care Center, Patna between 1 st July 03 to 30th June 05. Eihics committees of both center approved study protocol and consent form. Written informed informed was taken from legal guardians of children.
All consecutive children aged I yr to 14 yr, presented with fever, splenomegaly and positive LD body in splenic aspirate examination, admitted in pediatric ward of Nalanda Medical College and Child Care Center were taken for study. Patients were randomized into four groups by slips kept separately in two small boxes for both newly diagnosed patients and those who had received 30 days course of sodium antimony gluconate (SAG):
Group 1: Patients who had not received prior anti-Ieishmanial drug and received Miltefosine,
Group 2: Patients who had received 30 days course of SAG (20 mg/Kg/day) and received Miltefosine
Group 3: Patients who had not received prior anti-Ieishmanial drug and received Amphotericin B and K
Group 4: Patients who had received 30 days course of SAG (20 mg/kg/day) and received Amphotericin B.
Children with bleeding diathesis, liver disorder (ALT & AST>3 times, serum bilirubin >2 times of normal), renal dysfunction (BUN and serum creatinine; 1.5 times of normal), co-existing malaria or HIV, neutrophil count less than 1000/cu mm and platelet count less than 40,000/ cu mm were excluded from study. Patients who had received incomplete course of sodium stibogluconate (SAG) were also excluded from study. All patients were monitored for adverse events, hematological variables, serum chemistry and splenic size below left costal margin.
The parasitological analyses of splenic aspirate were performed at completion of theapy, 1 month and at 6 months. The density of parasites was graded from 0(no paraste/10000 high power field) to 6(> 100 parasites/ field). The cure was defined as an absence of parasites at the end of therapy and no relapse during six months of follow up. Relapse was defined by appearance of symptoms and signs suggestive of leishmaniasis with demonstrable LD bodies in splenic aspirates after initial cure. Treatment failure was defined as either the lack of initial cure or relapse.
Miltefosine (Impavido) was administered orally for 28 days at a dose of 2.5 mg/Kg/day o.d or bid to a maximum of 100 mg daily to group-1 and 2 patients and Amphotericin B was given at a dose 1 mg/Kg i.v. after sensitivity testing to a total cumulative dose of 15 mg/Kg to group 3 and 4 patients. During therapy patients were monitored daily for vital signs, splenic size and adverse events. Hematological (CBC), biochemical (ALT, AST, BUN, Creatinine) and splenic size below left costal margin were monitored weekly during therapy, at completion, after 1 month and 6 months.
Statistical analysis
Student t-test and z-test were used to test the significance of difference between two means and proportions respectively.
Results
There were 125 children in the study; 44 in group- 1; 20 in group-2; 38 in-group 3 and 23 in-group 4. Their baseline characteristics (clinical and laboratory parameters) are, summarized in [Table - 1]. The baseline characteristics were similar in both groups except platelet count in-group 1 an 3; which may be due to prior sodium stibogluconate therapy. The mean parasite density in all groups was similar and there was no significant difference in splenic size below left costal margin in all groups. Majority of patients had pancytopenia.
The efficacy of treatment is shown in [Table - 2]. At the completion of miltefosine and Amphotericin therapy splenic aspirates were done in all patients. All patients were parasitologically negative except in one patient in-group 2, who required repeat course of miltefosine. In group I, one patient had persistent splenomegaly and USG of hepatobillary system showed cavernous transformation of splenic vein with portal vein diameter of 14 mm i.e. portal hypertension. Hence initial cure rate in all groups were 100%. In all groups, the mean splenic size had decreased to ~1.5 cm below costal margin. Two patients in group-I, 1 patient in group-2, 3 patients in group-3 and 2 in greup-4 were lost in follow up, hence a total of 117 were followed at 6 month i.e. 42 in group-I, 19 in group-2, 35 in group-3 and 21 in group-4. Majority of patients had persisting anemia but only one patient in group-I had clinical and parasitological relapse. The patient, who relapsed during follow up had no difference in baseline characteristics. The final cure rates on per protocol basis, in which all patients who could be followed for trial period analyzed, were 93.2%, 95%, 92.10% and 91.30% in-group 1, 2, 3 and 4 respectively.
Adverse events related to miltefosine and Amphotericin B therapy are mentioned in [Table - 3]. Diarrhea and vomiting were common side effects and were observed in 40.9% & 36.36 % in group-I and 40% and 35% in group-2 respectively but none in group-3 and 4. Diarrhea was mild, self-limiting ana got controlled in 2-3 days and did not require discontinuation of miltefosine therapy. Vomiting was also mild and gets controlled with oral antiemetic. Fever and chills occurred in all patients of group-3 and 4 during administration, which were controlled with paracetamol and antihistaminic. Miltefosine therapy resulted in rise of AL T and AST (>3 times of normal) and start rise during second week of therapy [Table - 3] and remained elevated till end of treatment and declined to base level after 2 weeks of completion. Although BUN urea was raised in 13.6%, 10%, 68.42% and 73.91% in group-I, 2, 3 and 4, none of the patient had raised serum creatinine before and after treatment. BUN returned to normal after one week of completion of therapy in all groups. Electrocardiogram and ophthalmologic examination in ail four groups did not revealed any abnormalities at completion and 6 months of therapy.
Discussion
This study shows that Miltefosine is an effective drug for treatment of visceral leishmaniasis in children older than 1 year and efficacy is almost similar to Amphotericin B. To authors knowledge this is largest trial on children. Of 125 children, who presented to us with clinical features suggestive of VL were treated with Miltefosine for 28 days (dose: 2.5 mg/Kg/day) and Amphotericin B (1 mg/Kg/day). At end of therapy all patients except one, who required repeat course of Miltefosine, had parasitological cure. At 6 month follow up; cure rate was 93.2%, 95%, 92.1 % and 91.3 % in-group 1, 2, 3 and 4 respectively.
Miltefosine was well tolerated in children. Diarrhea and vomiting were observed in 40.9% & 36.36 % in group-I and 40% & 35% in group-2 respectively. Diarrhea was mild, self limiting and controlled in 2-3 days and did not require discontinuation of miltefosine therapy. Vomiting was also mild and got controlled with oral antiemetics as reported by other workers.[5],[6] In the present study diarrhea occurred in approximately 40% of patients, who received Miltefosine. The increased ALT in group-2 and 4 may be due prior SAG therapy and disease per se. Further increase in ALT and AST may be its effect on hepatocyte but none of patient required discontinuation of therapy. Miltefosine did not substantially alter renal functions i.e. 13.6% in group-1 and 10% in-group-2, whereas with Amphotericin; 68.42% and 73.91% of patient's in-group -3 and 4 respectively had elevation of BUN only.
Miltefosine may be compared with other therapeutic agents available for VL in terms of efficacy, side effects, tolerance and cost of administration as observed by other workers the standard therapy till date for VL in authors part is pentavalent antimonials i.e. SAG or in regions with a high prevalence of antimony resistance, amphotericin B. SAG has the disadvantage of both toxicity and clinical resistance in approximately 40% of patients in certain regions of Bihar,[7] where it has been used for long period. Liposomal amphotericin B is highly effective and well tolerated, but high cost is a barrier for wide spread use in developing countries like India. Pentamidine has been used in SAG resistant cases, but tolerance is a great problem and resistance is now evident.[8],[9]
Oral Miltefosine was safe and effective in children. The efficacy is comparable with amphotericin B in both newly diagnosed and SAG resistant patients. This drug is now registered in India and available in endemic region with brand name Impavido. A large clinical study is required to evaluate further efficacy, relapse and future resistance to this drug.
Acknowledgements
The authors acknowledge patients and parents who had given consent and participated in study. They also thank the laboratory staff for taking pain in collection of data and hematological works.
References
1.Desjeux P. Leishmaniasis: public health aspects and control. Clin Dermatol 1996; 14 : 417-423. [PUBMED] [FULLTEXT]
2.Croft SL, Neal RA, Pendergast W, Chan JH. The activity of alkylphosphocholines and related derivatives against Leishmania donovani. Biochemical Parasitol 1987; 42: 2633-2636.
3.Kuhlencord A, Maniera T, Eibl H, Unger C. Hexadecyl phosphocholine: oral treatment of visceral leishmaniasis in mice. Antimicro agents Chenothe 1992; 36 : 1630-1634. [PUBMED] [FULLTEXT]
4.Jendrossek V, Handrick R. Membrane Targeted Anticancer Drugs: Potent Inducer of Apoptosis and putative Radiosesitisers. Curr Med Chem Anti-Canc Agents 2003; 3(5) : 343-353.
5.Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fishcer C, Junge K, Bryceson A, Berman J. Oral Miltefosine for Indian Visceral leishmaniasis. N Engl J Med 2002; 347 : 1739-1746.
6.Sundar S, Jha TK, Sindermann H, Junge K, Bachmann P, Berman J. Oral miltefosine in children with mild to moderate Indian visceral leishmanisis. Pediatr Infect Dis J 2003; 22(5) : 434-438.
7.Bryceson A. A policy for leishmaniasis with respect to the prevention and control of drug resistance. Trop Med Int Health 2001; 6: 928-934. [PUBMED] [FULLTEXT]
8.Jha SN, Singh NKP, Jha TK. Changing response to diamidine compounds in cases of kala-azar unresponsive to antimonial. J Assoc Physicians India 1991; 39 : 314-316.
9.Thakur CP, Kumar M, Pandey A K. Comparison of regimes of treatment of antimony resistant kala-azar patients: a randomized controlled study. Am J Trop Med Hyg 1991; 45 : 435-441.(Singh Utpal Kant, Prasad Rajniti, Mishra)
2 Institute of Medical Sciences, B.H.U., Varanasi, Uttar Pradesh, India
Objective. Miltefosine, an alkyl phospholipid has been found effective against visceral leishmaniasis (VL) in adults in various studies. The authors safety, tolerance and efficacy of Miltefosine and compared with available gold standard anti-Ieishmanial drug, Amphotericin B, a parenteral formulation in children with VL. Methods. All consecutive children aged 1 yr to 14 yr, presented with fever, splenomegaly and positive LD body in splenic smear examination, admitted in pediatric ward of Nalanda Medical college and Child care center between 1st July 03 to 30th June 05 were taken for study. Patients were randomized into four groups. Group-l and 2 patients were given Miltefosine in dose of 2.5 mg/Kg day o.d. or b.i.d. per orally to a maxiIpum of 100 mg and group 3 and 4 Amphotericin B at a dose of 1 mg/Kg/day (total: 15 mg/Kg). All patients were followed at completion of therapy, 3 months and 6 months for clinical response, splenic size and parasitologically. Results. Out of 125 children, 44 were in group-I, 20 in group-2, 38 in group-3 and 23 in group4, 124 patients had parasitological cure with relapse in one patient of group 1 during follow up. One patient in-group II had no response with first course but became parasitologically negative with 2nd course of Miltefosine. In-group I, one patient had persistent splenomegaly and found to have associated portal hypertension. Final cure rate with Miltefosine and Amphotericin B was 93.2%, 95%, 92.1% and 91.3% in-group 1, 2, 3 and 4 respectively, which are statistically insignificant. Majority of patients had pancytopenia. Eievated". AL T (>3 times of normal) were seen in 28, 11, 19 and 13 patients of group 1, 2, 3 and group 4 respectively which returned to normal in subsequent follow up. Raised BUN was observed more in patients who got Amphotericin B i.e. 65.42% and 73.91 % in-group 3 and 4 respectively. GI side effects i.e. diarrhea and vomiting were observed in 26 and 23 patients in-group 1 and 2 respectively. Conclusion. Miltefosine is safe, well tolerable, and highly effective and has same efficacy as Amphotericin B in newly diagnosed and SAG resistant children with visceral leishmaniasis.
Keywords: Miltefosine; Amphotericin B; Visceral leishmaniasis (VL); LD Body; SAG (Sodium antimony gluconate)
Visceral leishmaniasis (VL) or kala-azar is a human disease caused by hemoflagellate protozoan parasites of leishmania species and transmitted to human by the sand fly bites. VL is characterized by fever and splenomegaly and is fatal if left untreated. Leishmaniasis is distributed worldwide and 12 million people are estimated to be infected with about 500,0000 new cases each year. Approximately 50% of these patients are children.[1] In India, Bihar is highly infected state and complicated form of VL are referred to authors centers but disease has spread to eastern Uttarpradesh, West Bengal, adjoining areas of Nepal and sporadic cases have been reported from different parts of the country . Furthermore, leishmania has emerged as an opportunistic pathogen of HIV infected children. In recent years, the treatment of VL is far from satisfactory. All anti-leishmanial drugs are toxic and most have to be used parenterally for prolonged period. The therapy has been further complicated by large number of infected children and declining effectiveness of pentavalent antimonial compounds (SAG). Although the lipid formulations of Amphotericin B are an important advancement in therapy, their high cost precludes their use.
Miltefosine is a phosphocholine analogue, originally developed as anti-malignant drug. Although it proved to be ineffective as antimalignant drug, it has been found to be highly active against leishmanial donovani in vitro and animal model.[2],[3] It primarily interferes with cellular membranes without interacting with DNA and modulates membrane permeability and fluidity, membrane lipid composition, metabolism of phospholipids and proliferation signal transduction. It also induces apoptotic cell death. Unlike other chemotherapeutic agents, miltefosine lack pone marrow toxicity and exert growth-stimulating effects on hemopoitic progenitor cells.[4] Very few study have been done with miltefosine in children suffering from VL.[6] Authors studied the efficacy; tolerance, safety and drug related adverse reactions of miltefosine and compared with Amphotericin B in children with visceral leishmaniasis.
Materials and Methods
The authors undertook a prospective, multicentric observational study of miltefosine therapy in children with visceral leishmaniasis. The study was conducted in parallel at children ward of Nalanda Medical College and Child Care Center, Patna between 1 st July 03 to 30th June 05. Eihics committees of both center approved study protocol and consent form. Written informed informed was taken from legal guardians of children.
All consecutive children aged I yr to 14 yr, presented with fever, splenomegaly and positive LD body in splenic aspirate examination, admitted in pediatric ward of Nalanda Medical College and Child Care Center were taken for study. Patients were randomized into four groups by slips kept separately in two small boxes for both newly diagnosed patients and those who had received 30 days course of sodium antimony gluconate (SAG):
Group 1: Patients who had not received prior anti-Ieishmanial drug and received Miltefosine,
Group 2: Patients who had received 30 days course of SAG (20 mg/Kg/day) and received Miltefosine
Group 3: Patients who had not received prior anti-Ieishmanial drug and received Amphotericin B and K
Group 4: Patients who had received 30 days course of SAG (20 mg/kg/day) and received Amphotericin B.
Children with bleeding diathesis, liver disorder (ALT & AST>3 times, serum bilirubin >2 times of normal), renal dysfunction (BUN and serum creatinine; 1.5 times of normal), co-existing malaria or HIV, neutrophil count less than 1000/cu mm and platelet count less than 40,000/ cu mm were excluded from study. Patients who had received incomplete course of sodium stibogluconate (SAG) were also excluded from study. All patients were monitored for adverse events, hematological variables, serum chemistry and splenic size below left costal margin.
The parasitological analyses of splenic aspirate were performed at completion of theapy, 1 month and at 6 months. The density of parasites was graded from 0(no paraste/10000 high power field) to 6(> 100 parasites/ field). The cure was defined as an absence of parasites at the end of therapy and no relapse during six months of follow up. Relapse was defined by appearance of symptoms and signs suggestive of leishmaniasis with demonstrable LD bodies in splenic aspirates after initial cure. Treatment failure was defined as either the lack of initial cure or relapse.
Miltefosine (Impavido) was administered orally for 28 days at a dose of 2.5 mg/Kg/day o.d or bid to a maximum of 100 mg daily to group-1 and 2 patients and Amphotericin B was given at a dose 1 mg/Kg i.v. after sensitivity testing to a total cumulative dose of 15 mg/Kg to group 3 and 4 patients. During therapy patients were monitored daily for vital signs, splenic size and adverse events. Hematological (CBC), biochemical (ALT, AST, BUN, Creatinine) and splenic size below left costal margin were monitored weekly during therapy, at completion, after 1 month and 6 months.
Statistical analysis
Student t-test and z-test were used to test the significance of difference between two means and proportions respectively.
Results
There were 125 children in the study; 44 in group- 1; 20 in group-2; 38 in-group 3 and 23 in-group 4. Their baseline characteristics (clinical and laboratory parameters) are, summarized in [Table - 1]. The baseline characteristics were similar in both groups except platelet count in-group 1 an 3; which may be due to prior sodium stibogluconate therapy. The mean parasite density in all groups was similar and there was no significant difference in splenic size below left costal margin in all groups. Majority of patients had pancytopenia.
The efficacy of treatment is shown in [Table - 2]. At the completion of miltefosine and Amphotericin therapy splenic aspirates were done in all patients. All patients were parasitologically negative except in one patient in-group 2, who required repeat course of miltefosine. In group I, one patient had persistent splenomegaly and USG of hepatobillary system showed cavernous transformation of splenic vein with portal vein diameter of 14 mm i.e. portal hypertension. Hence initial cure rate in all groups were 100%. In all groups, the mean splenic size had decreased to ~1.5 cm below costal margin. Two patients in group-I, 1 patient in group-2, 3 patients in group-3 and 2 in greup-4 were lost in follow up, hence a total of 117 were followed at 6 month i.e. 42 in group-I, 19 in group-2, 35 in group-3 and 21 in group-4. Majority of patients had persisting anemia but only one patient in group-I had clinical and parasitological relapse. The patient, who relapsed during follow up had no difference in baseline characteristics. The final cure rates on per protocol basis, in which all patients who could be followed for trial period analyzed, were 93.2%, 95%, 92.10% and 91.30% in-group 1, 2, 3 and 4 respectively.
Adverse events related to miltefosine and Amphotericin B therapy are mentioned in [Table - 3]. Diarrhea and vomiting were common side effects and were observed in 40.9% & 36.36 % in group-I and 40% and 35% in group-2 respectively but none in group-3 and 4. Diarrhea was mild, self-limiting ana got controlled in 2-3 days and did not require discontinuation of miltefosine therapy. Vomiting was also mild and gets controlled with oral antiemetic. Fever and chills occurred in all patients of group-3 and 4 during administration, which were controlled with paracetamol and antihistaminic. Miltefosine therapy resulted in rise of AL T and AST (>3 times of normal) and start rise during second week of therapy [Table - 3] and remained elevated till end of treatment and declined to base level after 2 weeks of completion. Although BUN urea was raised in 13.6%, 10%, 68.42% and 73.91% in group-I, 2, 3 and 4, none of the patient had raised serum creatinine before and after treatment. BUN returned to normal after one week of completion of therapy in all groups. Electrocardiogram and ophthalmologic examination in ail four groups did not revealed any abnormalities at completion and 6 months of therapy.
Discussion
This study shows that Miltefosine is an effective drug for treatment of visceral leishmaniasis in children older than 1 year and efficacy is almost similar to Amphotericin B. To authors knowledge this is largest trial on children. Of 125 children, who presented to us with clinical features suggestive of VL were treated with Miltefosine for 28 days (dose: 2.5 mg/Kg/day) and Amphotericin B (1 mg/Kg/day). At end of therapy all patients except one, who required repeat course of Miltefosine, had parasitological cure. At 6 month follow up; cure rate was 93.2%, 95%, 92.1 % and 91.3 % in-group 1, 2, 3 and 4 respectively.
Miltefosine was well tolerated in children. Diarrhea and vomiting were observed in 40.9% & 36.36 % in group-I and 40% & 35% in group-2 respectively. Diarrhea was mild, self limiting and controlled in 2-3 days and did not require discontinuation of miltefosine therapy. Vomiting was also mild and got controlled with oral antiemetics as reported by other workers.[5],[6] In the present study diarrhea occurred in approximately 40% of patients, who received Miltefosine. The increased ALT in group-2 and 4 may be due prior SAG therapy and disease per se. Further increase in ALT and AST may be its effect on hepatocyte but none of patient required discontinuation of therapy. Miltefosine did not substantially alter renal functions i.e. 13.6% in group-1 and 10% in-group-2, whereas with Amphotericin; 68.42% and 73.91% of patient's in-group -3 and 4 respectively had elevation of BUN only.
Miltefosine may be compared with other therapeutic agents available for VL in terms of efficacy, side effects, tolerance and cost of administration as observed by other workers the standard therapy till date for VL in authors part is pentavalent antimonials i.e. SAG or in regions with a high prevalence of antimony resistance, amphotericin B. SAG has the disadvantage of both toxicity and clinical resistance in approximately 40% of patients in certain regions of Bihar,[7] where it has been used for long period. Liposomal amphotericin B is highly effective and well tolerated, but high cost is a barrier for wide spread use in developing countries like India. Pentamidine has been used in SAG resistant cases, but tolerance is a great problem and resistance is now evident.[8],[9]
Oral Miltefosine was safe and effective in children. The efficacy is comparable with amphotericin B in both newly diagnosed and SAG resistant patients. This drug is now registered in India and available in endemic region with brand name Impavido. A large clinical study is required to evaluate further efficacy, relapse and future resistance to this drug.
Acknowledgements
The authors acknowledge patients and parents who had given consent and participated in study. They also thank the laboratory staff for taking pain in collection of data and hematological works.
References
1.Desjeux P. Leishmaniasis: public health aspects and control. Clin Dermatol 1996; 14 : 417-423. [PUBMED] [FULLTEXT]
2.Croft SL, Neal RA, Pendergast W, Chan JH. The activity of alkylphosphocholines and related derivatives against Leishmania donovani. Biochemical Parasitol 1987; 42: 2633-2636.
3.Kuhlencord A, Maniera T, Eibl H, Unger C. Hexadecyl phosphocholine: oral treatment of visceral leishmaniasis in mice. Antimicro agents Chenothe 1992; 36 : 1630-1634. [PUBMED] [FULLTEXT]
4.Jendrossek V, Handrick R. Membrane Targeted Anticancer Drugs: Potent Inducer of Apoptosis and putative Radiosesitisers. Curr Med Chem Anti-Canc Agents 2003; 3(5) : 343-353.
5.Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fishcer C, Junge K, Bryceson A, Berman J. Oral Miltefosine for Indian Visceral leishmaniasis. N Engl J Med 2002; 347 : 1739-1746.
6.Sundar S, Jha TK, Sindermann H, Junge K, Bachmann P, Berman J. Oral miltefosine in children with mild to moderate Indian visceral leishmanisis. Pediatr Infect Dis J 2003; 22(5) : 434-438.
7.Bryceson A. A policy for leishmaniasis with respect to the prevention and control of drug resistance. Trop Med Int Health 2001; 6: 928-934. [PUBMED] [FULLTEXT]
8.Jha SN, Singh NKP, Jha TK. Changing response to diamidine compounds in cases of kala-azar unresponsive to antimonial. J Assoc Physicians India 1991; 39 : 314-316.
9.Thakur CP, Kumar M, Pandey A K. Comparison of regimes of treatment of antimony resistant kala-azar patients: a randomized controlled study. Am J Trop Med Hyg 1991; 45 : 435-441.(Singh Utpal Kant, Prasad Rajniti, Mishra)