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Is there any place for "second-line" medication in the treatment of canine leishmaniosis? The aminosidine paradigm

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Leishmaniosis is one of the most common diseases of dogs in the Mediterranean countries with zoonotic potential. Based on recent publications, the drugs currently in use for the treatment of this disease have been grouped into "first-line" (meglumine antimoniate, allopurinol, combination of the former, amphotericin B) and "second-line" (aminosidine, pentamidine, metronidazole in combination with enrofloxacin or with spiramycin, miltefosine, ketokonazole). For an objective comparison of the usefulness of these antileishmanial medications, various factors, such as route, dose and frequency of administration, clinical efficacy, toxicity, achievement of parasitological cure or change of the immunological response of the patient, and infectiousness of treated dogs to sandflies, should be taken into consideration. Clearly, if all remaining factors are constant, orally administered agents would be preferable, because no hospitalization is needed and local reactions at the injection sites are at best avoided. Dose and frequency of administration should be defined by performing drug pharmacokinetic and pharmacodynamic studies, in order to reduce toxicity, increase efficacy and avoid development of resistant parasite strains. Ideally, clinical efficacy and safety should be assessed in staged clinical trials, starting with toxicological studies, followed by observational trials, and finally by blinded-controlled trials. Unfortunatelly, such rigorous testing has not been performed for many antileishmanial medications applied to the dog. Also, dosing schedules that are considered sub-optimal from a pharmacological standpoint have been employed for some of them, most likely resulting in erroneous conclusions. Aminosidine is perhaps the most typical example, since it has been tested at a wrong dose (5mg/kg B.W.) and frequency of administration (every 12 hours) in all controlled trials so far conducted. Nowadays, it is clear that parasitological cure cannot be achieved in the majority of treated dogs, irrespectively of the therapeutic protocol employed. Furthermore, even if it had been feasible, the total elimination of the parasite would have been meaningless for dogs residing in the endemic areas of the disease. For these reasons, one of the most important ,but largely unexplored goals of antileishmanial treatment is to change the immunological response of the patient, thus rendering previously susceptible dogs resistant to disease and its relapses. Although the infectivity of treated dogs to sandflies is reduced, it is not usually eliminated. From an epidemiological point of view this may be of minor importance, given the high prevalence of the infection among the canine population. However, from a public health perspective, transmission of potentially drug-resistant strains of the parasite is a major consideration. Strategiesto avoid or delay their occurrence include optimal dosing and treatment duration, use of different medications in relapsing cases, combination of drugs with different mode of action and, when possible, preference for medications that are not currently in use for the treatment of human visceral leishmaniasis. Aminosidine, although injectable and contraindicated in dogs with renal failure, offers some advantages, such as the low cost, commercial availability in Greece, once daily administration and satisfactory efficacy and safety when used at the optimal dose. Also, it is not currently employed for the treatment of human disease, at least in the Mediterranean countries. For all these reasons, blinded-controlled trials are urgently needed to definitely prove if aminosidine can be really considered as a "first-line" drug for the treatment of canine leishmaniosis.


Dog; leishmaniosis; treatment; aminosidine

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Agut A, Corzo Ν, Murciano J, Laredo FG, Soler M (2003) Clinical and radiographic study of bone and joint lesions in 26 dogs with leishmaniasis. The Veterinary Record, 153:648-652.

Ashford RW, Snowden KF (2000) The leishmaniases. In: Dogs, Zoonoses and Public Health. CABI Publishing, Oxon and New York, pp 132-140.

Athanasiou LV, 2004. Contribution to the study of epidemiology, diagnosis and treatment of canine leishmaniosis. Thesis. Aristotles University of Thessaloniki, Thessaloniki, Greece.

Balana-Fouce R, Reguera RM, Cubria JC, Ordonez D (1998) The pharmacology of leishmaniasis. General Pharmacology 30:435-443.

Baneth G (2002) A review of the treatment of canine leishmaniasis. In: Canine Leishmaniasis: moving towards a solution. Proceedings of the 2nd International Canine Leishmaniasis Forum, (Sevilla, Spain), pp 15-19.

Baneth G, Aroch I (2008) Canine leishmaniasis: a diagnostic and clinical challenge. The Veterinary Journal, 175:14-15.

Baneth G, Koutinas AF, Solano-Gallego L, Bourdeau P, Ferrer L (2008) Canine leishmaniosis - new concepts and insights on an expanding zoonosis: part one. Trends in Parasitology, 24:324-330.

Cabrai M, O'Grady JE, Gomes S, Sousa JC, Thompson H, Alexander J (1998) The immunology of canine leishmaniosis: strong evidence for a developing disease spectrum from asymptomatic dogs. Veterinary Parasitology, 76:173-180.

Cabrai M, O'Grady J, Alexander J (1992) Demonstration of Leishmania specific cell mediated and humoral immunity in asymptomatic dogs. Parasite Immunology, 14:531-539.

Carrió J, Portus M (2002) In vitro susceptibility to pentavalent antimony in Leishmania infantum strains is not modified during in vitro or in vivo passages but is modified after host treatment with meglumine antimoniate. BMC Pharmacology, 2:11.

Carter KC, Baillie AJ, Alexander J, Dolan TF (1988) The therapeutic effect of sodium stibogluconate in BALB/c mice infected with Leishmania donovani is organ-dependent. The Journal of Pharmacy and Pharmacology 40:370-373.

Ciaramella Ρ, Corona S (2003) Canine leishmaniasis: clinical and diagnostic aspects. Compendium of Continuing Education for the Practicing Veterinarian, 25:358-368.

Croft SL, Sundar S, Fairlamb AH (2006) Drug resistance in leishmaniasis. Clinical Microbiology Reviews, 19:111-126.

da Costa-Val AP, Cavalcanti RR, de Figueiredo Gontijo N, Michalick MS, Alexander B, Williams P, Melo MN (2007) Canine visceral leishmaniasis: relationships between clinical status, humoral immune response, haematology and Lutzomyia (Lutzomyia) longipalpis infectivity. The Veterinary Journal, 174:636-643.

Dantas-Torres F (2007) The role of dogs as reservoirs of Leishmania parasites, with emphasis on Leishmania (Leishmania) infantum and Leishmania (Viannia) braziliensis. Veterinary Parasitology, 149:139-146.

De Luna R, Vuotto ML, Ielpo MT, Ambrosio R, Piantedosi D, Moscatiello V, Ciaramella Ρ, Scalone A, Gradoni L, Mancino D (1999) Early suppression of lymphoproliferative response in dogs with natural infection by Leishmania infantum. Veterinary Immunology and Immunopathology, 70:95-103.

Denerolle P, Bourdoiseau G (1999) Combination allopurinol and antimony treatment versus antimony alone and allopurinol alone in the treatment of canine leishmaniasis (96 cases). Journal of Veterinary Internal Medicine, 13:413-415.

Dereure J, Pratlong F, Dedet JP (1999) Geographical distribution and the identification of parasites causing canine leishmaniasis in the Mediterranean basin. In: Canine Leishmaniasis: an Update. Proceedings of the International Canine Leishmaniasis Forum,

(Barcelona, Spain), pp 18-25.

Ferrer L (1999) Clinical aspects of canine leishmaniasis. In: Canine Leishmaniasis: an Update. Proceedings of the International Canine Leishmaniasis Forum, (Barcelona, Spain), pp 6-10.

Foglia Manzillo V, Oliva G, Pagano A, Manna L, Maroli M, Gradoni L (2006) Deltamethrin-impregnated collars for the control of canine leishmaniasis: Evaluation of the protective effect and influence on the clinical outcome of Leishmania infection in kennelled stray dogs. Veterinary Parasitology, 142:142-145.

Garcia-Alonso M, Nieto CG, Blanco A, Requena JM, Alonso C, Navarrete I (1996) Presence of antibodies in the aqueous humour and cerebrospinal fluid during Leishmania infections in dogs. Pathological features at the central nervous system. Parasite Immunology, 18:539-546.

Gaskin AA, Schantz P, Jackson J, Birkenheuer A, Tomlinson L, Gramiccia M, Levy M, Steuer F, Kollmar E, Hegarty BC, Ahn A, Breitschwerdt EB (2002) Visceral leishmaniasis in a New York foxhound kennel. Journal of Veterinary Internal Medicine, 16:34-44.

Gradoni L (2002) The diagnosis of canine leishmaniasis. In: Canine Leishmaniasis: Moving Towards a Solution. Proceedings of the 2nd International Canine Leishmaniasis Forum, (Sevilla, Spain), pp7-14.

Gradoni L, Maroli M, Gramiccia M, Mancianti F (1987) Leishmania infantum infection rates in Phlebotomus perniciosus fed on naturally infected dogs under antimonial treatment. Medical and Veterinary Entomology, 1:339-342.

Gramiccia M, Gradoni L, Orsini S (1992) Decreased sensitivity to meglumine antimoniate (Glucantime) of Leishmania infantum isolated from dogs after several courses of drug treatment. Annals of Tropical Medicine and Parasitology, 86:613-620.

Guarga JL, Moreno J, Lucientes J, Gracia MJ, Peribânez MA, Alvar J, Castillo JA (2000) Canine leishmaniasis transmission: higher infectivity amongst naturally infected dogs to sand flies is associated with lower proportions of Τ helper cells. Research in Veterinary Science, 69:249-253.

Ikeda-Garcia FA, Lopes RS, Marques FJ, de Lima VM, Morinishi CK, Bonello FL, Zanette MF, Perri SH, Feitosa MM (2007) Clinical and parasitological evaluation of dogs naturally infected by Leishmania (Leishmania) chagasi submitted to treatment with meglumine antimoniate. Veterinary Parasitology, 143:254-259.

Koutinas AF, Saridomichelakis MN, Mylonakis ME, Leontides L, Polizopoulou Z, Billinis C, Argyriadis D, Diakou N, Papadopoulos Ο (2001) A randomised, blinded, placebo-controlled clinical trial with allopurinol in canine leishmaniosis. Veterinary Parasitology, 98:247-261.

Lamothe J (1997) Essai de traitement de la leishmaniose canine par l'amphotéricine Β (39 cas). Pratique Médicale et Chirurgicale de 1 Animal de Compagnie, 32:133-141.

Leontides LS, Saridomichelakis MN, Billinis C, Kontos V, Koutinas AF, Galatos AD, Mylonakis ME (2002) A cross-sectional study of Leishmania spp. infection in clinically healthy dogs with polymerase chain reaction and serology in Greece. Veterinary Parasitology, 109:19-27.

Lima WG, Oliveira PS, Caliari MV, Gonçalves R, Michalick MS, Melo MN, Tafuri WL, Tafuri WL (2007) Histopathological and immunohistochemical study of type 3 complement receptors (CDlib/CD 18) in livers and spleens of asymptomatic and symptomatic dogs naturally infected with Leishmania (Leishmania) chagasi. Veterinary Immunology and Immunopathology, 117:129-136.

Maarouf M, Lawrence F, Brown S, Robert-Gero M (1997) Biochemical alterations in paromomycin-treated Leishmania donovani promastigotes. Parasitology Research, 83:198-202.

Maarouf M, Lawrence F, Croft SL, Robert-Gero M (1995) Ribosomes of Leishmania are a target for the aminoglycosides. Parasitology Research, 81:421-425.

Michalsky EM, Rocha MF, da Rocha Lima AC, França-Silva JC, Pires MQ, Oliveira FS, Pacheco RS, dos Santos SL, Barata RA, Romanha AJ, Fortes-Dias CL, Dias ES (2007) Infectivity of seropositive dogs, showing different clinical forms of leishmaniasis, to Lutzomyia longipalpis phlebotomine sand flies. Veterinary Parasitology, 147:67-76.

Miles MA, Vexenat JA, Furtado Campos JH, Fonseca de Castro JA (1999) Canine leishmaniasis in Latin America: control strategies for visceral leishmaniasis. In: Canine Leishmaniasis: an Update. Proceedings of the International Canine Leishmaniasis Forum, (Barcelona, Spain), pp 46-53.

Mirò G, Cardoso L, Pennisi MG, Oliva G, Baneth G (2008) Canine leishmaniosis - new concepts and insights on an expanding zoonosis: part two. Trends in Parasitology, 24:371-377.

Moreno J, Alvar J (2002) Canine leishmaniasis: epidemiological risk and the experimental model. Trends in Parasitology, 18:399-405.

Noli C, Auxilia ST (2005) Treatment of canine Old World visceral leishmaniasis: a systematic review. Veterinary Dermatology, 16:213-232.

Oliva G, Gradoni L, Cortese L, Orsini S, Ciaramella Ρ, Scalone A, de Luna R, Persechino A (1998) Comparative efficacy of meglumine antimoniate and aminosidine sulphate, alone or in combination, in canine leishmaniasis. Annals of Tropical Medicine and Parasitology, 92:165-171.

Pena MT, Naranjo C, Klauss G, Fondevila D, Leiva M, Roura X, Davidson MG, Dubielzig RR (2008) Histopathological features of ocular leishmaniosis in the dog. Journal of Comparative Pathology, 138:32-39.

Plevraki K, Koutinas AF, Kaldrymidou H, Roumpies N, Papazoglou LG, Saridomichelakis MN, Sawas I, Leondides L (2006) Effects of allopurinol treatment on the progression of chronic nephritis in canine leishmaniosis (Leishmania infantum). Journal of Veterinary Internal Medicine, 20:228-233.

Plotnick AN (2000) Lipid-based formulations of amphotericin B. Journal of the American Veterinary Medical Association, 216:838-841.

Poli A, Sozzi S, Guidi G, Bandinelli Ρ, Mancianti F (1997) Comparison of aminosidine (paromomycin) and sodium stibogluconate for treatment of canine leishmaniasis. Veterinary Parasitology, 71:263-271.

Rallis T, Day MJ, Saridomichelakis MN, Adamama-Moraitou KK, Papazoglou L, Fytianou A, Koutinas AF (2005) Chronic hepatitis associated with canine leishmaniosis (Leishmania infantum): a clinicopathological study of 26 cases. Journal of Comparative Pathology, 132:145-152.

Saridomichelakis MN, Koutinas AF, Mylonakis ME (2001) Treatment of canine leishmaniosis: An update. Bulletin of the Hellenic Veterinary Medical Society, 52:97-106.

Saridomichelakis MN, Koutinas AF, Olivry T, Dunston SM, Farmaki R, Koutinas CK, Petanides Τ (2007) Regional parasite density in the skin of dogs with symptomatic canine leishmaniosis. Veterinary Dermatology, 18:227-233.

Sideris V, Karagouni E, Papadopoulou G, Garifallou A, Dotsika E (1996) Canine visceral leishmaniasis in the great Athens area, Greece. Parasite, 3:125-130.

Slappendel RJ, Ferrer L (1998) Leishmaniasis. In: Clinical Microbiology and Infectious Diseases of the Dog and Cat. 2nd ed, W.B. Saunders, Philadelphia, pp 450-458.

Toutain PL, del Castillo JR, Bousquet-Mélou A (2002) The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics. Research in Veterinary Science, 73:105-114.

Valladares JE, Riera C, Alberala J, Gallego M, Portus M, Cristòfol C, Franquelo C, ArboixM (1998) Pharmacokinetics of meglumine antimoniate after administration of a multiple dose in dogs experimentally infected with Leishmania infantum. Veterinary Parasitology, 75:33-40.

Vexenat JA, Olliaro PL, Fonseca de Castro JA, Cavalcante R, Furtado Campos JH, Tavares JP, Miles MA (1998) Clinical recovery and limited cure in canine visceral leishmaniasis treated with aminosidine (paromomycin). American Journal of Tropical Medicine and Hygiene, 58:448-453.

Warburg A, Schlein Y (1986) The effect of post-bloodmeal nutrition of Phlebotomus papatasi on the transmission oîLeishmania major. American Journal of Tropical Medicine and Hygiene, 35:926-930.


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