title: Drug unresponsiveness & combination therapy for kala-azar.
abstract: Pentavalent antimonials (SbV) have been successfully used for treatment of kala-azar since last six decades. Since 1970s its conventional dosages have failed to achieve with 60 per cent unresponsiveness reported with WHO regimen in Bihar (India). Pentamidine initially used as a second line of drug, acquired resistance (25%) even with prolonged dosage. Newer oral drug miltefosine is a potent antileishmanial drug with longer half-life, a property likely to acquire resistance. Paromomycin has undergone extensive clinical trials in Indian kala-azar patients. Being an aminoglycoside, acquired resistance is likely to occur when used as a monotherapy. To encounter the problem of treatment failure in kala-azar and to reduce length of therapy, combination of at least two effective antileishmanial agents is a desirable option. In India sodium stibogluconate (SSG) in standard dose has been combined with other antileishmanial agents including paromomycin without encouraging result. Infection with Leishmania donovani depresses cell-mediated immunity. Immunological balance is tilted in favour of Th2 suppressive cytokines over Th1 producing protective cytokines. Interferon gamma (IFN-gamma) has been used in combination with SbV in Indian kala-azar patients with unexpectedly discouraging results. Combination of two most potent leishmanicidal drugs amphotericin B and miltefosine which are not dependent on host immune system, may shorten the course of therapy besides encountering unresponsiveness. A combination therapy should be preferred when treating kala-azar associated with HIV/AIDS. Immunotherapy with exogenous Th1 stimulating cytokines or use of antileishmanial vaccine in combination with a potent chemotherapeutic agent is a future option.
authors.affiliation: Kalazar Research Centre, Muzaffarpur, Bihar, India. dr_tkjha@hotmail.com
authors.forename: T K
authors.initials: TK
authors.lastname: Jha
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D007194:India; D007891:Leishmania / Q000378:metabolism; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000628:therapy*; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine; D000666:Amphotericin B