Perceptions on therapeutic modalities regarding the virulence and immunity of cutaneous leishmaniasis

Despite the wide variety of Leishmania spp. virulence, the present repertoire of drugs has limited effects, showing increased resistance. The effect depends on host immune factors which differ between immunocompetent and immunocompromised patients, and among various clinical forms of the disease. Recently, metallocomplexes have been increasingly shown to be potent delivery systems for conventional treatments. Additionally, lasers were suggested as an efficacious treatment tool due to their potentials in the clinical applications and resolution of the disease. This review suggests that the promising leishmanicidal activity of the metallocomplexes and laser treatment comprise a new hopeful alternative in the search for definitive cutaneous leishmaniasis (CL) cure. PARASITOLOGISTS UNITED JOURNAL 230 subsets of CD4+ and CD8+ T cells, and their cytokines profiles[16] as well as the triggered production of reactive oxygen species (ROS) and nitric oxide (NO) in mouse macrophages[17]. Interestingly, co-treatment of infected macrophages with exogenous IFN-γ and TNF-α can considerably destroy the parasites and lead to SbV accumulation[16]. It is also organ-dependent, being more efficient in the liver than the spleen or bone marrow[18] due to the pharmacokinetic profile of the drug[19]. Side effects and drug resistance: Injection pain and systemic side effects have been recorded[20]. Sodium antimony gluconate despite being described with minor side effects at the therapeutic doses[6], has cumulative effects such as acute interstitial nephritis and cardiotoxicity during or after a long course of drug administration[20,21]. Dangerous cardiotoxicity features occur in 50% of the patients and include a concave ST segment, corrected QT interval prolongation followed by multiple ventricular ectopic foci, then ventricular tachycardia, torsade de pointes, ventricular fibrillation[15] and diminution in the height of T waves and T-wave inversion[22]. This was attributed to the high affinity for sulfhydryl groups that affect the calcium channels[23]. In accordance, it has been found to prolong the action potential of ventricular myocytes in guinea pigs at therapeutic doses with developed QT prolongation and life-threatening arrhythmias[24]. Higher doses of SbV were found to be associated with increased pancreatitis[25] especially in AIDS patients[26]. In New World CL, elevation of pancreatic and liver enzymes was also observed in a study at the dose of 20 mg/ kg/d for 20 d[27]. In Brazil, a higher frequency of skin reactions was observed in some patients with CL treated with meglumine antimoniate, due to the greater concentrations of total and trivalent antimony, lead, cadmium, arsenic and lower values of osmolarity and pH[28]. These effects can lead to cessation of treatment before attaining curative levels[29]. Additionally, the emergence of parasite resistance against SbIII was recorded in some areas suffering from VL e.g., India[30-32]. Drug resistance was suggested to be related to parasite proteins involved in the drug efflux e.g., aquaglyceroporin-1[33] and Leishmania adenosine triphosphate (ATP)-binding cassette-G2 (LABCG2)[34]. L. mexicana is less sensitive to SbV than L. braziliensis while L. major amastigotes in mouse macrophages were found to be less sensitive to SSG than L. donovani amastigotes[35]. Nevertheless, it has been considered as the first line treatment due to deficiency of vaccines and limited therapies[36]. 2. Pentamidine Dose and route of administration: The intramuscular dose of pentamidine is 4 mg/kg, and the peak plasma concentration is about 0.5 mg/l, reached within 1 h; and continues to be identified in the plasma for 6-8 w after administration, due to wide tissue binding of the drug[37]. Mechanism of action: It causes inhibition of the active transport system and mitochondrial topoisomerase II, which ultimately destroys the parasite[38]. Side effects and drug resistance: Tubular nephrotoxicity due to renal accumulation of the drug[39]. In addition, it is believed that direct cytotoxic effect on pancreatic islet cells can cause hypoglycemia (through initial insulin release), followed by hyperglycemia (through cell lysis and insulin consumption)[40]. Other adverse reactions include hypotension, and abnormal Fig. 1. Paradigm showing the actions of the SbIII on parasite-derived molecular targets: (1) TR system. (2) Zinc finger print protein. (3) Synergistic action with adenine and deoxynucleoside complexes. IFN-γ: Interferon-γ; TR: Trypanotione reductase; Gp63: Glycoprotein 63; ROS: Reactive oxygen species. Illustrated by E. Elsaftawy. Macrophage ROS++