Road‐map of pre‐clinical treatment for Visceral Leishmaniasis

Abstract

Visceral leishmaniasis (VL) or Kala‐azar, is the most lethal form of leishmaniasis, is still prevalent in many countries where it is endemic. It is a threat to human life caused by protozoan parasite Leishmania donovani. The severity of the disease is further increased as the treated individuals might have a chance of developing Post Kala‐azar Dermal Leishmaniasis (PKDL) in the long run. Moreover, several countries have reported high number of HIV‐VL co‐infected patients. Therefore, there is a dire need for the development of efficient diagnostic methods and drugs in order to combat the disease and to control the spread of disease. At present, the treatment for VL entirely relies on therapeutic drugs as no vaccine is available yet. Ever since 1900s a series of drugs have been invented and used for treatment of VL; but the need for one such cost‐effective treatment that would completely cure the disease with minimal side‐effects, low relapse rate with high efficacy and less toxicity remains yet to be fulfilled. Therefore, identifying novel compounds is very crucial to develop potent antileishmanial agents. Thus, this review enlists several instances of drug development, including the pharmacokinetic and pharmacodynamic properties of antileishmanial drugs, different experimental animal models used to investigate the disease progression and to analyze treatment dosage and pharmacological aspect of drugs. Furthermore, the existing gap in drug development and future measures to improve the process are also discussed in this review.

Visceral Leishmaniasis: Epidemiology, Diagnosis, and Treatment Regimens in Different Geographical Areas with a Focus on Pediatrics

“…Pentavalent antimonials, such as SSG, are parenteral drugs that are given in doses of 20 mg/kg for 28–30 days when used as monotherapy; their mechanism of action is still poorly understood [ 61 ]. Despite the need for prolonged parenteral treatment and the risk of adverse affects, including cardiotoxicity (ventricular tachycardia, prolonged QTc interval, ventricular fibrillation, torsades de pointe), pancreatitis, pancytopenia, and nephrotoxicity, since their discovery in 1923, these drugs have been used for decades for the treatment of VL in the vast majority of endemic regions [ 7 , 62 , 63 ]. This probably happened because of the affordability and the time-tested effectiveness of this drug [ 64 ].…”

“…PM, an aminoglycoside antibiotic which blocks protein synthesis, was shown to be a cheap and effective parenteral drug easily administered intramuscularly with a dosage of 15 mg/kg/day, but it requires a 21-days course. Moreover, it is potentially nephrotoxic and ototoxic [ 51 , 63 ].…”

“…It is a teratogenic compound so it cannot be used for pregnant females. Its main adverse effects are diarrhea, vomiting, and dehydration [ 63 , 65 , 66 ]…”

“…LAMB, known as Ambisome, is the only AmpB preparation approved by the Food and Drug Administration (FDA). It is expensive and requires a good cold chain, and there is remarkable geographical variation regarding the total dose administered [ 63 , 65 , 67 ]…”

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling

“…Studies in the design of antileishmanial compounds have identified some novel pathways and protein targets necessary for the parasite’s survival [ 17 , 18 ]. Some of these targets have been validated [ 19 , 20 ], while investigation on others is still ongoing. Ergosterol biosynthesis is involved in various biological functions including plasma membrane formation, membrane fluidity, distribution of membrane proteins, and control of the cell cycle [ 21 ].…”