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Macrophage Targeting: A Promising Strategy for Delivery of Chemotherapeutics in Leishmaniasis and Other Visceral Diseases
Published in Sarwar Beg, Mahfoozur Rahman, Md. Abul Barkat, Farhan J. Ahmad, Nanomedicine for the Treatment of Disease, 2019
Jaya Gopal Meher, Pankaj K. Singh, Yuvraj Singh, Mohini Chaurasia, Anita Singh, Manish K. Chourasia
Leishmaniasis is a group of neglected vector-borne disease, mainly prevalent in the tropical and subtropical countries. Clinically there are three major forms of leishmaniasis (i) visceral, (ii) cutaneous, and (iii) mucocutaneous. It is estimated (report by World Health Organization (WHO)) that approximately 556- and 399-million people are affected by visceral and cutaneous leishmaniasis, respectively in twelve high-burden countries. Amongst the three major forms of leishmaniasis, visceral leishmaniasis is most dangerous and may cause death if left untreated. Although these diseases are predominant in countries like India, Nepal, Bangladesh, Brazil, and Sudan, in last few decades the disease has spread in other parts of the world as well. Emergence of drug resistance and poor preventive and curative measures are thought to be reasons for its prevalence. Leishmaniasis is caused by more than 20 species of protozoan parasites of genus Leishmania, family Trypanosomatidae and is spread by more than 30 species of sand fly. Parasites of this vector-borne disease have a digenetic life cycle (i) gut of sand fly in promastigote form and (ii) mammalian host in amastigote form. In mammalian host, i.e., inside macrophages instead of being killed, these parasites damage the inherent immuno-mechanisms of macrophages and reprogram them in their favor. Then they start fulfilling their nutritional and metabolic needs, proliferate inside the macrophages and continue to cause infection to host cells (2016; Lamotte et al., 2017). Initially, antimonials were used for treatment of leishmaniasis, and progressively other drugs viz. amphotericin B, miltefosine, paromomycin, and pentamidine started emerging. Liposomal formulation of amphotericin B is known to be highly effective in visceral leishmaniasis. However, since last few decades, leishmaniasis has developed resistance to several drugs, which has been attributed to inherent genome instability of the parasite, directly correlated to irrational usage of anti-leishmanial drugs. Recurrent gene and chromosome amplifications can lead to fitness gains by parasites. Even though numerous pre-clinical reports are available describing outstanding performance of novel drug delivery systems in treatment of experimental leishmanial models, only few have gained commercial footprint. However, it is anticipated that better understanding of host-pathogen interaction as well as identification of novel target sites in both host and pathogens might contribute in advancement of chemotherapy against leishmaniasis. As macrophages are reservoir of Leishmania, passive, and active targeting of these infected cells is an appropriate strategy to destroy the causative pathogens.
Four new cycloartane-type triterpenoids from the leaves of Combretum mellifluum Eichler: assessment of their antioxidant and antileishmanial activities
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Jaelson Santos Silva, Éverton Leandro França Ferreira, Amanda Maciel Lima, Ruth Raquel Soares de Farias, Bruno Quirino Araújo, José Carlos Quilles Junior, Rodolfo Ritchelle Lima Santos, Fernando Aécio de Amorim Carvalho, Mahendra Rai, Gerardo Magela Vieira Júnior, Mariana Helena Chaves
Pentavalent antimonials (Sbv) have been used for a long period as a standard treatment for leishmaniasis, but its efficacy is markedly variable taking into consideration considered different Leishmania species and geographic regions (Chakravarty and Sundar 2010; Friedrich et al. 2012). Other drawbacks include a need for prolonged period of treatment and induction of several adverse consequences (Chávez-Fumagalli et al. 2015). As a neglected disease, some second-choice drugs have been applied to treat leishmaniasis including miltefosine and amphotericin B, originally developed for cancer treatment and antifungal purposes, respectively (Wyllie et al. 2012). However, several side effects such as gastrointestinal discomfort, fever, and myocarditis have limited the use and efficiency of these drugs in leishmaniasis patients (Ghorbani and Farhoudi 2018).
Co-delivery of trifluralin and miltefosin with enhanced skin penetration and localization in Leishmania affected macrophages
Published in Journal of Dispersion Science and Technology, 2022
In this study, the author opt to prepare a TRF-MTF co-loaded drug delivery system in order to achieve efficient, convenient and affordable antileishmanial treatment option. TRF is herbicide with antileishmanial potential. TRF shows it antileishmanial effect by inhibiting the polymerization of microtubules and tubulin formation.[13,14] However, owing to its inadequate aqueous solubility, it may not be efficiently used in CL management. Moreover, it displays narrow response against CL when used topically.[15] Similarly, MTF, an amphiphilic and zwitterionic compound, used as a first oral anti-leishmanial agent with excellent lesihmanicial effects. Its antileishmanial effects are well established and reported in various experimental trials.[16,17] MTF exhibit its intended effect by distressing the various life phases of Lesihmania species including promastigote and amastigote phases. Most importantly, Miltefosine interact with lipids, obstructing cytochrome c oxidase, which may upset the membrane integrity and leads to mitochondrial dysfunction. All these activities ultimately results in apoptosis-like cell death.[16] It is an FDA approved antileishmanial agent and is included in the list of essential medicines by WHO.[18] Although different topical formulations with MTF as active pharmaceutical agent (API) have recently been reported, however, they exhibited limited efficacy owing to their inability to reach the macrophages, the Leishmania effected amastigotes.[19–21]