Drug For Visceral Leishmaniasis Research Articles

DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1.

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.

Evaluation of in vitro antileishmanial efficacy of cyclosporin A and its non-immunosuppressive derivative, dihydrocyclosporin A

BackgroundNew therapeutic drugs are urgently needed against visceral leishmaniasis because current drugs, such as pentavalent antimonials and miltefosine, produce severe side effects and development of resistance. Whether cyclosporine A (CsA) and its derivatives can be used as therapeutic drugs for visceral leishmaniasis has been controversial for many years.MethodsIn this study, we evaluated the efficacy of CsA and its derivative, dihydrocyclosporin A (DHCsA-d), against promastigotes and intracellular amastigotes of Leishmania donovani. Sodium stibogluconate (SSG) was used as a positive control.ResultsOur results showed that DHCsA-d was able to inhibit the proliferation of L. donovani promastigotes (IC50: 21.24 μM and 12.14 μM at 24 h and 48 h, respectively) and intracellular amastigotes (IC50: 5.23 μM and 4.84 μM at 24 and 48 h, respectively) in vitro, but CsA treatment increased the number of amastigotes in host cells. Both DHCsA-d and CsA caused several alterations in the morphology and ultrastructure of L. donovani, especially in the mitochondria. However, DHCsA-d showed high cytotoxicity towards cells of the mouse macrophage cell line RAW264.7, with CC50 values of 7.98 μM (24 h) and 6.65 μM (48 h). Moreover, DHCsA-d could increase IL-12, TNF-α and IFN-γ production and decrease the levels of IL-10, IL-4, NO and H2O2 in infected macrophages. On the contrary, CsA decreased IL-12, TNF-α, and IFN-γ production and increased the levels of IL-10, IL-4, NO and H2O2 in infected macrophages. The expression of L. donovani cyclophilin A (LdCyPA) in promastigotes and intracellular amastigotes and the expression of cyclophilin A (CyPA) in RAW 264.7 cells were found to be significantly downregulated in the CsA-treated group compared to those in the untreated group. However, no significant changes in LdCyPA and CyPA levels were found after DHCsA-d or SSG treatment.ConclusionsOur findings initially resolved the dispute regarding the efficacy of CsA and DHCsA-d for visceral leishmaniasis treatment. CsA showed no significant inhibitory effect on intracellular amastigotes. DHCsA-d significantly inhibited promastigotes and intracellular amastigotes, but it was highly cytotoxic. Therefore, CsA and DHCsA-d are not recommended as antileishmanial drugs.

Oral Presentations

Antimony and arsenic are elements that have a long history of use as poisons, therapeutic agents, or cosmetics. For over a century, compounds containing pentavalent antimony (antimonials) have formed the basis of treatment of the leishmaniases worldwide. Antimonial preparations remain first-line drugs for visceral leishmaniasis in Sub-Saharan Africa and Brazil [1], but in the hyperendemic state of Bihar, India, the cure rate of antimonial compounds has declined over the past 30 years from over 85% to less than 50% (Figure 1) [2] and resistance in parasites has been demonstrated [3]. This marked decrease in efficacy has been attributed to long-term, widespread misuse of antimonials, with patients undergoing inappropriate treatment courses often administered by the largely unregulated Indian private health care system [4], [5]. Here we propose an additional hypothesis to explain the substantially lower efficacy of antimony in Bihar compared to other regions in the world. Figure 1 Results of consecutive clinical studies of antimonials at 20 mg/kg dosing in Bihar, India. Since the 1970s, millions of inhabitants of Asia have been chronically exposed to naturally occurring arsenic on a daily basis through the large-scale insertion of multiple shallow tubewells which were originally installed for provision of clean and safe drinking water [6]. Antimony and arsenic are metalloids belonging to Group 15 of the periodic table that share many structural and chemical properties [7]. Antimony resistance in Leishmania parasites can be induced experimentally by exposure to stepwise increasing concentrations of sublethal concentrations of trivalent arsenite in culture [8]. If an individual who is chronically exposed to arsenic is infected with Leishmania, the parasites would be exposed to arsenic due to its presence within organs of the lymphoreticular system [9]. This could lead to the development of an arsenic-resistant Leishmania strain that would be cross-resistant to antimonial therapy. This viewpoint article will expand on, and discuss the evidence for, the possible contribution of arsenic to decreased antimonial efficacy in Bihar.

Visceral leishmaniasis: elimination with existing interventions

The world's burden of infectious diseases can be substantially reduced by more-effective use of existing interventions. Advances in case detection, diagnosis, and treatment strategies have made it possible to consider the elimination of visceral leishmaniasis in the Indian subcontinent. The priority must now be to effectively implement existing interventions at the community level by actively finding cases in endemic villages and treating them with single-dose liposomal amphotericin B at primary-health-care centres. Once the elimination target of one case per 10,000 population has been reached, combination therapies involving miltefosine and paromomycin can be introduced to ensure long-term availability of several drugs for visceral leishmaniasis and to protect against resistance.

Combination therapy for visceral leishmaniasis

Drugs for visceral leishmaniasis (also known as kala-azar) have several drawbacks, such as long regimen duration, parenteral administration, toxic effects, or high costs. 1 Alvar J Croft S Olliaro P Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol. 2006; 61: 223-274 Crossref PubMed Scopus (204) Google Scholar Furthermore, drug resistance against antimonials is widespread in India, and could also emerge in new drugs. 2 Bryceson A A policy for leishmaniasis with respect to the prevention and control of drug resistance. Trop Med Int Health. 2001; 6: 928-934 Crossref PubMed Scopus (146) Google Scholar , 3 Croft SL Sundar S Fairlamb AH Drug resistance in leishmaniasis. Clin Microbiol Rev. 2006; 19: 111-126 Crossref PubMed Scopus (1274) Google Scholar Combination therapy could be the way forward: a shorter regimen might be more affordable, easier to administer, and better adhered to than are current, longer regimens, and might protect the lifespan of the individual drugs. 4 Van Griensven J Balasegaram M Meheus F Alvar J Lynen L Boelaert M Combination therapy for visceral leishmaniasis. Lancet Infect Dis. 2010; 10: 184-194 Summary Full Text Full Text PDF PubMed Scopus (242) Google Scholar In The Lancet, Shyam Sundar and colleagues 5 Sundar S Sinha PK Rai M et al. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet. 2011; (published online Jan 20.)https://doi.org/10.1016/S0140-6736(10)62050-8 Summary Full Text Full Text PDF Scopus (253) Google Scholar report a phase 3 non-inferiority trial in India, in which they compared three drug combinations (10 days each of paromomycin and miltefosine; single-dose liposomal amphotericin B and 10-day paromomycin; and single-dose liposomal amphotericin B and 7-day miltefosine) with the standard treatment for visceral leishmaniasis (conventional amphotericin B). All three combinations were efficacious and well tolerated with 6-month definitive cure rates of at least 97%. Regimen duration ranged from 8 to 11 days—shorter than the 21–28 days for current monotherapies. These data are very encouraging and further support the rationale of combination therapy for visceral leishmaniasis because they provide several safe and efficacious options. However, several issues still need to be addressed. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trialCombination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites. Full-Text PDF

Safety and Efficacy of High-Dose Infusions of a Preformed Amphotericin B Fat Emulsion for Treatment of Indian Visceral Leishmaniasis

Amphotericin B deoxycholate is used as a first-line drug for visceral leishmaniasis (VL) in India. Its major drawbacks are prolonged hospitalization of treated patients and toxicity. An open label phase II study with pre-formed amphotericin B lipid emulsion (ABLE) was conducted to evaluate safety and efficacy of four regimens of 15 mg/kg each administered in 1-2 doses. Regimen 1 was 7.5 mg/kg/day on day 1 and day 3, and regimen 4 was a single bolus infusion of 15 mg/kg. The safety profile was excellent with mild infusion reactions seen in 38% of the patients. Definitive cure was achieved in 100% of the patients treated with regimen 4. The overall cure rate was 87% (95% confidence interval = 75-94%). In this study, ABLE was safe and had excellent efficacy when given as a bolus of 15 mg/kg. More studies with larger number of patients and higher doses are needed to establish acceptable, safe and efficacious regimen.