Efficacy of Orally Administered 2-Substituted Quinolines in Experimental Murine Cutaneous and Visceral Leishmaniases

ABSTRACT We report in this study the in vivo efficacy of nine 2-substituted quinolines on the Leishmania amazonensis cutaneous infection murine model and on the Leishmania infantum and Leishmania donovani visceral infection murine models. In the case of the L. amazonensis model, quinolines were administered orally at 25 mg/kg twice daily for 15 days. Quinolines 1, 2, 3, and 7 reduced by 80 to 90% the parasite burdens in the lesion, whereas N-methylglucamine antimoniate (Glucantime), administered by subcutaneous injections at 100 mg [28 mg Sb(V)] per kg of body weight daily, reduced the parasite burdens by 98%. In visceral leishmaniasis due to L. infantum, mice treated orally at 25 mg/kg daily for 10 days with quinolines 1, 4, 5, and 6 showed a significant reduction of parasite burdens in the liver and spleen. These quinolines were significantly more effective than meglumine antimoniate to reduce the parasite burden in both the liver and spleen. Also, the oral in vivo activity of three quinolines (quinolines 4, 5, and 2-n-propylquinoline) were determined against L. donovani (LV 9) at 12.5 and 25 mg/kg for 10 days. Their activity was compared with that of miltefosine at 7.5 mg/kg. Miltefosine, 2-n-propylquinoline, and quinoline 5 at 12.5 mg/kg significantly reduced the parasite burdens in the liver by 72, 66, and 61%, respectively. From the present study, quinoline 5 is the most promising compound against both cutaneous and visceral leishmaniasis. The double antileishmanial and antiviral activities of these compounds suggest that this series could be a potential treatment for coinfection of Leishmania-human immunodeficiency virus.

Download Full-text

Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01129-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 4

Author(s):

April C. Joice ◽

Sihyung Yang ◽

Abdelbasset A. Farahat ◽

Heidi Meeds ◽

Mei Feng ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Treatment Strategies ◽

Parasite Burden ◽

Pharmacokinetic Analysis ◽

Content Type ◽

New Treatment ◽

Almost All

ABSTRACT Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority. In vitro combination studies with DB766 and antifungal azoles against intracellular Leishmania donovani showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In L. donovani-infected BALB/c mice, DB766-posaconazole combinations given orally for 5 days were more effective than DB766 or posaconazole alone. For example, 81% ± 1% (means ± standard errors) inhibition of liver parasite burden was observed for 37.5 mg/kg of body weight DB766 plus 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40% ± 5% and 21% ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups, while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations in vivo is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.

Download Full-text

Antileishmanial Activities of Stearylamine-Bearing Liposomes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.6.1739-1742.2000 ◽

2000 ◽

Vol 44 (6) ◽

pp. 1739-1742 ◽

Cited By ~ 37

Author(s):

Tuhina Dey ◽

Khairul Anam ◽

Farhat Afrin ◽

Nahid Ali

Keyword(s):

Single Dose ◽

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Therapeutic Potential ◽

Parasite Burden ◽

Intracellular Amastigotes ◽

Antileishmanial Activities

ABSTRACT Here we report the activity of liposomes comprising egg phosphatidylcholine (PC) and stearylamine (SA) against Leishmania donovani parasites. Both promastigotes and intracellular amastigotes in vitro and in vivo were susceptible to SA-PC liposomes. A single dose of 55 mg of SA-PC liposomes/animal could significantly reduce the hepatic parasite burden by 85 and 68% against recent and established experimental visceral leishmaniasis, respectively, suggesting their strong therapeutic potential.

Download Full-text

PREPARATION AND CHARACTERIZATION OF ANDROGRAPHOLIDE NANOPARTICLES FOR VISCERAL LEISHMANIASIS CHEMOTHERAPY: IN VITRO AND IN VIVO EVALUATIONS

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2016v8i12.14773 ◽

2016 ◽

Vol 8 (12) ◽

pp. 102

Author(s):

Pallab Ghosh ◽

Subhasish Mondal ◽

Tanmoy Bera

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Parasite Burden ◽

Plga Nanoparticles ◽

Antileishmanial Activity ◽

Infection Model ◽

Vitamin E Tpgs ◽

Polyethylene Glycol 1000

Objective: To overcome low physiological solubility, poor bioavailability, the short plasma half-life of andrographolide (AG), a delivery system based on poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were developed to increase the efficiency of AG against visceral leishmaniasis (VL). Methods: Andrographolide-PLGA nanoparticles (AGnp) were prepared with Pgp efflux inhibitor vitamin E TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) by emulsion solvent evaporation method and characterized. Antileishmanial activity was evaluated using in vitro and in vivo VL infection model. Results: The particle size of AGnp was found to be171.4±11.5 nm with an encapsulation efficiency of 81%. The AGnp reduced AG cellular toxicity, retained it's in vitro antileishmanial activity and lead to a reduction (99.9%) of parasite burden in the Leishmania donovani infected spleen and liver. AGnp was more active in infected mice liver at low dose than in spleen. Therapeutic indexes (TI) were 6.9-fold greater in AG and 68-fold in AGnp compared to amphotericin B (AmB) when evaluated in L. donovani infected spleen. Conclusion: Incorporation of AG in PLGA nanoparticles, provided controlled and improved in vivo performance against VL

Download Full-text

Efficacy of the Triazole SCH 56592 againstLeishmania amazonensis and Leishmania donovani in Experimental Murine Cutaneous and Visceral Leishmaniases

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.12.2910 ◽

1999 ◽

Vol 43 (12) ◽

pp. 2910-2914 ◽

Cited By ~ 52

Author(s):

Hail M. Al-Abdely ◽

John R. Graybill ◽

David Loebenberg ◽

Peter C. Melby

Keyword(s):

Visceral Leishmaniasis ◽

Amphotericin B ◽

Oral Therapy ◽

Leishmania Donovani ◽

Parasite Burden ◽

Current Therapy ◽

Cutaneous Infection ◽

Unit Reduction ◽

Visceral Infection ◽

Draining Lymph Nodes

ABSTRACT Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral therapy would be ideal. We examined the efficacy of SCH 56592, an investigational triazole antifungal agent, against cutaneous infection with Leishmania amazonensis and visceral infection with Leishmania donovani in BALB/c mice. Mice were infected in the ear pinna and tail with L. amazonensispromastigotes and were treated with oral SCH 56592 or intraperitoneal amphotericin B for 21 days. At doses of 60 and 30 mg/kg/day, SCH 56592 was highly efficacious in treating cutaneous disease, and at a dose of 60 mg/kg/day, it was superior to amphotericin B at a dose of 1 mg/kg/day. The means of tail lesion sizes were 0.32 ± 0.12, 0.11 ± 0.06, 0.17 ± 0.07, and 0.19 ± 0.08 mm for controls, SCH 56592 at 60 and 30 mg/kg/day, and amphotericin B recipients, respectively (P = 0.0003, 0.005, and 0.01, respectively). Parasite burden in draining lymph nodes confirmed these efficacy findings. In visceral leishmaniasis due to L. donovani infection, mice treated with SCH 56592 showed a 0.5- to 1-log-unit reduction in parasite burdens in the liver and the spleen compared to untreated mice. Amphotericin B at 1 mg/kg/day was superior to SCH 56592 in the treatment of visceral infection, with a 2-log-unit reduction in parasite burdens in both the liver and spleen. These studies indicate very good activity of SCH 56592 against cutaneous leishmaniasis due to L. amazonensis infection and, to a lesser degree, against visceral leishmaniasis due to L. donovani infection in susceptible BALB/c mice.

Download Full-text

TheREnantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00722-13 ◽

2013 ◽

Vol 57 (10) ◽

pp. 4699-4706 ◽

Cited By ~ 38

Author(s):

Stephen Patterson ◽

Susan Wyllie ◽

Laste Stojanovski ◽

Meghan R. Perry ◽

Frederick R. C. Simeons ◽

...

Keyword(s):

Clinical Trials ◽

Visceral Leishmaniasis ◽

Phase Ii ◽

Leishmania Donovani ◽

Oral Treatment ◽

Parasite Burden ◽

Content Type ◽

Phase Ii Clinical Trials

ABSTRACTThe novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity againstMycobacterium tuberculosisin vitroandin vivoand is currently in phase II clinical trials for tuberculosis (TB). In contrast toM. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity againstLeishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although thein vitroandin vivopharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body weight−1, twice daily for 5 days. InM. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent inLeishmaniaspp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studiesin vitroindicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL.

Download Full-text

Identification of Vaccine Candidates for Experimental Visceral Leishmaniasis by Immunization with Sequential Fractions of a cDNA Expression Library

Infection and Immunity ◽

10.1128/iai.68.10.5595-5602.2000 ◽

2000 ◽

Vol 68 (10) ◽

pp. 5595-5602 ◽

Cited By ~ 69

Author(s):

Peter C. Melby ◽

Gary B. Ogden ◽

Hector A. Flores ◽

Weiguo Zhao ◽

Christopher Geldmacher ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Cdna Library ◽

Leishmania Donovani ◽

Parasite Burden ◽

Public Health Problem ◽

Cdna Expression Library ◽

Sequential Fractionation ◽

Expression Library ◽

Vaccine Candidates

ABSTRACT Visceral leishmaniasis caused by the intracellular parasiteLeishmania donovani is a significant public health problem in many regions of the world. Because of its large genome and complex biology, developing a vaccine for this pathogen has proved to be a challenging task and, to date, protective recombinant vaccine candidates have not been identified. To tackle this difficult problem, we adopted a reductionist approach with the intention of identifying cDNA sequences in an L. donovani amastigote cDNA library that collectively or singly conferred protection against parasite challenge in a murine model of visceral leishmaniasis. We immunized BALB/c mice with plasmid DNA isolated and pooled from 15 cDNA sublibraries (∼2,000 cDNAs/sublibrary). Following systemic challenge with L. donovani, mice immunized with 6 of these 15 sublibraries showed a significantly reduced (35- to 1,000-fold) hepatic parasite burden. Because of the complexity and magnitude of the sequential fractionation-immunization-challenge approach, we restricted our attention to the two sublibraries that conferred the greatest in vivo protection. From one of these two sublibraries, we identified several groups of cDNAs that afforded protection, including a set of nine novel cDNAs and, surprisingly, a group of five cDNAs that encoded L. donovani histone proteins. At each fractionation step, the cDNA sublibraries or the smaller DNA fractions that afforded in vivo protection against the parasite also induced in vitro parasite-specific T helper 1 immune responses. Our studies demonstrate that immunization with sequential fractions of a cDNA library is a powerful strategy for identifying anti-infective vaccine candidates.

Download Full-text

Activity of oral atovaquone alone and in combination with antimony in experimental visceral leishmaniasis.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.3.586 ◽

1996 ◽

Vol 40 (3) ◽

pp. 586-587 ◽

Cited By ~ 21

Author(s):

H W Murray ◽

J Hariprashad

Keyword(s):

Body Weight ◽

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Potential Role ◽

Oral Agent ◽

Pentavalent Antimony ◽

Suboptimal Dose ◽

Parasite Replication ◽

Visceral Infection

BALB/c mice with established visceral infection caused by the intracellular protozoan Leishmania donovani were treated with oral atovaquone for 7 days. Treatment with 100 mg/kg of body weight per day was optimal and halted parasite replication in the liver. In mice treated with atovaquone, the effect of a suboptimal dose of pentavalent antimony was converted from partially leishmanistatic to leishmanicidal. These results demonstrate the in vivo antileishmanial effect of atovaquone and suggest a potential role for this oral agent in visceral leishmaniasis as an adjunct to conventional antimony treatment.

Download Full-text

Expression of Inducible Nitric Oxide Synthase in Skin Lesions of Patients with American Cutaneous Leishmaniasis

Infection and Immunity ◽

10.1128/iai.70.8.4638-4642.2002 ◽

2002 ◽

Vol 70 (8) ◽

pp. 4638-4642 ◽

Cited By ~ 53

Author(s):

Muna Qadoumi ◽

Inge Becker ◽

Norbert Donhauser ◽

Martin Röllinghoff ◽

Christian Bogdan

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Cutaneous Leishmaniasis ◽

Leishmania Donovani ◽

Leishmania Major ◽

Parasite Burden ◽

Skin Lesions ◽

And Function ◽

Oxide Synthase

ABSTRACT Cytokine-inducible (or type 2) nitric oxide synthase (iNOS) is indispensable for the resolution of Leishmania major or Leishmania donovani infections in mice. In contrast, little is known about the expression and function of iNOS in human leishmaniasis. Here, we show by immunohistological analysis of skin biopsies from Mexican patients with local (LCL) or diffuse (DCL) cutaneous leishmaniasis that the expression of iNOS was most prominent in LCL lesions with small numbers of parasites whereas lesions with a high parasite burden (LCL or DCL) contained considerably fewer iNOS-positive cells. This is the first study to suggest an antileishmanial function of iNOS in human Leishmania infections in vivo.

Download Full-text

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820175116 ◽

2019 ◽

Vol 116 (19) ◽

pp. 9318-9323 ◽

Cited By ~ 37

Author(s):

Susan Wyllie ◽

Stephen Brand ◽

Michael Thomas ◽

Manu De Rycker ◽

Chun-wa Chung ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Proteasome Inhibition ◽

New Drugs ◽

Resource Poor Setting ◽

Drug Candidate ◽

Proteasome Subunits ◽

Current Therapies ◽

Mouse Model Of Infection

Visceral leishmaniasis (VL), caused by the protozoan parasitesLeishmania donovaniandLeishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasiteTrypanosoma cruzi. Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevantL. donovaniandL. infantumisolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of theL. donovaniproteasome. High-resolution cryo-EM structures of apo and compound 8-boundLeishmania tarentolae20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

Download Full-text

PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmania donovani

Infection and Immunity ◽

10.1128/iai.00019-18 ◽

2018 ◽

Vol 86 (6) ◽

Cited By ~ 19

Author(s):

Samar Habib ◽

Abdeljabar El Andaloussi ◽

Khaled Elmasry ◽

Aya Handoussa ◽

Manar Azab ◽

...

Keyword(s):

T Cells ◽

Protective Immunity ◽

Leishmania Donovani ◽

Parasite Burden ◽

Parasite Clearance ◽

Interleukin 10 ◽

Cell Mediated Immunity ◽

Th1 Cell ◽

Content Type

ABSTRACT Leishmania donovani is a causative pathogen of potentially fatal visceral leishmaniasis (VL). Therapeutic agents are available; however, their use is limited because of high cost, serious side effects, and development of antimicrobial resistance. Protective immunity against VL depends on CD4 + Th1 cell-mediated immunity. Studies have shown that progression of VL is due to exhaustion of T cells; however, the mechanism involved is not clearly understood. Here, we examined the role of PD1/PDL-1 in the pathogenesis of VL by using a murine model of VL. Our data indicate that L. donovani is able to elicit initial expansion of gamma interferon-producing CD4 + Th1 and CD8 + T cells at day 7 postinfection (p.i.); however, the frequency of those cells and inflammatory response decreased at day 21 p.i., despite persistence of parasites. Persistent infection-induced expansion of interleukin-10 + FOXP3 + Treg and CD4 + and CD8 + T cells expressing PD1. Blocking of PDL-1 signaling in vivo resulted in restoration of protective type 1 responses by both CD4 + and CD8 + T cells, which resulted in a significant decrease in the parasite burden. Mechanistically, PDL-1 blocking inhibited autophagy, a cellular degradation process hijacked by Leishmania to acquire host cell nutrients for their survival. Inhibition of autophagy was marked by decreased lipidation of microtubule-associated protein 1 light chain 3, a marker of autophagosome formation, and P62 accumulation. Together, our findings show for the first time that anti-PDL-1 antibody is an effective therapeutic approach for restoration of effector arms of protective immunity against VL and subsequent parasite clearance.

Download Full-text