In vitro and in vivo antileishmanial efficacy of a combination therapy of diminazene and artesunate against Leishmania donovani in BALB/c mice

The in vitro and in vivo activity of diminazene (Dim), artesunate (Art) and combination of Dim and Art (Dim-Art) against Leishmania donovani was compared to reference drug; amphotericin B. IC50 of Dim-Art was found to be 2.28 ± 0.24 µg/mL while those of Dim and Art were 9.16 ± 0.3 µg/mL and 4.64 ± 0.48 µg/mL respectively. The IC50 for Amphot B was 0.16 ± 0.32 µg/mL against stationary-phase promastigotes. In vivo evaluation in the L. donovani BALB/c mice model indicated that treatments with the combined drug therapy at doses of 12.5 mg/kg for 28 consecutive days significantly (p < 0.001) reduced parasite burden in the spleen as compared to the single drug treatments given at the same dosages. Although parasite burden was slightly lower (p < 0.05) in the Amphot B group than in the Dim-Art treatment group, the present study demonstrates the positive advantage and the potential use of the combined therapy of Dim-Art over the constituent drugs, Dim or Art when used alone. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.

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In vitro and in vivo immunomodulatory properties of octyl-β-d-galactofuranoside during Leishmania donovani infection

Parasites & Vectors ◽

10.1186/s13071-019-3858-0 ◽

2019 ◽

Vol 12 (1) ◽

Author(s):

Hélène Guegan ◽

Kevin Ory ◽

Sorya Belaz ◽

Aurélien Jan ◽

Sarah Dion ◽

...

Keyword(s):

Immune Response ◽

Leishmania Donovani ◽

Parasite Burden ◽

Human Monocyte ◽

Fold Increase ◽

Control Group ◽

End Of Treatment ◽

Immunosuppressed Patients

Abstract Background The chemotherapeutic arsenal available to treat visceral leishmaniasis is currently limited, in view of many drawbacks such as high cost, toxicity or emerging resistance. New therapeutic strategies are particularly needed to improve the management and the outcome in immunosuppressed patients. The combination of an immunomodulatory drug to a conventional anti-Leishmania treatment is an emerging concept to reverse the immune bias from Th2 to Th1 response to boost healing and prevent relapses. Methods Here, immunostimulating and leishmanicidal properties of octyl-β-d-galactofuranose (Galf) were assessed in human monocyte-derived macrophages (HM) and in a murine model, after challenge with Leishmania donovani promastigotes. We recorded parasite loads and expression of various cytokines and immune effectors in HM and mouse organs (liver, spleen, bone marrow), following treatment with free (Galf) and liposomal (L-Galf) formulations. Results Both treatments significantly reduced parasite proliferation in HM, as well as liver parasite burden in vivo (Galf, P < 0.05). Consistent with in vitro results, we showed that Galf- and L-Galf-treated mice displayed an enhanced Th1 immune response, particularly in the spleen where pro-inflammatory cytokines TNF-α, IL-1β and IL-12 were significantly overexpressed compared to control group. The hepatic recruitment of myeloid cells was also favored by L-Galf treatment as evidenced by the five-fold increase of myeloperoxidase (MPO) induction, which was associated with a higher number of MPO-positive cells within granulomas. By contrast, the systemic level of various cytokines such as IL-1β, IL-6, IL-17A or IL-27 was drastically reduced at the end of treatment. Conclusions Overall, these results suggest that Galf could be tested as an adjuvant in combination with current anti-parasitic drugs, to restore an efficient immune response against infection in a model of immunosuppressed mice.

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In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives

Parasitology ◽

10.1017/s0031182017001123 ◽

2017 ◽

Vol 144 (13) ◽

pp. 1783-1790 ◽

Cited By ~ 5

Author(s):

ALVARO MARTIN-MONTES ◽

MERY SANTIVAÑEZ-VELIZ ◽

ELSA MORENO-VIGURI ◽

RUBÉN MARTÍN-ESCOLANO ◽

CARMEN JIMÉNEZ-MONTES ◽

...

Keyword(s):

Superoxide Dismutase ◽

Leishmania Donovani ◽

Mannich Base ◽

Neglected Diseases ◽

Leishmania Braziliensis ◽

Reference Drug ◽

Iron Superoxide Dismutase ◽

Therapeutic Tools

SUMMARYLeishmaniasis is one of the world's most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, we present 20 arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani and Leishmania braziliensis strains. Six out of the 20 Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy.

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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.

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Preclinical in vitro and in vivo evaluation of antitumor activity of poly (ADP-ribose) polymerase inhibition and trastuzumab combined therapy in HER2-overexpressing breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.622 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 622-622

Author(s):

Ignacio Tusquets ◽

Jetzabel Garcia-Parra ◽

Alba Dalmases ◽

Beatriz Morancho ◽

Oriol Arpi ◽

...

Keyword(s):

Breast Cancer ◽

Antitumor Activity ◽

Combined Therapy ◽

In Vivo Evaluation

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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.

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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

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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.

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In Vitro and In Vivo Antitumor Activity of Indolo[2,3-b] Quinolines, Natural Product Analogs from Neocryptolepine Alkaloid

Molecules ◽

10.3390/molecules26030754 ◽

2021 ◽

Vol 26 (3) ◽

pp. 754

Author(s):

Najla Altwaijry ◽

Samah El-Ghlban ◽

Ibrahim E.-T. El Sayed ◽

Mohamed El-Bahnsawye ◽

Asmaa I. Bayomi ◽

...

Keyword(s):

Cell Cycle ◽

Antitumor Activity ◽

Apoptotic Cell ◽

Ehrlich Ascites Carcinoma ◽

Immunological Study ◽

In Vivo Evaluation ◽

Reference Drug ◽

Dpph Method

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.

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In Vivo and In Vitro Anticancer Activity of Doxorubicin-loaded DNA-AuNP Nanocarrier for the Ovarian Cancer Treatment

Cancers ◽

10.3390/cancers12030634 ◽

2020 ◽

Vol 12 (3) ◽

pp. 634

Author(s):

Chang-Seuk Lee ◽

Tae Kim ◽

Da Oh ◽

Su Bae ◽

Jaesung Ryu ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Anticancer Activity ◽

Immunohistochemical Analysis ◽

Tumor Growth Inhibition ◽

Mice Model ◽

In Vivo Evaluation ◽

Cell Viability Assay

In this study, we have determined the anticancer activity of doxorubicin (Dox)-loaded DNA/gold nanoparticle (AuNP) nanocarrier (Dox-DNA-AuNP) for the treatment of ovarian cancer. The anticancer effect of Dox-DNA-AuNP was evaluated in vitro using the EZ-Cytox cell viability assay on three human ovarian cancer cell lines, SK-OV-3, HEY A8, and A2780. Dox-DNA-AuNP exhibited outstanding activity with good IC50 values of 4.8, 7.4, and 7.6 nM for SK-OV-3, HEY A8, and A2780, respectively. In vivo evaluation further demonstrated the superior anticancer effects of Dox-DNA-AuNP by inhibiting tumor growth compared to free Dox in an established SK-OV-3 xenograft mice model. Dox-DNA-AuNP showed about a 2.5 times higher tumor growth inhibition rate than free Dox. Furthermore, the immunohistochemical analysis of Ki67 antigen expression showed the lowest number of proliferative cells in the ovarian tumor tissue treated with Dox-DNA-AuNP. These results suggest Dox-DNA-AuNP might be a potential effective agent in ovarian cancer chemotherapy.

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Lupeol induces immunity and protective efficacy in a murine model against visceral leishmaniasis

Parasitology ◽

10.1017/s0031182019000659 ◽

2019 ◽

Vol 146 (11) ◽

pp. 1440-1450 ◽

Cited By ~ 1

Author(s):

Gurpreet Kaur ◽

Kalpana Chauhan ◽

Sukhbir Kaur

Keyword(s):

Nitric Oxide ◽

Immune Response ◽

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Protective Efficacy ◽

Parasite Burden ◽

Delayed Type Hypersensitivity ◽

Reference Drug ◽

Th2 Immune Response

AbstractThe available chemotherapeutics for the cure of visceral leishmaniasis (VL) are linked with many detrimental effects. Moreover, VL is associated with the suppression of protective Th1 immune response of the host and induction of disease exaggerating Th2 immune response. Therefore, there is an urgent requirement of therapeutics which can augment the immune status of the host to cure this disease. In the current investigation, the antileishmanial potential of lupeol was monitored in vitro and in vivo in inbred BALB/c mice against Leishmania donovani. Lupeol showed potent antipromastigote activity via arresting parasites at sub G0/G1 phase in vitro. Lupeol significantly decreased the splenic parasite burden by inducing strong delayed-type hypersensitivity responses in contrary to untreated infected animals. The therapeutic efficacy of lupeol was observed to be similar to the reference drug, AmB. Treatment of infected animals with lupeol depicted enhanced levels of T cells and Th1 cytokines in contrast to only infected controls. Further lupeol treatment upregulated the levels of nuclear factor κ B and nitric oxide synthase genes and elevated the production of reactive oxygen species and nitric oxide. Unlike AmB, lupeol-treated infected animals did not show any toxicity. These findings are promising and indicate that lupeol can serve as a prototype drug for the cure of VL.

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