The in vivo activity of 1,3,4-thiadiazolium-2-aminide compounds in the treatment of cutaneous and visceral leishmaniasis

Rodrigues, Renata; Charret, Karen S.; Campos, Mónica; Amaral, Verônica F.; Echevarrı́a, Aurea; Reis, Camila dos; Canto‐Cavalheiro, Marilene M.; Leon, Leonor L.

doi:10.1093/jac/dkr409

Cited by 10 publications

(10 citation statements)

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“…Then, the mice were divided into groups of seven. This experimental infection model, which has been reported before, 39 was chosen over a variety of infection models including the following variables: infection dose (10 7 or 10 8 parasites), parasite stage (amastigote or stationary-phase promastigote), sacrifice times and inoculation route (intraperitoneal or intravenous), and considering parasite load through qPCR, parasite isolation from target organs, and parasite load through imprint smears of liver and spleen. This approach provides a stable infection in the liver and spleen with high parasite loads (up to 2500 parasites per milligram for at least two months after infection) and reaches the bone marrow (data not shown).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

(−)-α-Bisabolol, a Promising Oral Compound for the Treatment of Visceral Leishmaniasis

et al. 2015

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The aim of the present study was to assess the in vitro and in vivo activity of (-)-α-bisabolol (1) against the etiological agents of visceral leishmaniasis. Bone-marrow-derived macrophages were infected with Leishmania infantum or L. donovani promastigotes and incubated with (-)-α-bisabolol at different concentrations. Pentamidine isethionate and meglumine antimoniate were used as reference drugs. Inhibitory concentration 50% (IC50) and cytotoxic concentration 50% (CC50) were calculated. Balb/c mice were infected intraperitoneally with stationary-phase promastigotes. They were treated with (-)-α-bisabolol at different doses orally, meglumine antimoniate at 104 mg Sb(V)/kg, or a combination of both. (-)-α-Bisabolol proved to be innocuous to mammal cells and active against L. infantum and L. donovani intracellular amastigotes (IC50 55 and 39 μM, respectively). Compound 1 also proved to be active in an in vivo model of visceral leishmaniasis due to L. infantum, as it reduced parasite load in the spleen and liver by 71.60% and 89.22%, respectively, at 200 mg/kg without showing toxicity. (-)-α-Bisabolol (1) is a nontoxic compound that was proven to be active against visceral leishmaniasis in an in vivo murine model orally. It was more effective than meglumine antimoniate at reducing spleen parasite load and as effective as this antimonial drug in the liver.

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Section: ■ Results and Discussionmentioning

confidence: 99%

(−)-α-Bisabolol, a Promising Oral Compound for the Treatment of Visceral Leishmaniasis

et al. 2015

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“…Supporting the hypothesis of the switch to a TH1 response, the treatment with IA, IH and SMIH immucillins causes IFN-γ to be the predominant secreted cytokine, an effect also observed after treatment with cisplatin [ 30 , 31 ], and low but detectable levels of TNF-α, which are correlated with resistance to infection and parasite death [ 47 ]. Treatment with immucillins or 1,3,4-tiadiazolium-2 aminide compounds [ 48 ] induced also higher IFN-γ responses than Glucantime. IL-10 is the hallmark of pathology in VL, and was 72% reduced, 1 day after complete treatment with immucillins, and was 50% and 75% reduced at the same time following treatment with cisplatin [ 30 , 31 ] or 1,3,4-tiadiazolium-2 aminide [ 48 ], respectively.…”

Section: Discussionmentioning

confidence: 99%

Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis

et al. 2015

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BackgroundImmucillins ImmA (IA), ImmH (IH) and SerMe-ImmH (SMIH) are synthetic deazapurine nucleoside analogues that inhibit Leishmania (L.) infantum chagasi and Leishmania (L.) amazonensis multiplication in vitro without macrophage toxicity. Immucillins are compared to the Glucantime standard drug in the chemotherapy of Leishmania (L.) infantum chagasi infection in mice and hamsters. These agents are tested for toxicity and immune system response.Methodology/Principal FindingsBALB/c mice were infected with 107 amastigotes, treated with IA, IH, SMIH or Glucantime (2.5mg/kg/day) and monitored for clinical variables, parasite load, antibody levels and splenocyte IFN-γ, TNF-α, and IL-10 expression. Cytokines and CD4+, CD8+ and CD19+ lymphocyte frequencies were assessed in uninfected controls and in response to immucillins. Urea, creatinine, GOT and GPT levels were monitored in sera. Anti-Leishmania-specific IgG1 antibodies (anti-NH36) increased in untreated animals. IgG2a response, high levels of IFN-γ, TNF-α and lower levels of IL-10 were detected in mice treated with the immucillins and Glucantime. Immucillins permitted normal weight gain, prevented hepato-splenomegaly and cleared the parasite infection (85–89%) without renal and hepatic toxicity. Immucillins promoted 35% lower secretion of IFN-γ in uninfected controls than in infected mice. IA and IH increased the CD4+ T and CD19+ B cell frequencies. SMIH increased only the proportion of CD-19 B cells. IA and IH also cured infected hamsters with lower toxicity than Glucantime.Conclusions/SignificanceImmucillins IA, IH and SMIH were effective in treating leishmaniasis in mice. In hamsters, IA and IH were also effective. The highest therapeutic efficacy was obtained with IA, possibly due to its induction of a TH1 immune response. Low immucillin doses were required and showed no toxicity. Our results disclose the potential use of IA and IH in the therapy of visceral leishmaniasis.

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“…To determine the course of infection of our model, 20 female BALB/c mice, 6 to 8 weeks old, were infected intraperitoneally with 1.0 ϫ 10 8 stationary-phase L. infantum promastigotes (21)(22)(23)(24). At days 7, 14, 21, and 30, five animals were euthanatized in a CO 2 chamber for parasite load determinations, as detailed below.…”

Section: Methodsmentioning

confidence: 99%

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

Cunha-Júnior

Martins

Canto‐Cavalheiro

et al. 2016

Antimicrob Agents Chemother

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e Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is the second major cause of death by parasites, after malaria. The arsenal of drugs against leishmaniasis is small, and each has a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. Our group has focused on studying new drug candidates as alternatives to current treatments. The pterocarpanquinone LQB-118 was designed and synthesized based on molecular hybridization, and it exhibited antiprotozoal and antileukemic cell line activities. Our previous work demonstrated that LQB-118 was an effective treatment for experimental cutaneous leishmaniasis. In this study, we observed that treatment with 10 mg/kg of body weight/day LQB-118 orally inhibited the development of hepatosplenomegaly with a 99% reduction in parasite load. An in vivo toxicological analysis showed no change in the clinical, biochemical, or hematological parameters. Histologically, all of the analyzed organs were normal, with the exception of the liver, where focal points of necrosis with leukocytic infiltration were observed at treatment doses 5 times higher than the therapeutic dose; however, these changes were not accompanied by an increase in transaminases. Our findings indicate that LQB-118 is effective at treating different clinical forms of leishmaniasis and presents no relevant signs of toxicity at therapeutic doses; thus, this framework is demonstrated suitable for developing promising drug candidates for the oral treatment of leishmaniasis.

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The in vivo activity of 1,3,4-thiadiazolium-2-aminide compounds in the treatment of cutaneous and visceral leishmaniasis

Abstract: Upon comparison of each MI compound, MI-4-NO(2) was clearly the compound with the greatest activity in these two in vivo infection models by each administration route tested.

Cited by 10 publications

References 37 publications

(−)-α-Bisabolol, a Promising Oral Compound for the Treatment of Visceral Leishmaniasis

(−)-α-Bisabolol, a Promising Oral Compound for the Treatment of Visceral Leishmaniasis

Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

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