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2.
Rev Soc Bras Med Trop ; 54: e0748, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33759927

RESUMO

Visceral leishmaniasis (VL) is an infectious disease caused by Leishmania spp. The recurrence of the disease occurs, in general, in patients with decreased or loss of T-cell function, whether due to the use of corticosteroids, immunosuppressive disease, or another cause. In some cases, splenectomy may be a therapeutic option. However, the effectiveness of splenectomy is not well defined. This report describes the evolution of a pediatric patient with seven recurrences of VL, who relapsed post-surgery after drug therapy and splenectomy.


Assuntos
Leishmania , Leishmaniose Visceral , Criança , Humanos , Leishmaniose Visceral/tratamento farmacológico , Recidiva , Esplenectomia
3.
Exp Parasitol ; 221: 108059, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33338468

RESUMO

Treatment for visceral leishmaniasis (VL) is hindered mainly by the toxicity and/or high cost of therapeutic drugs. In addition, parasite resistance has been registered. Thus, there is an urgent need for the identification of novel, effective and low-cost antileishmanial agents. Since drug discovery is a long and expensive process, drug repositioning for treatment of leishmaniasis should be considered. In the present study, Ivermectin (IVE), a broad-spectrum drug used for treatment of parasitic diseases, was evaluated in vitro and in vivo against Leishmania infantum species. Results in vitro showed that IVE presented 50% Leishmania and macrophage inhibitory concentrations (IC50 and CC50, respectively) of 3.64 ± 0.48 µM and 427.50 ± 17.60 µM, respectively, with a selectivity index (SI) of 117.45; whereas Amphotericin B (AmpB), which was used as control, showed IC50 and CC50 values of 0.12 ± 0.05 µM and 1.06 ± 0.23 µM, respectively, with a corresponding SI of 8.90. Treatment with IVE effectively reduced the infection percentage and parasite burden in infected and treated macrophages and displayed a prophylactic activity by inhibiting macrophage infection with pre-treated parasites. Furthermore, preliminary studies suggested that IVE targets the parasite's mitochondria. Activity of IVE in its free format or incorporated into Pluronic® F127-based polymeric micelles (IVE/Mic) was also evaluated in vivo as a treating drug for L. infantum-infected BALB/c mice. Miltefosine was used as a control. Results showed that Miltefosine, IVE and IVE/Mic-treated animals presented significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes, as well as development of an antileishmanial Th1-type immune response one and 15 days after treatment. Notably, IVE/Mic showed a better parasitological and immunological response in comparison to other alternative treatments. In conclusion, results suggest that IVE/Mic could be considered in future studies as a therapeutic alternative to treat VL.


Assuntos
Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Anfotericina B/farmacologia , Animais , Antiprotozoários/toxicidade , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Concentração Inibidora 50 , Ivermectina/toxicidade , Macrófagos Peritoneais/efeitos dos fármacos , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Baço/parasitologia
4.
PLoS Negl Trop Dis ; 14(12): e0008947, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33338041

RESUMO

Leishmaniasis is among the world's most neglected diseases. Dogs are the main reservoirs/hosts of Leishmania infantum, causative agent of both canine and human visceral leishmaniosis. Canine leishmaniasis (CanL) represents a public health problem as one of the most prevalent zoonotic diseases worldwide. Current therapeutics present drawbacks; thus, there is a need for more effective, safer, and cheaper drugs. The aim of this study was to evaluate and to compare the efficacy of oral administration of artesunate or meglumine antimoniate/allopurinol in dogs with clinical leishmaniasis. Forty-two dogs with naturally occurring clinical leishmaniasis were included in this open-label, simple randomized positive-control clinical field trial with 6 months of follow-up. Dogs received meglumine antimoniate 100 mg/kg/day and allopurinol 30 mg/kg/day for 28 days (control group, n = 26) or artesunate 25 mg/kg/day for 6 days (test group, n = 16). The animals were evaluated for their clinical evolution, parasite load (by qPCR) and humoral response at different time points: 0, 30, 90, and 180 days after treatment. Data analyses showed a significant improvement in both groups in clinical scores, parasitemia and antibody titers after treatment. Compared to the control group, the artesunate group showed significantly lower clinical score (P = 0.0001), lower parasitemia (P = 0.0001) and antibody titers after 6 months of follow-up. Compared to baseline values, a rapid, significant reduction (P < 0.012) in antibody levels, 2.28- versus 3.04-fold for the control versus artesunate groups, respectively, was observed 30 days after treatment. Antibody levels continued to decrease further in the artesunate group, where 58% of cases became seronegative at the 6-month follow-up. All qPCR-positive dogs were negative after treatment with artesunate, while 14.3% remained positive with the appearance of two new cases in the control group. Artesunate was well tolerated, and no side effects were recorded. Treatment failures were similar in both groups with 27.27% (6/22), including 18.18% (4/22) mortality in the control group, versus 26.66% (4/15), including 13.33% (2/15) mortality in the artesunate group. This is the first report showing the potential of artesunate in the treatment of dogs with clinical leishmaniasis. Artesunate showed higher efficacy than the current first-line treatment for CanL without any adverse effects. It could be a good alternative chemotherapy for CanL, and may be considered for further studies in human leishmaniases. Further clinical trials are needed to confirm these findings, to determine if there are relapses after treatment and if dogs remain infective to sandflies, to define the ideal therapeutic dosage and duration of treatment with artesunate.


Assuntos
Alopurinol/uso terapêutico , Antiprotozoários/uso terapêutico , Artesunato/uso terapêutico , Doenças do Cão/tratamento farmacológico , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/veterinária , Antimoniato de Meglumina/uso terapêutico , Animais , Doenças do Cão/parasitologia , Cães , Feminino , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Masculino , Carga Parasitária/veterinária , Parasitemia/tratamento farmacológico , Zoonoses
5.
Rev Soc Bras Med Trop ; 54: e20200208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338118

RESUMO

Post-kala-azar dermal leishmaniasis is a skin disorder occurring in 5-10% of visceral leishmaniasis patients after treatment with miltefosine,the first-line drug for this skin disorder. We reported a case of acute anterior uveitis,a rare adverse effect, experienced by a patient treated with miltefosine for post-kala-azar dermal leishmaniasis. This adverse effect developed after 15 days of miltefosine consumption, and the patient himself discontinued the treatment. The ophthalmic complication was completely resolved with antibiotics and steroid eye drops. After recovery from the ophthalmic complication, the patient was successfully treated with liposomal amphotericin B for the skin lesions.


Assuntos
Antiprotozoários , Leishmaniose Cutânea , Leishmaniose Visceral , Uveíte , Antiprotozoários/efeitos adversos , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico
6.
Medicine (Baltimore) ; 99(45): e22787, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157924

RESUMO

INTRODUCTION: Non-HIV-related visceral leishmaniasis (VL) is becoming increasingly prevalent in nontropical countries because of the increasing number of patients with chronic diseases and the development of immune-modulating drugs. PATIENT CONCERNS: Case 1 is a 60-year-old male patient of Senegalese origin presented with weight loss, lymphadenopathy, anemia, and elevated lactate dehydrogenases. Case 2 is a 46-year-old male patient of Algerian origin, with a negative HIV serology presented with cutaneous lesions. DIAGNOSIS: Patient 1: The diagnosis of stage IV lymphocytic lymphoma (LL) was confirmed by an inguinal nodal biopsy in 2013. Patient 2: The diagnosis of T-cell lymphoma was made in 2003. INTERVENTIONS: Patient 1 received 5 cycles of bendamustine and rituximab followed by a complete remission. Patient 2 was initially treated with >10 different treatments followed by 8 different chemotherapy regimens due to the disease progression. OUTCOMES: Patient 1: In 2017, after a follow-up of 4 years, the patient presented with fever, lymphadenopathy, splenomegaly, and pancytopenia in the setting of hemophagocytic syndrome. The initial diagnosis was a relapse of lymphoma and the patient was treated with ibrutinib. His status worsened, and Leishmania DNA was detected by polymerase chain reaction (PCR) on the blood and bone marrow aspirates. Ibrutinib was stopped. Amphotericin B treatment induced a complete clinical remission and clearance of Leishmania DNA from the blood.Patient 2: In 2017, after a follow-up of 14 years, the patient presented with fever, lymphadenopathy, hepatosplenomegaly, pancytopenia with hemophagocytic syndrome, and an increase in the tumor skin lesions. A skin biopsy was taken from the face and the patient. A careful reexamination of the skin biopsy revealed the presence of Leishmania bodies. He was treated with 40 mg/kg liposomal amphotericin B leading to a regression of the clinical symptoms and negativation of the blood PCR. CONCLUSIONS: This case study shows that VL may be a diagnostic challenge in patients with lymphoma. Reactivation or primary infection should be considered in the differential diagnosis. The purpose of this study is to remind clinicians to think of VL in patients with systemic symptoms that could be misdiagnosed as a progression of the underlying lymphoma.


Assuntos
Leishmaniose Visceral/complicações , Leishmaniose Visceral/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Diagnóstico Diferencial , Progressão da Doença , Humanos , Leishmaniose Visceral/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Indução de Remissão
7.
BMC Infect Dis ; 20(1): 867, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213392

RESUMO

BACKGROUND: Micronutrients are minerals and vitamins and they are essential for normal physiological activities. The objectives of the study were to describe the progress and determinants of micronutrient levels and to assess the effects of micronutrients in the treatment outcome of kalazar. METHODS: A prospective cohort study design was used. The data were collected using patient interviews, measuring anthropometric indicators, and collecting laboratory samples. The blood samples were collected at five different periods during the leishmaniasis treatments: before starting anti-leishmaniasis treatments, in the first week, in the second week, in the third week, and in the 4th week of anti-leishmaniasis treatments. Descriptive statistics were used to describe the profile of patients and to compare the treatment success rate. The generalized estimating equation was used to identify the determinants of serum micronutrients. RESULTS: The mean age of the patients were 32.88 years [SD (standard deviation) ±15.95]. Male constitute 62.3% of the patients and problematic alcohol use was present in 11.5% of the patients. The serum zinc level of visceral leishmaniasis patients was affected by alcohol (B - 2.7 [95% CI: - 4.01 - -1.5]), DDS (B 9.75 [95% CI: 7.71-11.79]), family size (B -1.63 [95% CI: - 2.68 - -0.58]), HIV (B -2.95 [95% CI: - 4.97 - -0.92]), and sex (B - 1.28 [95% CI: - 2.5 - -0.07]). The serum iron level of visceral leishmaniasis patients was affected by alcohol (B 7.6 [95% CI: 5.86-9.35]), family size (B -5.14 [95% CI: - 7.01 - -3.28]), malaria (B -12.69 [95% CI: - 14.53 - -10.87]), Hookworm (- 4.48 [- 6.82 - -2.14]), chronic diseases (B -7.44 [95% CI: - 9.75 - -5.13]), and HIV (B -5.51 [95% CI: - 8.23 - -2.78]). The serum selenium level of visceral leishmaniasis patient was affected by HIV (B -18.1 [95% CI: - 20.63 - -15.58]) and family size (B -11.36 [95% CI: - 13.02 - -9.7]). The iodine level of visceral leishmaniasis patient was affected by HIV (B -38.02 [95% CI: - 41.98 - -34.06]), DDS (B 25 .84 [95% CI: 22.57-29.1]), smoking (B -12.34 [95% CI: - 15.98 - -8.7]), chronic illness (B -5.14 [95% CI: - 7.82 - -2.46]), and regular physical exercise (B 5.82 [95% CI: 0.39-11.26]). The serum vitamin D level of visceral leishmaniasis patient was affected by HIV (B -9.43 [95% CI: - 10.92 - -7.94]), DDS (B 16.24 [95% CI: 14.89-17.58]), malaria (B -0.61 [95% CI: - 3.37 - -3.37]), and family size (B -1.15 [95% CI: - 2.03 - -0.28]). The serum vitamin A level of visceral leishmaniasis patient was affected by residence (B 0.81 [95% CI: 0.08-1.54]), BMI (B 1.52 [95% CI: 0.42-2.6]), DDS (B 1.62 [95% CI: 0.36-2.88]), family size (B -5.03 [95% CI: - 5.83 - -4.22]), HIV (B -2.89 [95% CI: - 4.44 - -1.34]),MUAC (B 0.86 [95% CI: 0.52-1.21]), and age (B 0.09 [95% CI: 0.07-0.12]). CONCLUSION: The micronutrient levels of visceral leishmaniasis patients were significantly lower. The anti-leishmaniasis treatment did not increase the serum micronutrient level of the patients.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Micronutrientes/sangue , Adulto , Consumo de Bebidas Alcoólicas , Feminino , Infecções por HIV/complicações , Infecções por HIV/patologia , Humanos , Entrevistas como Assunto , Leishmaniose Visceral/complicações , Leishmaniose Visceral/patologia , Malária/complicações , Malária/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Selênio/sangue , Zinco/sangue
8.
Ann Parasitol ; 63(3): 295-302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33128446

RESUMO

Visceral leishmaniosis is one of the most fatal old-world neglected disease with estimated 90 thousand worldwide cases emerge each year. In Iraq, the cutaneous and visceral form are endemic but available chemotherapies are either toxic with diverse side effects, expensive available drugs or parasite resistant is arising. Artemisinin (ART) is a semi-synthetic compound which proved its effectiveness against protozoan parasites, such as malaria and Leishmania. In this study, the efficacy of different concentrations of pure artemisinin was screened in vitro against promastigotes and axenic amastigotes by MTT assay after 24, 48 and 27 hours follow up. In addition, the infectivity ability and number was investigated of intra-cellular Leishman bodies in treated murine peritoneal macrophages after 24 and 48 hours ART treatment. The results verified ART efficacy against the promastigotes and axenic amastigotes viability with IC50 measured after 24, 48- and 72-hours treatment. Infectivity percentage of murine macrophages and parasite burden were significantly reduced in treated cells. These findings indicate the leishmanicidal activity of ART against the Iraqi isolate of L. donovani and further in vivo study is recommended for assigning ART as a natural anti visceral leishmaniosis compound.


Assuntos
Antiprotozoários , Artemisininas , Leishmania donovani , Leishmaniose Visceral , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Iraque , Leishmaniose Visceral/tratamento farmacológico , Macrófagos , Camundongos
9.
Am J Trop Med Hyg ; 103(5): 1927-1929, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32959758

RESUMO

Visceral leishmaniasis (VL) is a systemic infection caused by the protozoal parasite Leishmania, spread via the bloodstream to the reticuloendothelial system, through the bite of the sand fly. It is endemic in parts of Africa, South America, Asia, and Europe, including the Mediterranean. Here, we describe a case of VL that was initially diagnosed as Q fever based on positive Coxiella burnetii serology and showed a partial response to doxycycline treatment.


Assuntos
Coxiella burnetii/imunologia , Doxiciclina/uso terapêutico , Leishmania donovani/imunologia , Leishmaniose Visceral/diagnóstico por imagem , Abdome/diagnóstico por imagem , Animais , Diagnóstico Diferencial , Hepatomegalia/diagnóstico por imagem , Humanos , Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Masculino , Febre Q/diagnóstico por imagem , Esplenomegalia/diagnóstico por imagem , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto Jovem
10.
PLoS Negl Trop Dis ; 14(8): e0008575, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866156

RESUMO

BACKGROUND: Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments. METHODOLOGY/PRINCIPAL: Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK). FINDINGS: The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug. CONCLUSIONS/SIGNIFICANCE: All experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.


Assuntos
Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Suramina/farmacologia , Suramina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fosfoglicerato Quinase/efeitos dos fármacos , Células RAW 264.7/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
11.
Am J Trop Med Hyg ; 103(5): 1938-1941, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32815498

RESUMO

Interleukin-10 (IL-10) and interleukin-27 (IL-27) both exert counterregulatory immunodeactivation in visceral Leishmania donovani infection. We studied experimental L. donovani infection in the livers of IL-10-/- and IL-27Rα-/- mice and observed that in IL-27Rα-/-, but not IL-10-/- mice, interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) were required for heightened granulomatous inflammation and accelerated control of intracellular parasite replication. This difference in mechanism, along with residual IL-10 activity in IL-27Rα-/- mice, suggested targeting IL-27 in addition to IL-10 in a macrophage-activating, anti-counterregulatory cytokine treatment strategy. In C57BL/6 wild-type mice with established liver infection, a single injection of anti-IL-27 p28 or anti-IL-10R monoclonal antibody enhanced granuloma assembly, enabled macrophage activation, and induced comparable parasite killing (49-56%). However, anti-IL-27 p28 plus anti-IL-10R combination treatment did not increase leishmanicidal effects. These results suggest that IL-27 and IL-10 may operate in a linked deactivating mechanism and that in this intracellular infection, either IL-27 or IL-10 is a suitable immunotherapeutic target.


Assuntos
Interleucina-10/metabolismo , Interleucinas/metabolismo , Leishmania donovani/imunologia , Leishmaniose Visceral/tratamento farmacológico , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/patologia , Fígado/imunologia , Fígado/parasitologia , Fígado/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL
12.
Parasitol Res ; 119(9): 2991-3003, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32748038

RESUMO

Visceral leishmaniasis (VL, also known as kala-azar) is a vector borne disease caused by obligate intracellular protozoan parasite Leishmania donovani. To overcome the limitations of currently available drugs for VL, molecular target-based study is a promising tool to develop new drugs to treat this neglected tropical disease. One such target we recently identified from L. donovani (Ld) genome (WGS, clinical Indian isolate; BHU 1220, AVPQ01000001) is a small GTP-binding protein, Rab6 protein. We now report a specific inhibitor of the GTPase activity of Rab6 protein of L. donovani (LdRab6) without restricting host enzyme activity. First, to understand the nature of LdRab6 protein, we generated recombinant LdRab6 mutant proteins (rLdRab6) by systematically introducing deletion (two cysteine residues at C-terminal) and mutations [single amino acid substitutions in the conserved region of GTP (Q84L)/GDP(T38N) coding sequence]. The GTPase activity of rLdRab6:GTP and rLdRab6:GDP locked mutant proteins showed ~ 8-fold and ~ 1.5-fold decreases in enzyme activity, respectively, compared to the wild type enzyme activity. The mutant protein rLdRab6:ΔC inhibited the GTPase activity. Sequence alignment analysis of Rab6 protein of L. donovani with Homo sapiens showed identical amino acids in the G conserved region (GTP/GDP-binding sites) but it differed in the C-terminal region. We then evaluated the inhibitory activity of trans-dibenzalacetone (DBA, a synthetic analog of curcumin with strong antileishmanial activity reported earlier by us) in the GTPase activity of LdRab6 protein. Comparative molecular docking analysis of DBA and specific inhibitors of Rab proteins (Lovastatin, BFA, Zoledronate, and NE10790) indicated that DBA had optimum binding affinity with LdRab6 protein. This was further confirmed by the GTPase activity of DBA-treated LdRab6 which showed a basal GTP level significantly lower than that of the wild-type rLdRab6. The results confirm that DBA inhibits the GTPase activity of LdRab6 protein from L. donovani (LdRab6), a potential target for its antileishmanial effect.


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Pentanonas/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas rab de Ligação ao GTP/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Curcumina/farmacologia , Humanos , Leishmania donovani/química , Leishmania donovani/enzimologia , Leishmania donovani/genética , Leishmaniose Visceral/tratamento farmacológico , Simulação de Acoplamento Molecular , Pentanonas/química , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Alinhamento de Sequência , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
13.
PLoS Negl Trop Dis ; 14(7): e0008429, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32687498

RESUMO

BACKGROUND: Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: A Phase IV trial included 1761 VL patients treated between 2012-2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models. Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse. CONCLUSIONS/SIGNIFICANCE: Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Índia/epidemiologia , Leishmaniose Cutânea/patologia , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Adulto Jovem
14.
Am J Trop Med Hyg ; 103(4): 1490-1492, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32720633

RESUMO

Human visceral leishmaniasis (HVL) is a parasitic disease infecting children in the Mediterranean region. Here, we portray a case of a 2-year-old child with an epidemiological description of the situation surrounding the case. The patient was suffering from recurrent fever, weakness, and abdominal discomfort associated with loss of appetite. Routine blood investigations showed pancytopenia, whereas examination revealed hepatomegaly. A diagnosis of HVL was made by demonstrating amastigotes in a Giemsa-stained smear from a bone marrow aspirate followed by genotyping by PCR and sequencing. In conclusion, early detection of VL infection followed by appropriate treatment protocols is essential to saving the patient.


Assuntos
Medula Óssea/parasitologia , Leishmania infantum/isolamento & purificação , Leishmaniose Visceral , Animais , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/uso terapêutico , Pré-Escolar , Reservatórios de Doenças , Cães/parasitologia , Diagnóstico Precoce , Feminino , Humanos , Insetos Vetores , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/patologia , Oriente Médio/epidemiologia , Phlebotomus/parasitologia
15.
Exp Parasitol ; 217: 107947, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32628971

RESUMO

Visceral leishmaniasis (VL) is an infectious disease caused by the protozoan parasite Leishmania (Leishmania) infantum, an intracytoplasmic parasite that affects humans and other species of domestic and wild mammals. In Brazil, the treatment of canine visceral leishmaniasis (CVL) with miltefosine has been implemented since 2016, and the reports on the clinical and immunological conditions of treated dogs are scarce. Thus, this study aimed to assess and monitor the clinical, laboratory, and immunological condition of dogs with CVL before (D0) and after (D29) using three pharmacotherapeutic protocols: miltefosine monotherapy (Milteforan™, Virbac) (G1), miltefosine plus allopurinol (G2), and allopurinol monotherapy (G3). Forty-five dogs with CVL were assigned to one of three treatment groups. The dogs were evaluated for clinical signs, was well as haematological, biochemical, serological, and cytokine levels. Significant reduction in clinical scores was observed in all protocols, with no differences between groups. We did not observe a clinical cure in any of the dogs in the groups. Haematological and biochemical parameters showed slow recovery, with better results observed in G2. Anti-Leishmania antibody titre remained increased in all groups. The quantification of serum cytokines demonstrated a mixed Th1/Th2 profile in CVL. The IL-2 levels decreased in all groups after treatment. Evaluation of IFN-y and IL-10 did not show changes in the groups analysed, and it did not contribute to short term therapeutic monitoring. All therapeutic protocols promoted, to varying degrees, an improvement in the general condition (clinical signs, haematological, and biochemical levels) of the animals. Through clinical-pathological exams, we found that the combination of miltefosine plus allopurinol promoted better effects in the short-term, representing the best choice for the treatment of CVL, even when compared to the only therapeutic protocol allowed in Brazil, miltefosine monotherapy. Through the quantification of cytokines, IL-2 proved to be a potential therapeutic marker for the monitoring and follow-up of dogs with CVL.


Assuntos
Alopurinol/uso terapêutico , Antiprotozoários/uso terapêutico , Doenças do Cão/tratamento farmacológico , Leishmaniose Visceral/veterinária , Fosforilcolina/análogos & derivados , Animais , Citocinas/sangue , Doenças do Cão/parasitologia , Cães , Quimioterapia Combinada , Feminino , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Masculino , Fosforilcolina/uso terapêutico
16.
PLoS Negl Trop Dis ; 14(7): e0008221, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32614818

RESUMO

Leishmaniasis remains a public health concern around the world that primarily affects poor folks of the developing world spanning across 98 countries with mortality of 0.2 million to 0.4 million annually. Post kala-azar dermal leishmaniasis (PKDL) is the late skin manifestation of visceral leishmaniasis (VL). It has been reported that about 2.5% to 20% of patients recovered from VL develop PKDL having stilted macular or nodular lesions with parasites. In the Indian subcontinent (ISC), it manifests a few months after recovery from VL, though in Africa it can occur simultaneously with VL or a little later. New cases of PKDL are also observed without prior VL in the ISC. These individuals with PKDL represent an important but largely neglected reservoir of infection that perpetuates anthroponotic Leishmania donovani transmission in the ISC and can jeopardize the VL elimination program as these cases can infect the sand flies and spread the endemic. Therefore, it becomes imperative to eradicate PKDL as a part of the VL elimination program. With the limited treatment options besides little knowledge on PKDL, this review stands out in focusing on different aspects that should be dealt for sustained VL elimination.


Assuntos
Leishmaniose Cutânea/etiologia , Leishmaniose Visceral/complicações , Gluconato de Antimônio e Sódio/efeitos adversos , Biomarcadores , Predisposição Genética para Doença , Humanos , Memória Imunológica , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/prevenção & controle , Leishmaniose Visceral/tratamento farmacológico
17.
Exp Parasitol ; 217: 107948, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698076

RESUMO

Immunomodulation is an emerging concept to combat infection in recent years. Immunomodulators like arabinosylated-lipoarabinomannan (Ara-LAM) and glycyrrhizic-acid (GA) possess anti-leishmanial property, whereas sodium-antimony-gluconate (SAG) is still considered as the first choice for chemotherapy against leishmaniasis. During infection, invasion of Leishmania donovani needs the potential requirement of Ca2+, which is further responsible for apoptosis in intracellular amastigotes. However, suppression of elevated intracellular calcium by the activation of plasma-membrane-calcium-ATPase (PMCA4) facilitates survival of L. donovani in the host. In the present study, SAG, Ara-LAM, and GA were found to evoke significant increase in intracellular Ca2+ in L. donovani infected macrophages by inhibiting PMCA4. Moreover, PMCA4 inhibition by TFP or PMCA4 siRNA elevated the level of PKCß, whereas calcium-independent upregulation of PKCζ remained unchanged in infected macrophages. Furthermore, application of immunomodulators in infected macrophages resulted in down-regulation of PKCζ, conversion of anti-inflammatory to pro-inflammatory cytokines and inhibition of PMCA4. Plasma membrane-associated ceramide which is known to be elevated during leishmaniasis, triggered upregulation of PMCA4 via PKCζ activation. Interestingly, immunomodulators attenuated ceramide generation, which resulted into reduced PKCζ activation leading to the decreased PMCA expression in infected macrophages. Therefore, our study elucidated the efficacy of SAG, Ara-LAM, and GA in the reduction of parasite burden in macrophages by suppressing PMCA activation through inhibition of ceramide mediated upregulation of PKCζ.


Assuntos
Antiprotozoários/uso terapêutico , ATPases Transportadoras de Cálcio/sangue , Membrana Celular/enzimologia , Fatores Imunológicos/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Animais , Gluconato de Antimônio e Sódio/farmacologia , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/farmacologia , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Ceramidas/metabolismo , Meios de Cultura Livres de Soro , Densitometria , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/uso terapêutico , Imipramina/farmacologia , Immunoblotting , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/uso terapêutico , Macrófagos/fisiologia , Camundongos , RNA de Protozoário/genética , RNA de Protozoário/isolamento & purificação , RNA Interferente Pequeno/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Reversa , Transfecção
18.
Sci Rep ; 10(1): 12243, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699361

RESUMO

The development of an effective oral therapeutics is an immediate need for the control and elimination of visceral leishmaniasis (VL). We exemplify the preparation and optimization of 2-hydroxypropyl-ß-cyclodextrin (HPCD) modified solid lipid nanoparticles (SLNs) based oral combinational cargo system of Amphotericin B (AmB) and Paromomycin (PM) against murine VL. The emulsion solvent evaporation method was employed to prepare HPCD modified dual drug-loaded solid lipid nanoparticles (m-DDSLNs). The optimized formulations have a mean particle size of 141 ± 3.2 nm, a polydispersity index of 0.248 ± 0.11 and entrapment efficiency for AmB and PM was found to be 96% and 90% respectively. The morphology of m-DDSLNs was confirmed by scanning electron microscopy and transmission electron microscopy. The developed formulations revealed a sustained drug release profile upto 57% (AmB) and 21.5% (PM) within 72 h and were stable at both 4 °C and 25 °C during short term stability studies performed for 2 months. Confocal laser scanning microscopy confirmed complete cellular internalization of SLNs within 24 h of incubation. In vitro cytotoxicity study against J774A.1 macrophage cells confirmed the safety and biocompatibility of the developed formulations. Further, m-DDSLNs did not induce any hepatic/renal toxicities in Swiss albino mice. The in vitro simulated study was performed to check the stability in simulated gastric fluids and simulated intestinal fluids and the release was found almost negligible. The in vitro anti-leishmanial activity of m-DDSLNs (1 µg/ml) has shown a maximum percentage of inhibition (96.22%) on intra-cellular amastigote growth of L. donovani. m-DDSLNs (20 mg/kg × 5 days, p.o.) has significantly (P < 0.01) reduced the liver parasite burden as compared to miltefosine (3 mg/kg × 5 days, p.o.) in L. donovani-infected BALB/c mice. This work suggests that the superiority of as-prepared m-DDSLNs as a promising approach towards the oral delivery of anti-leishmanial drugs.


Assuntos
Anfotericina B/química , Anfotericina B/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Nanopartículas/química , Paromomicina/química , Paromomicina/farmacologia , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Linhagem Celular , Emulsões/química , Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão/métodos , Tamanho da Partícula , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/farmacologia
19.
Int J Infect Dis ; 97: 27-29, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32425641

RESUMO

BACKGROUND: Visceral leishmaniasis-related hemophagocytic lymphohistiocytosis (VL-HLH) is a secondary hemophagocytic syndrome, which can be life-threatening, caused by leishmania and transmitted by infected sandflies. Rapid and accurate identification of leishmania is crucial for clinical strategies. CASE REPORT: Here, we report an infantile infection in a non-epidemic area of China. The infant was a 9.5-month-old girl with fever, pancytopenia and hepatosplenomegaly, which meet the HLH-2004 standard, and the negative gene results exclude congenital HLH. However, chemotherapy is ineffective and is accompanied by severe infection. Fortunately, she is diagnosed with VL-HLH (visceral leishmaniasis-related hemophagocytic lymphohistiocytosis), as leishmania is detected by next-generation meta-genome sequencing (mNGS) and quickly relieved after treatment with libosomal amphotericin B (L-AMB). CONCLUSION: mNGS can detect leishmania in pediatric HLH, and should be performed as a new detection for VL-HLH, particularly for infants, who may not respond to HLH-2004 regimen.


Assuntos
Leishmaniose Visceral/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Leishmania/isolamento & purificação , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/parasitologia
20.
Am J Trop Med Hyg ; 103(1): 308-314, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32394874

RESUMO

Visceral leishmaniasis (VL) is endemic in Asia, East and North Africa, South America, and Southern Europe, and is a major public health problem in the Indian subcontinent. Miltefosine received approval in 2002 to treat VL in India, and the Indian National Vector Borne Disease Control Programme later adopted a single dose (10 mg/kg) of liposomal amphotericin B. We report results of a randomized trial comparing the efficacy of combination therapy with an Indian preparation of liposomal amphotericin B (single dose of 7.5 mg/kg) and short-course miltefosine (2.5 mg/kg/day for 14 days; n = 66) in comparison to miltefosine monotherapy (2.5 mg/kg/day for 28 days; n = 78). Nine patients in the miltefosine group and three in the combination therapy group had to discontinue therapy because of serious adverse events. At the end of the therapy, the clinical and parasitological cure rate was 100% in both groups. By per-protocol analysis, by 6 months after completion of treatment, 12 of 69 patients in the miltefosine monotherapy arm (17.4%, 95% CI: 10.24-28%) and none in the combination therapy arm had relapse. Over 5 years of follow-up, 10 patients in the miltefosine monotherapy arm (all within 0.5-2 years after completing therapy) and none in the combination therapy arm experienced post-kala-azar dermal leishmaniasis. Combination therapy offered benefits over miltefosine monotherapy for VL in India.


Assuntos
Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Adolescente , Adulto , Idoso , Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Criança , Quimioterapia Combinada , Feminino , Humanos , Índia , Leishmania donovani , Masculino , Pessoa de Meia-Idade , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , Adulto Jovem
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