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1.
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
2.
Am J Trop Med Hyg ; 103(2): 752-755, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32524951

RESUMO

An 88-year-old man with mutilating mucosal leishmaniasis (ML) involving septal perforation, with granulomas in the pharynx and larynx, was treated with oral miltefosine, 50 mg three times/day for 28 days. Miltefosine, an antineoplastic agent, is considered an alternative option for the treatment of ML, showing efficacies of 75-92% in Bolivia, Brazil, and Argentina. The patient denied having previous cutaneous (CL) leishmaniasis, and no CL lesions were recognized by physical examination. Parasites obtained from mucosal lesions were identified by cytochrome b gene sequencing as Leishmania guyanensis. Clinical cure was observed 2 months posttreatment, and no evidence of reactivation was observed in the 3-year follow-up. Adverse effects such as nausea, loss of appetite, and epigastric pain were experienced during treatment with miltefosine. There is a need for improved access to miltefosine in leishmaniasis-endemic areas of Latin America and a greater awareness of ML and its treatment among physicians working in endemic countries.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Mucocutânea/tratamento farmacológico , Doenças Nasais/tratamento farmacológico , Doenças Faríngeas/tratamento farmacológico , Fosforilcolina/análogos & derivados , Idoso de 80 Anos ou mais , Citocromos b/genética , Disfonia/etiologia , Humanos , Leishmania guyanensis/genética , Leishmania guyanensis/isolamento & purificação , Masculino , Perfuração do Septo Nasal/etiologia , Doenças Nasais/complicações , Doenças Nasais/patologia , Doenças Faríngeas/complicações , Doenças Faríngeas/patologia , Fosforilcolina/uso terapêutico , Índice de Gravidade de Doença
3.
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
4.
Parasite Immunol ; 42(6): e12719, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32248547

RESUMO

AIMS: Visceral leishmaniasis (VL), caused by Leishmania donovani in India, is fatal if untreated, having serious concern of limited chemotherapeutic options. In this study, we evaluated antileishmanial efficacy of purified chlorogenic acid (CGA) against promastigotes and intracellular amastigotes infected into RAW264.7 macrophages. METHODS AND RESULTS: Chlorogenic acid was effective both on promastigotes (IC50  = 78.394 µmol/L, i.e. 27.75 µg/mL) and intracellular amastigotes (ED50  = 26.752 µmol/L, i.e. 9.47 µg/mL). In promastigotes, significant retardation in mitotic growth was caused both by cell-death and reduction of metabolic activity, evidenced by propidium-iodide uptake and MTT assay, respectively. Flow cytometric analysis revealed that retardation of mitotic growth was due to cell-cycle arrest at G1/S checkpoint. Complete clearance of amastigotes from infected RAW264.7 cells, assessed by microscopic counting, was achieved with 60 µmol/L (21.24 µg/mL) CGA for 24 hours, with negligible toxicity to host macrophages. This parasite clearing efficacy was comparable to 1.0 µg/mL (1.082 µmol/L) Amphotericin B, and 20 µmol/L Miltefosine, two standard antileishmanial drugs. Cytokine-ELISA revealed that elevated IL-10 production by infected macrophages was reduced after parasite clearance. Consequently, IL-12, TNF and NO (assayed by Griess test) production by macrophages were significantly increased after successful resolution of infection. CONCLUSION: Chlorogenic acid might emerge as a potential antileishmanial drug.


Assuntos
Antiprotozoários/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ácido Clorogênico/uso terapêutico , Citocinas/metabolismo , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Óxido Nítrico/metabolismo , Animais , Linhagem Celular , Índia , Leishmaniose Visceral/mortalidade , Leishmaniose Visceral/parasitologia , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Células RAW 264.7
5.
Am J Trop Med Hyg ; 102(6): 1319-1322, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32228792

RESUMO

The six previously reported civilian cases of mucosal leishmaniasis (ML) diagnosed in the United States have all represented imported New World ML. We describe two new patients with ML diagnosed in New York City-a Syrian immigrant with a nasal mass (Leishmania tropica), the first report of Old World ML in the United States, and an American ecologist who worked in Bolivia and had been treated for cutaneous infection 23 years before developing lesions (L. (Viannia) braziliensis) initially of the uvula, soft palate, and posterior pharynx and subsequently the larynx.


Assuntos
Leishmaniose Mucocutânea/epidemiologia , Leishmaniose Mucocutânea/patologia , Idoso , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Humanos , Leishmania braziliensis/isolamento & purificação , Leishmaniose Mucocutânea/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico
6.
PLoS Negl Trop Dis ; 14(3): e0008052, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32203500

RESUMO

Post-kala-azar dermal leishmaniasis (PKDL) is clinical outcome of visceral leishmaniasis (VL) and is thought to be the potential reservoir of parasite. Miltefosine (MF) is the only oral drug existing for treatment of post-kala-azar dermal leishmaniasis (PKDL). Increased miltefosine tolerance in clinical isolates of Leishmania donovani has been reported and is one of the major concerns in the treatment of PKDL. Here, we report a highly ulcerated PKDL case that was successfully cured after miltefosine treatment.


Assuntos
Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/etiologia , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Antiprotozoários/uso terapêutico , Humanos , Índia , Leishmania donovani/isolamento & purificação , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Pele/diagnóstico por imagem , Pele/patologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-32058031

RESUMO

Hepatocellular carcinoma (HCC) is an aggressive and widespread cancer. Patients with liver cirrhosis of different aetiologies are at a risk to develop HCC. It is important to know that in approximately 20% of cases primary liver tumors arise in a non-cirrhotic liver. Lipid metabolism is variable in patients with chronic liver diseases, and lipid metabolites involved therein do play a role in the development of HCC. Of note, lipid composition of carcinogenic tissues differs from non-affected liver tissues. High cholesterol and low ceramide levels in the tumors protect the cells from oxidative stress and apoptosis, and do also promote cell proliferation. So far, detailed characterization of the mechanisms by which lipids enable the development of HCC has received little attention. Evaluation of the complex roles of lipids in HCC is needed to better understand the pathophysiology of HCC, the later being of paramount importance for the development of urgently needed therapeutic interventions. Disturbed hepatic lipid homeostasis has systemic consequences and lipid species may emerge as promising biomarkers for early diagnosis of HCC. The challenge is to distinguish lipids specifically related to HCC from changes simply related to the underlying liver disease. This review article discusses aberrant lipid metabolism in patients with HCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/sangue , Neoplasias Hepáticas/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Diagnóstico Diferencial , Modelos Animais de Doenças , Progressão da Doença , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/farmacologia , Lipídeos/uso terapêutico , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Éteres Fosfolipídicos/farmacologia , Éteres Fosfolipídicos/uso terapêutico , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Plasmalogênios/sangue , Plasmalogênios/metabolismo , Plasmalogênios/farmacologia , Plasmalogênios/uso terapêutico , Índice de Gravidade de Doença
8.
Biochem Biophys Res Commun ; 524(4): 1018-1024, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32063363

RESUMO

Pten deletion in the hematopoietic stem cells (HSC) causes a myeloproliferative disorder, which may subsequently develop into a T-cell acute lymphoblastic leukemia (T-ALL). ß-catenin expression was dramatically increased in the c-KitmidCD3+Lin- leukemia stem cells (LSC) and was critical for T-ALL development. Therefore, the inactivation of ß-catenin in LSC may have a potential to eliminate the LSC. In this study, we investigated the mechanism of enhancement of the ß-catenin expression and subsequently used a drug to inactivate ß-catenin expression in T-ALL. Western blot (WB) analysis revealed an increased level of ß-catenin in the leukemic cells, but not in the pre-leukemic cells. Furthermore, the WB analysis of the thymic cells from different stages of leukemia development showed that increased expression of ß-catenin was not via the pS9-GSK3ß signaling, but was dependent on the pT308-Akt activation. Miltefosine (Hexadecylphosphocholine) is the first oral anti-Leishmania drug, which is a phospholipid agent and has been shown to inhibit the PI3K/Akt activity. Treatment of the PtenΔ/Δ leukemic mice with Miltefosine for different durations demonstrated that the pT308-Akt and the ß-catenin expressions were inhibited in the leukemia blast cells. Miltefosine treatment also suppressed the TGFß1/Smad3 signaling pathway. Analysis of TGFß1 in the sorted subpopulations of the blast cells showed that TGFß1 was secreted by the CD3+CD4- subpopulation and may exert effects on the subpopulations of both CD3+CD4+ and CD3+CD4- leukemia blast cells. When a TGFßR1 inhibitor, SB431542 was injected into the PtenΔ/Δ leukemic mice, the Smad3 and ß-catenin expressions were down-regulated. On the basis of the results, we conclude that Miltefosine can suppress leukemia by degrading ß-catenin through repression of the pT308-Akt and TGFß1/Smad3 signaling pathways. This study demonstrates a possibility to inhibit Pten loss-associated leukemia genesis via targeting Akt and Smad3.


Assuntos
Antineoplásicos/uso terapêutico , Fosforilcolina/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Deleção de Genes , Humanos , Camundongos , PTEN Fosfo-Hidrolase/genética , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
9.
Molecules ; 25(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979089

RESUMO

A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.


Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/patogenicidade , Tetraoxanos/química , Tetraoxanos/uso terapêutico , Animais , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Camundongos , Fosforilcolina/análogos & derivados , Fosforilcolina/química , Fosforilcolina/uso terapêutico
10.
J Mycol Med ; 30(1): 100919, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31901425

RESUMO

We evaluated the in vitro activity of miltefosine against 29 Pythium spp. and the in vivo therapeutic response of 2mg/kg/day of miltefosine given orally to rabbit with pythiosis induced experimentally. The MICs (in µg/mL) of miltefosine was medium-dependent and ranged from 0.5 to 2 and 32-64 on RPMI 1640 and Mueller Hinton broth, respectively. The treatment with miltefosine demonstrated significantly lower subcutaneous lesion areas compared to the control group but was not sufficient for the complete remission of the lesions. This study indicates that miltefosine has limited efficacy against pythiosis and furthers in vitro and in vivo studies are necessary to determine the possible potential of this drug in the treatment of pythiosis.


Assuntos
Antifúngicos/uso terapêutico , Dermatomicoses/tratamento farmacológico , Fosforilcolina/análogos & derivados , Pitiose/tratamento farmacológico , Animais , Dermatomicoses/microbiologia , Dermatomicoses/patologia , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Testes de Sensibilidade Microbiana , Fosforilcolina/uso terapêutico , Pitiose/microbiologia , Pitiose/patologia , Pythium/isolamento & purificação , Pythium/patogenicidade , Coelhos , Tela Subcutânea/microbiologia , Resultado do Tratamento
11.
Trop Doct ; 50(1): 37-42, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31610724

RESUMO

A 12-week course of miltefosine (MF) is recommended in India for the treatment of post-kala-azar dermal leishmaniasis (PKDL). We report a case series of four patients with PKDL, across three districts of Bihar state, who developed eye complications during treatment. They presented with acute scleritis and corneal infiltration with or without corneal ulceration. One patient solely with corneal infiltration recovered completely. The three others with corneal ulceration healed with corneal opacificity. One patient with bilateral eye involvement underwent corneal transplantation to prevent blindness. All adverse events were graded as certain using the World Health Organization-Uppsala Monitoring Centre causality assessment scale. There is need to counsel patients regarding possible adverse ocular events during MF treatment, to expand pharmacovigilance to all primary health centres in kala-azar endemic areas, and to update drug safety information considering the emerging evidence.


Assuntos
Antiprotozoários/efeitos adversos , Oftalmopatias/induzido quimicamente , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Adulto , Antiprotozoários/uso terapêutico , Criança , Oftalmopatias/patologia , Oftalmopatias/fisiopatologia , Oftalmopatias/terapia , Feminino , Humanos , Índia/epidemiologia , Leishmaniose Visceral/epidemiologia , Masculino , Pessoa de Meia-Idade , Fosforilcolina/efeitos adversos , Fosforilcolina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
12.
J Infect Dis ; 221(4): 608-617, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31854451

RESUMO

BACKGROUND: No satisfactory canonical treatment is available for post-kala-azar dermal leishmaniasis (PKDL), clinical sequela of visceral leishmaniasis. Confined treatment options and substantial increase in relapse rate after miltefosine (MIL) treatment warrant the need to adapt resilient combination therapies. In this study, we assessed the safety and efficacy of combination therapy using liposomal amphotericin B (LAmB) and MIL for treating PKDL. METHODS: Thirty-two PKDL patients, confirmed by microscopy or quantitative polymerase chain reaction (qPCR), were included in the study. An equal number of cases (n = 16) were put on MIL monotherapy (100 mg/day for 90 days) or MIL and LAmB combination for 45 days (3 injections of LAmB, 5 mg/kg body weight, and 100 mg/day MIL). Parasite load in slit aspirate was monitored using qPCR. RESULTS: Patients treated with combination therapy demonstrated a rapid decline in parasite load and achieved 100% cure, with no reports of relapse. Those treated with MIL monotherapy attained clinical cure with a gradual decrease in parasite load; however, 25% relapsed within 18 months of follow-up. CONCLUSIONS: Liposomal amphotericin B and MIL combination for treating PKDL is efficacious and safe, with high tolerability. Furthermore, this study established the utility of minimally invasive slit aspirate method for monitoring of parasite load and assessment of cure in PKDL.


Assuntos
Anfotericina B/administração & dosagem , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania donovani/genética , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Adolescente , Adulto , Anfotericina B/efeitos adversos , Antiprotozoários/efeitos adversos , Criança , DNA de Protozoário/genética , Quimioterapia Combinada , Feminino , Humanos , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/parasitologia , Lipossomos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Carga Parasitária , Fosforilcolina/efeitos adversos , Fosforilcolina/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Recidiva , Resultado do Tratamento , Adulto Jovem
13.
Infez Med ; 27(4): 452-455, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846999

RESUMO

The management of mucosal leishmaniasis in immunocompromised patients is not standardized and limited data are available on the use of miltefosine for treatment and secondary prophylaxis. We describe a case of mucosal leishmaniasis in an HIV-coinfected patient treated with miltefosine due to a severe allergic reaction to liposomal amphotericin B.


Assuntos
Leishmaniose Mucocutânea/tratamento farmacológico , Fosforilcolina/análogos & derivados , Coinfecção , Infecções por HIV/complicações , Humanos , Leishmaniose Mucocutânea/complicações , Masculino , Pessoa de Meia-Idade , Fosforilcolina/uso terapêutico , Fatores de Tempo
14.
Kathmandu Univ Med J (KUMJ) ; 17(65): 77-79, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31734685

RESUMO

We report two cases of cutaneous leishmaniasis in natives of central region of Nepal. The first patient in our series, an adult female, presented with a small nodule on the philtrum of upper lip and the second case, a male child, presented with two crusted plaques on forehead. The final diagnosis was based on histopathological findings; however, species characterization was not possible because of its unavailability in the country. These patients responded well to the treatment with Miltefosine (First case) and Fluconazole (second case). Moreover, these cases sparks a question about the origin of diseases in this region and calls for further research in future to find out the cause and prevalence of this disease in Nepal. This case report also emphasizes to consider cutaneous leishmaniasis as differential diagnosis for granulomatous presentations in our context.


Assuntos
Leishmaniose Cutânea/diagnóstico , Adulto , Antifúngicos/uso terapêutico , Antiprotozoários/uso terapêutico , Criança , Diagnóstico Diferencial , Feminino , Fluconazol/uso terapêutico , Doença Granulomatosa Crônica/diagnóstico , Humanos , Masculino , Nepal/epidemiologia , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico
15.
PLoS Negl Trop Dis ; 13(9): e0007726, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557162

RESUMO

BACKGROUND: An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. METHODS: The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. RESULTS: Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. CONCLUSION: Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Anfotericina B/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Índia , Masculino , Paromomicina/uso terapêutico , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Recidiva , Resultado do Tratamento
16.
Int J Nanomedicine ; 14: 5187-5199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371955

RESUMO

Introduction and objective: Previous studies indicate that miltefosine (MFS) may be an alternative as an antifungal agent; however, it presents several adverse effects. Thus, the aim of this study was to produce miltefosine-loaded alginate nanoparticles (MFS.Alg) for toxicity reduction to be used as an alternative for the treatment of cryptococcosis and candidiasis. Methods: Alginate nanoparticles were produced using the external emulsification/gelation method, and their physicochemical and morphological characteristics were analyzed. MFS encapsulation efficiency, release assay and toxicity on red blood cells and on Galleria mellonella larvae were assessed. The antifungal activity was evaluated using in vitro and in vivo larval models of G. mellonella infected with Candida albicans (SC5314 and IAL-40), Cryptococcus neoformans H99 and Cryptococcus gattii ATCC 56990. The treatment efficacy was evaluated by survival curve, colony forming unit (CFU) counting and histopathological analysis. Results: MFS.Alg nanoparticles presented a mean size of 279.1±56.7 nm, a polydispersity index of 0.42±0.15 and a zeta potential of -39.7±5.2 mV. The encapsulation efficiency of MFS was 81.70±6.64%, and its release from the nanoparticles occurred in a sustained manner. MFS in alginate nanoparticles presented no hemolytic effect and no toxicity in G. mellonella larvae. Treatment with MFS.Alg extended the survival time of larvae infected with C. albicans and C. gattii. In addition, the fungal burden reduction was confirmed by CFU and histopathological data for all groups treated with 200 mg/Kg of MFS.Alg. Conclusion: These results support the use of alginate-based drug delivery systems as carriers for MFS for drug toxicity reduction and control of the fungal infection in the in vivo model of G. mellonella.


Assuntos
Alginatos/química , Candidíase/tratamento farmacológico , Criptococose/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Fosforilcolina/análogos & derivados , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/microbiologia , Criptococose/microbiologia , Liberação Controlada de Fármacos , Larva/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nanopartículas/ultraestrutura , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Fosforilcolina/toxicidade , Ovinos
17.
Chem Biol Interact ; 310: 108731, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265827

RESUMO

Lung cancer is one of the most common and lethal types of oncological diseases. Despite the advanced therapeutic approaches, the prognosis for lung cancer still remains poor. Apparently, there is an imperative need for more efficient therapeutic strategies. In this work we report that concurrent treatment of human adenocarcinoma A549 cells with specific concentrations of two antitumor agents, the sphingosine kinase 1 inhibitor N, N dimethylsphingosine (DMS) and the alkylphosphocholine miltefosine, induced synergistic cytotoxic effect, which was confirmed by calculation of the combination index. The simultaneous action of these agents, induced significant decrease of A549 cell number, as well as pronounced morphological alterations. Combined drugs caused substantial apoptotic events, and significant reduction of the pro-survival marker sphingosine- 1-phosphate (S1P), when compared to the individual treatments with each of the anticancer drugs alone. Miltefosine is known to affect the synthesis of choline-containing phospholipids, including sphingomyelin, but we report for the first time that it also reduces S1P. Here we suggest a putative mechanism underlying the effect of miltefosine on sphingosine kinase 1, involving miltefosine-induced inhibition of protein kinase C. In conclusion, our findings provide a possibility for treatment of lung cancer cells with lower concentrations of the two antitumor drugs, DMS and miltefosine, which is favorable, regarding their potential cytotoxicity to normal cells.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Apoptose/efeitos dos fármacos , Fosforilcolina/análogos & derivados , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Adenocarcinoma de Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica , Sinergismo Farmacológico , Humanos , Lisofosfolipídeos/análise , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Esfingosina/análogos & derivados , Esfingosina/análise
18.
J Neurooncol ; 144(2): 403-407, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325145

RESUMO

PURPOSE: Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM). METHODS: We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600 mg PRF (in 4 divided doses on day 1) followed by 100 mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort. RESULTS: Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n = 16): the PFS6 rate was 0%, median PFS was 1.58 months [95% CI (1.08, 1.84)], median overall survival was 3.68 months [95% CI (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n = 14). CONCLUSIONS: PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Fosforilcolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Adulto , Idoso , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Fosforilcolina/uso terapêutico , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-31316919

RESUMO

Concurrently, leishmaniasis and AIDS are global public health issues and the overlap between these diseases adds additional treats to the management of co-infected patients. Lopinavir (LPV) has a well characterized anti-HIV and leishmanicidal action, and to analyze its combined action with miltefosine (MFS) could help to envisage strategies to the management of co-infected patients. Here, we evaluate the interaction between LPV and MFS against Leishmania infantum infection by in vitro and in vivo approaches. The effect of the compounds alone or in association was assessed for 72 h in mouse peritoneal macrophages infected with L. infantum by the determination of the IC50s and FICIs. Subsequently, mice were orally treated twice daily during 5 days with the compounds alone or in association and evaluated after 30 days. The in vitro assays revealed an IC50 of 0.24 µM and 9.89 µM of MFS and LPV, respectively, and an additive effect of the compounds (FICI 1.28). The in vivo assays revealed that LPV alone reduced the parasite load in the spleen and liver by 52 and 40%, respectively. The combined treatment of infected BALB/c mice revealed that the compounds alone required at least two times higher doses than when administered in association to virtually eliminate the parasite. Mice plasma biochemical parameters assessed revealed that the combined therapy did not present any relevant hepatotoxicity. In conclusion, the association of MFS with LPV allowed a reduction in each compound concentration to achieve the same outcome in the treatment of visceral leishmaniasis. Although a pronounced synergistic effect was not evidenced, it does not discard that such combination could be useful in humans co-infected with HIV and Leishmania parasites.


Assuntos
Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Lopinavir/uso terapêutico , Fosforilcolina/análogos & derivados , Administração Oral , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Coinfecção/tratamento farmacológico , Modelos Animais de Doenças , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Concentração Inibidora 50 , Leishmaniose Visceral/sangue , Fígado/parasitologia , Lopinavir/administração & dosagem , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , Baço/parasitologia , Resultado do Tratamento
20.
Acta Trop ; 196: 142-149, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103698

RESUMO

Herein, we investigated the efficacy of liposomes for the topical delivery of miltefosine (ML) to treat cutaneous leishmaniasis (CL). Liposomes containing varying concentrations of ML (0.5, 1, 2 and 4%) were prepared and characterized by their size and entrapment efficiency. The liposome diameters were between 100-150 nm. The penetration of ML from liposomal formulations through and in the skin was assessed using ex-vivo Franz diffusion cells fitted with mouse skin at 37 °C for 24 h. Data indicated that Lip-ML-4% showed the highest percent of retention across mouse skin (82%). in vitro promastigote and amastigote assays showed that ML and Lip-ML inhibit the growth of parasites either in the culture medium or intracellularly. Lip-ML formulations were topically applied twice a day for 4 weeks to the skin of BALB/c mice infected with L. major. Results showed a significantly (p < 0.001) smaller lesion size in Lip-ML-2 and 4% when compared to controls. At week 8 post-infection, the number of parasites was higher in Lip-ML-0.5% compared to Lip-ML-2 and 4%, however, the difference was not significant. At week 12, the splenic parasite burden was significantly (p < 0.001) lower in mice treated with different Lip-ML formulations when compared to controls. The lesion parasite burden was significantly (p < 0.001) lower in mice treated with either Lip-ML-2 and 4% compared to Lip-ML-0.5% at week 12 post-infection. The results suggested that topical Lip-ML-4% showed optimal ex-vivo penetration and in vivo anti-leishmanial activity against CL caused by L. major when compared to ML cream and other liposomes and thus, merits further investigation.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania major , Leishmaniose Cutânea/parasitologia , Fosforilcolina/análogos & derivados , Administração Tópica , Animais , Antiprotozoários/administração & dosagem , Lipossomos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , Pele/patologia , Baço/parasitologia
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