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1.
PLoS Negl Trop Dis ; 13(12): e0007856, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31805052

RESUMEN

Cutaneous leishmaniasis (LC) is a complex and variable disease in terms of epidemiology, aetiology, pathology and clinical characteristics. The mainstay of treatment is still pentavalent antimony (Sbv) compounds administered systemically, despite their recognized toxicity. The advantages of antimony intralesional (IL) infiltration are the use of lower doses of Sbv and, therefore, less toxic effects. The objective of this study was to estimate the cost-effectiveness ratio of intralesional meglumine antimoniate therapy (IL-MA) compared with endovenous meglumine antimoniate therapy (EV-MA) for the treatment of CL in the context of the Brazilian National Health System (SUS). An analytical decision model (decision tree) was developed using TreeAge Pro 2018 software. Data from the open-label, uncontrolled phase II clinical trial evaluating IL-MA were used as a reference for posology, efficacy, and adverse event rates (AE). The same premises for the intravenous approach (EV-MA) were extracted from systematic literature reviews. Macro and micro calculations of spending were included in the analysis. The IL-MA and EV-MA strategies had a total cost per patient cured of US$330.81 and US$494.16, respectively. The intralesional approach was dominant, meaning it was more economic and effective than was endovenous therapy. The incremental cost-effectiveness ratio showed that IL-MA could result in savings of US$864.37 for each additional patient cured, confirming that the IL-MA strategy is cost effective in the context of the Brazilian public health scenario.


Asunto(s)
Antiprotozoarios/administración & dosificación , Análisis Costo-Beneficio , Leishmaniasis Cutánea/tratamiento farmacológico , Antimoniato de Meglumina/administración & dosificación , Administración Tópica , Adulto , Brasil , Ensayos Clínicos como Asunto , Humanos , Inyecciones Intravenosas , Persona de Mediana Edad , Adulto Joven
2.
Pan Afr Med J ; 34: 8, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31762877

RESUMEN

We report here a case of simultaneous cutaneous and visceral manifestations due to Leishmania L. infantum diagnosed in an immunocompetent adult. We describe a 74-year-old woman from Tunis, Tunisia, who presented a biologically confirmed visceral leishmaniasis infection concomitant with arm ulceration which appeared 2 years before. Leishmania DNA was detected by ITS PCR in both buffy coat and dermal scrapping of the arm lesion. Sequencing revealed that the 2 isolated strains corresponded to L. infantum and were 100% identical. The symptoms of visceral leishmaniasis responded to amphotericin B with rapid healing. However, the skin lesion did not improve although Leishmania PCR on dermal sample became negative. This location is probably secondarily to lymphatic or blood dissemination during the systemic visceral leishmaniasis infection. It would be favored by the inflammatory environment induced by the basal cell carcinoma subsequently diagnosed.


Asunto(s)
Carcinoma Basocelular/diagnóstico , Leishmaniasis Cutánea/diagnóstico , Leishmaniasis Visceral/diagnóstico , Neoplasias Cutáneas/diagnóstico , Anciano , Anfotericina B/administración & dosificación , Antiprotozoarios/administración & dosificación , Carcinoma Basocelular/patología , Femenino , Humanos , Leishmania infantum/aislamiento & purificación , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Visceral/tratamiento farmacológico , Reacción en Cadena de la Polimerasa , Neoplasias Cutáneas/patología , Túnez
3.
Internist (Berl) ; 60(12): 1305-1310, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31549186

RESUMEN

MEDICAL HISTORY AND INITIAL PRESENTATION: A 35-year-old patient with a previous history of persistent episodic fever, sore throat, myalgia, and cephalgia presented for evaluation of pancytopenia. He had no recent travel history, except for a stay in Italy 1 year prior to admission and in Spain several years in the past. DIAGNOSTIC WORKUP: Laboratory evaluation confirmed pancytopenia, agranulocytosis, and elevated infection parameters without indicative serological results en par with lymphadenitis colli. Computed tomography scanning revealed cervical lymphadenopathy, hepatosplenomegaly, and colitis with occult perforation of the sigmoid colon. Bone marrow biopsy showed an infiltration of polyclonal plasma cells. Lymph node biopsy was compatible with necrotizing lymphadenitis. DIAGNOSIS: Polymerase chain reaction analysis of a lymph node specimen confirmed the presence of Leishmania species, thereby enabling the diagnosis of visceral Leishmania. THERAPY COURSE: Treatment with liposomal amphotericin B was initiated. Both fever and lymphadenopathy quickly resolved. CONCLUSION: VL is a clinically pleiotropic, severe disease with fatal outcome if left untreated. It often presents with distinct similarities to hematologic malignancies. Exacerbation can occasionally occur as fulminant macrophage activation syndrome. Disease incidence is globally increasing and has not peaked as yet. A complex interplay between pathogen and the immune system is the key pathophysiological mechanism.


Asunto(s)
Fiebre/etiología , Leishmania donovani/aislamiento & purificación , Leishmaniasis Visceral/diagnóstico , Pancitopenia/etiología , Adulto , Anfotericina B/administración & dosificación , Anfotericina B/uso terapéutico , Antiprotozoarios/administración & dosificación , Antiprotozoarios/uso terapéutico , Diagnóstico Diferencial , Hepatomegalia/diagnóstico por imagen , Hepatomegalia/tratamiento farmacológico , Hepatomegalia/microbiología , Humanos , Leishmania donovani/genética , Leishmaniasis Visceral/tratamiento farmacológico , Liposomas , Masculino , Pancitopenia/diagnóstico , Esplenomegalia/diagnóstico por imagen , Esplenomegalia/tratamiento farmacológico , Esplenomegalia/microbiología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
4.
Korean J Parasitol ; 57(4): 359-368, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31533402

RESUMEN

In this study, we carried out extensive in vitro studies on various concentrations of tioxolone along with benzoxonium chloride and their niosomal forms against Leishmania tropica. Niosomes were prepared by the hydration method and were evaluated for morphology, size, release study, and encapsulation efficiency. This study measured leishmanicidal activity against promastigote and amastigote, apoptosis and gene expression levels of free solution and niosomal-encapsulated tioxolone along with benzoxonium chloride. Span/Tween 60 niosome had good physical stability and high encapsulation efficiency (more than 97%). The release profile of the entrapped compound showed that a gradual release rate. The combination of niosomal forms on promastigote and amastigote were more effective than glucantime. Also, the niosomal form of this compound was significantly less toxic than glucantime (P≤0.05). The flowcytometric analysis on niosomal form of drugs showed that higher number of early apoptotic event as the principal mode of action (89.13% in 200 µg/ml). Also, the niosomal compound increased the expression level of IL-12 and metacaspase genes and decreased the expression level of the IL-10 gene, which further confirming the immunomodulatory role as the mechanism of action. We observed the synergistic effects of these 2 drugs that induced the apoptotic pathways and also up regulation of an immunomodulatory role against as the main mode of action. Also, niosomal form of this combination was safe and demonstrated strong anti-leishmaniasis effects highlights further therapeutic approaches against anthroponotic cutaneous leishmaniasis in future planning.


Asunto(s)
Antiprotozoarios/farmacología , Compuestos de Benzalconio/farmacología , Lactonas/farmacología , Leishmania tropica/efectos de los fármacos , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/química , Compuestos de Benzalconio/administración & dosificación , Compuestos de Benzalconio/química , Línea Celular , Quimioterapia Combinada , Citometría de Flujo , Humanos , Lactonas/administración & dosificación , Lactonas/química , Liposomas
5.
Tidsskr Nor Laegeforen ; 139(13)2019 Sep 24.
Artículo en Inglés, Noruego | MEDLINE | ID: mdl-31556531

RESUMEN

BACKGROUND: Febrile illness is a common clinical problem and frequently caused by bacterial and viral infections. When blood cultures are negative and symptoms persist despite empirical antibiotic treatment, clinicians must consider other differential diagnoses including malignancy, rheumatologic disease and parasitic infections. CASE PRESENTATION: A Norwegian male in his eighties experienced febrile illness during a stay in Southern Spain. Upon return to Norway, he was hospitalized with fever, weight-loss, enlarged spleen, pancytopenia and hypergammaglobulinemia. After failing to respond to broad-spectrum antibiotics and antifungals, he was diagnosed with visceral leishmaniasis and Leishmania infantum was confirmed by PCR and sequencing of spleen biopsy and blood. INTERPRETATION: With increasing migration and tourism, doctors in non-endemic countries should be familiar with visceral leishmaniasis.


Asunto(s)
Leishmaniasis Visceral/diagnóstico , Anciano de 80 o más Años , Anfotericina B/administración & dosificación , Anfotericina B/uso terapéutico , Antiprotozoarios/administración & dosificación , Antiprotozoarios/uso terapéutico , Artritis/parasitología , Fiebre/parasitología , Humanos , Leishmania infantum/crecimiento & desarrollo , Leishmania infantum/aislamiento & purificación , Leishmaniasis Visceral/complicaciones , Leishmaniasis Visceral/tratamiento farmacológico , Masculino , Pancitopenia/parasitología , España , Esplenomegalia/diagnóstico por imagen , Esplenomegalia/parasitología , Tomografía Computarizada por Rayos X , Enfermedad Relacionada con los Viajes
6.
Infez Med ; 27(3): 336-339, 2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31545780

RESUMEN

Caused by the protozoan Giardia lamblia, giardiasis is one of the most common parasitic diarrheal infections affecting humans. Although a variety of antigiardial drugs are available to treat infections in humans, failure of conventional treatment with nitroimidazoles for giardiasis has been increasingly reported. We describe the follow-up of a patient with recurrent giardiasis refractory to nitroimidazoles. Despite the different therapies received, the symptomatology and parasitic forms of G. lamblia persisted in the patient. There is no standard treatment regimen for giardiasis refractory to nitroimidazoles. When treatment failure is confirmed, it is necessary to switch to second-line regimens.


Asunto(s)
Antiprotozoarios/uso terapéutico , Giardia lamblia , Giardiasis/tratamiento farmacológico , Nitroimidazoles/uso terapéutico , Adulto , Albendazol/uso terapéutico , Antiprotozoarios/administración & dosificación , Furazolidona/uso terapéutico , Giardia lamblia/efectos de los fármacos , Humanos , Masculino , Metronidazol/administración & dosificación , Metronidazol/análogos & derivados , Metronidazol/uso terapéutico , Tiazoles/uso terapéutico , Tinidazol/uso terapéutico , Insuficiencia del Tratamiento
7.
Int J Parasitol Drugs Drug Resist ; 10: 125-132, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31493763

RESUMEN

Visceral leishmaniasis (VL) is associated with treatment complications due to the continued growth of resistant parasites toward currently available pathogen-directed therapeutics. To limit the emergence and combat resistant parasites there is a need to develop new anti-leishmanial drugs and alternative treatment approaches, such as host-directed therapeutics (HDTs). Discovery of new anti-leishmanial drugs including HDTs requires suitable in vitro assay systems. Herein, we modified and evaluated a series of resazurin assays against different life-stages of the VL causing parasite, Leishmania donovani to identify novel HDTs. We further analyzed the synergy of combinatorial interactions between traditionally used pathogen-directed drugs and HDTs for clearance of intracellular L. donovani. The inhibitory concentration at 50% (IC50) of the five evaluated therapies [amphotericin B (AMB), miltefosine, paromomycin, DNER-4, and AR-12 (OSU-03012)] was determined against promastigotes, extracellular amastigotes, and intracellular amastigotes of L. donovani via a resazurin-based assay and compared to image-based microscopy. Using the resazurin-based assay, all evaluated therapies showed reproducible anti-leishmanial activity against the parasite's different life-stages. These results were consistent to the traditional image-based technique. The gold standard of therapy, AMB, showed the highest potency against intracellular L. donovani, and was further evaluated for combinatorial effects with the HDTs. Among the combinations analyzed, pathogen-directed AMB and host-directed AR-12 showed a synergistic reduction of intracellular L. donovani compared to individual treatments. The modified resazurin assay used in this study demonstrated a useful technique to measure new anti-leishmanial drugs against both intracellular and extracellular parasites. The synergistic interactions between pathogen-directed AMB and host-directed AR-12 showed a great promise to combat VL, with the potential to reduce the emergence of drug-resistant strains.


Asunto(s)
Antiprotozoarios/administración & dosificación , Quimioterapia Combinada/métodos , Leishmania donovani/efectos de los fármacos , Leishmaniasis Visceral/tratamiento farmacológico , Anfotericina B/administración & dosificación , Animales , Sinergismo Farmacológico , Interacciones Huésped-Parásitos/efectos de los fármacos , Humanos , Leishmania donovani/crecimiento & desarrollo , Leishmaniasis Visceral/diagnóstico por imagen , Leishmaniasis Visceral/parasitología , Estadios del Ciclo de Vida/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Fosforilcolina/administración & dosificación , Fosforilcolina/análogos & derivados , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación
8.
Int J Parasitol Drugs Drug Resist ; 10: 101-108, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31430693

RESUMEN

Current treatment of cutaneous leishmaniasis includes pentavalent antimonials as first-line drugs, but this therapy has shown severe adverse effects. An alternative to minimize this issue is based on combination therapy scheme with other drugs. In this study we analyzed the potential of the association of meglumine antimoniate (MA) with the oxiranes epoxy-α-lapachone (LAP) or epoxymethyl-lawsone (LAW). Results demonstrated that association between these drugs enhanced leishmanicidal activity on Leishmania (Leishmania) amazonensis infection. The compounds were tested in monotherapy or in combinations (3:1; 1:1 and 1:3) and reduced intracellular parasite numbers, measured by the endocytic index, in all tested conditions. The most effective combination regimens were MA/LAP or MA/LAW in 3:1 ratio, which achieved a reduction of 98.3% and 93.6% in the endocytic index, respectively. BALB/c mice challenged with L. (L.) amazonensis showed significant reduction in lesion size and parasite load in both footpad and lymph nodes, after four weeks of treatment. Although, MA, LAP or LAW monotherapy were able to control the evolution of lesions when compared to untreated animals (30%, 40% and 40% of reduction, respectively), the combination of MA/LAP and LAW in 3:1 ratio showed better results reducing 61.7 and 54.4%, respectively. The results indicate that the association of meglumine antimoniate to oxiranes lead to an increment in the antileishmanial activity and represent a promising approach for the cutaneous leishmaniasis treatment.


Asunto(s)
Antiprotozoarios/administración & dosificación , Compuestos Epoxi/administración & dosificación , Leishmania/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Antimoniato de Meglumina/administración & dosificación , Animales , Antiprotozoarios/química , Quimioterapia Combinada , Compuestos Epoxi/química , Femenino , Humanos , Leishmania/fisiología , Leishmaniasis Cutánea/parasitología , Antimoniato de Meglumina/química , Ratones , Ratones Endogámicos BALB C
9.
J Agric Food Chem ; 67(34): 9630-9642, 2019 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-31365255

RESUMEN

Six series of (+)-usnic acid derivatives were synthesized. The IC50 values of these compounds were determined in T. gondii infected HeLa cells (µM) and in HeLa cells (µM), and their selectivity indexes (SI) were calculated. In vitro, most of the derivatives tested in this study exhibited more anti activity than that of the parent compound (+)-usnic acid and the positive control drugs. Among these derivatives, methyl (E)-(1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9b-dihydrodibenzo[b,d]furan-2(1H)-ylidene)ethyl)phenylalaninate (D3) showed the most effective anti-T. gondii activity (selectivity >2.77). In comparison with the clinically used positive control drugs sulfadiazine (selectivity 1.15), pyrimethamine (selectivity 0.89), spiramycin (selectivity 0.72), and the lead compound (+)-usnic acid (selectivity 0.96), D3 showed better results in vitro. Furthermore, D3 and (E)-6-acetyl-7,9-dihydroxy-8,9b-dimethyl-2-(1-(quinolin-6-ylamino)ethylidene)dibenzo[b,d]furan-1,3(2H,9bH)-dione (F3) had greater inhibitory effects on T. gondii (inhibition rates 76.0% and 64.6%) in vivo in comparison to spiramycin (inhibition rate 55.2%); in the peritoneal cavity of mice, the number of tachyzoites was significantly reduced (p < 0.001) in vivo. Additionally, some biochemical parameters were measured and spleen indexes were comprehensively evaluated, and the results indicated that mice treated with both compound D3 and compound F3 showed reduced hepatotoxicity and significantly enhanced antioxidative effects in comparison to the normal group. Granuloma and cyst formation were effected by the inhibition of compound D3 and compound F3 in liver sections. Overall, these results indicated that D3 and F3 for use as anti-T. gondii agents are promising lead compounds.


Asunto(s)
Antiprotozoarios/administración & dosificación , Benzofuranos/administración & dosificación , Toxoplasma/efectos de los fármacos , Toxoplasmosis/tratamiento farmacológico , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Benzofuranos/síntesis química , Benzofuranos/química , Evaluación Preclínica de Medicamentos , Femenino , Células HeLa , Humanos , Ratones , Estructura Molecular , Toxoplasma/crecimiento & desarrollo , Toxoplasmosis/parasitología
10.
Parasitol Res ; 118(10): 3077-3084, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31401656

RESUMEN

Clinically available drugs for mucocutaneous and cutaneous leishmaniases (CL) include mainly pentavalent antimony (Sb(V)) complexes, liposomal amphotericin B, and miltefosine (HePC). However, they present at least one of the following limitations: long-term parenteral administration through repeated doses, severe side effects, drug resistance, and high cost. HePC is the only oral drug available, but the appearance of resistance has resulted in changes of its use from monotherapy to combination therapy. Amphiphilic Sb(V) complexes, such as SbL8 obtained from reaction of Sb(V) with N-octanoyl-N-methylglucamide, were recently found to be orally active against experimental CL. The property of SbL8 to self-assemble in aqueous solution, forming nanostructures, led us to investigate the incorporation of HePC into SbL8 nanoassemblies and the therapeutic efficacy of SbL8/HePC nanoformulation by oral route in a murine model of CL. HePC incorporation into the SbL8 nanosystem was evidenced by using a fluorescent analog of HePC. The antileishmanial activity of SbL8/HePC nanoassemblies was evaluated after daily oral administration for 30 days in Leishmania amazonensis-infected BALB/c mice, in comparison with monotherapies (SbL8 or HePC) and saline control. All the treatments resulted in significant reduction in the lesion size growth, when compared with control. Strikingly, only SbL8/HePC nanoassemblies promoted a significant decrease of the parasite burden in the lesion. This work establishes the therapeutic benefit of SbL8/HePC association by oral route in a CL model and constitutes an important step towards the development of new orally active drug combination.


Asunto(s)
Antimonio/química , Antiprotozoarios/administración & dosificación , Leishmania mexicana/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Fosforilcolina/análogos & derivados , Administración Oral , Animales , Antimonio/administración & dosificación , Antiprotozoarios/química , Modelos Animales de Enfermedad , Femenino , Leishmaniasis Cutánea/parasitología , Ratones Endogámicos BALB C , Nanopartículas/administración & dosificación , Nanopartículas/química , Fosforilcolina/administración & dosificación , Fosforilcolina/química
11.
Nanotechnology ; 30(45): 455102, 2019 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-31365912

RESUMEN

Leishmaniasis is a group of diseases caused by a protozoa parasite from one of over 20 Leishmania species. Depending on the tissues infected, these diseases are classified as cutaneous, mucocutaneous and visceral leishmaniasis. For the treatment of leishmaniasis refractory to antimony-based drugs, pentamidine (PTM) is a molecule of great interest. However, PTM displays poor bioavailability through oral routes due to its two strongly basic amidine moieties, which restricts its administration by a parenteral route and limits its clinical use. Among various approaches, nanotechnology-based drug delivery systems (nano-DDS) have potential to overcome the challenges associated with PTM oral administration. Here, we present the development of PTM-loaded PLGA nanoparticles (NPs) with a focus on the characterization of their physicochemical properties and potential application as an oral treatment of leishmaniasis. NPs were prepared by a double emulsion methodology. The physicochemical properties were characterized through the mean particle size, polydispersity index (PdI), zeta potential, entrapment efficiency, yield process, drug loading, morphology, in vitro drug release and in vivo pharmacological activity. The PTM-loaded PLGA NPs presented with a size of 263 ± 5 nm (PdI = 0.17 ± 0.02), an almost neutral charge (-3.2 ± 0.8 mV) and an efficiency for PTM entrapment of 91.5%. The release profile, based on PTM dissolution, could be best described by a zero-order model, followed by a drug diffusion profile that fit to the Higuchi model. In addition, in vivo assay showed the efficacy of orally given PTM-loaded PLGA NPs (0.4 mg kg-1) in infected BALB/c mice, with significant reduction of organ weight and parasite load in spleen (p-value < 0.05). This work successfully reported the oral use of PTM-loaded NPs, with a high potential for the treatment of visceral leishmaniasis, opening a new perspective to utilization of this drug in clinical practice.


Asunto(s)
Antiprotozoarios/administración & dosificación , Leishmaniasis/tratamiento farmacológico , Pentamidina/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Administración Oral , Animales , Antiprotozoarios/química , Antiprotozoarios/farmacocinética , Disponibilidad Biológica , Modelos Animales de Enfermedad , Leishmaniasis/parasitología , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Tamaño de los Órganos/efectos de los fármacos , Carga de Parásitos , Tamaño de la Partícula , Pentamidina/química , Pentamidina/farmacocinética
12.
PLoS Negl Trop Dis ; 13(8): e0007673, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31419223

RESUMEN

Amphotericin B provides improved therapy for visceral leishmaniasis (VL) caused by Leishmania donovani, with single dose liposomal-encapsulated Ambisome providing the best cure rates. The VL elimination program aims to reduce the incidence rate in the Indian subcontinent to <1/10,000 population/year. Ability to predict which asymptomatic individuals (e.g. anti-leishmanial IgG and/or Leishmania-specific modified Quantiferon positive) will progress to clinical VL would help in monitoring disease outbreaks. Here we examined whole blood transcriptional profiles associated with asymptomatic infection, active disease, and in treated cases. Two independent microarray experiments were performed, with analysis focussed primarily on differentially expressed genes (DEGs) concordant across both experiments. No DEGs were identified for IgG or Quantiferon positive asymptomatic groups compared to negative healthy endemic controls. We therefore concentrated on comparing concordant DEGs from active cases with all healthy controls, and in examining differences in the transcriptome following different regimens of drug treatment. In these comparisons 6 major themes emerged: (i) expression of genes and enrichment of gene sets associated with erythrocyte function in active cases; (ii) strong evidence for enrichment of gene sets involved in cell cycle in comparing active cases with healthy controls; (iii) identification of IFNG encoding interferon-γ as the major hub gene in concordant gene expression patterns across experiments comparing active cases with healthy controls or with treated cases; (iv) enrichment for interleukin signalling (IL-1/3/4/6/7/8) and a prominent role for CXCL10/9/11 and chemokine signalling pathways in comparing active cases with treated cases; (v) the novel identification of Aryl Hydrocarbon Receptor signalling as a significant canonical pathway when comparing active cases with healthy controls or with treated cases; and (vi) global expression profiling support for more effective cure at day 30 post-treatment with a single dose of liposomal encapsulated amphotericin B compared to multi-dose non-liposomal amphotericin B treatment over 30 days. (296 words; 300 words allowed).


Asunto(s)
Anfotericina B/administración & dosificación , Antiprotozoarios/administración & dosificación , Biomarcadores/sangre , Células Sanguíneas , Leishmaniasis Visceral/tratamiento farmacológico , Leishmaniasis Visceral/patología , Transcriptoma , Adolescente , Adulto , Anciano , Enfermedades Asintomáticas , Niño , Femenino , Perfilación de la Expresión Génica , Humanos , India , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Adulto Joven
13.
Int J Pharm Compd ; 23(4): 288-293, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31315079

RESUMEN

Cutaneous leishmaniasis is the most common form of leishmaniasis with global incidence of about 1.5 million cases annually. The disease is endemic in Israel and caused by two types, leishmania major and leishmania tropica. The two types of cutaneous leishmaniasis in Israel are not life threatening, but the multiple skin lesions developed from the contaminated sand fly bites cause significant damage to the quality of life for a few months in patients with leishmania major and sometimes for more than a year in patients with leishmania tropica. Topical treatment for this localized skin disease is very attractive although only one medication is registered in Israel (15% paromomycin +12% methylbenzethonium chloride ointment), which is for the topical treatment of "leishmania major." Two significant disadvantages characterize this topical medication, 1) relatively low efficacy and 2) significant irritation and pain, which could result in failure of the registered treatment. This article (part 2 of a 3-part article), which also includes a compounded formulation, discusses the treatment option of paromomycin sulfate liposomal gel (free of the sensitizing methylbenzethonium chloride).


Asunto(s)
Leishmania tropica , Leishmaniasis Cutánea , Antiprotozoarios/administración & dosificación , Antiprotozoarios/uso terapéutico , Humanos , Israel , Leishmaniasis Cutánea/tratamiento farmacológico , Calidad de Vida
15.
Parasitol Res ; 118(9): 2669-2678, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31278518

RESUMEN

The aims of this study were to produce biogenic antimony sulfide nanoparticles (NPs) using Serratia marcescens (S. marcescens) and investigate the potential anti-leishmanial effects of these NPs on Leishmania major (L. major) (MRHO/IR/75/ER) in both in vitro and in vivo experiments. Biogenic antimony sulfide NPs were synthesized through intracellular biological methods using S. marcescens. The efficiency of various concentrations of antimony sulfide NPs was assessed using in vitro experiments on amastigotes of L. major at various times post-infection. In vivo experiments were carried out in BALB/c mice inoculated subcutaneously with 2 × 106L. major promastigotes (MHROM/IR/75/ER) and treated with antimony sulfide NPs (70 µg/mL, tropically), meglumine antimoniate (glucantime) as positive control and sterile phosphate-buffered saline (PBS, pH 7.4) as vehicle control. Results of in vitro experiments revealed that the anti-leishmanial activity increased when the antimony sulfide NPs concentration increased. The IC50 (50% inhibitory concentration) of antimony sulfide NPs against amastigotes was calculated as 62.5 µg/mL. In in vivo experiments, the average size of lesions significantly decreased to 8.6 ± 2.7 mm2 in mice inoculated with L. major promastigotes and treated with antimony sulfide NPs, compared with that in the negative control group (P = 0.015). Furthermore, results showed that antimony sulfide NPs significantly decreased the parasite load in the test group, compared with the negative control group (P = 0.001). Various concentrations of antimony sulfide NPs showed a great anti-leishmanial efficiency against L. major (MRHO/IR/75/ER), with the greatest efficiency shown by a concentration of 62.5 µg/mL in in vitro and in vivo experiments.


Asunto(s)
Antimonio/administración & dosificación , Antiprotozoarios/administración & dosificación , Antipruriginosos/administración & dosificación , Leishmania major/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Nanopartículas/administración & dosificación , Sulfuros/administración & dosificación , Animales , Humanos , Concentración 50 Inhibidora , Leishmania major/fisiología , Leishmaniasis Cutánea/parasitología , Ratones , Ratones Endogámicos BALB C
16.
Parasitol Res ; 118(9): 2705-2713, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31359134

RESUMEN

Artemisinin, extracted from a medicinal herb Artemisia annua, is widely used to treat malaria and has shown potent anticancer activity. Artemisinin has been found to be effective against experimental visceral and cutaneous leishmaniasis. Despite extensive research to understand the complex mechanism of resistance to artemisinin, several questions remain unanswered. The artesunate (ART)-resistant line of Leishmania donovani was selected and cellular mechanisms associated with resistance to artemisinin were investigated. ART-resistant (AS-R) parasites showed reduced susceptibility towards ART both at promastigote and amastigote stage compared with ART sensitive (WT) parasites. WT and AS-R parasites were both more susceptible to ART at the early log phase of growth compared with late log phase. AS-R parasites were more infective to the host macrophages (p < 0.05). Evaluation of parasites' tolerance towards host microbicidal mechanisms revealed that AS-R parasites were more tolerant to complement-mediated lysis and nitrosative stress. ROS levels were modulated in presence of ART in AS-R parasites infected macrophages. Interestingly, infection of macrophages by AS-R parasites led to modulated levels of host interleukins, IL-2 and IL-10, in addition to nitric oxide. Additionally, AS-R parasites showed upregulated expression of genes of unfolded protein response pathway including methyltransferase domain-containing protein (HSP40) and flagellar attachment zone protein (prefoldin), that are reported to be associated with ART resistance in Plasmodium falciparum malaria. This study presents in vitro model of artemisinin-resistant Leishmania parasite and cellular mechanisms associated with ART resistance in Leishmania.


Asunto(s)
Antiprotozoarios/administración & dosificación , Artemisininas/administración & dosificación , Leishmania donovani/efectos de los fármacos , Leishmaniasis Visceral/genética , Leishmaniasis Visceral/inmunología , Extractos Vegetales/administración & dosificación , Respuesta de Proteína Desplegada/efectos de los fármacos , Animales , Artemisia annua/química , Artesunato/administración & dosificación , Femenino , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/inmunología , Interacciones Huésped-Parásitos , Humanos , Interleucina-10/genética , Interleucina-10/inmunología , Leishmania donovani/crecimiento & desarrollo , Leishmaniasis Visceral/parasitología , Leishmaniasis Visceral/fisiopatología , Macrófagos/inmunología , Ratones Endogámicos BALB C
17.
Exp Parasitol ; 204: 107728, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31348915

RESUMEN

BACKGROUND: Co-infection with Leishmania major and Schistosoma mansoni may have significant consequences for disease progression, severity and subsequent transmission dynamics. Pentavalent antimonials and Praziquantel (PZQ) are used as first line of treatment for Leishmania and Schistosoma infections respectively. However, there is limited insight on how combined therapy with the standard drugs impacts the host in comorbidity. The study aimed to determine the efficacy of combined chemotherapy using Pentostam (P) and PZQ in murine model co-infected with L. major and S. mansoni. METHODS: A 3 × 4 factorial design with three parasite infection groups (Lm, Sm, Lm + Sm to represent L. major, S. mansoni and L. major + S. mansoni respectively) and four treatment regimens [P, PZQ, P + PZQ, and PBS designating Pentostam (GlaxoSmithKline UK), Praziquantel (Biltricide®, Bayer Ag. Leverkusen, Germany), Pentostam + Praziquantel and Phosphate buffered saline] as factors was applied. RESULTS: Significant changes were observed in the serum Interferon gamma (IFN-γ), and Macrophage inflammatory protein-one alpha (MIP-1α) levels among various treatment groups between week 8 and week 10 (p < 0.05). There was increased IFN-γ in the L. major infected mice subjected to PZQ and PBS, and in L. major + S. mansoni infected BALB/c mice treated with P + PZQ. Subsequently, MIP-1α levels increased significantly in both the L. major infected mice under PZQ and PBS and in L. major + S. mansoni infected BALB/c mice undergoing concurrent chemotherapy with P + PZQ between 8 and 10 weeks (p < 0.05). In the comorbidity, simultaneous chemotherapy resulted in less severe histopathological effects in the liver. CONCLUSION: It was evident, combined first line of treatment is a more effective strategy in managing co-infection of L. major and S. mansoni. The findings denote simultaneous chemotherapy compliments immunomodulation in the helminth-protozoa comorbidity hence, less severe pathological effects following the parasites infection. Recent cases of increased incidences of polyparasitism in vertebrates call for better ways to manage co-infections. The findings presented necessitate intrinsic biological interest on examining optimal combined chemotherapeutic agents strategies in helminth-protozoa concomitance and the related infections abatement trends vis-a-vis host-parasite relationships.


Asunto(s)
Antihelmínticos/uso terapéutico , Antiprotozoarios/uso terapéutico , Comorbilidad , Leishmania major/patogenicidad , Leishmaniasis Cutánea/complicaciones , Esquistosomiasis mansoni/complicaciones , Análisis de Varianza , Animales , Antihelmínticos/administración & dosificación , Gluconato de Sodio Antimonio/administración & dosificación , Gluconato de Sodio Antimonio/uso terapéutico , Antiprotozoarios/administración & dosificación , Quimiocina CCL3/sangre , Modelos Animales de Enfermedad , Quimioterapia Combinada , Interferón gamma/sangre , Leishmania major/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/patología , Hígado/parasitología , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Praziquantel/administración & dosificación , Praziquantel/uso terapéutico , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/patogenicidad , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/patología
18.
Artículo en Inglés | MEDLINE | ID: mdl-31316919

RESUMEN

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.


Asunto(s)
Leishmania infantum/efectos de los fármacos , Leishmaniasis Visceral/complicaciones , Leishmaniasis Visceral/tratamiento farmacológico , Lopinavir/uso terapéutico , Fosforilcolina/análogos & derivados , Administración Oral , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/uso terapéutico , Coinfección/tratamiento farmacológico , Modelos Animales de Enfermedad , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Concentración 50 Inhibidora , Leishmaniasis Visceral/sangre , Hígado/parasitología , Lopinavir/administración & dosificación , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/parasitología , Ratones , Ratones Endogámicos BALB C , Carga de Parásitos , Fosforilcolina/administración & dosificación , Fosforilcolina/uso terapéutico , Bazo/parasitología , Resultado del Tratamiento
19.
Int J Antimicrob Agents ; 54(4): 496-501, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31323307

RESUMEN

Leishmania parasites are the causative agents of a wide spectrum of human diseases. The clinical manifestations of leishmaniasis range from self-healing skin lesions to fatality. The World Health Organization has classed leishmaniasis as a category 1 neglected tropical disease. Leishmaniasis represents a major international health challenge, affecting 12 million people per year and with nearly 310 million people at risk. The first-line chemotherapies used to treat leishmaniasis are intravenous pentavalent antimonials; however, these drugs are highly toxic. As the use of oral treatment options such as paromomycin and miltefosine has increased, the incidence of disease relapse has increased and drug resistance to antimonials has developed, emphasizing the importance of identifying new chemotherapies. A novel, target-free fluorometric high-throughput screen with an average Z-score of 0.73 +/- 0.13 has been developed to identify small molecules with antileishmanial activity. Screening of 10,000 small molecules from the ChemBridge DIVER-set™ library cassette #5 yielded 210 compounds that killed 80% of parasites, resulting in a hit rate of 2.1%. One hundred and nine molecular scaffolds were represented within the hit compounds, and one scaffold that exhibited potent antileishmanial activity was 2,4-diaminoquinazoline. Host cell toxicity was determined prior to in-vitro infection of human THP-1 macrophages with Leishmania donovani mCherry expressing promastigotes; successful drug treatment was considered when the half maximal inhibitory concentration was <10 µM. BALB/c mice were infected with Leishmania major mCherry promastigotes and treated with small molecules that were successful during in-vitro infections. Several small molecules tested were as efficacious at resolving cutaneous leishmaniasis lesions in mice as known antimonial treatments.


Asunto(s)
Antiprotozoarios/aislamiento & purificación , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento , Leishmania donovani/efectos de los fármacos , Leishmania major/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/farmacología , Modelos Animales de Enfermedad , Femenino , Fluorometría/métodos , Humanos , Ratones Endogámicos BALB C , Recurrencia , Células THP-1/parasitología , Resultado del Tratamiento
20.
Emerg Infect Dis ; 25(8): 1574-1576, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31310225

RESUMEN

We describe the outcomes of 16 cases of imported loiasis in Italy. Patients had microfilaremia <20,000/mL and were treated with high-dose albendazole for 28 days and a single dose of ivermectin. This combination might be an effective treatment option in nonendemic areas, when diethylcarbamazine, the drug of choice, is not available.


Asunto(s)
Albendazol/administración & dosificación , Antiprotozoarios/administración & dosificación , Enfermedades Transmisibles Importadas/tratamiento farmacológico , Enfermedades Transmisibles Importadas/parasitología , Ivermectina/administración & dosificación , Loiasis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Biomarcadores , Quimioterapia Combinada , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Italia , Loiasis/parasitología , Masculino , Persona de Mediana Edad , Evaluación de Síntomas , Resultado del Tratamiento , Adulto Joven
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