Comparación de la eficacia y toxicidad del estibogluconato de sodio y antimoniato de meglumina en el tratamiento de leishmaniasis cutánea en Perú / Efficacy and safety of sodium stibogluconate compared to meglumine antimoniate in the treatment of cutaneous leishmaniasis in Peru

Objetivos : Comparar la eficacia y toxicidad del antimoniato de meglumina (AM) y estibogluconato sódico (EGS) en el tratamiento de leishmaniasis cutánea (LC) en un hospital general. Material y métodos : Serie de casos comparativa de 193 pacientes con LC tratados en tres ensayos clínicos con AM (n=69) y EGS (n=124) durante 2001-2010. La administración de ambas drogas fue vía endovenosa lenta de 20 mg Sb5+/kg/día por 20 días consecutivos siguiendo las normativas de la OPS y OMS. La información clínica, toxicidad y eficacia fue obtenida de las historias clínicas almacenadas en el centro de investigación según la normativa local e internacional. Resultados : Las características demográficas fueron similares entre grupos, pero el tamaño y número de lesiones fueron mayores en el grupo AM. La eficacia del tratamiento con AM fue 76,0% versus 68,4% con EGS (p=0,340) y 55,1% versus 50,8% (p=0,570) en el análisis por protocolo y de intención de tratar, respectivamente. No se observaron efectos adversos inmediatos. Los síntomas más frecuentemente reportados fueron disgeusia (37,0%), mareos (32,0%), cefalea (36,0%), artralgias (31,0%) y linfangitis (21,0%). Los tres primeros síntomas, así como elevación de transaminasas, leucopenia, trombocitopenia y QTc prolongado fueron frecuentes en el grupo EGS, pero clínica y estadísticamente no significativos. El tratamiento fue suspendido definitivamente por toxicidad severa únicamente con EGS por emesis refractaria (2 participantes) y QTc prolongado con extrasístoles (1 participante). Conclusiones : La eficacia del tratamiento con AM y EGS fue comparable. La administración endovenosa de ambos no produjo efectos adversos inmediatos, aunque sí alteraciones clínicas y laboratoriales usuales.

SUMMARY Objectives : To compare the efficacy and safety of sodium stibogluconate (SS) and meglumine antimoniate (MA) in the treatment of cutaneous leishmaniasis (CL) in a general hospital. Methods: Case-series of 193 patients with CL treated in three clinical trials with MA (n=69) and SS (n=124) during 2001-2010. Both study drugs were administered intravenously at a slow speed at 20 mg Sb5+/kg/day for 20 consecutive days following WHO-PAHO recommendations. Clinical and safety data were gathered from clinical files. Results: Demographic characteristics were similar between the study groups, but the size and number of lesions were higher in the MA group. Efficacy was 76.0% in the MA vs. 68.4% in the SS group (p=0.340) and 55.1% vs. 50.8% (p=0.570) in the per protocol and intention to treat analysis. respectively. Side effects more frequently reported were dysgeusia (37.0%). dizziness (32.0%). headache (36.0%). arthralgia (31.0%) and lymphangitis (21.0%). These first three symptoms as well as elevation of transaminases, leukopenia, thrombocytopenia and prolonged QTc were numerically more frequent in the SS group but without reaching statistical significance. Treatment was stopped definitively for severe toxicity in the SS group due to refractory emesis (two patients) and prolonged QTc (one patient). Conclusions: The efficacy of MA and SS is comparable. The intravenous administration of these compounds did not produce immediate reactions, but it was associated with unusual clinical and laboratory abnormalities.

Epidemiological characteristics and clinical features of visceral leishmaniasis in 41 children / 中华传染病杂志

Objective:To investigate the epidemiological and clinical characteristics of visceral leishmaniasis (VL) in children, and to analyze the distinguishing features of VL associated hemophagocytic lymphohistiocytosis (HLH), so that to provide reference for the diagnosis and treatment of VL.Methods:Forty-one children with VL admitted to Xi′an Children′s Hospital from July 2012 to June 2021 were enrolled. The clinical data were retrospectively analyzed, including epidemiology, clinical manifestations, laboratory data, diagnostic methods, treatment regimens and outcomes. The patients were divided into VL group and VL+ HLH group according to whether combined with HLH or not, and the clinical characteristics and laboratory findings of the two groups were compared. Two independent samples t test, Mann-Whitney U test and chi-square test were used for statistical analysis. Results:Forty-one children with VL were from different provinces, including Shaanxi Province (70.73%(29/41)), Gansu Province (14.63%(6/41)), Shanxi Province (12.20%(5/41)) and Ningxia Hui Autonomous Region (2.44%(1/41)), and 87.80%(36/41) of them lived in rural areas. The peak age was >1.0 to 3.0 years old (63.41%(26/41)). They were sporadic throughout the year. The main clinical manifestations included fever (97.56%(40/41)), splenomegaly (95.12%(39/41)), lymphadenopathy (82.93%(34/41)) and hepatomegaly (60.98%(25/41)). The numbers of cases that Leishman-Donovan bodies were detected in the first, second and third bone marrow smears were 36, four and one, respectively. Anemia, thrombocytopenia and leukopenia detected by blood routine test were 100.00%(41/41), 78.05%(32/41) and 58.54%(24/41), respectively. There were statistically significant differences in the platelet count, lactate dehydrogenase, alanine aminotransferase, triglycerides, fibrinogen and ferritin between VL group (28 cases) and VL+ HLH group (13 cases) ( t=-2.56, t=2.64, Z=-2.66, t=7.15, t=-5.76 and t=3.86, respectively, all P<0.050). The proportions of hepatomegaly and hemophagocytes found in the bone marrow smears in VL group were both lower than those in VL+ HLH group, and the differences were both statistically significant ( χ2=4.47 and 10.93, respectively, both P<0.050). Twelve cases with VL+ HLH were treated with antimony (for six days) and intravenous immunoglobulin, and the others were treated with antimony only. The cure rates of the patients treated with antimony for one and two courses were 92.68%(38/41) and 4.88%(2/41), respectively. The dose of antimony was increased one third and treatment course was prolonged to eight days in one cured case. After (41.36±31.49) months of follow-up, three cases recurred after five to eight months of cure and all of them were cured after one more course of treatment with antimony. Conclusions:Children with VL are mainly distributed in rural areas. The common clinical manifestations are fever and involvement of reticuloendothelial system, which are not specific. The positive rate of Leishman-Donovan bodies found in bone marrow smears is high, and a few negative cases need repeated bone marrow aspiration. Standardized treatment with antimony for VL in children is effective, and combination therapy with immunoglobulin can be considered if patients with VL associated HLH. Very few cases may recur and antimony is still effective.

Successful treatment of diffuse cutaneous leishmaniasis caused by Leishmania amazonensis

Abstract Diffuse cutaneous leishmaniasis is a rare universal disease associated with an inadequate host cell immune response, caused by different species: infantum, aethiopica, major, mexicana, and others, which presents the challenge of a poor therapeutic response. In Brazil, it is caused by L. amazonensis. A case confirmed by histopathology with an abundance of vacuolated macrophages full of amastigotes and lymphocyte scarcity, identified by RFLP-ITS1PCR and in vitro decrease and exhaustion of the host cell immune response to L. amazonensis antigen, was treated early (3 months after the onset) with Glucantime (2 months) and allopurinol (29 months) with clinical cure, after a follow-up for 30 months after treatment.

Nuclear Factor-κB Signaling Mediates Antimony-induced Astrocyte Activation / 生物医学与环境科学（英文）

Objective@#Antimony (Sb) has recently been identified as a novel nerve poison, although the cellular and molecular mechanisms underlying its neurotoxicity remain unclear. This study aimed to assess the effects of the nuclear factor kappa B (NF-κB) signaling pathway on antimony-induced astrocyte activation.@*Methods@#Protein expression levels were detected by Western blotting. Immunofluorescence, cytoplasmic and nuclear fractions separation were used to assess the distribution of p65. The expression of protein in brain tissue sections was detected by immunohistochemistry. The levels of mRNAs were detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and reverse transcription-polymerase chain reaction (RT-PCR).@*Results@#Antimony exposure triggered astrocyte proliferation and increased the expression of two critical protein markers of reactive astrogliosis, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP), indicating that antimony induced astrocyte activation @*Conclusion@#Antimony activated astrocytes by activating the NF-κB signaling pathway.

Amphotericin B or its liposome combined with antimony sodium gluconate in the treatment of refractory Kala-azar: a report of 4 cases / 中华地方病学杂志

Objective:To investigate the effect of amphotericin B or its liposomes combined with antimony sodium gluconate (antimonial) in the treatment of refractory Kala-azar.Methods:Four patients with Kala-azar who relapsed or were resistant to antimony after treatment were admitted to the First Hospital of Lanzhou University. The clinical medical records were retrospectively analyzed, including the general information (gender, age, etc), diagnosis and treatment process, clinical manifestations, treatment methods and treatment effect.Results:The clinical symptoms of four patients were relieved after treatment with amphotericin B or its liposomes combined with antimonial. Reexamination of bone marrow smear showed no Leishman-Donovan body. There was no recurrence after six months of follow-up.Conclusion:Amphotericin B or its liposomes combined with antimonial can be used in the treatment of refractory Kala-azar.

Respuesta al tratamiento con estibogluconato sódico para leishmaniasis cutánea en población indígena y mestiza, Amazonas 2014-2018 / Response to treatment with sodium stibogluconate for cutaneous leishmaniasis in indigenous and mestizo population, Amazonas, 2014-2018

Objetivo. Determinar la respuesta al tratamiento con Estibogluconato Sódico en población indígena y mestiza con diagnóstico de leishmaniasis cutánea según ciclo de tratamiento, sexo y etapa de vida, pertenecientes a las Microredes Nieva, Galilea, Tingo y Pedro Ruiz Gallo de la Región Amazonas del 2014 ­ 2018, en Perú. Material y métodos: Estudio descriptivo, retrospectivo, de corte longitudinal, teniendo como universo muestral 559 fichas de pacientes; el método fue inductivo, técnica análisis de datos y el instrumento fue la ficha de registro de datos. Resultados: En la población indígena el 98,1% respondió al tratamiento con primer ciclo de Estibogluconato Sódico y en la población mestiza fue el 94%, los demás pacientes respondieron con segundo ciclo de tratamiento; asimismo del total de pacientes mestizos, el 47,5% fue femenino y de la población indígena el 70,4% fue masculino (p=0,000); de las etapas de vida más afectadas con segundo ciclo de tratamiento fueron la adulta 50% (población indígena) y en la etapa niño 11,2% (población mestiza). Conclusión: El mayor porcentaje de los pacientes presentaron una respuesta adecuada (curaron con el primer ciclo de tratamiento) al Estibogluconato Sódico en ambas poblaciones asimismo las etapas de vida más afectadas fueron la adultez y la niñez

Objetive. To determine the response to treatment with Sodium Stibogluconate in indigenous and mestizo population with diagnosis of cutaneous leishmaniasis according to treatment cycle, sex and life stage, belonging to the Microredes Nieva, Galilea, Tingo and Pedro Ruiz Gallo of the Amazon Region of 2014 - 2018, in Pe r u . M a t e r i a l a n d m e t h o d s : D e s c r i p t i v e , retrospective, longitudinal-sectional study, having as sample universe 559 patient records; the method was inductive, technical data analysis and the instrument was the data record. Results: In the indigenous population, 98.1% responded to the treatment with the first cycle of Sodium Stibogluconate and in the mestizo population it was 94%, the other patients responded with the second treatment cycle; also of the total mestizo patients, 47.5% were female and 70.4% of the indigenous population were male (p=0,000); of the most affected life stages with the second cycle of treatment were the adult 50% (indigenous population) and in the child stage 11.2% (mestizo population). Conclusion: The highest percentage of the patients presented an adequate response (they cured with the first cycle of treatment) to Sodium Stibogluconate in both populations also the most affected life stages were adulthood and childhood

Pharmacokinetics of neutron-irradiated meglumine antimoniate in Leishmania amazonensis-infected BALB/c mice

Cutaneous leishmaniasis (CL) is a parasitic disease caused by the protozoan Leishmania spp. Pentavalent antimonial agents have been used as an effective therapy, despite their side effects and resistant cases. Their pharmacokinetics remain largely unexplored. This study aimed to investigate the pharmacokinetic profile of meglumine antimoniate in a murine model of cutaneous leishmaniasis using a radiotracer approach. Methods: Meglumine antimoniate was neutron-irradiated inside a nuclear reactor and was administered once intraperitoneally to uninfected and L. amazonensis-infected BALB/c mice. Different organs and tissues were collected and the total antimony was measured. Results: Higher antimony levels were found in infected than uninfected footpad (0.29% IA vs. 0.14% IA, p = 0.0057) and maintained the concentration. The animals accumulated and retained antimony in the liver, which cleared slowly. The kidney and intestinal uptake data support the hypothesis that antimony has two elimination pathways, first through renal excretion, followed by biliary excretion. Both processes demonstrated a biphasic elimination profile classified as fast and slow. In the blood, antimony followed a biexponential open model. Infected mice showed a lower maximum concentration (6.2% IA/mL vs. 11.8% IA/mL, p = 0.0001), a 2.5-fold smaller area under the curve, a 2.7-fold reduction in the mean residence time, and a 2.5-fold higher clearance rate when compared to the uninfected mice. Conclusions: neutron-irradiated meglumine antimoniate concentrates in infected footpad, while the infection affects antimony pharmacokinetics.(AU)

Antimony resistance in Leishmania (Viannia) braziliensis clinical isolates from atypical lesions associates with increased ARM56/ARM58 transcripts and reduced drug uptake

BACKGROUND In addition to the limited therapeutic arsenal and the side effects of antileishmanial agents, drug resistance hinders disease control. In Brazil, Leishmania braziliensis causes atypical (AT) tegumentary leishmaniasis lesions, frequently refractory to treatment. OBJECTIVES The main goal of this study was to characterise antimony (Sb)-resistant (SbR) L. braziliensis strains obtained from patients living in Xakriabá indigenous community, Minas Gerais, Brazil. METHODS The aquaglyceroporin 1-encoding gene (AQP1) from L. braziliensis clinical isolates was sequenced, and its function was evaluated by hypo-osmotic shock. mRNA levels of genes associated with Sb resistance were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Atomic absorption was used to measure Sb uptake. FINDINGS Although clinical isolates presented delayed recovery time in hypo-osmotic shock, AQP1 function was maintained. Isolate 340 accumulated less Sb than all other isolates, supporting the 65-fold downregulation of AQP1 mRNA levels. Both 330 and 340 isolates upregulated antimony resistance marker (ARM) 56/ARM58 and multidrug resistant protein A (MRPA); however, only ARM58 upregulation was an exclusive feature of SbR field isolates. CA7AE seemed to increase drug uptake in L. braziliensis and represented a tool to study the role of glycoconjugates in Sb transport. MAIN CONCLUSIONS There is a clear correlation between ARM56/58 upregulation and Sb resistance in AT-harbouring patients, suggesting the use of these markers as potential indicators to help the treatment choice and outcome, preventing therapeutic failure.

Increased thiol levels in antimony-resistant Leishmania infantum isolated from treatment-refractory visceral leishmaniasis in Brazil

BACKGROUND Treatment-refractory visceral leishmaniasis (VL) has become an important problem in many countries. OBJECTIVES We evaluated the antimony-resistance mechanisms of Leishmania infantum isolated from VL patients refractory or responsive to treatment with pentavalent antimony. METHODS Strains isolated from antimony-refractory patients (in vitro antimony-resistant isolates) and antimony-responsive patients (in vitro antimony-sensitive isolates) were examined. Morphological changes were evaluated by transmission electron microscopy after trivalent antimony exposure. P-glycoprotein (P-gp) efflux pump activity was evaluated using the pump-specific inhibitor verapamil hydrochloride, and the role of thiol in trivalent antimony resistance was investigated using the enzymatic inhibitor L-buthionine sulfoximine. FINDINGS Antimony treatment induced fewer alterations in the cellular structure of L. infantum resistant isolates than in that of sensitive isolates. P-gp efflux activity was not involved in antimony resistance in these isolates. Importantly, the resistant isolates contained higher levels of thiol compared to the sensitive isolates, and inhibition of thiol synthesis in the resistant isolates recovered their sensitivity to trivalent antimony treatment, and enhanced the production of reactive oxygen species in promastigotes exposed to the drug. MAIN CONCLUSIONS Our results demonstrate that isolates from patients with antimony-refractory VL exhibited higher thiol levels than antimony-sensitive isolates. This indicates that redox metabolism plays an important role in the antimony-resistance of New World VL isolates.

Ascorbate peroxidase overexpression protects Leishmania braziliensis against trivalent antimony effects

Ascorbate peroxidase (APX) is a redox enzyme of the trypanothione pathway that converts hydrogen peroxide (H2O2) into water molecules. In the present study, the APX gene was overexpressed in Leishmania braziliensis to investigate its contribution to the trivalent antimony (SbIII)-resistance phenotype. Western blot results demonstrated that APX-overexpressing parasites had higher APX protein levels in comparison with the wild-type line (LbWTS). APX-overexpressing clones showed an 8-fold increase in the antimony-resistance index over the parental line. In addition, our results indicated that these clones were approximately 1.8-fold more tolerant to H2O2 than the LbWTS line, suggesting that the APX enzyme plays an important role in the defence against oxidative stress. Susceptibility tests revealed that APX-overexpressing L. braziliensis lines were more resistant to isoniazid, an antibacterial agent that interacts with APX. Interestingly, this compound enhanced the anti-leishmanial SbIII effect, indicating that this combination represents a good strategy for leishmaniasis chemotherapy. Our data demonstrate that APX enzyme is involved in the development of L. braziliensis antimony-resistance phenotype and may be an attractive therapeutic target in the design of new strategies for leishmaniasis treatment.

Síndrome hemofagocítico secundario a leishmaniasis visceral en un lactante mayor: reporte de caso / Hemophagocytic síndrome secondary to visceral leishmaniasis in a toddler: report of a case

El síndrome hemofagocítico está caracterizado por la activación anómala del sistema inmune. De etiología primaria o secundaria a enfermedades infecciosas, metabólicas, inmunitarias o neoplásicas. Con incidencia de 0,12 a 1 casos por cada 100 000 niños y una sobrevida de dos meses de no recibir tratamiento. Se diagnostica con 5 de 8 criterios propuestos por la Asociación Internacional de Histocitosis, y tratamiento según etiología. . Se presenta el caso de un paciente masculino de 15 meses de edad, procedente una zona endémica de leishmaniasis (Choluteca, Honduras), que ingresó al Hospital Escuela Universitario con cuadro clínico de fiebre prolongada y hepatoesplenomegalia. En los exámenes auxiliares de detectó: pancitopenia, serología positiva para leishmania, hipertrigliceridemia y valor de ferritina aumentada. Se hizo el diagnóstico de leishmaniasis visceral y síndrome hemofagocítico. Se trató con antimoniato de meglumina por 28 días, metilprednisolona y prednisona; con evolución favorable. El síndrome hem ofagocítico podría ocurrir secundario a leishmaniasis visceral por lo que su diagnóstico debería sospecharse tempranamente para un tratamiento oportuno y mejor pronóstico

The hemophagocytic syndrome is characterized by an abnormal activation of the immune system. This condition may be primary or secondary to infectious, metabolic, immunological, or malignant conditions. Its incidence is 0.12 to 1 case per 100,000 children, and the survival time is around two months with no therapy. The condition is diagnosed with the occurrence of 5 of 8 criteria proposed by the International Histiocytosis Association, and its therapy is according the original etiology. We present the case of a 15-month old male patient, who was brought from Choluteca (an endemic area for leishmaniasis), who was admitted to the University Hospital with prolonged fever and hepatosplenomegaly. Laboratory tests showed pancytopenia, positive serology for Leishmania, hypertriglyceridemia, and increased ferritin levels. Visceral leishmaniasis and hemophagocytic syndrome were diagnosed. The patient received meglumine antimoniate for 28 days, and also methylprednisolone and prednisone; and he had a favorable outcome. The hemophagocytic syndrome may be secondary to visceral leishmaniasis, and its diagnosis should be promptly suspected in order to have timely therapy and a better prognosis

Determination of Arsenic and Antimony Released from Pharmaceutical Glass Packing Materials with Graphite Furnace Atomic Absorption Spectrometry / 中国药学杂志

OBJECTIVE: To establish a method for determining arsenic (As) and antimony (Sb) released from pharmaceutical glass packing materials to provide reference for improving the existing quality standard. METHODS: The samples were filled with 4% acetic acid to leach As and Sb. The extracting temperature was 98℃, and the extracting time was 2 h. Graphite furnace atomic absorption spectrometry (GFAAS) was used for the determination. RESULTS: As and Sb showed good linear relationship in a certain concentration range with linear correlation coefficients of 0.999 9 and 0.999 5. The recovery rates were 94.7%-106.9% and 100.0%-106.3%. The relative standard deviations of precision were 2.3% and 2.9%. The relative standard deviations of repeatability were 6.5% and 6.9%. The limits of detection were 1.67 and 2.54 ng·mL-1, respectively. The elements were nearly not detected in 16 batches of samples. CONCLUSION: The method is efficient and accurate and can be used for determination of As and Sb released from pharmaceutical glass packing materials, which brings supplementary contents to the existing quality standard.

Manifestaciones oftalmológicas de la leishmaniasis: reporte de un caso / Ophthalmologic manifestations of leishmaniasis: a case report

Fundamento: la leishmaniasis es una enfermedad producida por un protozoo del género leishmanias, que se transmite por la picadura del mosquito del género phlebotomus y una mosca del tipo lutzomyia (mosca de arena o sandfly, en inglés) y puede causar enfermedad de la piel y enfermedad sistémica. Se pueden distinguir tres formas: leishmaniasis visceral, leishmaniasis cutánea y leishmaniasis mucocutánea. La forma sistémica puede ser mortal, pero el tratamiento compuestos que contengan antimonio logra una tasa de curación alta. Objetivo: presentar un caso típico de leishmaniasis que desarrolló alteraciones oftalmológicas no comunes en el mismo. Caso clínico: se recogió el antecedente de haber estado en zona endémica de leishmaniasis antes de la presentación clínica. El cuadro clínico, los antecedentes, los exámenes de laboratorio y los cultivos de piel, confirmaron la presencia de una leishmaniasis. Conclusiones: las leishmaniasis son un conjunto de enfermedades de manifestaciones diversas, pero todas ellas tienen efectos devastadores, por ello siempre se debe tener presente esta enfermedad en el diagnóstico diferencial sobre todo en zonas endémicas.

Background: leishmaniasis is a disease caused by protozoan of the genus leishmanias, transmitted by the bite of the sand fly of the genus phlebotomus and a sand fly of genus Lutzomyia(mosca de arena en español). It can cause skin disease and systemic disease. Three forms can be distinguished clinically: visceral leishmaniasis, cutaneous leishmaniasis, and mucocutaneous leishmaniasis. Systemic form can be deadly, but treatments that contain antimony achieve a high percent of recovery. Objective: to present a typical case of leishmaniasis that developed uncommon ophthalmic alterations in the disease. Clinical case: it was found out that the person had been in an endemic area of leishmaniasis before having the clinical symptoms. Clinical manifestation, backgrounds, laboratory tests and skin culture confirmed the presence of leishmaniasis. Conclusions: leishmaniasis are a group of diseases of diverse manifestations, however all of them have potentially devastating effects. Consequently, this disease should be always taken into account in differential diagnosis, mainly in endemic areas.

Antimonial drugs entrapped into phosphatidylserine liposomes: physicochemical evaluation and antileishmanial activity

Abstract: INTRODUCTION: Leishmaniasis is a disease caused by the protozoan Leishmania that resides mainly in mononuclear phagocytic system tissues. Pentavalent antimonials are the main treatment option, although these drugs have toxic side effects and high resistance rates. A potentially alternative and more effective therapeutic strategy is to use liposomes as carriers of the antileishmanial agents. The aims of this study were to develop antimonial drugs entrapped into phosphatidylserine liposomes and to analyze their biological and physicochemical characteristics. METHODS: Liposomes containing meglumine antimoniate (MA) or pentavalent antimony salt (Sb) were obtained through filter extrusion (FEL) and characterized by transmission electron microscopy. Promastigotes of Leishmania infantum were incubated with the drugs and the viability was determined with a tetrazolium dye (MTT assay). The effects of these drugs against intracellular amastigotes were also evaluated by optical microscopy, and mammalian cytotoxicity was determined by an MTT assay. RESULTS: Liposomes had an average diameter of 162nm. MA-FEL showed inhibitory activity against intracellular L. infantum amastigotes, with a 50% inhibitory concentration (IC50) of 0.9μg/mL, whereas that of MA was 60μg/mL. Sb-FEL showed an IC50 value of 0.2μg/mL, whereas that of free Sb was 9μg/mL. MA-FEL and Sb-FEL had strong in vitro activity that was 63-fold and 39-fold more effective than their respective free drugs. MA-FEL tested at a ten-times higher concentration than Sb-FEL did not show cytotoxicity to mammalian cells, resulting in a higher selectivity index. CONCLUSIONS: Antimonial drug-containing liposomes are more effective against Leishmania-infected macrophages than the non-liposomal drugs.

Varicella zoster virus reactivation during or immediately following treatment of tegumentary leishmaniasis with antimony compounds

Antimony compounds are the cornerstone treatments for tegumentary leishmaniasis. The reactivation of herpes virus is a side effect described in few reports. We conducted an observational study to describe the incidence of herpes zoster reactivation during treatment with antimony compounds. The global incidence of herpes zoster is approximately 2.5 cases per 1,000 persons per month (or 30 cases per 1,000 persons per year). The estimated incidence of herpes zoster in patients undergoing antimony therapy is higher than previously reported.

Determination of Ruthenium, Rhodium, Palladium, Iridium and Platinum in Copper-Nickel Sulfide Ores by Bismuth-Antimony Fire Assay / 分析化学

A bismuth-antimony fire assay method for the preconcentration of ruthenium, rhodium, palladium, iridium and platinum in copper-nickel sulfide ores was developed. 40. 0 g bismuth trioxide, 25. 0 g boric acid, 10. 0 g sodium carbonate and 1. 00 g starch were mixed with 10. 0 g sample in a 120 mL porcelain bowl, which was put in a furnace at 850 ℃. After 20 min the temperature was raised to 1000 ℃ and held for another 40 min, and then the bowl was taken out, with the slag poured, which left the bismuth button to air cooling. A two-step cupellation procedure was developed. During the first step, the bismuth button was cupellated in a magnesia cupel until its diameter reached 5 mm or so, then it was transferred to a crucible cover containing 20 g melting antimony and kept cupellating, at last a bead with a diameter of 1 mm was obtained. The bead was microwave-digested, after cooling down to room temperature, the solvent of which was transferred to a volumetric flask and diluted to 10 ml with water. Pt and Pd were analyzed by inductively coupled plasma-atomic emission spectrometry ( ICP-AES), while 99 Ru, 103 Rh, 191 Ir were analyzed by inductively coupled plasma-mass spectrometry (ICP-MS), with 115 In, 185 Re as internal standard. RSD (n = 12) of the analysis results of five platinum group elements ( PGEs) in standard reference material GBW07196 ranged from 7. 04% to 9. 48% . Under the condition of 10 g sample, the detection limits (ng / g) for PGEs are 0. 027 for Ru, 0. 016 for Rh, 0. 11 for Pd, 0. 10 for Ir and 0. 11 for Pt. The method was applied to the determination of PGEs in GBW07194, GBW07195, GBW07196 with satisfactory results.

Biodistribution of meglumine antimoniate in healthy and Leishmania (Leishmania) infantum chagasi-infected BALB/c mice

Pentavalent antimonials such as meglumine antimoniate (MA) are the primary treatments for leishmaniasis, a complex disease caused by protozoan parasites of the genus Leishmania . Despite over 70 years of clinical use, their mechanisms of action, toxicity and pharmacokinetics have not been fully elucidated. Radiotracer studies performed on animals have the potential to play a major role in pharmaceutical development. The aims of this study were to prepare an antimony radiotracer by neutron irradiation of MA and to determine the biodistribution of MA in healthy and Leishmania (Leishmania) infantum chagasi-infected mice. MA (Glucantime(r)) was neutron irradiated inside the IEA-R1 nuclear reactor, producing two radioisotopes, 122Sb and 124Sb, with high radionuclidic purity and good specific activity. This irradiated compound presented anti-leishmanial activity similar to that of non-irradiated MA in both in vitro and in vivo evaluations. In the biodistribution studies, healthy mice showed higher uptake of antimony in the liver than infected mice and elimination occurred primarily through biliary excretion, with a small proportion of the drug excreted by the kidneys. The serum kinetic curve was bi-exponential, with two compartments: the central compartment and another compartment associated with drug excretion. Radiotracers, which can be easily produced by neutron irradiation, were demonstrated to be an interesting tool for answering several questions regarding antimonial pharmacokinetics and chemotherapy.

Overexpression of Ubiquitin and Amino Acid Permease Genes in Association with Antimony Resistance in Leishmania tropica Field Isolates

The mainstay therapy against leishmaniasis is still pentavalent antimonial drugs; however, the rate of antimony resistance is increasing in endemic regions such as Iran. Understanding the molecular basis of resistance to antimonials could be helpful to improve treatment strategies. This study aimed to recognize genes involved in antimony resistance of Leishmania tropica field isolates. Sensitive and resistant L. tropica parasites were isolated from anthroponotic cutaneous leishmaniasis patients and drug susceptibility of parasites to meglumine antimoniate (Glucantime(R)) was confirmed using in vitro assay. Then, complementary DNA-amplified fragment length polymorphism (cDNA-AFLP) and real-time reverse transcriptase-PCR (RT-PCR) approaches were utilized on mRNAs from resistant and sensitive L. tropica isolates. We identified 2 known genes, ubiquitin implicated in protein degradation and amino acid permease (AAP3) involved in arginine uptake. Also, we identified 1 gene encoding hypothetical protein. Real-time RT-PCR revealed a significant upregulation of ubiquitin (2.54-fold), and AAP3 (2.86-fold) (P<0.05) in a resistant isolate compared to a sensitive one. Our results suggest that overexpression of ubiquitin and AAP3 could potentially implicated in natural antimony resistance.

The effect of PAT on PCNA of human colon carcinoma implants in nude mice / 中国医师杂志

Objective To study the potential therapeutic effect of potassium antimonyl tartrate (PAT) on human colon cancer in transplanted tumor nude mice models. MethodsSixty transplanted animal models were constructed with colon cancer cell line SW480 injected in nude mice. Nude mice were then random divided into 4 groups ( n = 15) :Normal saline group, 5-Fu group and different dose of PAT groups [ (20 mg/( Kg · d) ,40 mg/( Kg · d) ]. The volume of mass was measured every 3 days. After final-administration for 24 hours, immunohistochemical staining was used to detect the expression of PCNA in colon cancer cells. ResultsAfter the use of PAT, the growth of mass slowed down. PCNA levels [ (63. 63 ±8. 88)％ ,(59. 13 ±6. 15)％ ,(33. 38 ± 12. 76)％ ] in SW480 cells was reduced by PAT( P <0. 05, P <0. 01 ). ConclusionPAT potentially inhibited the growth of colon cell lines and induced apoptosis of SW480 colon cancer cells.

Efeito do Antimoniato de Meglumina durante o período fetal sobre o desenvolvimento físico da prole em camundongos / Effect of the Meglumine Antimoniate during fetal period on physical development of pups in mice

A exposição a agentes químicos durante a prenhez podealterar o desenvolvimento animal e a maturação dos sistemasfisiológicos. O Antimoniato de Meglumina (AM) é a primeiraescolha no tratamento das leishmanioses, mesmoapresentando toxicidade e suposta impregnação neural.Objetivo: O objetivo desde estudo foi verificar odesenvolvimento físico da prole de camundongos Swiss,expostos ao AM durante o período fetal. Material e método:Fêmeas prenhes foram tratadas com AM (100mg/kg/dia)durante o 13° ao 18° dia de gestação – ddg e o grupo controlefoi tratado com o veículo. No dia zero pós-natal - dpn foiregistrado o número e peso da prole de cada ninhada eavaliou-se o desenvolvimento físico (nascimento de pêlos,abertura de olhos e orelhas, dente inciso, abertura da vaginae descida dos testículos) do 0 ao 31º dpn. Os filhotes forampesados no 3°, 5°, 7°, 14° e 21° dpn. Resultados: Não houvediferenças significativas no número e peso da prole no 0 dpnentre os grupos experimental e controle. O desenvolvimentoponderal da prole de ambos os grupos foi semelhante, assimcomo o aparecimento dos indicadores de desenvolvimentofísico. Conclusão: A exposição ao AM durante o períodofetal em camundongos não interferiu no desenvolvimentofísico das crias...

The exposition to the quimical agents during the pregnantcan alter the animal development and the maturation of thephysiological systems. The Meglumine antimoniate (MA) isthe first-choice of treatment of of leishmaniosis samepresented toxicity and suppond neural impregnation.Objective: The aim this work was verify the physicaldevelopmental of the pups of Swiss mice exposed to MAduring the fetal period. Material and methods: Pregnant damsreceived MA (100mg/kg/day) during day 13° to 18° of gestation– ddg. Control group received deionized water. At birth day(0 postnatal – dpn) the number and corporal weight of thepups of each litter was registered. The corporal weight ofthe pups was realized on day 3°, 5°, 7°, 14° and 21° postnatal.Physical development was assessed by monitoring daily onthe 0 to 31º dpn the following parameters in 16 litters: birt ofpilus, eye opening, ear unfolding, incisor eruption, vaginaopening and descent of the testis. Results: No statisticdifference was observed in the number and corporal weightbetween the experimental and control pups at 0 dpn.Conclusion: The ponderal development of the pups of boththe groups was similar, as well the appearance of indicatorsof the physical development. The maternal exposition in miceto MA throughout the fetal period did not interfere in thephysical development of the pups...