Liposomal formulations in the pharmacological treatment of leishmaniasis: a review.

Conventional chemotherapy for leishmaniasis includes considerably toxic drugs and reports of drug-resistance are not uncommon. Liposomal encapsulated drugs appear as an option for the treatment of leishmaniasis, providing greater efficacy for the active and reducing its side effects by promoting superior tissue absorption, favouring drug penetration into the macrophages, and retarding its clearance from the site of action. In this paper, a review on the advances achieved with liposome-based anti-leishmaniasis drug delivery systems is presented. Formulations prepared with either conventional or modified (sugar-coated, cationic, niosomes, peptides- and antibodies-bounded) liposomes for the delivery of pentavalent antimonials, amphotericin B, pentamidine, paromomycyn, and miltefosine were covered. This literature review depicts a scenario of no effective therapeutic agents for the treatment of this neglected disease, where liposomal formulations appear to improve the effectiveness of the available antileishmania agents.

Improved efficacy of meglumine antimoniate incorporated in anionic liposomes against Leishmania infantum infecting canine macrophages.

OBJECTIVES: Leishmaniasis is a zoonotic disease and several drugs have been used in the treatment, including meglumine antimoniate (AME). The chemotherapy reaches clinical cure but does not eliminate parasites, contributing to drug resistance. To improve AME efficacy we incorporated it in anionic liposomes. The antiparasitic activity and intracellular localization were investigated in canine macrophages infected with Leishmania infantum. METHODS: Liposomes (L-AME) is composed of egg phosphatidylcholine, cholesterol, palmitoyl oleoyl phosphatidyl serine and α-tocopherol (4 : 3 : 0.4 : 0.07 mol%) plus AME. L-AME size, polydispersity, zeta potential and morphology were analysed as well as antileishmanial activity and intracellular localization in DH82 macrophages. KEY FINDINGS: Liposomes (360 nm) zeta potential range from -40 to -65 mV, had 23% encapsulation efficiency and were stable for 180 days at 4°C. Free AME was cytotoxic towards L. infantum infected macrophages (ID50 = 0.012 M) while L-AME did not reduce cell viability. L-AME colocalized with parasites inside macrophages in a time-dependent manner, and reduced the percentage of infected cells and the number of intracellular parasites, decreasing the infection index (75-80%) twice as compared with AME treatment. CONCLUSIONS: Liposomal AME is a promising delivery system for treating visceral leishmaniasis, improving meglumine efficacy against L. infantum and minimizing its cytotoxicity towards canine macrophages.

T-bet+ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity.

Obesity is accompanied by inflammation in adipose tissue, impaired glucose tolerance, and changes in adipose leukocyte populations. These studies of adipose tissue from humans and mice revealed that increased frequencies of T-bet+ B cells in adipose tissue depend on invariant NKT cells and correlate with weight gain during obesity. Transfer of B cells enriched for T-bet+ cells exacerbates metabolic disorder in obesity, while ablation of Tbx21 specifically in B cells reduces serum IgG2c levels, inflammatory cytokines, and inflammatory macrophages in adipose tissue, ameliorating metabolic symptoms. Furthermore, transfer of serum or purified IgG from HFD mice restores metabolic disease in T-bet+ B cell-deficient mice, confirming T-bet+ B cell-derived IgG as a key mediator of inflammation during obesity. Together, these findings reveal an important pathological role for T-bet+ B cells that should inform future immunotherapy design in type 2 diabetes and other inflammatory conditions.

Non-selective beta blockers inhibit angiosarcoma cell viability and increase progression free- and overall-survival in patients diagnosed with metastatic angiosarcoma.

Patients with metastatic angiosarcoma undergoing chemotherapy, radiation, and/or surgery experience a median progression free survival of less than 6 months and a median overall survival of less than 12 months. Given the aggressive nature of this cancer, angiosarcoma clinical responses to chemotherapy or targeted therapeutics are generally very poor. Inhibition of beta adrenergic receptor (ß-AR) signaling has recently been shown to decrease angiosarcoma tumor cell viability, abrogate tumor growth in mouse models, and decrease proliferation rates in preclinical and clinical settings. In the current study we used cell and animal tumor models to show that ß-AR antagonism abrogates mitogenic signaling and reduces angiosarcoma tumor cell viability, and these molecular alterations translated into patient tumors. We demonstrated that non-selective ß-AR antagonists are superior to selective ß-AR antagonists at inhibiting angiosarcoma cell viability. A prospective analysis of non- selective ß-AR antagonists in a single arm clinical study of metastatic angiosarcoma patients revealed that incorporation of either propranolol or carvedilol into patients' treatment regimens leads to a median progression free and overall survival of 9 and 36 months, respectively. These data suggest that incorporation of non-selective ß-AR antagonists into existing therapies against metastatic angiosarcoma can enhance clinical outcomes.

Immune response after experimental allergic encephalomyelitis in rats subjected to calorie restriction.

Male Lewis rats (6 weeks-old) were submitted to a calorie restriction equivalent to 33% or 66% of food restriction. Fifteen days later, groups of 7 animals were injected with complete Freund's adjuvant plus spinal cord homogenate (SCH) to induce experimental allergic encephalomyelitis (EAE) or with complete Freund's adjuvant alone. EAE was defined solely on clinical grounds. Rats were assessed daily for clinical signs of EAE and were killed on day 15 after immunization. Both diet and SCH injection diminished body weight significantly. In contrast to rats receiving a normal diet or a 33% calorie-restricted diet, rats subjected to severe calorie restriction did not exhibit clinical signs of EAE. Concomitantly with the lack of disease manifestation, 66% of calorie-restricted rats injected with SCH showed significantly less splenic and lymph node mitogenic response to concanavalin A (Con A) and a higher splenic response to lipopolysaccharide. Fewer splenic, lymph node and thymic CD4+ cells, greater numbers of splenic and lymph node CD8+ and CD4+- CD8+ cells, and fewer splenic T, B and T-B cells, and lymph node and thymic B and T-B cells were observed. There was impaired interferon (IFN)-gamma production occurred in the three examined tissues. The results are compatible with the view that the acute phase of EAE can be curtailed by severe calorie restriction, presumably through impaired IFN-gamma production.

Seroprevalence of Pandemic A(H1N1) pmd09 Virus Antibodies in Mexican Health Care Workers Before and After Vaccination.

BACKGROUND AND AIMS: In April 2009, a new strain of influenza A(H1N1) was identified in Mexico and in the U.S. In June 2009, WHO declared this a pandemic. Health care workers constituted a risk group for their close contact with infected individuals. The aim was to estimate seropositivity for A(H1N1)pdm09 in health staff at the Instituto Mexicano del Seguro Social. METHODS: A two-stage cross-sectional study, before and after vaccination in the same workers, was performed on a random sample of health-care workers. A socio-occupational questionnaire was applied and serum antibodies against influenza A(H1N1)pdm09 were determined through neutralization of retroviral pseudotypes; two logistic regression models for both were constructed. RESULTS: The average (median/mean) age of 1378 participants from 13 work centers was 41.7 years and 68.7% (947) were women. Seroprevalence for the first stage was 26.5% (365) (7.4-43%) vs. 20.8% (11) in a control group from the blood bank; for the second stage, the vaccinated group was 33% (215) (18.2-47%) and 27% (196) (11.6-50%) for the unvaccinated group. In regression models, seropositivity was associated with occupational exposure to suspected influenza infected patients, being physicians, and being vaccinated. CONCLUSIONS: Seropositivity against pandemic virus is similar to what was reported, both for vaccinated (2.8-40.9%) and unvaccinated (18.8-64.7%). Low seroprevalence in the vaccinated group indicates that between 67% and 73% were susceptible to infection. Given the relatively low vaccine-induced seropositivity, it is imperative to increase, hygiene and safety for health staff and at-risk populations, and strengthen epidemiological surveillance.