Thrombophylaxis with low molecular weight heparin (LMWH) in hospitalized patients with COVID-19 is mandatory, unless contraindicated. Given the links between inflammation and thrombosis, the use of higher doses of anticoagulants could improve outcomes. We conducted an open-label, multicenter, randomized, controlled trial in adult patients hospitalized with non-severe COVID-19 pneumonia and elevated D-dimer. Patients were randomized to therapeutic-dose bemiparin (115 IU/Kg daily) vs. standard prophylaxis (bemiparin 3,500 IU daily), for 10 days. The primary efficacy outcome was a composite of death, intensive care unit admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress and venous or arterial thrombosis within 10 days of enrollment. The primary safety outcome was major bleeding (ISTH criteria). A prespecified interim analysis was performed when 40% of the planned study population was reached. From October 2020 to May 2021, 70 patients were randomized at 5 sites and 65 were included in the primary analysis; 32 patients allocated to therapeutic-dose and 33 to standard prophylactic-dose. The primary efficacy outcome occurred in 7 patients (21.9%) in the therapeutic-dose group and 6 patients (18.2%) in the prophylactic-dose (absolute risk difference 3.6% [95% CI, -16%- 24%]; odds ratio 1.26 [95% CI, 0.37-4.26]; p=0.95). Discharge in the first 10 days was possible in 66% and 79% of patients, respectively. No major bleeding event was registered. Therefore, in patients with COVID-19 hospitalized with non-severe pneumonia but elevated D-dimer, the use of a short course of therapeutic-dose bemiparin did not improve clinical outcomes compared to standard prophylactic doses.

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Patients affected by cutaneous leishmaniasis need a topical treatment which cures lesions without leaving scars. Lesions are produced not only by the parasite but also by an uncontrolled and persistent inflammatory immune response. In this study, we proposed the loading of β-lapachone (β-LP) in lecithin-chitosan nanoparticles (NP) for targeting the drug to the dermis, where infected macrophages reside, and promote wound healing. The loading of β-LP in lecithin-chitosan NP was critical to achieve important drug accumulation in the dermis and permeation through the skin. In addition, it did not influence the drug antileishmanial activity. When topically applied in L. major infected BALB/c mice, 2 β-LP NP achieved no parasite reduction but they stopped the lesion progression. Immuno-histopatological assays in CL lesions and quantitative mRNA studies in draining lymph nodes confirmed that β-LP exhibited anti-inflammatory activity leading to the downregulation of IL-1β and COX-2 expression and a decrease of neutrophils infiltrate.

The efficacy of a topical treatment against CL depends not only on the intrinsic antileishmanial activity of the drug but also on the amount of drug available in the dermis. NPs as sustained release systems and permeation enhancers could favour the creation of a drug reservoir in the dermis. Additionally, certain NPs have immunomodulatory properties or wound healing capabilities of benefit in CL treatment. Pending task is the selective delivery of active compounds to intracellular amastigotes, because even small NPs are unable to penetrate deeply into the skin to encounter infected macrophages (except in ulcerative lesions).

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In terms of parasite elimination and inflammation reduction, topical application of Ab in combination with PM was more effective than the drug alone.

Vaccine delivery using microneedles (MNs) represents a safe, easily disposable and painless alternative to traditional needle immunizations. The MN delivery of DNA vaccines to the dermis may result in a superior immune response and/or an equivalent immune response at a lower vaccine dose (dose-sparing). This could be of special interest for immunization programs against neglected tropical diseases such as leishmaniasis. In this work, we loaded a MN device with 60μg of a plasmid DNA cocktail encoding the Leishmania infantum nucleosomal histones H2A, H2B, H3 and H4 and compared its immunogenicity and protective capacity against conventional s.c. or i.d. injection of the plasmid. Mice immunized with MNs showed increased ratios of IFN-γ/IL-10, IFN-γ/IL-13, IFN-γ/IL-4, and IFN-γ/TGF-β in the spleens and lymph nodes compared with mice immunized by s.c. and i.d. routes. Furthermore, CCXCL9, CXCL10 and CCL2 levels were also higher. These data suggest that the nucleic acid immunization using MNs produced a better bias towards a Th1 response. However, none of the immunizations strategies were able to control Leishmania major infection in BALB/c mice, as illustrated by an increase in lesion size and parasite burden.

The oral administration of dapsone (DAP) for the treatment of cutaneous leishmaniasis (CL) is effective, although serious hematological side effects limit its use. In this study, we evaluated this drug for the topical treatment of CL. As efficacy depends on potency and skin penetration, we first determined its antileishmanial activity (IC50 = 100 μM) and selectivity index in vitro against Leishmania major-infected macrophages. In order to evaluate the skin penetration ex vivo, we compared an O/W cream containing DAP that had been micronized with a pluronic lecithin emulgel, in which the drug was solubilized with diethylene glycol monoethyl ether. For both formulations we obtained similar low flux values that increased when the stratum corneum and the epidermis were removed. In vivo efficacy studies performed on L. major-infected BALB/c mice revealed that treatment not only failed to cure the lesions but made their evolution and appearance worse. High plasma drug levels were detected and were concomitant with anemia and iron accumulation in the spleen. This side effect was correlated with a reduction of parasite burden in this organ. Our results evidenced that DAP in these formulations does not have an adequate safety index for use in the topical therapy of CL.