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Mario Jug,1 Flavia Laffleur,2 Gioconda Millotti3 1Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, 10 000, Croatia; 2Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, 6020, Austria; 3Faculty of Natural Sciences, Juraj Dobrila University of Pula, Pula, 52100, CroatiaCorrespondence: Gioconda Millotti, Faculty of Natural Sciences, Juraj Dobrila University of Pula, Zagrebačka 30, Pula, 52100, Croatia, Email gmillotti@unipu.hrAbstract: Niclosamide (NIC), an anthelmintic drug, has garnered recent attention for its potential as an antiviral, antibacterial, and chemotherapeutic agent, among other applications. Repurposing NIC presents a current trend, offering significant time and cost savings compared to developing entirely new therapeutic chemical entities. However, its drawback lies in poor solubility, resulting in notably low oral bioavailability. This review consolidates efforts to overcome this limitation by summarizing twelve categories of formulations, spanning derivatives, amorphous solid dispersions, co-crystals, nanocrystals, micelles, nanohybrids, lipid nanoparticles and emulsions, cyclodextrins, polymeric nanoparticles, dry powders for inhalation, 3D printlets, and nanofibers. These formulations cover oral, injectable, inhalable and potentially (trans)dermal routes of administration. Additionally, we present a comprehensive overview of NIC characteristics, including physico-chemical properties, metabolism, safety, and pharmacokinetics. Moreover, we identify gaps in formulation and administration pathways that warrant further investigation to address NIC poor bioavailability.Keywords: niclosamide, drug repurposing, solubility, formulations, administration pathways, pharmaco-kinetics

Background: Tick-borne diseases, caused by bacterial pathogens, pose a growing threat to public health in Europe. This paper provides an overview of the historical context of the discovery of the most impactful pathogens transmitted by ticks, including Borrelia burgdorferi sensu lato, Rickettsia spp., Anaplasma spp., Francisella spp., Ehrlichia spp., and Neoehrlichia mikurensis. Understanding the historical context of their discovery provides insight into the evolution of our understanding of these pathogens., Methods and Results: Systematic investigation of the prevalence and transmission dynamics of these bacterial pathogens is provided, highlighting the intricate relationships among ticks, host organisms, and the environment. Epidemiology is explored, providing an in-depth analysis of clinical features associated with infections. Diagnostic methodologies undergo critical examination, with a spotlight on technological advancements that enhance detection capabilities. Additionally, the paper discusses available treatment options, addressing existing therapeutic strategies and considering future aspects., Conclusions: By integrating various pieces of information on these bacterial species, the paper aims to provide a comprehensive resource for researchers and healthcare professionals addressing the impact of bacterial tick-borne diseases in Europe. This review underscores the importance of understanding the complex details influencing bacterial prevalence and transmission dynamics to better combat these emerging public health threats., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71-93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. Controlled clinical trials are necessary to establish efficacy of ruxolitinib in COVID-19.

Cardiovascular disease (CVD) in the HIV population accounts for a large proportion of morbidity and mortality and, with the increased life expectancy, the burden of CVD is expected to rise. Inflammation, immune dysfunction, side effects of HIV medications, high prevalence of other risk factors are the likely pathogenic mechanisms for accelerated atherosclerosis. We aimed to evaluate the diagnostic yield of a cardiovascular multimodality diagnostic work-up in a contemporary cohort of HIV-infected patients. From November 2017 to October 2019, HIV infected patients were screened in a cardiovascular diagnostic work-up program including clinical history, physical examination, arterial blood pressure measurement, 12-lead ECG, and Transthoracic Echocardiogram (TTE). Advanced non-invasive cardiovascular imaging tests, like Coronary Computed Tomography Angiography (CCTA), stress-echocardiography, Cardiac Magnetic Resonance (CMR), were performed in patients with suspicion of chronic coronary syndrome (CCS) or non-ischemic heart disease (NIHD). 117 HIV-infected consecutive patients underwent this cardiovascular diagnostic work-up and were included in our study. Fifty-two patients (45%) had evidence of CVD. Of them, 22 presented Coronary Artery Disease (CAD), whereas 47 cases showed NIHD. In 17 cases both conditions were present. Among patients with CAD, 8 showed critical coronary stenosis; among them, 5 were treated with percutaneous coronary intervention, 2 with Aorto-Coronary By-Pass Grafting (CABG), and one with medical therapy. Hypertension and diabetes were significantly associated with the development of CVD (respectively p<0.001 and p< 0.05), while current smoking (p<0.02) and hypertension (p<0.007) were positively associated to CAD. A comprehensive cardiovascular diagnostic work-up including advanced multimodality diagnostic imaging modalities led to early detection of CVD in nearly half of an HIV population with immediate interventions required in 6.8% of them, and aggressive prevention treatment started in the remaining HIV patients.

This study is a comprehensive evaluation of praziquantel (PZQ) behavior upon grinding considering the influence of milling temperature (cryogenic vs room temperature), frequency and time and presence of polymers (milled raw PZQ vs comilled PZQ/povidone and PZQ/crospovidone at 50:50 w/w) on two experimental responses (residual crystallinity and PZQ recovery). To this aim a full factorial design was set up and the responses of the experimental design were statistically assessed. The powder temperature, measured in different milling conditions, was found to increase with increasing milling frequency and time, up to a maximum recorded value of 46.9 °C (after 90 min at R.T.), for all the three powder systems. When PZQ was ground in RT environment, the recovery was 100%, independently from frequency and time of milling. Its residual crystallinity remained pronounced (>70%) upon milling, even if treated at the most severe conditions. Conversely, when the drug was milled in presence of the polymers, it showed a higher tendency to degradation and amorphysation, independently from the choice of the polymer. The use of cryogenic conditions, operating at temperatures lower than PZQ glass transition, permitted to dramatically reduce PZQ residual crystallinity when the drug was ground by itself. In the case of binary mixtures, the switch to a cryogenic environment did not affect significantly the experimental responses, but permitted to obtain a more predictable trend of both drug recovery and residual crystallinity when varying time and frequency of milling., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The purpose of this study was to develop a microparticulate formulation for nasal delivery of exenatide utilizing a thiolated polymer. Poly(acrylic acid)-cysteine (PAA-cys) and unmodified PAA microparticles loaded with exenatide were prepared via coprecipitation of the drug and the polymer followed by micronization. Particle size, drug load and release of incorporated exenatide were evaluated. Permeation enhancing properties of the formulations were investigated on excised porcine respiratory mucosa. The viability of the mucosa was investigated by histological studies. Furthermore, ciliary beat frequency (CBF) studies were performed. Microparticles displayed a mean size of 70-80 µm. Drug encapsulation was ∼80% for both thiolated and non-thiolated microparticles. Exenatide was released from both thiolated and non-thiolated particles in comparison to exenatide in buffer only within 40 min. As compared to exenatide dissolved in buffer only, non-thiolated and thiolated microparticles resulted in a 2.6- and 4.7-fold uptake, respectively. Histological studies performed before and after permeation studies showed that the mucosa is not damaged during permeation studies. CBF studies showed that the formulations were cilio-friendly. Based on these results, poly(acrylic acid)-cysteine-based microparticles seem to be a promising approach starting point for the nasal delivery of exenatide.