Development of a Formulation and In Vitro Evaluation of a Pulmonary Drug Delivery System for a Novel Janus Kinase (JAK) Inhibitor, CPL409116.

The pursuit of targeted therapies for cytokine-dependent diseases has led to the discovery of Janus kinase (JAK) inhibitors, a promising class of drugs. Among them, CPL409116, a selective dual JAK and rho-associated protein kinase inhibitor (ROCK), has demonstrated potential for treating conditions such as pulmonary fibrosis exacerbated by the COVID-19 pandemic. This study investigated the feasibility of delivering CPL409116 via inhalation, with the aim of minimizing the systemic adverse effects associated with oral administration. Two micronization methods, jet milling and spray drying, were assessed for CPL409116, with spray drying chosen for its ability to produce an amorphous form of the compound. Moreover, parameters such as the mixing energy, drug load, and force control agent significantly influenced the fine particle fraction (FPF), a critical parameter for pulmonary drug delivery. This study provides insights into optimizing the formulation parameters to enhance the delivery efficiency of CPL409116 to the lungs, offering potential for improved therapeutic outcomes in cytokine-dependent pulmonary diseases.

Foaming and Physico-Mechanical Properties of Geopolymer Pastes Manufactured from Post-Metallurgical Recycled Slag.

This paper presents a research program aimed towards developing a method of producing lightweight, porous geopolymer composites for the construction industry based on industrial wastes. A direct method involving the addition of chemicals is currently most commonly used to produce the porous mineral structure of a geopolymer matrix. This relies on a reaction in a highly alkaline environment of the geopolymer to produce a gas (usually hydrogen or oxygen) that forms vesicles and creates a network of pores. This paper demonstrates the feasibility of producing a slag-based geopolymer paste foamed with aluminum powder, taking into account different parameters of fresh paste production: the mixing duration, its speed and the timing of foaming agent addition. The foaming process of the fresh paste in terms of the volumetric changes and temperature development of the fresh paste during the curing of the material are observed. After hardening, the physical properties (density and porosity) as well as the mechanical parameters (compressive strength and work of damage) are determined for the nine manufactured foamed pastes. Image analysis software was used to assess the porosity distribution of the material across the cross-section of the samples. The results enabled the design of the mixing procedure to be adopted during the manufacture of such composites.

Mechanical Properties and Water Permeability of Textile-Reinforced Reactive Powder Concrete with Lightweight Aggregate.

This paper focuses on the development of thin-walled panels with specific properties for applications such as water-tight structures. The authors propose the use of textile-reinforced concrete (TRC) as a composite material and highlight its advantages, which include high tensile strength, improved crack resistance, and design flexibility. The study presents a novel approach which combines TRC with reactive powder concrete (RPC) as a matrix and a lightweight aggregate. RPC, known for its brittle behaviour, is reinforced with glass fibres and a textile fabric to increase its flexural strength. The research includes a comprehensive analysis of the physical and mechanical properties of both the unreinforced RPC matrix and the TRC composite. In particular, the lightweight aggregate RPC matrix has a porosity of 41%, and its mechanical properties, such as flexural and compressive strength, are discussed. The TRC composites, produced in thicknesses ranging from 1 mm to 4 mm, are subjected to flexural tests to evaluate their behaviour under load. The thicker elements show typical damage phases, while the thinner elements show greater flexibility and elasticity. SEM observations confirm good adhesion between the glass fibres and the RPC matrix. Water permeability tests show that the TRC composite, despite its highly porous structure, achieves a water permeability two orders of magnitude higher than that of a reference material, highlighting the roles of both the porous aggregate and the matrix hydration. The paper concludes with a proof of concept-a canoe called the PKanoe, which is constructed from the developed TRC composite. The design of the canoe is supported by numerical analysis to ensure its optimal shape and structural integrity under load. The research contributes to the exploration of innovative materials for sustainable civil engineering applications and addresses both structural and environmental considerations.

Feasibility Review of Aerated Materials Application in 3D Concrete Printing.

Recent years have witnessed a growing global interest in 3D concrete printing technology due to its economic and scientific advantages. The application of foamed concrete, renowned for its exceptional thermal and acoustic insulation properties, not only holds economic attractiveness but also aligns seamlessly with the principles of sustainable development. This study explores various solutions related to 3D printing technology in construction, discussing the design, production, and properties of foamed concrete mixtures. The integration of 3D printing and the potential for automating the entire process offers opportunities to boost productivity and reduce construction costs. Furthermore, the utilization of foamed concrete with its commendable insulation properties will enable a reduction in the usage of materials other than concrete (e.g., mineral wool, facade mesh, and polystyrene), significantly facilitating the recycling process during building demolition. This, in turn, will lead to the preservation of nonrenewable natural resources and a decrease in CO2 emissions. Despite the promising results, there have been limited studies focusing on 3D printing with foamed materials, whereas a survey of the existing body of literature indicates a notable absence of endeavors pertaining to the utilization of aerated concrete within the realm of 3D printing, especially geopolymer composites (GP) and hybrid geopolymer composites (HGP). The outcomes delineated in the ensuing discourse are demonstrative for conventionally used materials rather than the additive manufacturing variant. Hence, this work aims to systematically review existing practices and techniques related to producing foamed concrete with 3D printing technology. This analysis also contributes to the establishment of a foundational framework and furnishes a preliminary basis upon which future endeavors aimed at the 3D printing of aerated concrete can be embarked. The findings from the literature analysis justify the desirability of continuing research on this topic, particularly when considering the potential for large-scale industrial implementation. This article provides a comprehensive state of the knowledge on the development of 3D printing techniques for foamed concrete mixtures. By consolidating and analyzing findings from different studies, this article offers insights into the advancements, challenges, and potential applications of foamed concrete in additive manufacturing processes. This, in turn, contributes to the overall understanding and advancement of 3D printing technologies using foamed concrete as a versatile and sustainable construction material. The encouraging results obtained from the analysis further underscore the need for the continued exploration of 3D printing, especially with an eye towards its industrial-scale implementation.

Interlayer Bond Strength Testing in 3D-Printed Mineral Materials for Construction Applications.

There are no standards for testing the properties of 3D-printed materials; hence, the need to develop guidelines for implementing this type of experiment is necessary. The work concerns the development of a research methodology for interlayer bond strength evaluation in 3D-printed mineral materials. In additive manufactured construction elements, the bond strength is a significant factor as it determines the load-bearing capacity of the entire structural element. After we completed a literature review, the following three test methods were selected for consideration: direct tensile, splitting, and shear tests. The paper compares the testing procedure, results, and sample failure modes. The splitting test was found to be the most effective for assessing layer adhesion, by giving the lowest scatter of results while being an easy test to carry out.

Lung Ultrasound Examination in Patients with SARS-CoV-2 Infection: Multicenter Study.

BACKGROUND: The COVID-19 pandemic has, by necessity, contributed to rapid advancements in medicine. Owing to the necessity of following strict anti-epidemic sanitary measures when taking care of infected patients, the accessibility of standard diagnostic methods may be limited. Consequently, the significance and potential of bedside diagnostic modalities increase, including lung ultrasound (LUS). METHOD: Multicenter registry study involving adult patients with confirmed COVID-19, for whom LUS was performed. RESULTS: A total of 228 patients (61% males) qualified for the study. The average age was 60 years (±14), 40% were older than 65 years of age. In 130 from 173 hospitalized patients, HRCT (high-resolution computed tomography) was performed. In 80% of patients, LUS findings indicated interstitial pneumonia. In hospitalized patients multifocally located single B-lines, symmetrical B-lines, and areas of white lung were significantly more frequent as compared to ambulatory patients. LUS findings, both those indicating interstitial syndrome and consolidations, were positively correlated with HRCT images. As compared to HRCT, the sensitivity and specificity of LUS in detecting interstitial pneumonia were 97% and 100%, respectively. CONCLUSIONS: As compared to HRCT, LUS is characterized by a very high sensitivity and specificity in detecting interstitial pneumonia in COVID-19 patients. Potentially, LUS can be a particularly useful diagnostic modality for COVID-19 patients pneumonia.

Feasibility Study of Digital Image Correlation in Determining Strains in Concrete Exposed to Fire.

Concrete is prone to spalling when exposed to fire. During fire tests, the strains of concrete elements are hard to identify, both from the fire-exposed face and the non-exposed face. This paper presents a field experiment which employed the original CivEng digital image correlation (DIC) method developed at the Cracow University of Technology to measure the strain fields of elements exposed to heating by a pin-point gas burner. The paper presents experimental proof that it is possible to analyze the deformation of both unheated and fire-exposed sides of heated concrete by the DIC method. The strain fields, crack patterns and modes of crack development are presented. The study shows the encouraging results of employing the DIC method to test concrete behavior under fire attack.

Role of Polypropylene Fibres in Concrete Spalling Risk Mitigation in Fire and Test Methods of Fibres Effectiveness Evaluation.

The explosive behaviour of concrete in fire is observed in rapidly heated concrete. The main factors controlling the occurrence of spalling are related to the material's low porosity and high density as well as the limited ability to transport gases and liquids. Thus, for high-strength, ultrahigh-strength, and reactive powder concrete, the risk of spalling is much higher than for normal-strength concrete. The paper presents the discussion on the leading hypothesis concerning the occurrence of concrete spalling. Moreover, the methods for spalling prevention, such as polypropylene fibre application, which has been found to be an effective technological solution for preventing the occurrence of spalling, are presented. Various tests and testing protocols are used to screen concrete mixes propensity toward spalling and to evaluate the polypropylene fibres' effectiveness in spalling risk mitigation. The most effective testing methods were selected and their advantages were presented in the paper. The review was based mainly on the authors' experiences regarding high performance concrete, reactive powder concrete testing, and observations on the effect of polypropylene fibres on material behaviour at high temperature.

Effect of Cement Type on the Mechanical Behavior and Permeability of Concrete Subjected to High Temperatures.

The paper presents experimental investigations concerning the influence of the cement type (CEMI 42.5 R Portland cement and CEMIII/A 42.5 N slag cement-with 53% granulated blast furnace slag) on the mechanical and transport properties of heated concretes. The evolution of properties due to high temperature exposure occurring during a fire was investigated. High temperature exposure produces changes in the transport and mechanical properties of concrete, but the effect of cement type has not been widely studied in the literature. In this paper, concretes were made with two cement types: CEMI and CEMIII, using basalt (B) and riverbed aggregates (RB). The compressive and tensile strength, as well as the static modulus of elasticity and Cembureau permeability, were tested after high temperature exposure to 200, 400, 600, 800, and 1000 °C. The evaluation of damage to the concrete and crack development due to high temperature effects was performed on the basis of the change in the static modulus of elasticity. The test results clearly demonstrated that permeability increases with damage, and it follows an exponential type formula for both types of cement.

Effects of androsterone on the protective action of various antiepileptic drugs against maximal electroshock-induced seizures in mice.

This study evaluated the effect of androsterone (AND), a metabolite of testosterone, on the ability of selected classical and novel antiepileptic drugs to prevent seizures caused by maximal electroshock (MES), which may serve as an experimental model of human generalized tonic-clonic seizures in mice. Single intraperitoneal (i.p.) administration of AND (80 mg kg-1) significantly raised the threshold for convulsions in the MES seizure threshold test. Lower doses of AND (5, 10, 20, and 40 mg kg-1) failed to change the threshold. AND at a subthreshold dose of 40 mg kg-1 significantly enhanced the protective activity of carbamazepine, gabapentin, and phenobarbital against MES-induced seizures decreasing their median effective doses (ED50) values ± SEM from 8.59 ± 0.76 to 6.05 ± 0.81 mg kg-1 (p = 0.0308) for carbamazepine, from 419.9 ± 120.6 to 111.5 ± 41.1 mg kg-1 (p = 0.0405) for gabapentin, and from 20.86 ± 1.64 to 10.0 ± 1.21 mg kg-1 (p = 0.0007) for phenobarbital. There were no significant changes in total brain concentrations of carbamazepine, gabapentin, and phenobarbital following AND administration. This suggests that the enhancing effects of AND on the protective activity of these antiepileptic drugs are not related to pharmacokinetic factors. A lower dose of AND (20 mg kg-1) had no effect on the protective activity of carbamazepine, gabapentin, and phenobarbital. AND administered at a dose of 40 mg kg-1 failed to change the anticonvulsant activity of lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate in the MES test. In the chimney test, AND given at a dose enhancing the protective activity of carbamazepine, gabapentin, and phenobarbital (which alone was without effect on motor performance of mice) did not affect impairment of motor coordination produced by the antiepileptics. Our findings recommend further preclinical and clinical research on AND in respect of its use as adjuvant therapy in the management of epilepsy in men with deficiency of androgens.

Clinical approach to visceral pain in irritable bowel syndrome - pathophysiology, symptoms, and treatment.

Visceral pain has been defined as a pain resulting from activation of pain receptors localized in mucous membrane, serous membrane, and smooth muscles of hollow organs. The great majority of these organs are innervated by parasympathetic and sympathetic outflows. Afferent nerve fibres are involved in conduction of both acute and persistent pain and hyperalgesia. Visceral pain differs significantly from other types of pain in the way it originates and in clinical presentation. It can be misleading as a symptom, producing several problems in the diagnostic process. Sometimes, severe visceral pain is observed in the course of non-lifethreatening functional gastrointestinal disorders, while slight abdominal discomfort may be a first symptom of malignant tumours. For many years, the treatment of visceral pain has been considered as not satisfactory enough and covered a wide variety of pharmacological substances. For example, the complex therapy of pain and other manifestations associated with irritable bowel syndrome include psychotherapy/behavioural therapy, bulk-forming agents, probiotics, laxatives, antidiarrheals, antibacterial agents, antispasmodics, and antidepressants. The current knowledge about the pathogenesis of visceral pain gives a rationale for the development of new, more efficacious drugs with a positive benefit/risk ratio. Unfortunately, experience gained so far with the use of some agents affecting serotoninergic transmission in the gastrointestinal tract have shown a serious danger associated with their administration for patients with irritable bowel syndrome.

[Androgens and epilepsy]. / Androgeny a padaczka.

Nowadays there are increasing experimental and clinical data indicating an important role of an endocrine system (especially its neuroendocrine part and sex hormones) in the pathogenesis of epilepsy. The relationships between patomechanisms of epilepsy and activity of hypothalamo-pituitary-ovarian axis in animals and humans are quite well recognized but the role of male sex hormones, i.e androgens, in seizure susceptibility processes is less known. Epidemiological data clearly show that adrogens-related disorders occur more frequently in epileptic men than in general male population. Usually, they appear in the form of hypogonadism associated with low levels of plasma free testosterone and with low excretion of its 17-ketosteroid metabolites in the urine. Reproductive and sexual disorders can be attributed to hypogonadism. Androgen abnormalities in epileptics men are often affected by chronically used anti-epileptic drugs. Antiepileptic drugs, particularly classical ones, substantially modify bioavailability of androgens and can inhibit the activity of hypothalamo-pituitary-testicular axis, and--in a consequence--aggravate hypogonadism. Since neuroactive androgens cross the blood-brain barrier and modify seizure susceptibility, changes in their plasma concentrations can affect the course and clinical outcome of epilepsy. Effects of testosterone on seizures seem to depend on its different metabolic pathways. Aromatization of testosterone leads to formation of 17beta-estradiol that is believed to have proconvulsive activity. Activation of 5alpha-reductase pathway leads to formation of ketosteroid metabolites, primarily andosterone and etiocholanolone that demonstrate the ability to prevent convulsions in majority of animal studies. Recently, it has been shown that androsterone enhances the antiepileptic activity of phenobarbital, carbamazepine, and gabapentin in animal model of epilepsy. Antiepileptic activity of testosterone and its metabolites encourage further investigation of androgens as promising candidates for treatment of epilepsy in men with androgens-related disorders.

Effects of androsterone on convulsions in various seizure models in mice.

It is believed that a deficiency of androgens, including free testosterone, may promote the development of convulsions. The present study revealed differences in the action of androsterone (AND), a major excreted metabolite of testosterone and a neurosteroid, in three commonly used seizure models in mice. AND administered intraperitoneally exhibited dose-dependent protection against tonic-clonic convulsions caused by maximal electroshock (MES) with ED(50) (effective dose(50)) of 227 mg/kg. The compound also inhibited the convulsive action of pentylenetetrazole (PTZ), increasing its CD(50) (convulsive dose(50)) for clonic convulsions from 77.2 (PTZ + saline) to 93.9 (p < 0.05) for PTZ + AND 40 mg/kg and 113.9 mg/kg (p < 0.001) for PTZ + AND 60 mg/kg. In mice pretreated with 60 mg/kg AND, the CD(50) for PTZ-induced tonic convulsions increased from 102 to 127.6 mg/kg (p < 0.01). Surprisingly, doses of 50 and 100 mg/kg AND lowered the CD(50) for kainate (KA)-induced convulsions from 40.8 to 28.7 (p < 0.05) and 25.4 mg/kg (p < 0.001), respectively. In summary, for two of the mouse seizure models, our findings confirmed previous studies that demonstrated protective activity of AND. However, the potentiation of KA-induced convulsions by AND was somewhat unexpected and suggested that AND may also possess proconvulsant activity.