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Abstract Background An important limiting factor in the development of centrally acting pharmaceuticals is the blood-brain barrier (BBB). Transport of therapeutic peptides through this highly protective physiological barrier remains a challenge for peptide drug delivery into the central nervous system (CNS). Because the most common strategy to treat moderate to severe pain consists of the activation of opioid receptors in the brain, the development of active opioid peptide analogues as potential analgesics requires compounds with a high resistance to enzymatic degradation and an ability to cross the BBB. Results Herein we report that tetrapeptide analogues of the type H-Dmt1-Xxx2-Yyy3-Gly4-NH2 are transported into the brain after intravenous and subcutaneous administration and are able to activate the μ- and δ opioid receptors more efficiently and over longer periods of time than morphine. Using the hot water tail flick test as the animal model for antinociception, a comparison in potency is presented between a side chain conformationally constrained analogue containing the benzazepine ring (BVD03, Yyy3: Aba), and a "ring opened" analogue (BVD02, Yyy3: Phe). The results show that in addition to the increased lipophilicity through amide bond N-methylation, the conformational constraint introduced at the level of the Phe3 side chain causes a prolonged antinociception. Further replacement of NMe-D-Ala2 by D-Arg2 in the tetrapeptide sequence led to an improved potency as demonstrated by a higher and maintained antinociception for AN81 (Xxx2: D-Arg) vs. BVD03 (Xxx2: NMe-D-Ala). A daily injection of the studied opioid ligands over a time period of 5 days did however result in a substantial decrease in antinociception on the fifth day of the experiment. The compact opioid agonist - NK1 antagonist hybrid SBCHM01 could not circumvent opioid induced tolerance. Conclusions We demonstrated that the introduction of a conformational constraint has an important impact on opioid receptor activation and subsequent antinociception in vivo. Further amino acid substitution allowed to identify AN81 as an opioid ligand able to access the CNS and induce antinociception at very low doses (0.1 mg/kg) over a time period up to 7 hours. However, tolerance became apparent after repetitive i.v. administration of the investigated tetrapeptides. This side effect was also observed with the dual opioid agonist-NK1 receptor antagonist SBCHM01.

Abstract Background The clinical treatment of various types of pain relies upon the use of opioid analgesics. However most of them produce, in addition to the analgesic effect, several side effects such as the development of dependence and addiction as well as sedation, dysphoria, and constipation. One solution to these problems are chimeric compounds in which the opioid pharmacophore is hybridized with another type of compound to incease antinociceptive effects. Neurotensin-induced antinociception is not mediated through the opioid system. Therefore, hybridizing neurotensin with opioid elements may result in a potent synergistic antinociceptor. Results Using the known structure-activity relationships of neurotensin we have synthesized a new chimeric opioid-neurotensin compound PK20 which is characterized by a very strong antinociceptive potency. The observation that the opioid antagonist naltrexone did not completely reverse the antinociceptive effect, indicates the partial involvement of the nonopioid component in PK20 in the produced analgesia. Conclusions The opioid-neurotensin hybrid analogue PK20, in which opioid and neurotensin pharmacophores overlap partially, expresses high antinociceptive tail-flick effects after central as well as peripheral applications.

The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs (including enzymatic stability, efficacy and pharmacokinetic and pharmacodynamic profiles). In addition, considering various complex diseases and/or disorders, the conjugate chemistry approach is highly acceptable and justified. Opioids have long been recognized as the most potent analgesics and serve as the basic pharmacophore for potent hybrid compounds that may be useful in pain management. However, a risk of tolerance and physical dependence exists. Since dopamine receptors have been implicated in the aforementioned adverse effects of opioids, the construction of a hybrid with dual action at opioid and dopamine receptors is of interest. Herein, we present nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation results for LENART01, an opioid–ranatensin hybrid peptide. Apart from molecular docking, protein–ligand interactions were also assessed in vitro using a receptor binding assay, which proved LENART01 to be bound to mu-opioid and dopamine receptors, respectively.

Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on the surface of various cancer cells. However, their biological properties proceed far beyond this, given a broad spectrum of activity. Bombesin receptor ligands are effective drugs for the treatment of rheumatoid arthritis or gastrointestinal diseases. However, most diseases are complex, and the use of polytherapy may lead to pharmacokinetic and pharmacodynamic drug–drug interactions, resulting in side effects. Therefore, there is a need to develop effective compounds that also contain BN or its analogs, which are combined with other structural entities, thus generating a so-called hybrid drug. Hybrid drugs that contain bombesin pharmacophore(s) may be proposed as a solution to the problem of polytherapy or the lack of an effective cure. Such structures have now demonstrated the desired efficacy, though information on these aforementioned compounds is relatively scarce. Therefore, our paper aims to encourage researchers to focus on bombesins. Herein, we indicate that the hybrid approach should also be firmly applied to bombesins and the BN receptor family. This paper’s structure is divided into two main sections demonstrating bombesins and their properties, as well as recent data on bombesin-based hybrid compounds and their potential usefulness in medicine. Overall, it refers to the discovery and synthesis of modified bombesin-based hybrid compounds.

Finding the ideal antimicrobial drug with improved efficacy and a safety profile that eliminates antibiotic resistance caused by pathogens remains a difficult task. Indeed, there is an urgent need for innovation in the design and development of a microbial inhibitor. Given that many promising antimicrobial peptides with excellent broad-spectrum antibacterial properties are secreted by some frog species (e.g., bombesins, opioids, temporins, etc.), our goal was to identify the antimicrobial properties of amphibian-derived dermorphin and ranatensin peptides, which were combined to produce a hybrid compound. This new chimera (named LENART01) was tested for its antimicrobial activity against E. coli strains K12 and R1–R4, which are characterized by differences in lipopolysaccharide (LPS) core oligosaccharide structure. The results showed that LENART01 had superior activity against the R2 and R4 strains compared with the effects of the clinically available antibiotics ciprofloxacin or bleomycin (MIC values). Importantly, the inhibitory effect was not concentration dependent; however, LENART01 showed a time- and dose-dependent hemolytic effect in hemolytic assays.

In 2017, the Lancet Commission on Dementia Prevention, Intervention, and Care included air pollution in its list of potential risk factors for dementia; in 2018, the Lancet Commission on Pollution concluded that the evidence for a causal relationship between fine particulate matter (PM) and dementia is encouraging. However, few interventions exist to delay or prevent the onset of dementia. Air quality data are becoming increasingly available, and the science underlying the associated health effects is also evolving rapidly. Recent interest in this area has led to the publication of population-based cohort studies, but these studies have used different approaches to identify cases of dementia. The purpose of this article is to review recent evidence describing the association between exposure to air pollution and dementia with special emphasis on fine particulate matter of 2.5 microns or less. We also summarize here the proposed detailed mechanisms by which air pollutants reach the brain and activate the innate immune response. In addition, the article also provides a short overview of existing limitations in the treatment of dementia.

This paper presents an analysis of DSC/TG/DTG thermal studies for PA6 polyamide, coal fuels and polyamide composites with these materials. The test results are aimed at comparing the thermal effects and behavior of these materials under high temperature conditions and are the basics to know of the creation and use of polymer composites with various coal fillers.

Psychosis is known as a broad term of symptoms that cause serious disorganization of behavior, thinking, and perception of reality. One of the medicines that recently gained much attention in terms of its psychotic potential is dextromethorphan (DXM). DXM, a widely used antitussive drug, is a commonly abused drug because of its euphoric, hallucinogenic, and dissociative properties. To date, DXM is a legally marketed cough suppressant that is neither a controlled substance nor a regulated chemical under the Controlled Substances Act. The management of DXM-related psychosis is dependent on the type of psychotic symptoms. Atypical neuroleptics (i.e., olanzapine, risperidone, quetiapine) and typical haloperidol have been used in symptomatic treatment due to their efficacy, especially in positive symptoms (hallucinations and delusions). These agents are also recognized as the preferred option in the symptomatic treatment of DXM-related psychosis due to their better efficacy and safety profile than typical haloperidol in the short-term course. The focus of the present review concerns the current stage of knowledge about DXM psychotic potency as well as the management of DXM-related psychoses with a special emphasis on atypical antipsychotic drugs (i.e., olanzapine, risperidone, quetiapine, and haloperidol).

W lutym 2019 r. Międzynarodowy Trybunał Sprawiedliwości (MTS) wydał opinię doradczą dotyczącą prawnych konsekwencji oddzielenia archipelagu Czagos od Mauritiusa w 1965 r. Celem niniejszego artykułu jest przeanalizowanie metodologii, za pomocą której MTS dokonał identyfikacji norm międzynarodowego prawa zwyczajowego odnoszących się do samostanowienia, które następnie stały się podstawą rozstrzygnięcia Trybunału. Przedmiotem badania będzie więc czwarta część opinii doradczej, „Pytania zadane Trybunałowi przez Zgromadzenia Ogólne”. Artykuł opiera się na tezie, że metodologia identyfikacji zwyczaju, wykorzystana przez Trybunał w omawianej opinii doradczej, znacznie różni się od sposobu badania zwyczaju stosowanego dotychczas przez Trybunał, z uwagi na połączenie kilku czynników, w tym w szczególności oparcie identyfikacji zwyczaju wyłącznie o rezolucje Zgromadzenia Ogólnego ONZ. Artykuł został podzielony na cztery części: pierwsza przedstawia zwięźle najważniejsze wątki rozważań Trybunału co do prawa zwyczajowego. W drugiej części porównano dotychczasową metodologię MTS, jeśli chodzi o identyfikację zwyczaju, z rozważaniami z opinii doradczej ws. archipelagu Czagos. W trzeciej części omówiono to, jak Trybunał przedstawił w opinii doradczej sposób formowania się zwyczaju. Czwarta część została natomiast poświęcona rezolucji ZO ONZ 1514.

Glasses and devitrificates from the SiO2–B2O3–P2O5–K2O–CaO–MgO system with constant contents of SiO2 and P2O5 network formers, modified by the addition of B2O3, were analyzed. All materials were synthesized by the traditional melt-quenching technique. The glass stability (GS) parameters (Krg, ∆T, KW, KH) were determined. The effect of the addition of B2O3 on the GS, liquation phenomenon, crystallization process, and the type of crystallizing phases were examined using SEM-EDS, DSC, XRD, and Raman spectroscopy imaging methods. It was observed that the addition of B2O3 increased the tendency of the glass to crystallize. Both phosphates (e.g., Ca9MgK(PO4)7, Mg3Ca3(PO4)4), and silicates (e.g., K2Mg5(Si12O30), CaMg(Si2O6), MgSiO3) crystallized in the studied system. The Raman spectrum for the orthophosphate Mg3Ca3(PO4)4 stanfieldite type was obtained. Boron ions were introduced into the structures of crystalline compounds at high crystallization temperatures. The type of crystallizing phases was found to be related to the phenomenon of liquation, and the order of their occurrence was dependent on the Gibbs free enthalpy.

This article advances the thesis that there is no threshold of the use of force. i.e. no level of the use of force which decides whether and which forcible actions undertaken by States are prohibited. The examples of actions discussed in the doctrine of law which supposedly would be ‘below’ such a threshold in fact either are regulated by other prin-ciples of international law, are not considered as regulated by ius ad bellum, or States deliberately resign from calling them a use of force for both legal and extra-legal reasons. Thus, the existence of such a threshold is not confirmed by States’ practice. This thesis will be explored using three examples: the cases of the evacuation of nationals, the extra-territorial and the Falklands/Malvinas Islands invasion of 2 April 1982. The article starts with a brief discussion of the opinions expressed in the doctrine of international law on the threshold, as well as the applicable case law.

The paper presents the application of thermal analysis methods in the study of various materials: coal sludge, polymeric material and composites of a polymer with coal sludge (fraction of coal sludge in composites: 1%, 3% and 5%). TG/DTG/DSC curves obtained during measurements in air atmosphere were analyzed. Polymers are used in many industries, that is why their thermal characteristics are so important. On the other hand, the mining industry, forced to supply power plants better quality fuel, must perform more thorough coal cleaning. This results in a continuous increase in waste in the form of coal sludge. The best method of disposing of these wastes is thermal utilisation (combustion and co-combustion), as well as use in composites with other materials. The aim of the study was to demonstrate the effect of the addition of coal sludge to the polymer on the energetic effect and the rate of mass change of the material sample during the thermal process by TG/DTG/DSC methods.

W związku ze zjawiskiem wielokulturowości coraz większe znaczenie zyskuje koncepcja cultural defence, czyli uwzględniania przez sąd kulturowych korzeni oskarżonego, które miały wpływ na popełnione przestępstwo. Debata, która toczy się nad takimi „kulturowymi argumentami” na sali sądowej, dotyka problemów zarówno dogmatycznych, jak i praktycznych. Sądy, rozpatrując sprawy, w których pojawia się cultural defence, muszą przede wszystkim rozstrzygnąć, czy oskarżony może w ogóle powołać się na taką motywację swoich czynów. W dalszej kolejności sąd powinien zdecydować, jak uwzględnić czynnik kulturowy: czy jako przyczynę niepoczytalności, błędu w zakresie nieświadomości czynu, błędu co do faktów i tak dalej. Pogodzenie stanu faktycznego sprawy i sprawiedliwej oceny czynu może w świetle obowiązującego prawa okazać się bardzo trudne. Ważne jest też, żeby nie pozwolić na korzystanie z cultural defence wbrew prawom kobiet. Skodyfikowanie przestępstw o podłożu kulturowym może okazać się niemożliwe do zrealizowania, dlatego to organy wymiaru sprawiedliwości powinny w toku stosowania prawa pamiętać o kulturowym tle przestępstw.

The ashes from sewage sludge combustion in air versus O2/CO2 atmospheres with oxygen concentrations in the range of 21–40% vol. at temperature of 850°C in a 12 kW bench-scale CFB combustor were characterised. The chemical and phase composition of ashes were studied by XRF and XRD. The morphology of studied ashes were examined by SEM method. The slagging and fouling indices were calculated to study the deposition tendencies of ash. The thermal behaviour of ashes was studied by TG-DSC techniques, focusing on the mass loss and thermic effects with the increasing of temperature up to 1200°C.

The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration (in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics. PK23 is a bifunctional compound consisting of both opioid and neurotensin fragments fused into one molecule. It mediates dose- and time-dependent antinociceptive responses when administered either centrally or peripherally, likely due to its interaction with μ opioid and neurotensin type 1 (NTS1) receptors. Image 1 [ABSTRACT FROM AUTHOR]

Neurotensin (NT) and its analog neuromedin N (NN) are formed by the processing of a common precursor in mammalian brain tissue and intestines. The biological effects mediated by NT and NN (e.g. analgesia, hypothermia) result from the interaction with G protein-coupled receptors. The goal of this study consisted of the synthesis and radiolabeling of NN, as well as the determination of the binding characteristics of [ 3 H]NN and G protein activation by the cold ligand. In homologous displacement studies a weak affinity was determined for NN, with IC 50 values of 454 nM in rat brain and 425 nM in rat spinal cord membranes. In saturation binding experiments the K d value proved to be 264.8 ± 30.18 nM, while the B max value corresponded to 3.8 ± 0.2 pmol/mg protein in rat brain membranes. The specific binding of [ 3 H]NN was saturable, interacting with a single set of homogenous binding sites. In sodium sensitivity experiments, a very weak inhibitory effect of Na + ions was observed on the binding of [ 3 H]NN, resulting in an IC 50 of 150.6 mM. In [ 35 S]GTPγS binding experiments the E max value was 112.3 ± 1.4% in rat brain and 112.9 ± 2.4% in rat spinal cord membranes and EC 50 values of 0.7 nM and 0.79 nM were determined, respectively. NN showed moderate agonist activities in stimulating G proteins. The stimulatory effect of NN could be maximally inhibited via use of the NTS2 receptor antagonist levocabastine, but not by the opioid receptor specific antagonist naloxone, nor by the NTS1 antagonist SR48692. These observations allow us to conclude that [ 3 H]NN labels NTS2 receptors in rat brain membranes. [ABSTRACT FROM AUTHOR]