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Béla Kiss, Zsolt Némethy, Károly Fazekas, Dalma Kurkó, István Gyertyán, Katalin Sághy, István Laszlovszky, Bence Farkas, Norbert Kirschner, Etelka Bolf-Terjéki, Ottilia Balázs, Balázs Lendvai Pharmacological and Drug Safety Research, Gedeon Richter Plc, Budapest, HungaryCorrespondence: Béla KissPharmacological and Drug Safety Research, Gedeon Richter Plc, P.O. Box 27, Budapest H-1475, HungaryTel +361 431 4226Fax +361 889 8400Email b.kiss@richter.huIntroduction: Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.Methods: In vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. Results: Similar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.Conclusion: Overall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.Keywords: dopamine, serotonin, schizophrenia, bipolar disorder, desmethyl-cariprazine, didesmethyl-cariprazine

Abstract Background Over the last century, technological progress has been tremendous, and technological advancement is reflected in the development of medicine. This research assessed attitudes towards surgical robots and identified correlations with willingness to participate in robotic surgery based on factors influencing trust in automated systems. Method Using data from a survey, which included the Multi-dimensional Robot Attitude Scale (MdRAS) and a questionnaire consisting of attitude statements regarding the factors affecting trust in automated systems, the experiment assessed the attitudes of healthcare workers and potential patients towards surgery robots, and attempted to find a correlation between these attitudes, age, and gender. Results and Conclusion Statistical evaluation of the responses (N = 197) showed that positive attitude towards surgical robots showed a high correlation with the willingness to participate in robotic surgery and gave the strongest correlations with the MdRAS utility and negative attitude towards robots subscales. For the assessment of willingness, the MdRAS subscales alone did not provide a strong enough correlation. All factors examined showed a significant correlation with participation. Having faith in the surgery robot, the propensity to trust technology, the designer’s reputation, the ease of work that a surgical robot provides, positive experience with robots, and believing the surgeon is competent at operating the machine seemed to have been the most important positive correlations, while fear of errors gave the highest negative correlation. The healthcare workers and potential patients showed significant differences in the subscales of the questionnaire perceived risk and knowledge but no significant difference in the characteristics of the surgical robot. There was no difference in willingness to participate between the samples. Age did not show a significant correlation with the score achieved and willingness in any of the samples. Significant differences were found between male and female respondents, with men having more positive attitudes and being more likely to participate in surgeries using surgery robots than women. As a result, the research potentially sheds light on the factors that need to be considered when building trust in robotic surgery.

Collaboration with robots requires robot acceptance, but it can have adverse consequences when people accept a robot's request against their best intuition or another request from a superior human. In our research, we aim to explore how attitudes toward robots and the interdependency in human-robot interaction (equal versus superior position held by the human) influence their reaction to an unexpected request from a social robot, contradicting a human request. Hundred and six participants met the request from a robot not to turn it off at the end of a collaboration. The request counteracted the instruction given by the experimenter at the beginning of the experiment. Thirty-three percent of the participants complied with the robot's request and refrained from turning it off. Analyses showed that positive robot attitudes increased the likelihood of leaving the robot on. The superior position in the interaction made the rejection of the robot's unexpected request faster and slowed down the acceptance of the robot's request. According to the results from the follow-up questionnaire, discomfort, and tension caused by the unexpected request also increased the likelihood of accepting the request of the robot.

Abstract In this study, we describe the synthesis of cinchona (thio)squaramide and a novel cinchona thiourea organocatalyst. These catalysts were employed in pharmaceutically relevant catalytic asymmetric reactions, such as Michael, Friedel–Crafts, and A3 coupling reactions, in combination with Ag(I), Cu(II), and Ni(II) salts. We identified several organocatalyst‐metal salt combinations that led to a significant increase in both yield and enantioselectivity. To gain insight into the active catalyst species, we prepared organocatalyst‐metal complexes and characterized them using HRMS, NMR spectroscopy, and quantum chemical calculations (B3LYP‐D4/def2‐TZVP), which allowed us to establish a structure‐activity relationship.

IntroductionPatients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce.MethodsWe created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes.ResultsFifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 ± 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having “non-severe” COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 ± 17.91 versus 39.77 ± 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 ± 0.80 g/dL versus 3.99 ± 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p

The brain has a unique macroscopic waste clearance system, termed the glymphatic system which utilises perivascular tunnels surrounded by astroglia to promote cerebrospinal-interstitial fluid exchange. Rodent studies have demonstrated a marked increase in glymphatic clearance during sleep which has been linked to a sleep-induced expansion of the extracellular space and concomitant reduction in intracellular volume. However, despite being implicated in the pathophysiology of multiple human neurodegenerative disorders, non-invasive techniques for imaging glymphatic clearance in humans are currently limited.Here we acquired multi-shell diffusion weighted MRI (dwMRI) in twenty-one healthy young participants (6 female, 22.3 ± 3.2 years) each scanned twice, once during wakefulness and once during sleep induced by a combination of one night of sleep deprivation and 10 mg of the hypnotic zolpidem 30 min before scanning. To capture hypothesised sleep-associated changes in intra/extracellular space, dwMRI were analysed using higher order diffusion modelling with the prediction that sleep-associated increases in interstitial (extracellular) fluid volume would result in a decrease in diffusion kurtosis, particularly in areas associated with slow wave generation at the onset of sleep.In line with our hypothesis, we observed a global reduction in diffusion kurtosis (t15=2.82, p = 0.006) during sleep as well as regional reductions in brain areas associated with slow wave generation during early sleep and default mode network areas that are highly metabolically active during wakefulness. Analysis with a higher-order representation of diffusion (MAP-MRI) further indicated that changes within the intra/extracellular domain rather than membrane permeability likely underpin the observed sleep-associated decrease in kurtosis. These findings identify higher-order modelling of dwMRI as a potential new non-invasive method for imaging glymphatic clearance and extend rodent findings to suggest that sleep is also associated with an increase in interstitial fluid volume in humans.

ObjectivesPathways contributing to endothelial dysfunction in patients with limited cutaneous systemic sclerosis (lcSSc) are largely unknown. The aim of this study was to investigate potential associations of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathy-related changes in patients with lcSSc and early-stage vasculopathy.MethodsAmino acids, calciotropic parameters, including 25-hydroxyvitamin D and parathyroid hormone (PTH), and bone turnover parameters, including osteocalcin and N-terminal peptide of procollagen-3 (P3NP), were measured in 38 lcSSc patients and 38 controls. Endothelial dysfunction was assessed by biochemical parameters, pulse-wave analysis, flow-mediated and nitroglycerine-mediated dilation. Additionally, vasculopathy-related and SSc-specific clinical changes including capillaroscopic, skin, renal, pulmonary, gastrointestinal and periodontal parameters were recorded.ResultsNo significant differences in amino acids, calciotropic and bone turnover parameters were observed between lcSSc patients and controls. In patients with lcSSc, several significant correlations were found between selected amino acids, parameters of endothelial dysfunction, vasculopathy-related and SSc-specific clinical changes (all with p

We report a case of a patient double-seropositive for anti-glomerular basement membrane (anti-GBM) and anti-neutrophil cytoplasmic antibodies (ANCA) who reported retrosternal chest pain during a regular hemodialysis session associated with ST-segment depression in electrocardiogram and an increase of serum high-sensitivity troponin T. Urgent coronary angiography excluded obstructive coronary artery disease, suggesting the diagnosis of ischemia with non-obstructive coronary arteries. This case illustrates an unusual presentation of cardiovascular involvement in a patient with double-positive ANCA/anti-GBM disease, emphasizing the possible relevance of coronary microvascular dysfunction and the need for close cardiovascular follow-up in this patient population.

Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification of phospholipase A2 receptor (PLA2R) as target antigen in most patients changed the management of MN dramatically, and provided a rationale for B-cell depleting agents such as rituximab. The efficacy of rituximab in inducing remission has been investigated in several studies, including 3 randomized controlled trials, in which complete and partial remission of proteinuria was achieved in approximately two-thirds of treated patients. Due to its favorable safety profile, rituximab is now considered a first-line treatment option for MN, especially in patients at moderate and high risk of deterioration in kidney function. However, questions remain about how to best use rituximab, including the optimal dosing regimen, a potential need for maintenance therapy, and assessment of long-term safety and efficacy outcomes. In this review, we provide an overview of the current literature and discuss both strengths and limitations of “the new standard.”

In the present study, the effect of long-term exercise training was investigated on myocardial morphological and functional remodeling and on proarrhythmic sensitivity in a rabbit athlete’s heart model. New-Zealand white rabbits were trained during a 12-week long treadmill running protocol and compared with their sedentary controls. At the end of the training protocol, echocardiography, in vivo and in vitro ECG recordings, proarrhythmic sensitivity with dofetilide (nM) were performed in isolated hearts, and action potential duration (APD) measurements at different potassium concentrations (4.5 and 2 mM) were made in the isolated papillary muscles. Expression levels of the slow component of delayed rectifier potassium current and fibrosis synthesis and degradation biomarkers were quantified. Echocardiography showed a significantly dilated left ventricle in the running rabbits. ECG PQ and RR intervals were significantly longer in the exercised group (79 ± 2 vs. 69 ± 2 ms and 325 ± 11 vs. 265 ± 6 ms, p < 0.05, respectively). The in vivo heart rate variability (HRV) (SD of root mean square: 5.2 ± 1.4 ms vs. 1.4 ± 0.2 ms, p < 0.05) and Tpeak-Tend variability were higher in the running rabbits. Bradycardia disappeared in the exercised group in vitro. Dofetilide tended to increase the QTc interval in a greater extent, and significantly increased the number of arrhythmic beats in the trained animals in vitro. APD was longer in the exercised group at a low potassium level. Real-time quantitative PCR (RT-qPCR) showed significantly greater messenger RNA expression of fibrotic biomarkers in the exercised group. Increased repolarization variability and higher arrhythmia incidences, lengthened APD at a low potassium level, increased fibrotic biomarker gene expressions may indicate higher sensitivity of the rabbit “athlete’s heart” to life-threatening arrhythmias.

Hemodialysis patients (HD) are expected to have excess mortality in coronavirus disease 2019 (COVID-19). This was challenged by a recent study reporting HD patients to have comparable mortality and less ICU admissions when hospitalized with COVID-19. An altered immune system due to chronic inflammation might protect HD-patients from severe COVID-19. Therefore, we aimed to describe the peripheral blood immune phenotype in HD-patients and respective controls with COVID-19.MethodsSixty-four patients (31 HD, 33 non-HD) with PCR-confirmed COVID-19 and 16 control patients (10 HD, 6 non-HD) were prospectively included. According to symptoms, COVID-19 patients were categorized as asymptomatic/mild, moderate or severe COVID-19 phenotypes. Cytokine profiling and immune phenotyping was performed.ResultsTh1 and Th17 plasma cytokine levels were highly increased in HD patients without COVID-19 and were not significantly regulated during COVID-19. In non-HD COVID-19 patients these cytokines increased significantly with disease severity. While all patients with moderate or severe COVID-19 showed hallmarks of COVID-19 such as decreased CD3+, CD4+ and CD8+ and CD4+CD25hiFoxP3+ regulatory T cells, significantly increased CD38+CD8+ effector memory and CD38+CD8+ TEMRA T cells were detected in moderate/severe COVID-19 HD patients, which was not observed in non-HD patients with moderate or severe COVID-19. Furthermore, CD161+CD8+ T cells decreased significantly in non-HD COVID-19 patients dependent on disease severity, but not in HD patients. Dynamics of B cells and subtypes were comparable in HD and non-HD COVID-19 patients.ConclusionsHD patients might be protected from severe COVID-19 due to their chronic inflammatory state with increased CD38+CD8+ effector memory and TEMRA T cells as well as CD161+CD8+ T cells.

ObjectiveTo characterize the incidence, type, and risk factors of severe infections (SI) in patients with autoimmune kidney diseases treated with rituximab (RTX).MethodsWe conducted a multicenter retrospective cohort study of adult patients with immune-related kidney diseases treated with at least one course of RTX between 2015 and 2019. As a part of the ABCDE Registry, detailed data on RTX application and SI were collected. SI were defined by Common Terminology Criteria for Adverse Events v5.0 as infectious complications grade 3 and above. Patients were dichotomized between “nephrotic” and “nephritic” indications. The primary outcome was the incidence of SI within 12 months after the first RTX application.ResultsA total of 144 patients were included. Twenty-five patients (17.4%) presented with SI, mostly within the first 3 months after RTX administration. Most patients in the nephritic group had ANCA-associated vasculitis, while membranous nephropathy was the leading entity in the nephrotic group. Respiratory infections were the leading SI (n= 10, 40%), followed by urinary tract (n=3, 12%) and gastrointestinal infections (n=2, 8%). On multivariable analysis, body mass index (BMI, 24.6 kg/m2versus 26.9 kg/m2, HR: 0.88; 95%CI: 0.79-0.99; p=0.039) and baseline creatinine (HR: 1.25; 95%CI: 1.04-1.49; p=0.017) were significantly associated with SI. All patients in the nephritic group (n=19; 100%) who experienced a SI received oral glucocorticoid (GC) treatment at the time of infection. Hypogammaglobulinemia was frequent (58.5%) but not associated with SI.ConclusionsAfter RTX administration, impaired kidney function and lower BMI are independent risk factors for SI. Patients with nephritic glomerular diseases having concomitant GC treatment might be at higher risk of developing SI.

Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current IKs. While mutant LQT5 KCNE1 variants are known to inhibit IKs amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged IKs amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of IKs channels minimizes the inhibitory effects of LQT5 KCNE1 variants on IKs amplitudes, while current deactivation is accelerated. Such changes recapitulate IKs properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the IKs ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the IKs channel complex that regulates IKs function in cardiomyocytes and modifies the development of the LQT5 phenotype.

Aim: Channelrhodopsins (ChRs) are a large family of light-gated ion channels with distinct properties, which is of great importance in the selection of a ChR variant for a given application. However, data to guide such selection for cardiac optogenetic applications are lacking. Therefore, we investigated the functioning of different ChR variants in normal and pathological hypertrophic cardiomyocytes subjected to various illumination protocols.Methods and Results: Isolated neonatal rat ventricular cardiomyocytes (NRVMs) were transduced with lentiviral vectors to express one of the following ChR variants: H134R, CatCh, ReaChR, or GtACR1. NRVMs were treated with phenylephrine (PE) to induce pathological hypertrophy (PE group) or left untreated [control (CTL) group]. In these groups, ChR currents displayed unique and significantly different properties for each ChR variant on activation by a single 1-s light pulse (1 mW/mm2: 470, 565, or 617 nm). The concomitant membrane potential (Vm) responses also showed a ChR variant-specific profile, with GtACR1 causing a slight increase in average Vm during illumination (Vplateau: −38 mV) as compared with a Vplateau > −20 mV for the other ChR variants. On repetitive activation at increasing frequencies (10-ms pulses at 1–10 Hz for 30 s), peak currents, which are important for cardiac pacing, decreased with increasing activation frequencies by 17–78% (p < 0.05), while plateau currents, which are critical for arrhythmia termination, decreased by 10–75% (p < 0.05), both in a variant-specific manner. In contrast, the corresponding Vplateau remained largely stable. Importantly, current properties and Vm responses were not statistically different between the PE and CTL groups, irrespective of the variant used (p > 0.05).Conclusion: Our data show that ChR variants function equally well in cell culture models of healthy and pathologically hypertrophic myocardium but show strong, variant-specific use-dependence. This use-dependent nature of ChR function should be taken into account during the design of cardiac optogenetic studies and the interpretation of the experimental findings thereof.

A vizsgálatunkban arra kerestük a választ, a Debreceni Kosárlabda Akadémia utánpótlás korú játékosai (U11 – 76 fő) motiválásában mely tényezők játszák a leginkább meghatározó szerepet, különös tekintettel a kontrollhelyük és a célkitűzésük alakulására a teljesítmény fejlődésük felmérése kapcsán. Ehhez a célkitűzéses vizsgálatok egy olyan követéses eljárását vettük alapul, amely a kontrollhely és a célkitűzés vizsgálatok felmérésén túl a fizikai állóképesség alakulása is a nyomon követhető volt. Eredményeink azt mutatják, hogy mind a választás minősége (hogy mennyire nehéz feladatot vállalnak a vizsgálat során a sportolók), mind a kontrollhely alakulása, valamint a motiváció forrása befolyásoló tényezők lehetnek a sportolók célkitűzéses fejlődése terén. A kapott eredmények arra is rávilágítottak, hogy bár számos objektív mérőeszköz és vizsgálati eljárás áll az edzők és a sportpszichológusok rendelkezésére a sportolók csúcsteljesítményének felmérésére és annak alakulására nézve, azonban az edzésmódszerek változtatásával és újabb motiváló erők bevezetésével további esetleges eredményjavulást lehetne elérni az utánpótlás csapatok esetében.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide widely distributed in the nervous system, where it exerts strong neuroprotective effects. PACAP is also expressed in peripheral organs but its peripheral protective effects have not been summarized so far. Therefore, the aim of the present paper is to review the existing literature regarding the cytoprotective effects of PACAP in non-neuronal cell types, peripheral tissues, and organs. Among others, PACAP has widespread expression in the digestive system, where it shows protective effects in various intestinal pathologies, such as duodenal ulcer, small bowel ischemia, and intestinal inflammation. PACAP is present in both the exocrine and endocrine pancreas as well as liver where it reduces inflammation and steatosis by interfering with hepatic pathology related to obesity. It is found in several exocrine glands and also in urinary organs, where, with its protective effects being mainly published regarding renal pathologies, PACAP is protective in numerous conditions. PACAP displays anti-inflammatory effects in upper and lower airways of the respiratory system. In the skin, it is involved in the development of inflammatory pathology such as psoriasis and also has anti-allergic effects in a model of contact dermatitis. In the non-neuronal part of the visual system, PACAP showed protective effects in pathological conditions of the cornea and retinal pigment epithelial cells. The positive role of PACAP has been demonstrated on the formation and healing processes of cartilage and bone where it also prevents osteoarthritis and rheumatoid arthritis development. The protective role of PACAP was also demonstrated in the cardiovascular system in different pathological processes including hyperglycaemia-induced endothelial dysfunction and age-related vascular changes. In the heart, PACAP protects against ischemia, oxidative stress, and cardiomyopathies. PACAP is also involved in the protection against the development of pre-senile systemic amyloidosis, which is presented in various peripheral organs in PACAP-deficient mice. The studies summarized here provide strong evidence for the cytoprotective effects of the peptide. The survival-promoting effects of PACAP depend on a number of factors which are also shortly discussed in the present review.

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate between normal rhythm and arrhythmia based on frequency-dependent gating and ii) generate an ionic current for termination of the detected arrhythmia. We show in silico, that for both human atrial and ventricular arrhythmias, activation of these channels leads to rapid and repeated restoration of normal excitation rhythm. Experimental validation is provided by injecting the designed channel current for arrhythmia termination in human atrial myocytes using dynamic clamp.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT-proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide with widespread occurrence throughout the body including the gastrointestinal system. In the small and large intestine, effects of PACAP on cell proliferation, secretion, motility, gut immunology and blood flow, as well as its importance in bowel inflammatory reactions and cancer development have been shown and reviewed earlier. However, no current review is available on the actions of PACAP in the stomach in spite of numerous data published on the gastric presence and actions of the peptide. Therefore, the aim of the present review is to summarize currently available data on the distribution and effects of PACAP in the stomach. We review data on the localization of PACAP and its receptors in the stomach wall of various mammalian and non-mammalian species, we then give an overview on PACAP’s effects on secretion of gastric acid and various hormones. Effects on cell proliferation, differentiation, blood flow and gastric motility are also reviewed. Finally, we outline PACAP’s involvement and changes in various human pathological conditions.

In this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined.Ion currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively. Ca2+ transients and cell shortening were measured in fluorescent dye loaded isolated dog myocytes. Antiarrhythmic effects of ORM-10962 were studied in anesthetized ouabain (10 μg/kg/min i.v.) pretreated guinea pigs and in ischemia-reperfusion models (I/R) of anesthetized coronary artery occluded rats and Langendorff perfused guinea pigs hearts.ORM-10962 significantly reduced the inward/outward NCX currents with estimated EC50 values of 55/67 nM, respectively. The compound, even at a high concentration of 1 μM, did not modify significantly the magnitude of ICaL in CMs, neither had any apparent influence on the inward rectifier, transient outward, the rapid and slow components of the delayed rectifier potassium currents, the late and peak sodium and Na+/K+ pump currents. NCX inhibition exerted moderate positive inotropic effect under normal condition, negative inotropy when reverse, and further positive inotropic effect when forward mode was facilitated. In dog Purkinje fibres 1 μM ORM-10962 decreased the amplitude of digoxin induced delayed afterdepolarizations (DADs). Pre-treatment with 0.3 mg/kg ORM-10962 (i.v.) 10 min before starting ouabain infusion significantly delayed the development and recurrence of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30%) in anesthetized guinea pigs. On the contrary, ORM-10962 pre-treatment had no apparent influence on the time of onset or the severity of I/R induced arrhythmias in anesthetized rats and in Langendorff perfused guinea-pig hearts.The present study provides strong evidence for a high efficacy and selectivity of the NCX-inhibitory effect of ORM-10962. Selective NCX inhibition can exert positive as well as negative inotropic effect depending on the actual operation mode of NCX. Selective NCX blockade may contribute to the prevention of DAD based arrhythmogenesis, in vivo, however, its effect on I/R induced arrhythmias is still uncertain.

Background: Over the past two decades, the global incidence of gout has markedly increased, affecting people worldwide. Considering the side effects of xanthine oxidase (XO) inhibitor drugs (e.g. allopurinol and febuxostat) used in the treatment of hyperuricemia and gout, the potential application of phytochemicals has been widely studied. In addition, XO also takes part in the elimination of certain drugs, including 6-mercaptopurine. In the current explorative study, we aimed to examine the potential effects of tea catechins, resveratrol, silymarin flavonolignans and some of their conjugated metabolites on XO-catalyzed xanthine and 6-mercaptopurine oxidation, applying in vitro assays and modeling studies., Results: Catechins, resveratrol and resveratrol conjugates exerted no or only weak inhibitory effects on XO. Silybin A, silybin B and isosilybin A were weak, silychristin was a moderate, while 2,3-dehydrosilychristin was a potent inhibitor of the enzyme. Sulfate metabolites of silybin A, silybin B and isosilybin A were considerably stronger inhibitors compared to the parent flavonolignans, and the sulfation of 2,3-dehydrosilychristin slightly increased its inhibitory potency. Silychristin was the sole flavonolignan tested, where sulfate conjugation decreased its inhibitory effect., Conclusion: 2,3-Dehydrosilychristin seems to be a promising candidate for examining its in vivo antihyperuricemic effects, because both the parent compound and its sulfate conjugate are highly potent inhibitors of XO. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Background: Over the past 4 decades, obesity has escalated into a global epidemic, with its worldwide prevalence nearly tripling. Pharmacological treatments have evolved with the recent development of glucagon-like peptide 1 agonists, such as semaglutide. However, off-label use of drugs such as Ozempic for cosmetic weight loss has surged in popularity, raising concerns about potential misuse and the emergence of substandard and falsified products in the unregulated supply chain., Objective: This study aims to conduct a multifactor investigation of product quality and patient safety risks associated with the unregulated online sale of semaglutide by examining product availability and vendor characteristics and assessing product quality through test purchases., Methods: We used a complex risk and quality assessment methodology combining online market surveillance, search engine results page analysis, website content assessment, domain traffic analytics, conducting targeted product test purchases, visual quality inspection of product packaging, microbiological sterility and endotoxin contamination evaluation, and quantitative sample analysis using liquid chromatography coupled with mass spectrometry., Results: We collected and evaluated 1080 links from search engine results pages and identified 317 (29.35%) links belonging to online pharmacies, of which 183 (57.7%) led to legal pharmacies and 134 (42.3%) directed users to 59 unique illegal online pharmacy websites. Web traffic data for the period between July and September 2023 revealed that the top 30 domains directly or indirectly affiliated with illegal online pharmacies accumulated over 4.7 million visits. Test purchases were completed from 6 illegal online pharmacies with the highest number of links offering semaglutide products for sale without prescription at the lowest price range. Three injection vial purchases were delivered; none of the 3 Ozempic prefilled injection pens were received due to nondelivery e-commerce scams. All purchased vials were considered probable substandard and falsified products, as visual inspection indicated noncompliance in more than half (59%-63%) of the evaluated criteria. The semaglutide content of samples substantially exceeded labeled amounts by 28.56%-38.69%, although no peptide-like impurities were identified. The lyophilized peptide samples were devoid of viable microorganisms at the time of testing; however, endotoxin was detected in all samples with levels ranging between 2.1645 EU/mg and 8.9511 EU/mg. Furthermore, the measured semaglutide purity was significantly low, ranging between 7.7% and 14.37% and deviating from the 99% claimed on product labels by manufacturers., Conclusions: Glucagon-like peptide 1 agonist drugs promoted for weight loss, similar to erectile dysfunction medications more than 2 decades ago, are becoming the new blockbuster lifestyle medications for the illegal online pharmacy market. Protecting the pharmaceutical supply chain from substandard and falsified weight loss products and raising awareness regarding online medication safety must be a public health priority for regulators and technology platforms alike., (©Amir Reza Ashraf, Tim Ken Mackey, Róbert György Vida, Győző Kulcsár, János Schmidt, Orsolya Balázs, Bálint Márk Domián, Jiawei Li, Ibolya Csákó, András Fittler. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 07.11.2024.)

In recent years, several changes have occurred in the management of chronic immunological conditions with the emerging use of targeted therapies. This two-phase cross-sectional study was conducted through structured in-person interviews in 2018-2019 and 2022. Additional data sources included ambulatory medical records and the itemized reimbursement reporting interface of the National Health Insurance Fund. Drug interactions were analyzed using the UpToDate Lexicomp, Medscape drug interaction checker, and Drugs.com databases. The chi-square test was used, and odds ratios (ORs) were calculated. In total, 185 patients participated. In 53% of patients (n = 53), a serious drug-drug interaction (DDI) was identified (mean number: 1.07 ± 1.43, 0-7), whereas this value was 38% (n = 38) for potential drug-supplement interactions (mean number: 0.58 ± 0.85, 0-3) and 47% (n = 47) for potential targeted drug interactions (0.72 ± 0.97, 0-5) in 2018. In 2022, 78% of patients (n = 66) were identified as having a serious DDI (mean number: 2.27 ± 2.69, 0-19), 66% (n = 56) had a potential drug-supplement interaction (mean number: 2.33 ± 2.69, 0-13), and 79% (n = 67) had a potential targeted drug interactions (1.35 ± 1.04, 0-5). Older age (>60 years; OR: 2.062), female sex (OR: 3.387), and polypharmacy (OR: 5.276) were identified as the main risk factors. Screening methods and drug interaction databases do not keep pace with the emergence of new therapeutics.

Steroid-based histamine H 3 receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H 3 receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H 3 R activity together with significant in vivo H 3 antagonism. Optimization of the chemotype was initiated with special emphasis on the elimination of the hERG and muscarinic affinity. Additionally, ligand-based SAR considerations and molecular docking studies were performed to predict binding modes of the molecules. The most promising compounds ( XXI , XXVIII , and XX ) showed practically no muscarinic and hERG affinity. They showed antagonist/inverse agonist property in the in vitro functional tests that was apparent in the rat in vivo dipsogenia test. They were considerably stable in human and rat liver microsomes and provided significant in vivo potency in the place recognition and novel object recognition cognitive paradigms.

During optimization of a previously identified lead compound, attempts were made to optimize the reactive indole structural element, the suboptimal metabolic stability, as well as the low kinetic solubility. It was concluded that the indole was important for in vitro activity. With the aim of further improvements, more thorough modifications were also carried out. As a result, a new chemotype (the azetidinespirochromone family) was identified, which proved to be 1 order of magnitude less lipophilic retaining the same high level of in vitro potency as the lead series itself, however, with improved metabolic stability and kinetic solubility. Compound 53 showed the most balanced physicochemical and pharmacological profile with significant in vivo efficacy in the scopolamine-induced amnesia test. Based on these promising results, cognitive enhancement through the positive modulation of α7 nAChRs appears to be a viable approach. Compound 53 was selected to be a preclinical development candidate (as RGH-560 ).

Luteolin, naringenin, myricetin, and ampelopsin are abundant flavonoids in nature, and several dietary supplements also contain them at very high doses. After the peroral intake, flavonoids go through extensive presystemic biotransformation; therefore, typically their sulfate/glucuronic acid conjugates reach high concentrations in the circulation. Xanthine oxidase (XO) enzyme is involved in uric acid production, and it also takes part in the elimination of certain drugs (e.g., 6-mercaptopurine). The inhibitory effects of flavonoid aglycones on XO have been widely studied; however, only limited data are available regarding their sulfate and glucuronic acid conjugates. In this study, we examined the impacts of luteolin, naringenin, myricetin, ampelopsin, and their sulfate/glucuronide derivatives on XO-catalyzed xanthine and 6-mercaptopurine oxidations employing in vitro enzyme incubation assays and molecular modeling studies. Our major results/conclusions are the following: (1) Sulfate metabolites were stronger while glucuronic acid derivatives were weaker inhibitors of XO compared to the parent flavonoids. (2) Naringenin, ampelopsin, and their metabolites were weak inhibitors of the enzyme. (3) Luteolin, myricetin, and their sulfates were highly potent inhibitors of XO, and the glucuronides of luteolin showed moderate inhibitory impacts. (4) Conjugated metabolites of luteolin and myricetin can be involved in the inhibitory effects of these flavonoids on XO enzyme., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Mycotoxins are frequent toxic contaminants in foods and beverages, causing a significant health threat. Interactions of mycotoxins with biotransformation enzymes (e.g., cytochrome P450 enzymes, sulfotransferases, and uridine 5'-diphospho-glucuronosyltransferases) may be important due to their possible detoxification or toxic activation during enzymatic processes. Furthermore, mycotoxin-induced enzyme inhibition may affect the biotransformation of other molecules. A recent study described the strong inhibitory effects of alternariol and alternariol-9-methylether on the xanthine oxidase (XO) enzyme. Therefore, we aimed to test the impacts of 31 mycotoxins (including the masked/modified derivatives of alternariol and alternariol-9-methylether) on XO-catalyzed uric acid formation. Besides the in vitro enzyme incubation assays, mycotoxin depletion experiments and modeling studies were performed. Among the mycotoxins tested, alternariol, alternariol-3-sulfate, and α-zearalenol showed moderate inhibitory actions on the enzyme, representing more than tenfold weaker impacts compared with the positive control inhibitor allopurinol. In mycotoxin depletion assays, XO did not affect the concentrations of alternariol, alternariol-3-sulfate, and α-zearalenol in the incubates; thus, these compounds are inhibitors but not substrates of the enzyme. Experimental data and modeling studies suggest the reversible, allosteric inhibition of XO by these three mycotoxins. Our results help the better understanding of the toxicokinetic interactions of mycotoxins.

Introduction: The public health threat of substandard and falsified medicines has been well known in the last two decades, and several studies focusing on the identification of products affected and preventing consumption have been published. However, the number of these products reaching patients and causing health consequences and adverse drug reactions is not a well-researched area. Objectives: Our aim was to identify and describe the characteristics of cases that are related to adverse drug reactions potentially originating from counterfeit medication using publicly available pharmacovigilance data. Methods: A descriptive study was performed based on pharmacovigilance data retrieved from Individual Case Safety Reports (ICSRs) identified in the European Medicines Agency's EudraVigilance and FDA Adverse Event Reporting System (FAERS) databases in April 2022 using selected MedDRA preferred terms: counterfeit product administered, product counterfeit, product label counterfeit, product packaging counterfeit, suspected counterfeit product, adulterated product, product tampering, and suspected product tampering. ICSRs were analyzed by age and gender, by year of reporting, region of origin, reporter's profession, and severity of the outcome. The disproportionality method was used to calculate pharmacovigilance signal measures. Results: A total of 5,253 cases in the FAERS and 1,049 cases in the EudraVigilance database were identified, generally affecting middle-aged men with a mean age of 51.055 (±19.62) in the FAERS and 64.18% of the cases between 18 and 65 years, while the male to female ratios were 1.18 and 1.5. In the FAERS database, we identified 138 signals with 95% confidence interval including sildenafil ( n = 314; PRR, 12.99; ROR, 13.04; RRR, 11.97), tadalafil ( n = 200; PRR, 11.51; ROR, 11.55; RRR, 10.94), and oxycodone ( n = 190; PRR, 2.47; ROR, 2.14; RRR, 2.47). While in the EV data 31, led by vardenafil ( n = 16, PRR = 167.19; 101.71-274.84; 95% CI, RRR = 164.66; 100.17-270.66; 95% CI, ROR = 169.47; 103.09-278.60; 95% CI, p < 0.001), entecavir ( n = 46, PRR = 161.26, RRR = 154.24, ROR = 163.32, p < 0.001), and tenofovir ( n = 20, PRR = 142.10, RRR = 139.42, ROR = 143.74, p < 0.001). Conclusion: The application of pharmacovigilance datasets to identify potential counterfeit medicine ADRs can be a valuable tool in recognition of potential risk groups of consumers and the affected active pharmaceutical ingredients and products. However, the further development and standardization of ADR reporting, pharmacovigilance database analysis, and prospective and real-time collection of potential patients with health consequences are warranted in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pozsgai, Szűcs, Kőnig-Péter, Balázs, Vajda, Botz and Vida.)

The histamine H 3 receptor is a favourable target for the treatment of cognitive deficits. Here we report the in vitro and in vivo profile of RGH-235, a new potent, selective, and orally active H 3 receptor antagonist/inverse agonist developed by Gedeon Richter Plc. Radioligand binding and functional assays were used for in vitro profiling. Procognitive efficacy was investigated in rodent cognitive tests, in models of attention deficit hyperactive disorder (ADHD) and in cognitive tests of high translational value (rat touch screen visual discrimination test, primate fixed-foreperiod visual reaction time task). Results were supported by pharmacokinetic studies, neurotransmitter release, sleep EEG and dipsogenia. RGH-235 displayed high affinity to H 3 receptors (K i  = 3.0-9.2 nM, depending on species), without affinity to H 1 , H 2 or H 4 receptors and >100 other targets. RGH-235 was an inverse agonist ([ 35 S] GTPγS binding) and antagonist (pERK1/2 ELISA), showing favourable kinetics, inhibition of the imetit-induced dipsogenia and moderate effects on sleep-wake EEG. RGH-235 stimulated neurotransmitter release both in vitro and in vivo. RGH-235 was active in spontaneously hypertensive rats (SHR), generally considered as a model of ADHD, and revealed a robust pro-cognitive profile both in rodent and primate tests (in 0.3-1 mg/kg) and in models of high translational value (e.g. in a rodent touch screen test and in non-human primates). The multiple and convergent procognitive effects of RGH-235 support the view that beneficial cognitive effects can be linked to antagonism/inverse agonism of H 3 receptors., (Copyright © 2021. Published by Elsevier B.V.)

HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of α7 nAChRs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized. A promising, pyrazole-containing new chemotype with good physicochemical and in vitro parameters was identified. Retrospective analysis based on homology modeling was also carried out. Besides its favorable in vitro characteristics, the most advanced derivative 69 also showed in vivo efficacy in a rodent model of cognition (scopolamine-induced amnesia in the mouse place recognition test) and acceptable pharmacokinetic properties. Based on the in vivo data, the resulting molecule with advanced drug-like characteristics has the possibility to improve cognitive performance in a biologically relevant dose range, further strengthening the view of the supportive role of α7 nACh receptors in the cognitive processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Cariprazine is a dopamine D 3 -preferring D 3 /D 2 receptor partial agonist compound recently introduced to treat schizophrenia and bipolar disorder. Although cariprazine is clinically classified as a low-somnolence drug, to date no detailed polysomnographic study is available on its effect on sleep., Aims: This study examined the acute systemic effects of cariprazine on the rat sleep architecture and electroencephalography spectral power., Methods: Sprague Dawley rats were recorded during their normal sleep period for four hours, and their sleep stages were classified., Results: Cariprazine (0.3 mg/kg i.p.) reduced the time spent in rapid eye movement (REM) sleep and increased REM latency. This dose of cariprazine decreased the gamma (40-80 Hz) band frequency oscillations and increased the theta (4-9 Hz) and alpha (9-15 Hz) frequencies during the wake periods but not during slow-wave sleep. The 0.03 mg/kg dose of cariprazine only increased the alpha power during the wake periods, while the 0.003 mg/kg dose was without any effect., Conclusion: Taken together, the present results suggest that the REM-suppressing effect of cariprazine may be related to its effectiveness in improving depressive symptoms, as various drugs with similar REM-reducing properties effectively treat the depressive state, whereas the gamma power-reducing effect of cariprazine may be indicative of its efficacy in schizophrenia or mania, as similar effects have been observed with other D 2 and 5-HT 2 receptor antagonist drugs. These data contribute to our understanding of the complex mechanism of action that may stand behind the clinical efficacy of cariprazine.

To further proceed with our previous work, novel steroid-based histamine H 3 receptor antagonists were identified and characterized. Using an 'amine-to-amide' modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity. The 15α-carboxamido derivative 10 was not only highly active at human and rat H 3 receptors, but also showed negligible activity at rat muscarinic receptors. Furthermore, it proved to be considerably stable in human and rat microsomes and showed significant in vivo potency in the pharmacodynamic rat dipsogenia test and in the water-labyrinth cognitive model. Based on all of these considerations, compound 10 was appointed to be a preclinical candidate., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Emerging from an HTS campaign, novel steroid-based histamine H 3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H 3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.