Search

Haloperidol, butyrophenone derivative, is a typical antipsychotic drug used in the treatment of schizophrenia, manic phase of bipolar disorder, and acute psychomotor agitations. According to the recent guidelines for therapeutic drug monitoring, it is strongly recommended to measure plasma level during the therapy with haloperidol. The objective of this study was to develop and validate a simple liquid chromatography–tandem mass spectrometry-based method to quantitate haloperidol in human plasma. After one-step extraction procedure using OSTROTM plate, gradient elution on Acquity UPLC BEH C18 (50 ×2.1mm, 1.7μm) column over 3.2 min was performed. The detection was conducted on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode in positive ionization mode with transitions at m/z 376.29 → 165.14 and m/z 380.28 → 169.17 for haloperidol and haloperidol-d4 (used as an internal standard), respectively. The method was fully validated to cover wide concentration range of 0.05–80 ng/mL in human plasma and meets the criteria for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effect, extraction recovery, carryover, dilution integrity and stability. The extraction recovery was nearly 100%, and no significant matrix effects were observed. Therefore, the method is applicable to routine therapeutic drug monitoring in patients' plasma. [ABSTRACT FROM AUTHOR]

Objective This experimental study evaluated the anti-asthmatic capacity of the dihydroxyflavone chrysin in the settings of ovalbumin (OVA)-induced allergic inflammation. Methods The parameters that were used to assess the anti-asthmatic activity of chrysin included the specific airway resistance to histamine, the sensitivity to a chemically induced cough and the activity of chrysin on the ciliary beat frequency (CBF) of the respiratory epithelium. The anti-inflammatory potential was confirmed by the measurement of cytokine concentrations Th2 (IL-4, IL-5 and IL-13), Th1 (Granulocyte-macrophage colony-stimulating factor [GM-CSF], INF-γ and IL-12), leucocyte count in the bronchoalveolar lavage fluid (BALF) and growth factor TBF-β1 in lung homogenate. Key findings Chronic administration of chrysin (30 mg/kg/day for 21 days) to OVA-sensitised guinea pigs showed bronchodilatory activity comparable to that of long-acting β 2 receptors agonist (LABA) salmeterol. Chrysin revealed antitussive efficiency but was not able to abolish the negative effect of OVA on CBF. Chrysin managed to ameliorate the progression of chronic airway inflammation by decreasing the count of eosinophils, lymphocytes and basophils, IL-5, L-13, GM-CSF, INF-γ in BALF, and TGF-β1 in lung homogenate. Conclusions The acquired results support the complex anti-asthmatic profile of chrysin. The flavone may represent an attractive compound for further studies concerning the prevention or treatment of asthma. [ABSTRACT FROM AUTHOR]

The Rho-kinase signalling pathway plays a significant role in regulating allergic inflammation. Rho-associated kinases belong to the Ser/Thr-protein kinases family, and two isoforms of ROCK--ROCK1 and ROCK2--have been identified. Cytokines involved in allergic inflammation produced by Th2 cells such as IL-4, IL-5, IL-9, and IL-13 increase the Rho-kinase pathway activity. Rho-kinase signalling presumably contributes to profibrotic processes of both epithelial and endothelial cells in response to tissue damage. This assumption has been confirmed in idiopathic pulmonary fibrosis. However, Rho-kinases are supposed to be involved even in other processes; for example, airway remodelling in allergic asthma. Based on the existing knowledge, this study aimed to evaluate the pharmacological profile of Rho-kinase inhibitor hydroxyfasudil in conditions of experimentally induced allergic inflammation in guinea pigs after 14 days of its systemic administration. Chronic allergic airway inflammation was induced by 28-day sensitisation of guinea pigs with allergen ovalbumin (OVA). The effect of the Rho-kinase inhibitor on airway reactivity and cough reflex sensitivity was evaluated in vivo, and the cilia beating frequency (CBF) was tested in vitro. The multiplex method (BioPlex) and the ELISA method were used to determine the levels of inflammatory cytokines, factors involved in tissue remodelling, and transcription factors. The results of our experiments demonstrated the bronchodilatory, anti-inflammatory, and antiremodelling effects of hydroxyfasudil after its systemic administration. These findings indicate that RhoA/Rho-kinase is involved in the pathophysiology of allergic airway inflammation and suggest that Rho-kinase inhibitors have therapeutic potential for the treatment of asthma. [ABSTRACT FROM AUTHOR]

Background: The presented study evaluated the suppositional changes in the airway expression of Nav1.8 and Nav1.7 and their role in the airway defense mechanisms in healthy animals and in an experimental asthma model. Methods: The effects of the blockers inhalation on the reactivity of guinea pig airways, number of citric-acid-induced coughs and ciliary beating frequency (CBF) were tested in vivo. Chronic inflammation simulating asthma was induced by repetitive exposure to ovalbumin. The expression of Nav1.7 and Nav1.8 was examined by ELISA. Results: The Nav 1.8 blocker showed complex antitussive and bronchodilatory effects and significantly regulated the CBF in healthy and sensitized animals. The Nav1.7 blockers significantly inhibited coughing and participated in CBF control in the ovalbumin-sensitized animals. The increased expression of the respective ion channels in the sensitized animals corresponded to changes in CBF regulation. The therapeutic potency of the Nav1.8 blocker was evidenced in combinations with classic bronchodilators. Conclusion: The allergic-inflammation-upregulated expression of Nav1.7 and Nav1.8 and corresponding effects of blocker inhalation on airway defense mechanisms, along with the Nav1.8 blocker's compatibility with classic antiasthmatic drugs, bring novel possibilities for the treatment of various respiratory diseases. However, the influence of the Nav1.8 blocker on CBF requires further investigation. [ABSTRACT FROM AUTHOR]

An abstract of the medical research "THE RELATIONSHIP BETWEEN POTASSIUM ION CHANNELS AND DEFENCE REFLEXES OF THE AIRWAYS," by Martina Sutovska and Gabriela Nosalova is presented.

Background: In asthma, airway remodeling changes contribute to thickening of airway walls and, consequently, lead to poor clinical outcomes among asthmatic patients. Airway remodeling changes include subepithelial fibrosis, increased smooth muscle mass, gland enlargement, neovascularization and epithelial alterations. All these processes are mediated though the Ca2+-dependent pathways. Recently Orai-STIM coupling was proposed as one of the extracellular Ca2+ main sources that mediated airway remodeling. Objective: This study was focused mechanisms of airway remodeling, Orai-STIM pathway involvement in these processes and mechanisms of anti-remodeling effect seen on long-term Orai-STIM pathway inhibition. Methods: The ovalbumin-induced guinea pig model of airway remodeling was in experimental group followed by long-term administration of 3-fluoropyridne-4-carboxylic acid (FPCA, inhibitor of Orai-STIM coupling) and control drugs in control groups (positive control budesonide, negative. [ABSTRACT FROM AUTHOR]

An abstract of the medical research "THE ANTITUSSIVE AND IMMUNOMODULATORY ACTIVITIES OF PECTIN AND HEMICELLULOSE POLYSACCHARIDES ORIGINATED FROM SALVIA OFFICINALIS L.," by Martina Sutovska, Gabriela Nosalova, Sona Franova, Peter Capek and Vera Hribalova is presented.

An abstract of the medical research "PHARMACOLOGICAL INFLUENCE OF UTERINE SMOOTH MUSCLE REACTIVITY," by Sona Franova, Frantisek Janicek, Gabriela Nosalova, Martina Sutovska and Jozef Visnovsky is presented.

This experimental study evaluated the anti-asthmatic potential of the Rho-kinase inhibitor hydroxyfasudil in the settings of allergen-induced allergen-induced experimental asthma. Chronic allergic airway inflammation was caused by 28 days-sensitisation of guinea pigs with ovalbumin (OVA). Hydroxyfasudil was administered intraperitoneally in two doses for the last two weeks (1 mg/kg b.w.; 10 mg/kg b.w.). The degree of allergic inflammation was determined based on concentrations of inflammatory Th2 cytokines (IL-4, IL-13), Th1 cytokines (TNF-α and IFN-γ) in the lung homogenate and leukocyte count in the bronchoalveolar lavage fluid (BALF). The markers of remodelling and fibrosis, the growth factors (TGF-β1, EGF), EGF receptor, collagen type III and V were estimated in lung homogenate. The changes in specific airway resistance (sRaw) were used as an in vivo bronchial hyperreactivity parameter. Hydroxyfasudil administration at both doses significantly reduced sRaw after a week of therapy. We observed a decline of IL-13, TNF-α and IFN-γ in lung homogenate and a lower presence of lymphocytes in BALF after 14 days of hydroxyfasudil administration at both tested doses. Hydroxyfasudil 14 days-treatment at both doses effectively reduced the concentrations of TGF-β1, EGF receptors, collagen type III and V in BALF and modulated EGF levels. These findings indicate that RhoA/Rho-kinase is involved in the pathophysiology of allergic airway inflammation and suggest that Rho-kinase inhibitor hydroxyfasudil has therapeutic potential for asthma management. [Display omitted] • RhoA/Rho-kinase pathway is involved in the pathophysiology of asthma. • Rho-kinase inhibitor hydroxyfasudil has therapeutic potential in managing allergic inflammatory conditions in airways. • The hydroxyfasudil after two weeks of administration in the dose 1 a 10 mg/kg b.w. reduced the concentration of Th2 cytokine IL-13 and Th1 cytokines TNF-α and IFN-γ in lung tissue. • Hydroxyfasudil, after systemic intraperitoneal administration, affected the presence of inflammatory cells in the bronchoalveolar lavage fluid of OVA-sensitised guinea pigs. • Hydroxyfasudil decreased chronic inflammation markers and airway remodelling in an animal model of allergic asthma. [ABSTRACT FROM AUTHOR]

Introduction: Clear cell renal cell carcinoma (ccRCC) is mostly diagnosed incidentally and has relatively high recurrence rates. Alterations in VHL/HIF and mTOR pathways are commonly present in ccRCC. The present study attempted to identify potential diagnostic markers at the biochemical and molecular level. Methods: In total, 54 subjects (36 patients with ccRCC and 18 cancer-free controls) were enrolled. ELISA was used to measure the levels of HIF-1α in the tumor and healthy kidney tissue. The association between five selected SNPs (rs779805, rs11549465, rs2057482, rs2295080 and rs701848) located in genes of pathologically relevant pathways (VHL/HIF and mTOR) and the risk of ccRCC in the Slovak cohort was studied using real-time PCR. Results: Significant differences in HIF-1α tissue levels were observed between the tumor and healthy kidney tissue ( p < 0.001). In the majority (69%) of cases, the levels of HIF-1α were higher in the kidney than in the tumor. Furthermore, the concentration of HIF-1α in the tumor showed a significant positive correlation with CCL3 and IL-1β ( p (R2) 0.007 (0.47); p (R2) 0.011 (0.38). No relationship between intratumoral levels of HIF-1α and clinical tumor characteristics was observed. Rs11549465, rs2057482 in the HIF1A gene did not correlate with the expression of HIF-1α either in the tumor or in the normal kidney. None of the selected SNPs has influenced the susceptibility to ccRCC. Conclusion: More research is neccesary to elucidate the role of HIF-1α in the pathogenesis of ccRCC and the association between selected SNPs and susceptibility to this cancer., 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 © 2024 Vargova, Kolková, Dargaj, Bris, Luptak, Dankova, Franova, Svihra, Slávik and Sutovska.)

This study specified the role of several key calcium-operating ion channels in contraction/relaxation of human detrusor muscle as possible target for overactive bladder (OAB) treatment. Detrusor samples, obtained from 18 males (average age 61.5 ± 5.9 years), were investigated by organ tissue bath method with following agents: diltiazem for L-type voltage-gated calcium channels; 3-fluropyridine-4-carboxylic acid (FPCA) for Orai-STIM channels; SKF 96365-hydrochloride for transient receptor potential (TRP) channels, T-type channels and Orai-STIM channels; 2- aminoethoxydiphenyl borate (2-APB) for inositol-triphosphate receptors (IP3Rs) and Orai-STIM channels. Oxybutynin and mirabegron were tested under the same conditions as controls. Mirabegron, 2-APB and FPCA exhibited the best suppressive effect on carbachol-induced detrusor contractility. As expressed by area under the contractile curve (AUCC), 2-APB, FPCA and mirabegron have similar AUCC: 1.79, 1.73, 1.73. The highest AUCC was 3.64 for diltiazem+SKF, followed by 3.21 for diltiazem, 3.16 for SKF and 2.94 for oxybutynin. The lowest median amplitude and contraction variability is for 2-APB followed by mirabegron and FPCA. There were significant differences between: 2-APB/FPCA vs.: ditiazem, diltiazem+SKF and SKF. Summary of results suggested the principal role of IP3Rs, Orai-STIM coupling and large-conductance calcium-activated potassium channels in detrusor contraction and pointed on Orai-STIM channels as possible targets for OAB pharmacotherapy.

Background: The objective of the study was to observe the effect of rolipram, the prototype phosphodiesterase 4 selective inhibitor, on oxytocin-induced contractions of human term myometrial strips, and compare the effect with salbutamol, beta(2)-adrenergic agonist, in single and the simultaneous application., Methods: Human myometrium was obtained from pregnant women in term that had a term delivery by the caesarian section. Myometrial strips were excised from the lower uterine segment and placed into an organ-bath with Krebs-Henseleit buffer. The mean peak amplitude of contraction (mN) of the myometrial smooth muscle to the doses of oxytocin (10(-6) mmol/L(-1)) with subsequent single administration of rolipram (10(-4) mmol/L(-1)), salbutamol (10(-4) mmol/L(1)) and simultaneous administration of rolipram and salbutamol (both 10(-4) mmol/L(-1)), was used as a parameter of myometrial reactivity., Results: Rolipram alone decreased the oxytocin-induced contractile amplitude to 47.98%, single salbutamol application resulted in amplitudinal decrease to 56.07%, and the combination of both compounds in their simultaneous administration resulted in the decrease of oxytocin-induced contractile amplitude to 29.1%., Conclusion: Our data are consistent with previous studies of the enhanced efficiency of the beta(2)-adrenergic agonist, when administered together with the phosphodiesterase 4-inhibitor. Moreover we have shown that rolipram alone has a more profound effect on oxytocin-induced contractions than salbutamol alone.