OBJECTIVE: Emergence delirium (ED) is a postoperative complication in pediatric anesthesia characterized by a perception and psychomotor disorder, with a negative impact on postoperative recovery. As the use of inhalation anesthesia is associated with a higher incidence of ED, we investigated whether titrating the depth of general anesthesia with BIS monitor can reduce the incidence of ED. DESIGN: Randomized, prospective, and double-blind. SETTING: Patients undergoing endoscopic adenoidectomy under general anesthesia according to a uniform protocol. PATIENTS: A total of 163 patients of both sexes aged 3-8 years were enrolled over 18 months. INTERVENTIONS: Immediately after the induction of general anesthesia, a bispectral index (BIS) electrode was placed on the patient's forehead. In the study group, the depth of general anesthesia was monitored with the aim of achieving BIS values of 40-60. In the control group, the dose of sevoflurane was determined by the anaesthesiologist based on MAC (minimum alveolar concentration) and the end-tidal concentration. MEASUREMENTS: The primary objective was to compare the occurrence of ED during the PACU (post-anesthesia care unit) stay in both arms of the study. The secondary objective was to determine the PAED score at 10 and 30 min in the PACU and the need for rescue treatment of ED. MAIN RESULTS: 86 children were randomized in the intervention group and 77 children in the control group. During the entire PACU stay, 23.3% (38/163) of patients developed ED with PAED score >10: 35.1% (27/77) in the control group and 12.8% (11/86) in the intervention group (p = 0.001). Lower PAED scores were also found in the intervention group at 10 (p < 0.001) and 30 (p < 0.001) minutes compared to the control group. The need for rescue treatment did not differ between groups (p = 0.067). CONCLUSION: Individualization of the depth of general anesthesia with BIS monitoring is an effective method of preventing ED in children. CLINICAL TRIAL REGISTRATION: NCT04466579.
- MeSH
- celková anestezie * škodlivé účinky MeSH
- dítě MeSH
- inhalační anestezie * škodlivé účinky MeSH
- lidé MeSH
- pooperační delirium * epidemiologie prevence a kontrola etiologie MeSH
- předškolní dítě MeSH
- probouzení z anestezie MeSH
- prospektivní studie MeSH
- sevofluran MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors. Compounds with balanced inhibitory potencies for the target proteins (K1578 and K1599) or increased potency for AChE (K1592 and K1594) were studied to identify the most promising pro-cognitive compound. Their effects were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the impacts on locomotion in the open field and AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit in memory acquisition, however, it was unaffected by the compounds, and a deficit in reversal learning that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in the striatum, potentially explaining the behavioral observations. The glutamatergic antagonist dizocilpine (MK-801) induced a deficit in memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. In vitro patch-clamp corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistent with intended dual effect. We conclude that tacrine has the potential for development of derivatives with dual in vivo effects. Our findings contributed to the elucidation of the structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive efficacy.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antagonisté excitačních aminokyselin farmakologie MeSH
- bludiště - učení * účinky léků MeSH
- cholinesterasové inhibitory * farmakologie MeSH
- dizocilpinmaleát * farmakologie MeSH
- kognice * účinky léků MeSH
- krysa rodu rattus MeSH
- paměť účinky léků MeSH
- potkani Wistar * MeSH
- receptory N-methyl-D-aspartátu * antagonisté a inhibitory metabolismus MeSH
- skopolamin MeSH
- takrin * farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Spontaneously hypertensive rats (SHR) are characterized by sympathetic hyperactivity and insufficient parasympathetic activity, and their high blood pressure (BP) can be lowered by long-term inhibition of the renin-angiotensin system. The aim of our study was to determine the influence of chronic inhibition of angiotensin converting enzyme (ACE) by captopril on cardiovascular regulation by the sympathetic and parasympathetic nervous system. Implanted radiotelemetric probes or arterial cannulas were used to measure mean arterial pressure (MAP), heart rate (HR), and arterial baroreflex in adult SHR and Wistar-Kyoto (WKY) rats under basal or stress conditions. MAP and the low-frequency component of systolic blood pressure variability (LF-SBPV, marker of sympathetic activity) were greater in SHR than in WKY rats. Under basal conditions chronic captopril treatment reduced both parameters more effectively in SHR, and the same was true during acute restraint stress. HR was similar in control rats of both strains, but WKY rats showed greater heart rate variability (HRV), indicating higher parasympathetic activity. Captopril administration increased HR in both strains, whereas HRV was decreased only in WKY. Chronic captopril treatment improved the impaired baroreflex-HR control in SHR by increasing the sensitivity but not the capacity of vagal arm of arterial baroreflex. Captopril treatment attenuated BP changes elicited by dimethylphenylpiperazinium (DMPP, agonist of nicotinic acetylcholine receptors), especially in SHR, indicating that sympathetic nerve transmission is facilitated by angiotensin II more in hypertensive than in normotensive animals. Thus, chronic ACE inhibition improves baroreflex sensitivity and lowers BP through both central and peripheral attenuation of sympathetic tone.
- MeSH
- baroreflex * účinky léků MeSH
- hypertenze farmakoterapie patofyziologie enzymologie MeSH
- inhibitory ACE * farmakologie MeSH
- kaptopril * farmakologie MeSH
- krevní tlak * účinky léků MeSH
- krysa rodu rattus MeSH
- potkani inbrední SHR MeSH
- potkani inbrední WKY MeSH
- srdeční frekvence * účinky léků MeSH
- sympatický nervový systém * účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.
- MeSH
- antipsychotika farmakologie škodlivé účinky MeSH
- benzodiazepiny farmakologie škodlivé účinky MeSH
- glukagonu podobné peptidy * analogy a deriváty farmakologie MeSH
- hmotnostní přírůstek účinky léků MeSH
- imunoglobuliny - Fc fragmenty * farmakologie MeSH
- kalorická restrikce metody MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- olanzapin * farmakologie škodlivé účinky MeSH
- potkani Sprague-Dawley * MeSH
- přijímání potravy účinky léků MeSH
- receptor pro glukagonu podobný peptid 1 agonisté metabolismus MeSH
- rekombinantní fúzní proteiny * farmakologie MeSH
- tělesná hmotnost účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Ageing of the global population has led to an increase in the demand for the treatment of wounds, especially considering the challenges of managing wounds in the elderly. Therefore, more effective treatment strategies need to be explored. In this article, we aimed to compare medical-grade honey (MGH) products with other wound care products and to provide guidelines on using MGH in wounds commonly found in the elderly. METHODS: Based on literature research and expert opinion, an overview of commonly used wound care products and their wound healing characteristics is provided. In addition, literature-based classification of wounds in the elderly and the recommendations for treatments are provided. RESULTS: Frequently used wound care products include povidone-iodine, enzymatic products, absorbing dressings, larvae, silver dressings, and MGH dressings. Supported by systematic reviews and meta-analyses, MGH dressings were identified as the most potent and all-round wound care product compared to the others. Next, we provided basic guidelines for managing the most common wounds in the elderly, both acute and chronic, and specified how and which MGH products can be used in these wounds. CONCLUSION: MGH is a widely applicable, safe, easy-to-use, and cost-effective product to manage wounds in the elderly. In case of doubt, refer to a trained wound care specialist who can support the treatment of difficult-to-heal wounds.
- Publikační typ
- časopisecké články MeSH
The World Health Organization (WHO) identifies several bunyaviruses as significant threats to global public health security. Developing effective therapies against these viruses is crucial to combat future outbreaks and mitigate their impact on patient outcomes. Here, we report the synthesis of some isoindol-1-one derivatives and explore their inhibitory properties over an indispensable metal-dependent cap-snatching endonuclease (Cap-ENDO) shared among evolutionary divergent bunyaviruses. The compounds suppressed RNA hydrolysis by Cap-ENDOs, with IC50 values predominantly in the lower μM range. Molecular docking studies revealed the interactions with metal ions to be essential for the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold activity. Calorimetric analysis uncovered Mn2+ ions to have the highest affinity for sites within the targets, irrespective of aminoacidic variations influencing metal cofactor preferences. Interestingly, spectrophotometric findings unveiled sole dinuclear species formation between the scaffold and Mn2+. Moreover, the complexation of two Mn2+ ions within the viral enzymes appears to be favourable, as indicated by the binding of compound 11 to TOSV Cap-ENDO (Kd = 28 ± 3 μM). Additionally, the tendency of compound 11 to stabilize His+ more than His- Cap-ENDOs suggests exploitable differences in their catalytic pockets relevant to improving specificity. Collectively, our results underscore the isoindolinone scaffold's potential as a strategic starting point for the design of pan-antibunyavirus drugs.
- MeSH
- antivirové látky farmakologie chemie chemická syntéza MeSH
- Bunyaviridae účinky léků metabolismus MeSH
- endonukleasy * metabolismus antagonisté a inhibitory MeSH
- inhibitory enzymů farmakologie chemie chemická syntéza MeSH
- isoindoly chemická syntéza farmakologie chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- racionální návrh léčiv * MeSH
- simulace molekulového dockingu * MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: Rituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug. METHODS: We compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients' characteristics, rituximab levels and anti-rituximab antibodies. RESULTS: The analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria. CONCLUSION: In order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases.
- MeSH
- biologické modely MeSH
- dospělí MeSH
- glomerulonefritida farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- membranózní glomerulonefritida farmakoterapie MeSH
- mladý dospělý MeSH
- rituximab * farmakokinetika aplikace a dávkování terapeutické užití MeSH
- rozvrh dávkování léků MeSH
- senioři MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg-1.day-1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding.
- MeSH
- benzhydrylové sloučeniny * farmakologie MeSH
- dieta s vysokým obsahem tuků * škodlivé účinky MeSH
- glifloziny * farmakologie MeSH
- glukosidy * farmakologie MeSH
- hypertenze farmakoterapie MeSH
- játra * účinky léků metabolismus patologie MeSH
- kardiotonika farmakologie MeSH
- krevní glukóza metabolismus účinky léků MeSH
- krevní tlak účinky léků MeSH
- krysa rodu rattus MeSH
- ledviny účinky léků metabolismus patologie MeSH
- ochranné látky farmakologie MeSH
- potkani inbrední SHR * MeSH
- ztučnělá játra prevence a kontrola farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
An international joint statement about the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer was published in 2016, warning about the uncritical use of HIPEC outside controlled studies. This statement has now been updated after the most recent literature was reviewed by the participating study groups and societies. HIPEC became a treatment option in patients with advanced colon cancer after positive results of a randomized trial comparing surgery and HIPEC versus palliative treatment alone. Although this trial did not compare the added value of HIPEC to surgery alone, HIPEC for the treatment of peritoneal metastases was in the subsequent years generalized to many other cancer types associated with peritoneal carcinomatosis including epithelial ovarian cancer (EOC). In the meantime, new evidence from prospective randomized trials specifically for EOC-patients emerged, with however contradicting results and several quality aspects that made the interpretation of their findings critical. Moreover, three additional trials in colorectal cancer failed to confirm the previously presumed survival benefit through the implementation of HIPEC in peritoneally disseminated colorectal cancers. Based on a still unclear and inconsistent landscape, the authors conclude that HIPEC should remain within the remit of clinical trials for EOC-patients. Available evidence is not yet sufficient to justify its broad endorsement into the routine clinical practice.
- MeSH
- epiteliální ovariální karcinom patologie MeSH
- hypertermická intraperitoneální peroperační chemoterapie MeSH
- indukovaná hypertermie * metody MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- nádory vaječníků * farmakoterapie patologie MeSH
- prospektivní studie MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Rakousko MeSH
- Švýcarsko MeSH
The global shortage of corneal endothelial graft tissue necessitates the exploration of alternative therapeutic strategies. Rho-associated protein kinase inhibitors (ROCKi), recognized for their regenerative potential in cardiology, oncology, and neurology, have shown promise in corneal endothelial regeneration. This study investigates the repurposing potential of additional ROCKi compounds. Through screening a self-assembled library of ROCKi on B4G12 corneal endothelial cells, we evaluated their dose-dependent effects on proliferation, migration, and toxicity using live-cell imaging. Nine ROCKi candidates significantly enhanced B4G12 proliferation compared to the basal growth rate. These candidates were further assessed for their potential to accelerate wound closure as another indicator for tissue regeneration capacity, with most demonstrating notable efficacy. To assess the potential impact of candidate ROCKi on key corneal endothelial cell markers related to cell proliferation, leaky tight junctions and ion efflux capacity, we analyzed the protein expression of cyclin E1, CDK2, p16, ZO-1 and Na+/K+-ATPase, respectively. Immunocytochemistry and western blot analysis confirmed the preservation of corneal endothelial markers post-treatment with ROCKi hits. However, notable cytoplasm enlargement and nuclear fragmentation were detected after the treatment with SR-3677 and Thiazovivin, indicating possible cellular stress. In compared parameters, Chroman-1 at a concentration of 10 nM outperformed other ROCKi, requiring significantly 1000-fold lower effective concentration than established ROCKi Y-27632 and Fasudil. Altogether, this study underscores the potential of repurposing ROCKi for treating corneal endothelial dysfunctions, offering a viable alternative to conventional grafting methods, and highlights Chroman-1 as a promising candidate structure for hit-to-lead development.
- MeSH
- buněčné linie MeSH
- endoteliální buňky účinky léků MeSH
- inhibitory proteinkinas * farmakologie MeSH
- kinázy asociované s rho * antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- pohyb buněk účinky léků MeSH
- přehodnocení terapeutických indikací léčivého přípravku MeSH
- proliferace buněk * účinky léků MeSH
- regenerace * účinky léků MeSH
- rohovkový endotel * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH