Lu, N H*
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Depresivní a úzkostné obtíže jsou časté, nezřídka vedou ke snížení kvality života a zvyšují mortalitu i morbiditu. Mnoho pacientů netoleruje léčbu současně dostupnými preparáty pro výskyt nežádoucích účinků. Vývoj nových látek nabízí možnosti léčby těchto pacientů, ale i další možnost v terapii rezistentních stavů. Nové antidepresivum Lu-AA21004, vortioxetin, vykazuje kombinované antidepresivní a anxiolytické působení v serotoninovém neurotransmiterovém systému, antagonizuje 5-HT3 a 5-HT7 receptory, agonizuje 5HT1A receptory, parciálně agonizuje 5-HT receptory a je inhibitorem serotoninového transportéru. Je účinný v terapii depresivních i úzkostných obtíží, což bylo opakovaně prokázáno v pokusech na zvířatech a později v preklinických studiích. Metabolizuje se cestou cytochromoxidázových izoenzymů skupiny P450 s průměrným poločasem vylučování 57 hodin. Při podání nebyly nalezeny významnější lékové interakce avliv etanolu na metabolizmus vortioxetinu byl zanedbatelný. Látka se jeví jako bezpečná a nebyla prokázána její kardiovaskulární toxicita. Vortioxetin lze považovat za účinné psychofarmakum ve všech věkových skupinách dospělých nemocných V akutní i udržovací etapě léčby depresivní poruchy a existují první pozitivní výsledky na poli akutní i udržovací etapy léčby generalizované úzkostné poruchy. V současnosti byly dokončeny potřebné registrační studie III. fáze a výrobce již podal žádost o registraci pro léčbu depresivních epizod v Evropě i USA.
Depression and anxiety are common; they often lead to decreased quality of life and increased mortality and morbidity. A number of patients can not be treated with currently available antidepressants due to intolerability of adverse effects. Development of n ew drugs offers new possibilities for them, and brings another treatment option in resistant episodes. Lu-AA21004, vortioxetine, shows c ombined antidepressive and anxiolytic effect. It is antagonist of 5-HT3 and 5-HT7 receptors, agonist 5-HT1A, partial agonist 5-HT1B and inhi- bitor of serotonin transporter. Vortioxe tine is e fficient in treatment of depression and anxiety, which was repeat edly proven b y tests both in animal models and in preclinical trials. It is metabolized by CYP 450 isoenzymes with average half life about 57 hours. The re was no significant drug interaction found and influence of ethanol was insignificant. There was no cardiovascular effect. Vo rtioxetine appears to be safe and useful in acute and maintenance treatment of depressive disorder in adult and elderly population and seems to be eff ective in acute and maintenance treatment of generalized anxiety disorder. Nowadays, all necessary registration studies in III. phase were com pleted and manufacturer has submitted registration application for treatment of depression in Europe and USA .
- Klíčová slova
- Lu-AA21004, 5-HT3, 5-HT7, 5-HT1A, 5-HT1B, SERT, CYP 450,
- MeSH
- agonisté serotoninových receptorů chemická syntéza MeSH
- antidepresiva * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- deprese diagnóza etiologie farmakoterapie MeSH
- farmakokinetika MeSH
- hodnocení léčiv MeSH
- klinické zkoušky jako téma MeSH
- klinické zkoušky, fáze III jako téma MeSH
- krysa rodu rattus MeSH
- lékové interakce MeSH
- lidé MeSH
- recidiva MeSH
- sekundární prevence MeSH
- úzkostné poruchy diagnóza etiologie farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Environmental cues modulate the balance of carbon (C) and nitrogen (N) which are essential elements for plant metabolism and growth. In Arabidopsis, photochemical efficiency of PSII, phosphorylation status and localization of many enzymes, and the level of total soluble sugars were affected by an unbalanced C/N ratio. Since differences in C/N affect these parameters, here we checked whether different sources of N have different effects when a high C/N ratio is imposed. NO3- and NH4+ were separately provided in C/N medium. We investigated the effects on photochemical efficiency of PSII, the level of total soluble sugars and nitrate reductase activity under stressful C/N conditions compared with control conditions. We found that treated plants accumulated more total soluble sugars when compared with control. Photochemical efficiency of PSII did not show significant differences between the two sources of nitrogen after 24 h. The actual nitrate reductase activity was the result of a combination of activity, activation state and protein level. This activity constantly decreased starting from time zero in control conditions; in contrast, the actual nitrate reductase activity showed a peak at 2 h after treatment with NO3-, and at 30 min with NH4+. This, according to the level of total soluble sugars, can be explained by the existence of a cross-talk between the sugars in excess and low nitrate in the medium that blocks the activity of nitrate reductase in stressful sugar conditions until the plant is adapted to the stress.
- MeSH
- amoniové sloučeniny metabolismus MeSH
- Arabidopsis enzymologie genetika MeSH
- dusičnany metabolismus MeSH
- dusík metabolismus MeSH
- fosforylace MeSH
- nitrátreduktasa genetika metabolismus MeSH
- proteiny 14-3-3 genetika metabolismus MeSH
- regulace genové exprese u rostlin * MeSH
- uhlík metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [(89)Sr]SrCl2 and [(153)Sm]Sm-EDTMP. No-carrier-added (n.c.a.) (177)Lu is remarkably suitable for an application in this scope. METHODS: Five 1,4,7,10-tetraazacyclododecane N,N',N'',N''-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. (177)Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [(177)Lu]citrate. RESULTS: Radiolabelling yields for [(177)Lu]Lu-DOTA and [(177)Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All (177)Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. (177)Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [(177)Lu]Lu-DO2A(P(BP))2; SUVfemur = 5.41 ± 0.46 for [(177)Lu]Lu-DOTA(M(BP))2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [(177)Lu]Lu-DO2A(P(BP))2; SUVblood = 1.43 ± 0.32 for [(177)Lu]Lu-DOTA(M(BP))2). CONCLUSIONS: Lu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.
- Publikační typ
- časopisecké články MeSH
Adolescents' excessive electronic device use is associated with psychological problems. However, it is unknown which psychological symptom, including emotional symptoms and sleep difficulty, correlates with excessive electronic device use most strongly. Besides, according to the social displacement theory, parent-adolescent communication might mediate the relationship between excessive electronic device use and psychological symptoms. Using the Czech national survey Health Behaviour in School-aged Children (HBSC) data in the years 2006 (n = 4782) and 2014 (n = 5082), we used network analysis to explore the relationship between psychological symptoms and excessive electronic device use. In addition, we conducted a mediation analysis to examine the role of parent-adolescent communication. The results revealed that excessive electronic device use correlated most strongly with adolescents' irritability or bad temper, and this conclusion was stable in 2006 and 2014. In 2014, parent-adolescent communication mediated the relationship between adolescents' excessive electronic device use and their psychological symptoms. The findings suggest that as the internet industry grows, it is essential to improve parent-adolescent communication quality to prevent adolescents' psychological problems caused by excessive electronic device use.
- Publikační typ
- časopisecké články MeSH
High-quality teacher-child interactions in early learning environments have been regarded as a key contributor to children's early language and cognitive development in international scholarships. Little is known, however, about the longitudinal effects of children's receptive vocabularies in the Chinese context. In this study, we addressed the question of such longitudinal effects by examining the predictive effect of preschool teacher-child interaction quality on children's subsequent receptive vocabulary development in 42 kindergartens in Guangdong Province China. The results in a nested design showed that except for the factor of Emotional Support, the other two factors (Classroom Management and Instructional Support) were positive predictors to children's vocabulary competency from K2 (T1) to K3 (T2) at preschools. Findings contribute to the growing international literature on the critical role teacher-child interaction quality plays in children's language and literacy learning and development. Implications for enhancing communication channels between early childhood (EC) educators and decision-makers, and the strategies of the improvement of language and literacy teachers' professional development are also discussed.
- Publikační typ
- časopisecké články MeSH
Since methamphetamine reemerged in China, it has become a severe problem. Following the epidemic of methamphetamine in western countries, the methamphetamine use entered in China in the late 1990s. In the last decade, new type drugs, including methamphetamine, MDMA and ketamine, rapidly spread from some cities in southeast coast to other inland areas. The impact of methamphetamine abuse on public health and social stability has drawn government's attention to solve the problem. Chinese government has adopted complex measures both in treatment and prevention of methamphetamine abuse. However, the different characteristics of methamphetamine from traditional addictive drugs such as heroin call for China to adjust its policy and strategy on drug control. With the continuous efforts by government and changing attitudes of public to drug, we believe methamphetamine abuse would be brought under control in China. Dr. Lin Lu is Director of China‘s National Institute on Drug Dependence (NIDD), and a Professor in the Department of Psychiatry and Pharmacology at Peking University. Before taking the position at NIDD, China, he worked at NIDA/IRP, NIH in the United States, focusing on the area of the neurobiology of cocaine withdrawal and relapse. NIDD is China‘s premiere national organization focusing on addiction, from basic science to clinical treatment. Its departments include neuroscience, epidemiology, medication development, clinical pharmacology and an addiction treatment center. In 2005, Dr. Lu organized NIDD‘s Methadone Maintenance Treatment program (MMT), Since 2006, Dr. Lu has researched harm reduction efforts in China. Professor Lu has worked in the addiction field for 19 years. In that time he has pub- lished more than 100 peer-reviewed papers ranging from molecular to behavioral issues of addiction. As a clinical physician, he also published more than 50 papers on treatment and medication development for addiction and depression. Dr. Lu was trained as a clinical doctor and received his Ph.D. after working as a physician in the field of mental health and addiction. His development of an internet-based psychotherapy and suicide-management program for patients with mental health and addiction problems won him recognition as an expert in addiction treatment in China. During Dr. Lu‘s five years at NIDA/NIH, he published more than 20 papers in interna- tional peer-reviewed journals such as Nature, Neurosciences, Trends in Neurosciences, J o u r n a l o f Ne u r o s c i e n c e , B i o l o g i c a l Psychiatry, Neuropsychopharmacology, and Psychopharmacology.
Objects: Health Behaviours in School-aged Children (HBSC) is an international survey programme aiming to investigate adolescents' health behaviours, subjective perception of health status, wellbeing, and the related contextual information. Our scoping review aimed to synthesise the evidence from HBSC about the relationship between family environmental contributors and adolescents' health-related outcomes. Methods: We searched previous studies from six electronic databases. Two researchers identified the qualified publications independently by abstract and full-text screening with the assistance of an NLP-based AI instrument, ASReview. Publications were included if they were based on HBSC data and investigated the effects of family environment on adolescents' health outcomes. Researches addressed family-related factors as mediators or moderators were also included. Results: A total of 241 articles were included. Family environmental contributors could be mapped into six categories: (1) Demographic backgrounds (N = 177); (2) General family's psycho-socio functions (N = 44); (3) Parenting behaviours (N = 100); (4) Parental health behaviours (N = 7); (5) Family activities (N = 24); and (6) Siblings (N = 7). Except for 75 papers that assessed family variables as moderators (N = 70) and mediators (N = 7), the others suggested family environment was an independent variable. Only five studies employed the data-driven approach. Conclusion: Our results suggest most research studies focussed on the influences of family demographic backgrounds on adolescents' health. The researches related to parental health behaviours and siblings are most inadequate. Besides, we recommend further research studies to focus on the mediator/moderator roles of the family, for exploring the deep mechanism of the family's impacts. Also, it would be valuable to consider data-driven analysis more in the future, as HBSC has mass variables and data.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
This study investigated whether each part of the heart is evenly innervated by the left or right vagus and observed the mechanism of compensatory recovery after unilateral cervical vagotomy. HR, BP, LVSP and ±dp/dt max all decreased one week after left vagotomy, whereas only BP and -dp/dt max decreased one week after right vagotomy. Western blot analyses revealed that the expression of M2 receptors in the left atrium and left ventricle was upregulated after subacute (1 week) left/right vagotomy. However, significantly more cholinesterase-positive nerves in LV and RV were seen one week after unilateral vagotomy compared to the sham-operated group. In addition, baroreflex sensitivity was increased after subacute right vagotomy. The decreasing effects of ACh (0.5 µg/kg) on LVSP and ±dp/dt max (but not on HR and BP) were facilitated by subacute unilateral vagotomy. Our present experiments indicate that 1) the working myocardium is innervated bilaterally by the vagus, 2) ventricular contractility is influenced more by denervation of the left than the right vagus and 3) up-regulation of M2 muscarinic receptors in the left heart, increase of cholinergic nerves, and high baroreflex sensitivity could be involved in the mechanism of compensatory hemodynamic recovery via contralateral vagus overactivity, thereby amplifying contralateral vagal activity and decreasing cardiac contractility.
- MeSH
- acetylcholin fyziologie MeSH
- baroreflex fyziologie MeSH
- cholinergní vlákna fyziologie MeSH
- funkční lateralita fyziologie MeSH
- fyziologická adaptace MeSH
- hemodynamika fyziologie MeSH
- krevní tlak genetika MeSH
- krysa rodu rattus MeSH
- nervus vagus fyziologie MeSH
- potkani Sprague-Dawley MeSH
- receptor muskarinový M2 fyziologie MeSH
- srdeční frekvence fyziologie MeSH
- srdeční komory metabolismus MeSH
- srdeční síně inervace MeSH
- vagotomie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
Ulinastatin [or called as urinary trypsin inhibitor (UTI)] plays a role in regulating neurological deficits evoked by transient cerebral ischemia. However, the underlying mechanisms still need to be determined. The present study was to examine the effects of UTI on autophagy, Nrf2-ARE and apoptosis signal pathway in the hippocampus in the process of neurological functions after cerebral ischemia using a rat model of cardiac arrest (CA). CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. Western blot analysis was employed to determine the expression of representative autophagy (namely, Atg5, LC3, Beclin 1), p62 protein (a maker of autophagic flux), and Nrf2-ARE pathways. Neuronal apoptosis was assessed by determining expression levels of Caspase-3 and Caspase-9, and by examining terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL). The modified neurological severity score (mNSS) and spatial working memory performance were used to assess neurological deficiencies in CA rats. Our results show that CA amplified autophagy and apoptotic Caspase-3/Caspase-9, and downregulated Nrf2-ARE pathway in the hippocampus CA1 region. Systemic administration of UTI attenuated autophagy and apoptosis, and largely restored Nrf2-ARE signal pathway following cerebral ischemia and thereby alleviated neurological deficits with increasing survival of CA rats. Our data suggest that UTI improves the worsened protein expression of autophagy and apoptosis, and restores Nrf2-ARE signals in the hippocampus and this is linked to inhibition of neurological deficiencies in transient cerebral ischemia. UTI plays a beneficial role in modulating neurological deficits induced by transient cerebral ischemia via central autophagy, apoptosis and Nrf2-ARE mechanisms.
- MeSH
- antioxidační responzivní elementy účinky léků fyziologie MeSH
- apoptóza účinky léků fyziologie MeSH
- autofagie účinky léků fyziologie MeSH
- faktor 2 související s NF-E2 metabolismus MeSH
- glykoproteiny farmakologie terapeutické užití MeSH
- hipokampus účinky léků metabolismus patologie MeSH
- inhibitory trypsinu farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- náhodné rozdělení MeSH
- neuroprotektivní látky farmakologie terapeutické užití MeSH
- potkani Sprague-Dawley MeSH
- signální transdukce účinky léků fyziologie MeSH
- tranzitorní ischemická ataka farmakoterapie metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
