Cognitive-enhancing effects of angiotensin IV

Angiotensin IV is a derivative of the potent vasoconstrictor angiotensin II and it has been shown to enhance acquisition, consolidation and recall in animal models of learning and memory when administered centrally or peripherally. Whether changes in angiotensin IV activity underlie the cognitive effects of those cardiovascular drugs designed to disrupt the peripheral renin-angiotensin system in humans remains undetermined, but angiotensin IV appears to be a worthy candidate for consideration in drug development programmes. The mechanism of action of angiotensin IV is still debated, although its AT4 receptor has been convincingly identified as being insulin-regulated amino peptidase, which is also known as oxytocinase and placental leucine aminopeptidase. It is speculated that angiotensin IV may interact with insulin-regulated amino peptidase to enhance neuronal glucose uptake, prevent metabolism of other neuroactive peptides, induce changes in extracellular matrix molecules, or induce release of acetylcholine and/or dopamine. All of these things may be responsible for the beneficial effects on cognition, but none of them are yet proven. Importantly, strain differences in murine responses to angiotensin IV suggest that some individuals may benefit from drugs targeted to the AT4 receptor whilst others may be refractory. At present it thus appears that those individuals with the poorest baseline cognition may receive greatest benefit, but possible genetic differences in responses to angiotensin IV cannot be ruled-out

Histone dependent signalization during pharmacotherapy of chronic obstructive pulmonary disease

Przewlekła obturacyjna choroba płuc (POChP) jest czwartą co do częstości przyczyną zgonów na świecie. Molekularne mechanizmy odpowiadające za rozwój choroby nie zostały dotychczas poznane, ale wiadomo, że u podłoża POChP leży przewlekły proces zapalny i stres oksydacyjny/nitrozacyjny spowodowany paleniem tytoniu. Wyniki ostatnich badań wskazują, że zaburzenia funkcji histonów, które prowadzą, poprzez wzrost transkrypcji genów, do syntezy cytokin prozapalnych, mogą odgrywać zasadniczą rolę w patomechanizmie choroby. Reakcje acetylacji i deacetylacji histonów wpływają na ich aktywność transkrypcyjną, a zmiany intensywności tych reakcji, wywołane przez leki, mogą stanowić interesujące pole do dalszych badań. W artykule autorzy prezentują aktualne opinie na temat roli steroidów jako inhibitorów stanu zapalnego, jak również zjawiska steroidooporności. Wyniki badań, w których oceniano aktywność przeciwzapalną i zdolność do hamowania stresu oksydacyjnego takich leków, jak teofilina i N-acetylocysteina, mogą prowadzić do zastosowania tych leków w leczeniu przyczynowym POChP, jednakże obserwacje te wymagają potwierdzenia w przebiegu dalszych badań.Chronic obstructive pulmonary disease (COPD) is a 4th major cause of morbidity and mortality worldwide. Cigarette smoking and oxidative/nitrosative stress leading to chronic inflammation is considered as a major cause of COPD but up to now, details of molecular pathways responsible for development of disease are unknown. Recent reports indicate the role of disruption in histone function in promoting synthesis of inflammatory cytokines through increased gene transcription which underlies disease development. Core histone acetylation/deacetylation regulate their transcription activity and drug induced changes of its intensity may be an interesting field of further research. In this article the opinions about the role of steroids as inhibitors of the inflammatory process as well as resistance to steroids have been presented. Findings from studies which aimed to explore the anti-inflammatory activity of drugs such as theophylline and N-acetylcysteine and their ability to suppress oxidative stress may suggest the usefullness of these drugs in causative treatment of COPD. However, further studies are necessary to confirm these findings

Leczenie przewlekłej obturacyjnej choroby płuc - bronchodylatacja i przeciwzapalna farmakoterapia celowana

Currently available pharmacological treatment of COPD relies mostly on prophylaxis (smoking cessation) and symptomatic treatment, i.e. inhaled anticholinergic agents, β2-agonists and phosphodiesterase inhibitors, aiming in their bronchodilatation capacity. Inhaled corticosteroid therapy is mainly prescribed in far advanced stages of the disease and its role in disease modification is still controversial. The authors analize currently available treatment modalities with regards to their potential anti-inflammatory and pleiotropic mode of action, which may lead to disease course modification. Pneumonol. Alergol. Pol. 2011; 79, 1: 32-38Stosowane obecnie farmakologiczne leczenie POChP opiera się na profilaktyce - terapii antynikotynowej oraz leczeniu objawowym, czyli stosowaniu wziewnych leków antycholinergicznych, β2-agonistów, inhibitorów fosfodiesterazy, głównie pod kątem ich skuteczności bronchodylatacyjnej. W zaawansowanym stadium stabilnej choroby zaleca się leczenie wziewnymi steroidami kory nadnerczy, chociaż ich wpływ na przebieg choroby w dalszym ciagu wzbudza kontrowersje. Autorzy niniejszej pracy zanalizowali wybrane grupy leków stosowanych w POChP pod kątem ich potencjalnego mechanizmu działania przeciwzapalnego i plejotropowego, który może mieć wpływ na modyfikację przebiegu choroby. Pneumonol. Alergol. Pol. 2011; 79, 1: 32-3

Ocena skuteczności fentanylu podawanego przezśluzówkowo w terapii bólów przebijających u chorych na nowotwory

Background. In cancer patients persistent pain can co-exist with acute, severe pain, so called breakthrough pain. This kind of pain is relatively common, and difficult to treat. Breakthrough pain is usually managed with supplemental strong and short-acting analgesic medications. The objective of this work was to evaluate effectiveness of oral transmucosal fentanyl citrate for the management of the breakthrough pain. Materials and methods. 26 adult patients of Hospice of Białystok with persistent cancer pain were recruited into this study. Patients received transdermal fentanyl for persistent pain and oral morphine or transmucosal fentanyl for breakthrough pain. Chronic and breakthrough pain intensity, time to pain relief and patients’ satisfaction scores were recorded. Results. The median of chronic pain intensity was 2.1 and median of breakthrough pain was 6 according to visual analogue scale (VAS). There was no difference between oral morphine and submucosal fentanyl in pain relief, but time to pain relief was significantly shorter in case of fentanyl. Plasma fentanyl concentrations ranged between 0.39 and 1.86 ng/ml and did not increase after transmucosal administration of fentanyl. Conclusions. Transmucosal fentanyl appears effective in the management of breakthrough pain. Cancer patients found this therapy acceptable.Wstęp. Bóle przebijające, które występują u chorych na nowotwory leczonych z powodu bólu przewlekłego, stanowią ważny problem kliniczny. W terapii tego rodzaju bólu stosuje się tzw. dawki ratujące silnie i szybko działających leków przeciwbólowych. Celem badania była ocena przeciwbólowego efektu roztworu cytrynianu fentanylu podawanego przezśluzówkowo. Materiał i metody. Badaniem objęto 26 pacjentów Hospicjum w Białymstoku, u których stosowano fentanyl przezskórny jako podstawową terapię bólu oraz wodny roztwór morfiny doustnie lub roztwór cytrynianu fentanylu przezśluzówkowo w wypadku wystąpienia bólu przebijającego. Oceniano natężenie bólu podstawowego oraz przebijającego, czas od podania leku do ustąpienia bólu przebijającego, preferencje w wyborze leku oraz stężenie fentanylu w surowicy krwi. Wyniki. Średnie natężenie bólu podstawowego oceniono w skali VAS na 2,1, zaś bólu przebijającego na 6. Stopień analgezji po podaniu obu preparatów był analogiczny, przy czym fentanyl podany przezśluzówkowo działał znamiennie szybciej niż morfina podana doustnie. Stężenie fentanylu w surowicy krwi wahało się w granicach 0,39–1,86 ng/ml i nie ulegało wykrywalnemu podwyższeniu po podaniu dodatkowej dawki preparatu w formie przezśluzówkowej. Wnioski. Fentanyl podawany przezśluzówkowo stanowi skuteczną i akceptowaną przez pacjentów formę terapii bólów przebijających u chorych na nowotwory

Posttranslational p53 phosphorylation in non small cell lung cancer cells after radio/chemotherapy

Wstęp: Jednym z najważniejszych regulatorów cyklu komórkowego i apoptozy jest białko p53. Wiele czynników zmienia ekspresję tego białka i modyfikuje jego funkcje. Celem badań autorów było określenie stabilności i wybranych potranslacyjnych modyfikacji białka p53 w przebiegu terapii raka płuca. Materiał i metody: Oceniano zmiany ilości markera uszkodzenia DNA - poli-ADP-rybozy, ploidię DNA, ekspresję antygenu proliferacyjnego Ki-67, ekspresję natywnego i zmutowanego p53 oraz intensywność reakcji fosforylacji wybranych reszt serynowych tego białka, C-końcowej Ser392 i N-końcowych Ser15 i Ser20 w próbkach pobranych w trakcie bronchoskopii chorych na nawrotowego niedrobnokomórkowego raka płuca przed radio- i chemioterapią i po niej. Badania objęły 23 pacjentów będących po zabiegu chirurgicznym w stadiach I-IIIA.Wyniki: Terapia obniżyła liczbę komórek będących w fazie G2/M, ale zwiększyła frakcję komórek w fazie S o około 50%. Zwiększyła także ekspresję białka p53 oraz ilość białka fosforylowanego w pozycjach Ser392 i Ser20, a zmiany te korelowały ze zmianami ilości poli-ADP-rybozy i ekspresją Ki-67. Wnioski: Uzyskane przez autorów wyniki wskazują, że oprócz zmian ekspresji białka p53 jego potranslacyjna fosforylacja uczestniczy w regulacji proliferacji komórek nowotworowych pod wpływem leków.Introduction: p53 protein is a critical regulator of cell cycle and apoptosis. Many stimuli change its expression and modify its functions. The aim of our work was to determine stability and chosen posttranslational modification of p53 protein during the treatment of lung cancer. Material and methods: We investigated levels of poly-ADP-ribose- a marker of cellular DNA damage, DNA ploidy, Ki-67 expression, wild type and mutated p53 protein expression and intensity of phosphorylation of chosen p53 serine sites: C-terminal Ser392, and N-terminal Ser15, and Ser20 in fiberoptic bronchoscopy biopsy samples taken from patients suffering from recurrent squamous cell lung cancer before and after radio/chemotherapy. Analysis was based on results obtained from 23 patients after surgery in I-IIIA clinical stage of the disease. Results: Therapy lowered the number of G2/M cells, but increased S fraction cell population in about 50%. Therapy increased p53 expression and p53 phosphorylation at Ser392 and Ser20, and these changes correlated with poly-ADP-ribose levels and Ki-67 expression. Conclusions: Our results indicate that apart from changes in p53 quantity, p53 posttranslational phosphorylation play a role in regulation of neoplastic cells proliferation in response to drugs

Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase

The peptides angiotensin IV and LVV-hemorphin 7 were found to enhance memory in a number of memory tasks and reverse the performance deficits in animals with experimentally induced memory loss. These peptides bound specifically to the enzyme insulin-regulated aminopeptidase (IRAP), which is proposed to be the site in the brain that mediates the memory effects of these peptides. However, the mechanism of action is still unknown but may involve inhibition of the aminopeptidase activity of IRAP, since both angiotensin IV and LVV-hemorphin 7 are competitive inhibitors of the enzyme. IRAP also has another functional domain that is thought to regulate the trafficking of the insulin-responsive glucose transporter GLUT4, thereby influencing glucose uptake into cells. Although the exact mechanism by which the peptides enhance memory is yet to be elucidated, IRAP still represents a promising target for the development of a new class of cognitive enhancing agents

The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: Role of the renin angiotensin system inhibition

<p>Abstract</p> <p>Background</p> <p>Prior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC), to compare 1 year treatment of 3 antihypertensives (lisinopril, candesartan, or hydrochlorothiazide) in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments.</p> <p>Methods/Design</p> <p>The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older) with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control") for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP < 140 mm Hg and DBP < 90 mm Hg. Additional antihypertensives are added to achieve this goal if needed. Eligible participants are those with hypertension, defined as a blood pressure 140/90 mm Hg or greater, early cognitive impairment without dementia defined (10 or less out of 15 on the executive clock draw test or 1 standard deviation below the mean on the immediate memory subtest of the repeatable battery for the assessment of neuropsychological status and Mini-Mental-Status-exam >20 and without clinical diagnosis of dementia or Alzheimer's disease). Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives), 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory), cerebral blood flow, and carbon dioxide cerebral vasoreactivity.</p> <p>Discussion</p> <p>The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the threshold of dementia. Success of this trial will offer new therapeutic application of antihypertensives that inhibit the renin angiotensin system and new insights in the role of this system in aging.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov NCT00605072</p

Impact of chronic stress protocols in learning and memory in rodents: systematic review and meta-analysis

The idea that maladaptive stress impairs cognitive function has been a cornerstone of decades in basic and clinical research. However, disparate findings have reinforced the need to aggregate results from multiple sources in order to confirm the validity of such statement. In this work, a systematic review and meta-analyses were performed to aggregate results from rodent studies investigating the impact of chronic stress on learning and memory. Results obtained from the included studies revealed a significant effect of stress on global cognitive performance. In addition, stressed rodents presented worse consolidation of learned memories, although no significantly differences between groups at the acquisition phase were found. Despite the methodological heterogeneity across studies, these effects were independent of the type of stress, animals' strains or age. However, our findings suggest that stress yields a more detrimental effect on spatial navigation tests' performance. Surprisingly, the vast majority of the selected studies in this field did not report appropriate statistics and were excluded from the quantitative analysis. We have therefore purposed a set of guidelines termed PROBE (Preferred Reporting Orientations for Behavioral Experiments) to promote an adequate reporting of behavioral experiments.This work was funded by the European Commission (FP7) "SwitchBox" (Contract HEALTH-F2-2010-259772) project and co-financed by the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), and by Fundacao Calouste Gulbenkian (Portugal) (Contract grant number: P-139977; project "Better mental health during ageing based on temporal prediction of individual brain ageing trajectories (TEMPO)"). PSM is supported by an FCT fellowship grant, from the PhD-iHES program, with the reference PDE/BDE/113601/2015.info:eu-repo/semantics/publishedVersio

Harmonizing and improving European education in prescribing: An overview of digital educational resources used in clinical pharmacology and therapeutics

Aim: Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re-used widely across a variety of educational systems, they may be ideally suited for this purpose. Methods: With a cross-sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. Results: Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e-learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge-based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in-part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. Conclusion: Digital educational resources, ranging from e-learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real-life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials

EurOP2E – the European Open Platform for Prescribing Education, a consensus study among clinical pharmacology and therapeutics teachers

Purpose Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. Methods CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. Results Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. Conclusion Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system