Synthesis, in vitro and in vivo evaluation of 1,3,5-triazines as cannabinoid CB2 receptor agonists

The cannabinoid receptors type 2 (CBR2) are attractive therapeutic targets of the endocannabinoid signaling system (ECS) as they are not displaying the undesired psychotropic and cardiovascular side-effects seen with cannabinoid receptor type 1 (CB1R) agonists. In continuation of our previous work on 2,4,6-trisubstituted 1,3,5-triazines as potent CB2 agonists, we synthesized an additional series of more polar analogues (1-10), which were found to possess high CB2R agonist activity with enhanced water solubility. The most potent compound in the series was N-(adamantan-1-yl)-4-ethoxy-6-(4-(2-fluoroethyl)piperazin-1-yl)-1,3,5-triazin-2-amine (9) with EC50 value of 0.60nM. To further evaluate the biological effects of the compounds, the selected compounds were tested in vitro against four different cell lines. A human retinal pigment epithelial cell line (ARPE-19) was used to evaluate the cytotoxicity of the compounds whereas an androgen-sensitive human prostate adenocarcinoma cell line (LNCaP), a Jurkat leukemia cell line and a C8161 melanoma cell line were used to assess the antiproliferative activity of the compounds. The most interesting results were obtained for N-(adamantan-1-yl)-4-ethoxy-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (6), which induced cell viability decrease in prostate and leukemia cell lines, and diminished proliferation of C8161 melanoma cells. The results could be reversed in leukemia cells with the selective CB2R antagonist AM630, whereas in prostate cells the AM630 induced a significant cell viability decrease with a mechanism probably unlinked to CB2 cannabinoid receptor. The antiproliferative effect of 6 on the melanoma cells seemed not to be mediated via the CB1R or CB2R. No cytotoxicity was detected against ARPE-19 cell line at concentrations of 1 and 10μM for compound 6. However, at 30μM concentration the compound 6 decreased the cell viability. Finally, in order to estimate in vivo behavior of these compounds, (18)F labeled PET ligand, N-cyclopentyl-4-ethoxy-6-(4-(2-fluoro-18-ethyl)piperazin-1-yl)-1,3,5-triazin-2-amine ([(18)F]5), was synthesized and its biodistribution was determined in healthy male Sprague-Dawley rats. As a result, the tracer showed a rapid (<15min) elimination in urine accompanied by a slower excretion via the hepatobiliary route. In conclusion, we further demonstrated that 1,3,5-triazine scaffold serves as a suitable template for the design of highly potent CB2R agonists with reasonable water solubility properties. The compounds may be useful when studying the role of the endocannabinoid system in different diseases. The triazine scaffold is also a promising candidate for the development of new CB2R PET ligands

Hydroxychloroquine reduces interleukin-6 levels after myocardial infarction : The randomized, double-blind, placebo-controlled OXI pilot trial

Objectives: To determine the anti-inflammatory effect and safety of hydroxychloroquine after acute myocardial infarction. Method: In this multicenter, double-blind, placebo-controlled OXI trial, 125 myocardial infarction patients were randomized at a median of 43 h after hospitalization to receive hydroxychloroquine 300 mg (n = 64) or placebo (n = 61) once daily for 6 months and, followed for an average of 32 months. Laboratory values were measured at baseline, 1, 6, and 12 months. Results: The levels of interleukin-6 (IL-6) were comparable at baseline between study groups (p = 0.18). At six months, the IL-6 levels were lower in the hydroxychloroquine group (p = 0.042, between groups), and in the on-treatment analysis, the difference at this time point was even more pronounced (p = 0.019, respectively). The high-sensitivity C-reactive protein levels did not differ significantly between study groups at any time points. Eleven patients in the hydroxychloroquine group and four in the placebo group had adverse events leading to in-terruption or withdrawal of study medication, none of which was serious (p = 0.10, between groups). Conclusions: In patients with myocardial infarction, hydroxychloroquine reduced IL-6 levels significantly more than did placebo without causing any clinically significant adverse events. A larger randomized clinical trial is warranted to prove the potential ability of hydroxychloroquine to reduce cardiovascular endpoints after myocar-dial infarction. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Peer reviewe

The EU societal awareness of landscape indicator: a review of its meaning, utility and performance across different scales

There is increasing recognition that agricultural landscapes meet multiple societal needs and demands beyond provision of economic and environmental goods and services. Accordingly, there have been significant calls for the inclusion of societal, amenity and cultural values in agri-environmental landscape indicators to assist policy makers in monitoring the wider impacts of land-based policies. However, capturing the amenity and cultural values that rural agrarian areas provide, by use of such indicators, presents significant challenges. The EU social awareness of landscape indicator represents a new class of generalized social indicator using a top-down methodology to capture the social dimensions of landscape without reference to the specific structural and cultural characteristics of individual landscapes. This paper reviews this indicator in the context of existing agri-environmental indicators and their differing design concepts. Using a stakeholder consultation approach in five case study regions, the potential and limitations of the indicator are evaluated, with a particular focus on its perceived meaning, utility and performance in the context of different user groups and at different geographical scales. This analysis supplements previous EU-wide assessments, through regional scale assessment of the limitations and potentialities of the indicator and the need for further data collection. The evaluation finds that the perceived meaning of the indicator does not vary with scale, but in common with all mapped indicators, the usefulness of the indicator, to different user groups, does change with scale of presentation. This indicator is viewed as most useful when presented at the scale of governance at which end users operate. The relevance of the different sub-components of the indicator are also found to vary across regions

Cost-benefit analysis of multifunctional agriculture in Finland

This study aims at assessing the costs and benefits of multifunctional agriculture, and it is one of the very first studies using a quantitative approach to this new subject. The starting point is that if current farm subsidies are regarded as means to maintain the multifunctional characteristics of agriculture, what happens if subsidies are reduced. The effects of the decline in agricultural support on multifunctional characteristics of agriculture in Finland are estimated using the cost-benefit analysis (CBA). Only a part of the consequences can be assessed by the CBA due to lack of data on the economic value of many elements of multifunctional agriculture. Hence, the results should not be generalised too strongly, but they still provide useful information for the political decision-making. Concerning further research, we should study, inter alia, what the so-called correct level of compensation for the adequate supply of public goods would be, and what kind of means of agricultural policy are the most efficient to unambiguously enhance the multifunctional character of agriculture.Tässä tutkimuksessa arvioitiin monivaikutteisen maatalouden yhteiskunnallisia hyötyjä ja haittoja. Monivaikutteinen maatalous (MoMa) on maatalouden eurooppalaisen mallin tärkeä osa, jonka turvin EU pyrkii perustelemaan maataloustukien tarvetta ja siten turvaamaan maataloutensa jatkuvuuden. Perustelutarve on kasvanut mm. EU:n budjettikurin ja itälaajentumisen, maatalouden negatiivisten ulkoisvaikutusten sekä Maailman kauppajärjestön (WTO) vaikutuksesta.MoMan osat ovat maatalouden yhteistuotosprosessissa tuottamia markkinattomia hyödykkeitä, kuten ympäristöön ja maaseutumaisemaan liittyvät asiat, maaseudun elinvoimaisuuden turvaaminen ja ruokaturva. EU on tuonut MoMa-keskusteluun myös kotieläinten hyvinvointiin ja ruuan turvallisuuteen liittyviä tekijöitä. MoMa tuo uutta näkökulmaa myös teoriatarkasteluun. Koska MoMan osat ovat ulkoisvaikutuksia, ne jäävät tukien traditionaalisessa hyvinvointivaikutustarkastelussa ottamatta huomioon. Tässä tutkimuksessa laskettiin ensimmäisenä kvantitatiivisesti MoMan vaikutuksia. Kustannus-hyötyanalyysi osoittaa maatalouden tukien 30 % alentamisen 1598 miljoonasta eurosta 1119 miljoonaan euroon aiheuttavan yhteiskunnalle yhteensä 431-809 miljoonan euron kustannukset, vaikka veronmaksajien maksamat maataloustuet vähenisivätkin ja hyvinvointi paranisi ravinnehuuhtoutumien vähenemisen ansiosta. Hyvinvointitappiota synnyttäisivät muutokset kansalaisten kokemassa hyödyssä maisemasta ja ympäristöstä, ruokaturvan heikkeneminen, maataloustyövoiman vähentymisen aiheuttama työttömyys- ja eläkemaksujen lisäys sekä muuttoliikkeen aiheuttamat infrastruktuuri- ja yhdyskuntakustannukset. Laskelmassa ei ole tässä vaiheessa vielä otettu huomioon esimerkiksi mahdollisia ruoan turvallisuuden heikkenemisestä (mm. ruokamyrkytykset) koituvien sairauksien ja menetettyjen työpäivien kustannuksia eikä eläinten hyvinvoinnin heikkenemisen aiheuttamia hyvinvointitappioita. Kustannus-hyötyanalyysin tuloksia tarkasteltaessa on muistettava analyysin oletukset ja rajoitukset. Koska aineistoa oli saatavana hyvin rajoitetusti, analyysissä on otettu ainoastaan osa maatalouden monivaikutteisuuden tekijöistä huomioon. Nämäkin tekijät jo sinällään sisältävät yleistäviä oletuksia ja arvioita hyötyjen ja haittojen rahamääräisistä arvoista. Monivaikutteisen maatalouden sisältöön ja vaikutuksiin liittyy monia kysymyksiä, jotka vaativat lisätutkimusta. Keskeisimpiä tutkimuskohteita ovat seuraavat neljä teemaa: (i) mikä olisi oikea korvaus erilaisten julkishyödykkeiden tuottamisesta, (ii) minkälaiset politiikan keinot ovat tehokkaimpia monivaikutteisuuden edistämiseksi, (iii) mitä MoMan osia kuluttajat arvostavat eniten ja (iv) mitkä muut elinkeinot ja tuotannonalat tuottavat samoja julkishyödykkeitä kuin maatalous, ja tuottavatko nämä tuotannonalat julkishyödykkeitä kustannustehokkaammin kuin maatalous

Cost-benefit analysis of multifunctional agriculture in Finland

This study aims at assessing the costs and benefits of multifunctional agriculture, and it is one of the very first studies using a quantitative approach to this new subject. The starting point is that if current farm subsidies are regarded as means to maintain the multifunctional characteristics of agriculture, what happens if subsidies are reduced. The effects of the decline in agricultural support on multifunctional characteristics of agriculture in Finland are estimated using the cost-benefit analysis (CBA). Only a part of the consequences can be assessed by the CBA due to lack of data on the economic value of many elements of multifunctional agriculture. Hence, the results should not be generalised too strongly, but they still provide useful information for the political decision-making. Concerning further research, we should study, inter alia, what the so-called correct level of compensation for the adequate supply of public goods would be, and what kind of means of agricultural policy are the most efficient to unambiguously enhance the multifunctional character of agriculture

A systematic literature review:is military cognitive radio system on the brink of the “valley of death”?

Abstract Cognitive radio (CR) was coined to address evolving user needs two decades ago. Since then, it also has been considered a way to mitigate perceived spectrum scarcity in various application areas. In this article, the status of military CR research is assessed through a systematic literature review of 193 articles, from 2013 to 2020, using IEEE thematic topics, technology readiness levels, as well as comprehensive capability meta-model as analytical frameworks. The annual distribution of military CR research indicates continuing interest. The military CR research seems to be prolific on topics like waveform design and security, not forgetting a steady interest in CR networking topics. Significantly low numbers of papers address applications, services, and standardization. In general, military CR research seemed sporadic and scattered. Our data suggest that a transition from individual techniques, component-level subsystem research in the direction of systems engineering approach, and system-level studies has not yet happened, and the overall TRLs remain low. The absence of publicly articulated comprehensive treatment of the notion of military cognitive radio system is graphic and has led to disjointed, scattered research at the subsystem level