Jedinjenja prirodnog porekla koja stvaraju zavisnost - narkomanija

The term addiction is used in many contexts. It is not limited to substance abuse and can be applied to any activity characterized by compulsion, loss of control and continuation of the substance despite harm. Some researchers speak of two types of addictions: substance addictions (for example, alcoholism, drug abuse, and smoking); and process addictions (for example, gambling, spending, shopping, eating, and sexual activity). There is a growing recognition that many addicts, such as poly-drug abusers, are addicted to more than one substance or process. It has been shown that individuals turn to substance abuse that elicit a mood or level of arousal consistent with their mode of dealing with stress. Those who deal with stress by confrontation choose drug stimulants. Those who withdrawal from stress choose opiate drugs. Others who deal with stress through activities related to imagery or fantasy turn to hallucinogens. These relationships between behaviour and drug preference are thought to be biochemicaly driven. The biological mechanism of addiction is defined by Milkman. Milkman (1983) defines addiction as 'self-induced changes in neurotransmission that result in social problem behaviours'. This definition encompasses the psychological, biochemical and social aspects of addictive processes. Neurotransmission is the basis for biochemical activity. Small molecules known as neurotransmitters are released into the synaptic junction from the pre-synaptic terminal. After they are released, the neurotransmitters can be degraded by enzymes or be integrated into the post-synaptic membrane and activate adenylate cyclase. This enzyme converts adenosine triphosphate (ATP) into cyclic adenosine-monophosphate (cAMP). cAMP has the effect of increasing membrane sensitivity and subsequent neurotransmission. According to their ability to change the rate of neurotransmission all substances are classified to: stimulant (drugs that increase behavioural activity: amphetamines, methamphetamine, cocaine, nicotine); depressant (alcohol, heroin, morphine, cannabis, barbiturates) and hallucinogen (group of psychoactive chemical compounds which can produce visual or auditory hallucinations). Once a change in neurotransmission is brought about the brain attempts to re-establish the rate of neurotransmission that was present before the activity or substance intake. Once the rate is re-established, the individual becomes tolerant to the original level of the substance. There are two kinds of tolerance: metabolic and cellular. Metabolic tolerance reflects an individual's increased ability to metabolize the drug and cellular tolerance represents decreased sensitivity to a given drug concentration. It is an example of biochemical regulation at the cellular level to maintain homeostasis. Physical dependence is both a physiologic and a biochemical adaptation to an addicting drug that allows the addicted individual to appear seemingly normal while under a drug concentration that produces the desired effect. By definition, physical dependence is accompanied by some degree of tolerance. The 'withdrawal syndrome' is often characterized biologically by effects that are opposite to the acute pharmacological actions of the drug itself. Removal of the drug will unmask an underlying pathophysiology that is noted by odd behaviour. Re-establishing an effective drug concentration relieves these abnormalities. .Pojam zavisnosti se pominje u različitim kontekstima i nije ograničen samo na zloupotrebu lekova već i na aktivnosti koje karakteriše gubitak samokontrole i kontinuirano uzimanje raznih sredstava zavisnosti. Neki istraživači razlikuju dve vrste zavisnosti: jednu, koja nastaje korišćenjem sredstava zavisnosti (alkohol, lekovi, pušenje) i drugu, koju karakteriše rizično ponašanje (kockanje, zavisnost od hrane, šoping, seksualna zavisnost). Poznato je da su mnogi zavisnici uživaoci više sredstava zavisnosti istovremeno. Sredstva koja izazivaju zavisnost koriste osobe u stanju stresa, u želji da takvo stanje lakše prevaziđu. Tako će osobe koje probleme rešavaju konfrontacijom posegnuti za stimulansima dok će se osobe sklone 'povlačenju' okrenuti ka depresorima. Ljudi koji stres prevazilaze imaginacijom i fantazijom preferiraju halucinogena jedinjenja. Ova veza između ponašanja i određenih lekova je biohemijski determinisana. Biološki mehanizam nastanka zavisnosti definisao je Milkman: 'zavisnost jer samoindukovana promena u neurotransmisiji koja rezultira problematičnim socijalnim ponašanjem'. Ova definicija istovremeno obuhvata fiziološki, biohemijski i socijalni aspekt procesa nastanka zavisnosti. Neurotransmisija je osnova biohemijske aktivnosti. Male molekule, neurotransmiteri, oslobađaju se iz presinaptičkog neurona u sinaptičku pukotinu. Nakon oslobađanja neurotransmiteri bivaju izloženi delovanju enzima ili se vezuju za receptore na postsinaptičkoj membrani i aktiviraju enzim adenilat ciklazu. Ovaj enzim konvertuje adenozin trifosfat (ATP) u ciklični adenozin monofosfat (cAMP). cAMP povećava osetljivost membrane i omogućava dalju neurotransmisiju. Prema sposobnosti da menjaju brzinu neurotransmisije sva jedinjenja se mogu podeliti na: stimulanse (lekovi koji povećavaju biohemijsku aktivnost: amfetamini, metamfetamini, kokain, nikotin), depresore (alkohol, heroin, morfin, kanabis, barbiturati) i halucinogene (grupa psihoaktivnih jedinjenja koja izaziva vidne i slušne halucinacije). Kada se neurotransmisija jednom promeni, CNS nastoji da uspostavi stanje koje je postojalo pre unošenja sredstva zavisnosti. Uspostavljanjem prvobitne brzine neurotransmisije razvija se tolerancija prema unetom jedinjenju. Postoje dve vrste tolerancije: metabolička i ćelijska. Metabolička tolerancija se manifestuje kao povećani metabolizam unetih jedinjenja dok ćelijska nastaje kao posledica smanjene osetljivosti receptora. I jedna i druga vrsta tolerancije predstavljaju primer biohemijske regulacije homeostaze na ćelijskom nivou. Fizička zavisnost je fiziološko i biohemijsko prilagođavanje na sredstva zavisnosti; zavisnik izgleda 'normalno' dok je pod dejstvom unetih supstanci. Fizička zavisnost je, po definiciji, praćena određenim stepenom tolerancije. Prestankom uzimanja sredstava zavisnosti, kod fizički zavisnih osoba, javlja se apstinencijalni sindrom. Apstinencijalni sindrom prate biološki efekti suprotni od farmakološkog delovanja samog leka tj. dolazi do demaskiranja patofiziologije koje je praćeno 'čudnim' ponašanjem. Ponovnim uzimanjem efektivne koncentracije sredstva koje izaziva zavisnost prestaju simptomi.

In vitro procena i karakterizacija lek‐plazma protein interakcije

The characterization of drug-protein plasma interactions is a routinely performed part of drug discovery process. The unbound concentration of the drug depends on the binding affinity to plasma proteins, which consequently affects its therapeutic effect, absorption, distribution, metabolism and excretion (1). The most important plasma proteins are human serum albumin (HSA), lipoproteins and alpha-1 acid glycoproteins (AGP). The liquid chromatography can be successfully used for in vitro estimation of plasma protein binding affinity using HSA or AGP modified silica gel as a stationary phase (2). The interaction with HSA has been tested for a wide range of 33 pharmacologically active compounds including dipeptidyl peptidase IV inhibitors, angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers and serotonin/dopamine receptor ligands under reversed-phase conditions. The drug-HSA interaction was interpreted by using the retention modeling, and by selecting the most significant structural characteristics that have an influence on the retention mechanism. The small structural differences, which are reflected in different lipophilicity and polarity, affect the drug-HSA interaction. The retention of the compounds was successfully defined by using the quadratic equation. The isocratic (logk(14%)) and extrapolated factors (b0(LSS)) showed a high correlation with the experimentally available data, and in silico estimated affinity for HSA. The structural properties and charged parts of the molecule surface have been found to significantly affect the HSA mechanism. The obtained results can be successfully applied in further optimization of the structural characteristics of the newly synthesized compounds in order to achieve the desired therapeutic and pharmacokinetic effect.Karakterizacija interakcije novosintetisanih jedinjenja sa plazma proteinima je rutinski deo procesa proizvodnje i otkića novih lekova. Slobodna koncentracije lekovite supstance zavisi od stepena vezivanja za proteine plazme, što posledično utiče na njen terapijski efekat, apsorpciju, distribuciju, metabolizam i izlučivanje (1). Najznačajniji plazma proteini su humani serumski albumin (HSA), lipoproteini i alfa-1 kiseli glikoproteini (AGP). Tečna hromatografija se uspešno koristi za in vitro procenu afiniteta vezivanja lekovite supstance za plazma proteine primenom modifikovane silika gel stacionarne faze sa HSA-om ili AGP-om, i korišćenjem mobilne faze čiji sastav simulira fiziološke uslove (2). Za širok spektar 33 farmakološki aktivnih jedinjenja koja uključuju inhibitore dipeptidil peptidaze IV, inhibitore angiotenzin konvertujućeg enzima, β-blokatore, blokatore kalcijumovih kanala i ligande serotoninskih/dopaminskih receptora ispitana je interakcija sa HSA-om u uslovima reverzno-fazne tečne hromatografije. Lek-plazma protein interakcija je definisana na osnovu mehanizma zadržavanja na HSA stacionarnoj fazi, primenom metode retencionog modelovanja, kao i izdavajanjem najznačajnijih strukturnih karakteristika koje utiču na retenciono ponašanje. Utvrđeno je da male strukturne razlike, koje se ogledaju u različitoj lipofilnosti i polarnosti, utiču na interakciju sa HSA-om. Kvadratnim modelom je uspešno definisano retenciono ponašanje ispitivanih jedinjenja. Izokratski (logk(14%)) i ekstrapolisani retencioni faktor (b0(LSS)) su pokazali visok stepen slaganja sa eksperimentalno dostupnim i in silico procenjenim afinitetom za HSA. Ustanovljeno je da strukturna svojstva (broj dvostrukih veza, aromatični prstenovi, benzil, arlil supstituenti) i naleketrisani fragmenti površine molekula značajno utiču na HSA interakciju. Dobijeni rezultati se mogu uspešno primeniti u daljoj optimizaciji strukturnih karakteristika novosintetisanih jedinjenja i postizanja željenih terapijskih i farmakokinetičkih ciljeva.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

The fauna of hoverflies (Diptera: Syrphidae) of Vojvodina province, Serbia

Many hoverfly species of faunal and zoogeographical interest are found in Serbia's northern province of Vojvodina due to the diversity of its biotopes. In this paper, the presence of 252 species of hoverflies (Diptera: Syrphidae) from 69 genera is documented. Five species are here recorded for the first time in Serbia: Anasimyia contracta Claussen & Torp Pedersen, 1980; Anasimyia transfuga (Linnaeus, 1758); Eristalinus megacephalus (Rossi, 1794); Helophilus hybridus Loew, 1846; and Mallota fuciformis (Fabricius, 1794). One species is recorded for the first time in Vojvodina: Cheilosia brunnipennis (Becker, 1894). The records of 12 species from Vojvodina Province are the only ones on the Balkan Peninsula, while the records of 15 species are the only ones in Serbia

Fenotipska varijabilnost reproduktivnih osobina sanske rase koza

Phenotype variability of the basic reproductive parameters research was conducted on Sanska goat population. This research has determined gestation length of 150,52 days and goat fertility of 173,13%. Singles body weight at birth was 3,53 kg, and twins 2,75 kg. Reproductive parameters phenotype variability results that were determined in this research are in accordance with literature.Istraživanje fenotipske varijabilnosti osnovnih reproduktivnih osobina obavljeno je na populaciji koza sanske rase. Istraživanjem je obuhvaćeno 67 mladih koza koje se prvi put jare. Analizirana su sledeća svojstva: dužina bremenitosti, broj jaradi u leglu - plodnost koza i telesna masa jaradi na rođenju. Ovim istraživanjima je utvrđena dužina gestacionog perioda od 150,95 dana i plodnost koza od 173,13%. Telesna masa jaradi jedinaca na rođenju bila je 3,53 kg a blizanaca 2,75 kg. Dobijeni rezultati o fenotipskoj varijabilnosti reproduktivnih osobina koza sanske rase u saglasnosti su sa literaturom

Trendovi u dizajniranju antidepresiva i anksiolitika

Depression constitutes an international health problem. It is estimated that 320 million people worldwide are clinically depressed. Effective antidepressant treatments have been available for more than 40 years. Although modern antidepressants lack many of the side-effects and toxicity of the first generation tricyclics and monoamine oxidase inhibitors, their efficiency has not been substantially improved comparing to older agents. Unfortunately, the modern drug discovery technologies of combinatorial chemistry and throughput screening are based on relatively simple in vitro assays and lack pre-clinical model of depression make this research difficult. Most antidepressants require additional time to achieve therapeutic effects and there is a certain population of patients resistant to current therapies which means that etiology of depression is too complex. Coming research should clarify true depression mechanism and identify new targets of the third antidepressants generation. Anxiety is a normal emotion and essential part of response to stressful and threatening stimuli. At present, a numerous drugs with various mechanism of action are available for pharmacoterapy of anxiety disorders. The benzodiazepines represent the most important drugs in the treatment of anxiety. In addition to their anxiolytic properties, benzodiazepines possess sedative, hypnotic, anticonvulsant and other effects but side effects also-upon prolonged administration they produce withdrawal symptoms and dependency. Research has shown that cholecystokinin and corticotrophin-releasing factor are important neurotransmiters and may have role in the mediation of anxiety. Neuropeptide Y has shown an anxiolytic effect in several animal models. CCK, CRF and neuropeptid Y receptor agonists and antagonists are targets of new anxiolitic drugs.Anksioznost je normalna emocionalna reakcija na preteći ili stresni stimulans. U farmakoterapiji ove bolesti koristi se veliki broj lekova različitog mehanizma delovanja od kojih su benzodiazepini najvažniji. Benzodiazepini, pored anksiolitičkog poseduju sedativni, hipnotički, antikonvulzivni i druge efekte ali posle duže upotrebe razvija se tolerancija, dovode do zavisnosti i često su predmet zloupotrebe. Novija istraživanja su pokazala da, pored serotonina i noradrenalina i drugi neurotransmiteri kao što su holecistokinin (CCK) i oslobađajući faktor za kortikotropin (CRF) imaju značajnu ulogu u anksioznosti. Neuropeptid Y (NPY) takođe pokazuje anksiolitički efekat na životinjama. Agonisti i antagonisti receptora holecistokinina, oslobađajućeg faktora za kortikotropin i neuropeptida Y su cilj sinteze novih anksiolitika

Preliminary identification on key indicators for air quality risk assessment from landfill

Landfilling is still the most widely used form of waste disposal although it is associated with a number of environmental issues primarily related to unregulated and partially controlled landfills that are numerous in Serbia. Landfill gas, mostly composed of methane, represents a high risk for human health and environment. This paper gives preliminary identification of criteria for quantification of methane risk impact on air in the immediate vicinity of landfills in Serbia. Four types of criteria were defined. Those criteria consist of sub-criteria that must be considered when considering the potential risks to the environment and human health

Molecular Docking Analysis of Novel Thiourea Derivatives of Naproxen with Potential Antitumor Activity

Naproxen, as a propionic acid derivative, causes serious gastrointestinal side effects due to the presence of free carboxylic group. In that sense, masking of carboxylic group with other pharmacophores may be a promising strategy to decrease gastrointestinal toxicity. Thiourea derivatives have been intensively investigated as potential antitumor drugs, whereby their activity is based on potential inhibition of protein kinases, topoisomerases, carbonic anhydrase and sirtuins. In addition, it was shown that inhibition of certain protein kinases might reverse resistance to chemotherapeutic drugs by enhancing the cell death in the presence of low concentrations of drug. Twenty new thiourea derivatives of naproxen were designed and their binding to four selected protein kinases involved in tumor multidrug resistance (AKT2, mTOR, EGFR and VEGFR1) was estimated using two molecular docking programs (AutoDock Vina and OEDocking). According to OEDocking, the highest potential to inhibit AKT2 and mTor has derivative 1, while derivative 20 demonstrates the highest potential towards EGFR and VEGFR1. According to AutoDock Vina, the highest potential for inhibition of EGFR, AKT2 and VEGFR1 have derivatives 16 and 17. Therefore, derivatives 1, 16, 17 and 20 are potentially the most potent protein kinase inhibitors that could be further synthesized and tested for anticancer activity

HOVERFLY FAUNA (DIPTERA: SYRPHIDAE) OF THE LANDSCAPE OF OUTSTANDING FEATURES “VLASINA”

In the many years of research organized between 1977 and 2017, a total of 76 hoverfly species were collected in the protected Landscape of Outstanding Features “Vlasina” (southeastern Serbia) on six localities. Among the identified taxa there is a rare species, Cheilosia longula (Zetterstedt, 1838), which is protected in Serbia. Additionally, one potentially new hoverfly species is registered (Merodon aff. cinereus). The first species checklist of hoverflies for Vlasina is proposed

Uticaj uzrasta i različite doze prirodnog gonadotropnog hormona na reproduktivne pokazatelje ovaca u sezoni anestrije

In this paper results of age and different dosages of PMSG (500 and 750 i.u) on young II d’frans sheep fertility trait in anestric season are discussed. This research has clearly shown that first conception of young II d’frans sheep can be done at the age of 12-14 months as they reacted better at hormone dosages, compared to the group of sheep that was 11-13 months old. Higher dose of PMSG of 750i.u(for testing group) compared to 500i.u (control group) led to the result that test group had higher fertility rate by 30.66% compared to control group. Higher fertility of test group is represented by higher number of twins by 24.13% and triplets by 5.18% compared to control group.U radu se analizira uticaj uzrasta ovaca (dviski) i različite doze (500:750 i.j.) prirodnog gonadotropina PMSG-a na reproduktivne pokazatelje ovaca II d frans rase u periodu anestrije. Ova istraživanja su jasno pokazala da prva koncepcija dviski treba da se obavi u uzrastu grla 12-14 meseci. Veća doza PMSG-a od 750 i.j. (kod ogledne grupe) u odnosu na 500 i.j. (kod kontrolne grupe) dovela je do toga da je ogledna grupa imala veću plodnost za 30,66% u odnosu na kontrolnu grupu. Veća plodnost ogledne grupe je posledica rađanja većeg broja blizanaca za 24,13% i trojki za 5,18% kod ogledne u odnosu na kontrolnu grupu