magistrsko delo
Tadej Emeršič (Avtor), Aleš Fajmut (Mentor)

Povzetek

Skupina zdravil nesteroidni antirevmatiki (NSAR) lahko po zaužitju pri posameznih osebah povzroči značilne klinične znake, poznane kot aspirinska intoleranca. Astmatika, ki je preobčutljiv na NSAR in ima dva značilna klinična znaka - bronhokonstrikcijo in nosne polipe, imenujemo aspirinsko intolerantni astmatik. Za pojav aspirinske intolerance je ključna razgradnja arahidonske kisline (AA) v belih krvnih celicah. V splošnem ta poteka po ciklooksigenazni in lipoksigenazni poti. Po prvi poti se tvorijo prostanoidi, po drugi pa cisteinil levkotrieni. NSAR učinkujejo na ciklooksigenazno pot tako, da inhibirajo encime in posledično zmanjšujejo produkcijo prostanoidov, kar naj bi vodilo do povišanja produkcije cisteinil levkotrienov. Znižana produkcija prostanoidov in zvišana produkcija cisteinil levkotrienov sta tipični značilnosti aspirinske intolerance na metabolomski ravni. Raziskave, ki ločujejo aspirinsko intolerantne astmatike od aspirinsko tolerantnih astmatikov in neastmatikov, potekajo na različnih nivojih človeškega organizma. Na proteomskem nivoju potekajo raziskave v smeri študija razlik v ekspresiji posameznih ključnih encimov v metabolni mreži AA, na metabolomskem nivoju pa potekajo raziskave v smeri meritev in analize razmerij med posameznimi eikozanoidi. Raziskave na nivoju tkiv in organov so usmerjene v določanje povečane bronhialne reaktivnosti in preobčutljivosti pacientov na vrste in doze NSAR. To se izvaja s t. i. provokacijskimi testi, pri čemer se s spirometrijo meri forsirani izdihani volumen zraka v prvi sekundi (FEV1). V magistrski nalogi smo s fizikalno-matematičnim modelom povezali proteomski in metabolomski nivo na ravni celice ter napovedali dogajanje na ravni tkiva in organa virtualnega pacienta. Na celičnem nivoju smo z modelom napovedali koncentracije eikozanoidov za različna stanja ekspresij ključnih encimov v procesu metabolizma AA, ki bi naj karakterizirale različne skupine in podskupine pacientov - neastmatike ter astmatike tolerantne in intolerantne na aspirin. Na podlagi teh rezultatov smo najprej na celičnem nivoju napovedali razvito silo v gladkih mišičnih celicah dihalnih poti, nato pa še polmer tipične dihalne poti in končno FEV1. Vse izračune smo izvedli v bazalnem stanju (tj. brez zaužitega zdravila) in po simulaciji oralnega zaužitja različnih vrst NSAR z različnimi dozami. Z modelom smo določili mejne doze simuliranih NSAR (indometacina, ibuprofena, naproksena in celecoxiba) in paracetamola ter ovrednotili njihovo potentnost v smislu povzročitve bronhokonstrikcije in tveganja astmatičnega napada pri različnih modelnih populacijah aspirinsko intolerantnih astmatikov. Vse modelne simulacije smo izvedli v dveh modelnih stanjih. Prvo simulira stanje neinflamacije, drugo pa stanje inflamacije. Na tak način smo z modelom napovedali in simulirali, kako bi se individualni pacient ali skupina pacientov z razpoznavnim vzorcem v produkciji eikozanoidov in z značilnimi razlikami v ekspresiji posameznih ključnih encimov v metabolni mreži AA lahko odzivali na NSAR v primerih nezdravljene in kontrolirane astme, npr. s kortikosteroidi.

Ključne besede

fizikalni in matematični modeli;farmakokinetični modeli;encimska kinetika;inhibicija encimov;metabolne mreže;eikozanoidi;nesteroidni antirevmatiki;gladka mišična celica dihalnih poti;bronhokonstrikcija;astma;aspirinska intoleranca;sistemska farmakologija;magistrska dela;

Podatki

Jezik: Slovenski jezik
Leto izida:
Tipologija: 2.09 - Magistrsko delo
Organizacija: UM FNM - Fakulteta za naravoslovje in matematiko
Založnik: [T. Emeršič]
UDK: 519.87:615(043.2)
COBISS: 21565960 Povezava se bo odprla v novem oknu
Št. ogledov: 1069
Št. prenosov: 95
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Angleški jezik
Sekundarni naslov: Model prediction of forced expiratory volume in first second (FEV1) before and after ingestion of non-steroidal anti-inflammatory drugs
Sekundarni povzetek: In some individuals ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) induces typical clinical signs known as aspirin intolerance. Asthmatics with two typical symptoms - bronchoconstriction and nasal polyps, and with hypersensitivity to NSAIDs are identified as aspirin intolerant asthmatics. Degradation of arachidonic acid (AA) in white blood cells is essential for the occurrence of aspirin intolerance. Metabolism of AA is generally divided into the cyclooxygenase and the lipoxygenase pathway revealing prostanoids and leukotrienes as metabolites, respectively. NSAIDs have inhibitory impact on the enzymes of the cyclooxygenase pathway resulting in the reduction of the prostanoids production. As a consequence, this might result in higher cysteinyl leukotrienes production. Low prostanoid levels and high cisteinil leukotrienes levels are typical characteristics of aspirin intolerance at the metabolomic level. The occurrence of aspirin intolerance is studied on different levels of human organism. On the proteomic level, study is focused on detecting the differences in the expression of important enzymes in the AA metabolic pathway, and, on the metabolomic level, the ratios between particular eicosanoids are measured and analysed. Research on the tissue and organ level is oriented in determining the patients' bronchial hyperreactivity and hypersensitivity towards the type and the dose of different NSAIDs. This is carried out with provocation tests, whereby forced expiratory volume in first second (FEV1) is measured by spirometry technique. With our mathematical model, presented in this master's thesis, we coupled proteomic and metabolomic properties at the cellular level, and gave predictions at the tissue and organ level of a virtual patient. On the cellular level we predicted absolute concentrations of eicosanoids for different expressions of the key enzymes in the metabolism of AA, which characterize different groups and subgroups of patients - non-asthmatics as well as asthmatics tolerant and intolerant to aspirin. Based on these results, we first predicted stress developed in the airway smooth muscle cells, then the diameter of a typical airway, and, finally, FEV1. All calculations were carried out in the basal state (i.e. without drug) and after the simulated oral dosing of different NSAIDs with different doses. We determined and evaluated the limiting doses of each of the studied NSAIDs (indomethacin, ibuprofen, naproxen and celecoxib) and paracetamol in terms of the potency for the occurrence of bronchoconstriction and the risk for asthmatic attack in cases of different model populations of aspirin intolerant asthmatics. All model simulations were carried out in two different model states; the first one, simulating the state of no-inflammation, and the second one, simulating the state of inflammation. In this way we predicted and simulated, how an individual patient or a patient group with a distinguishing pattern in eicosanoid production as well as with characteristic differences in the expression of the key enzymes within the AA metabolic pathway would respond to NSAIDs in cases of untreated and treated asthma, e.g. with corticosteroids.
Sekundarne ključne besede: physical and mathematical models;pharmacokinetic models;enzyme kinetics;enzyme inhibition;metabolic pathway;eicosanoids;NSAID;airway smooth muscle cell;bronchoconstriction;asthma;aspirin intolerance;systems pharmacology;master theses;
URN: URN:SI:UM:
Vrsta dela (COBISS): Magistrsko delo/naloga
Komentar na gradivo: Univ. v Mariboru, Fak. za naravoslovje in matematiko, Oddelek za fiziko
Strani: 101 f.
ID: 8887750