17 research outputs found
Macrolides ā more than antibiotics
Makrolidni antibiotici zauzimaju važno mjesto u lijeÄenju zaraznih bolesti radi relativno Å”irokog spektra antimikrobnog djelovanja i neÅ”kodljivosti. Upravo je rasprostranjena primjena dovela do kliniÄkih zapažanja o uÄincima makrolida koja se ne mogu objasniti direktnim antibiotskim djelovanjem. Naime, postoje brojna izvjeÅ”Äa o djelotvornosti makrolidnih antibiotika u lijeÄenju kroniÄnih upalnih bolesti poput difuznog panbronhiolitisa, cistiÄne fibroze, bronhiolitis obliterans sindroma, itd. Rezultati detaljnih kliniÄkih i pretkliniÄkih istraživanja pokazuju da makrolidni antibiotici imaju imunomodulatorna svojstva, dok se u osnovi dijela takvih uÄinaka nalazi i inhibicija proizvodnje faktora virulencije Pseudomonas aeruginosa i nastanka biofilma. Posljedice imunomodulatornog djelovanja makrolida vidljive su i pri lijeÄenju zaraznih bolesti poput izvanbolniÄki steÄene pneumonije i sepse, a oÄituju se kroz veÄu stopu preživljenja i kraÄi boravak u bolnici. Na kliniÄarima je da prepoznaju potencijal imunomodulacije uzrokovane makrolidima, dok znanstvenici koji se bave otkrivanjem novih lijekova trebaju usmjeriti svoje snage u pravcu otkriÄa novih imunomodulatornih makrolida koji neÄe biti antibiotici.Macrolide antibiotics play an important role in the treatment of infectious diseases because of their relatively broad antimicrobial spectrum and good safety profile. A wide usage of macrolides has lead to certain clinical observations which cannot be explained by direct antibiotic action. There are numerous reports on macrolide effect in chronic inflammatory diseases, such as diffuse panbronchiolitis, cystic fibrosis, bronchiolitis obliterans syndrome, etc. Intensive preclinical and clinical research have shown that macrolides exhibit immunomodulatory activity and that macrolide-induced inhibition of Pseudomonas aeruginosa virulence factor production and biofilm formation is responsible for some of the effects. Beneficial results of the immunomodulation, increased survival rate and decreased hospital stay, have been reported for community acquired pneumonia and sepsis. It is up to clinicians to recognise further opportunities to exploit macrolide immunomodulation, whereas drug-discovery research efforts, based on reverse pharmacology approach, should be directed towards discovery of new immunomodulatory macrolides lacking antimicrobial activity
Smanjeno oslobaÄanje interleukina-1Ī² u miÅ”eva nakon poslijeupalnog davanja azitromicina i klaritromicina.
The literature indicates that, in addition to anti-bacterial effects, certain macrolide antibiotics, such as azithromycin and clarithromycin, also exert anti-inflammatory and immunomodulatory activity, by accumulating in inflammatory cells and inhibiting the secretion of pro-inflammatory cytokines. Previous reports have shown that pre-treatment with these macrolides attenuates induced immediate skin inflammatory reactions in mice. However, the anti inflammatory activity of the post-inflammatory induction of macrolide antibiotics in this experimental model has not been investigated. The aim of this study was to explore whether the anti-inflammatory activity of azithromycin and clarithromycin, applied transdermally, 30 min after a phorbol 12-myristate 13- acetate (PMA)-induced immediate skin inflammation in mice, could attenuate a Th1 inflammatory reaction. The capacity of azithromycin and clarithromycin (500 Ī¼g/ear) to exert anti-inflammatory effects, similar to those of dexamethasone (50 Ī¼g/ear), was confirmed by the inhibition by all three agents of ear swelling and interleukin- 1Ī² concentration in the ear tissue of PMA-treated mice, supporting this clinically relevant treatment mode.Literaturni podaci pokazuju da odgovarajuÄi makrolidni antibiotici, poput azitromicina i klaritromicina, osim protubakterijskih uÄinaka posjeduju i protuupalna i imunomodulacijska svojstva koja se oÄituju njihovim nakupljanjem u upalnim stanicama i sprjeÄavanjem oslobaÄanja proupalnih citokina. DosadaÅ”nja istraživanja pokazuju da davanje navedenih makrolida u miÅ”eva, prije izazivanja upale, umanjuje neposrednu upalnu reakciju kože. MeÄutim, njihova protuupalna svojstva nakon poslijeupalnog davanja u ovom pokusnom modelu nisu istražena. Cilj ovog istraživanja bio je istražiti da li azitromicin i klaritromicin, naneseni na povrÅ”inu uÅ”ke miÅ”eva 30 minuta nakon izazivanja neposredne upale kože s forbol 12-miristat 13-acetatom (PMA), svojim protuupalnim djelovanjem umanjuju Th1 upalni odgovor. Protuupalni uÄinci azitromicina i klaritromicina (500 Ī¼g / uÅ”ki) bili su podjednaki protuupalnom djelovanju deksametazona (50 Ī¼g / uÅ”ki), u smislu smanjenja otekline uÅ”ke i koncentracije interleukina-1Ī² u tkivu uÅ”ke miÅ”eva obraÄivanih s PMA om, Å”to ide u prilog kliniÄki relevantnom naÄinu lijeÄenja
Imunobiologija crijevne suznice: od lokalne imunosti i mikrobioma do zglobne upale
SagledavajuÄi evolucijski razvoj kralježnjaka i njihovu koevoluciju s vlastitom crijevnom mikrobiotom i okoliÅ”em,
postaje jasno važno mjesto imunoloŔkog sustava pridruženog sluznicama u razvoju ukupnog imunoloŔkog sustava
jedinke i jaÄanju obrambenog sustava organizma. Koncept limfatiÄkog tkiva pridruženog sluznici crijeva u Å”irem smislu
predstavlja strukturu i funkciju uroÄene i steÄene, humoralne i celularne imunosti pridružene sluznici u procesiranju
luminalnih antigena. Taj koncept ukljuÄuje integritet sluzniÄke barijere, sloj sluzi, oÄuvani epitelni sloj i uske veze
izmeÄu stanica, luÄenje antimikrobnih peptida, obrasce prepoznavanja antigena, ukljuÄivÅ”i mikrobne i one nastale
oÅ”teÄenjem tkiva, obrasce stvaranja signala i puteve prijenosa signala, mehanizme humoralne i celularne imunosti,
citokinsku mrežu i lokalni citokinski okoliÅ”, interakciju uroÄenih limfoidnih stanica s pomagaÄkim, izvrÅ”nim i regulacijskim
limfocitima T, interakciju s ostalim stanicama strome te metaboliÄku i imunoloÅ”ku interakciju s vlastitim mikrobiomom.
Rezultati brojnih istraživanja zabilježili su etiopatogenetsku povezanost izmeÄu crijevne i zglobne upale,
tvrdeÄi kako se u patogenetskom kolopletu isprepliÄu Äinitelji naslijeÄa, promijenjena imunoloÅ”ka reakcija te Äinitelji
okoliŔa, onog vanjskog i unutarnjeg pod kojim razumijevamo crijevnu mikrobiotu. Opravdano je ustvrditi kako za sve
skupine navedenih reumatoloŔkih bolesti postoji, kako za koji entitet, viŔe ili manje dokaza o povezanosti s crijevnom
upalom, odnosno patoloŔkom imunoloŔkom reakcijom i crijevnom disbiozom. Za sada, ne postoji dovoljno dokaza da
bi ta povezanost imala kauzalni karakter. Rezultati dobiveni primjenom umjetne inteligencije u obradi velikih koliÄina
podataka mogli bi izdvojiti fenotipski razliÄite skupine bolesnika s reumatoidnim artritisom i spondiloartropatijama,
uz dijagnostiÄke i terapijske implikacije. Prvenstveno u svjetlu pretpostavke da gensko naslijeÄe, imunoloÅ”ka reakcija i
crijevna disbioza na razliÄit naÄin doprinose nastanku bolesti u razliÄitih skupina bolesnika, odnosno u individualnom
bolesniku. Primjenom naÄela translacijske medicine u istraživanju, dijagnostici i terapiji crijevne i zglobne upale Äinimo
znaÄajan korak naprijed ka preciznoj i personaliziranoj medicini
Eksperimentalne konvulzije u Å”takora: uÄinci blokatora kanala kalcija na biokemijske pokazatelje oÅ”teÄenja moždanih stanica : doktorska disertacija
Sažetak disertacije "Eksperimentalne konvulzije u Å”takora: uÄinci blokatora kanala kalcija na biokemijske pokazatelje oÅ”teÄenja moždanih stanica" nije dostupan
Macrolactonolides: a novel class of anti-inflammatory compounds
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17Ī²-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described
Unprecedented Epimerization of an Azithromycin Analogue: Synthesis, Structure and Biological Activity of 2ā²-Dehydroxy-5ā³-Epi-Azithromycin
Certain macrolide antibiotics, azithromycin included, possess anti-inflammatory properties that are considered fundamental for their efficacy in the treatment of chronic inflammatory diseases, such as diffuse pan-bronchiolitis and cystic fibrosis. In this study, we disclose a novel azithromycin analog obtained via BartonāMcCombie oxidation during which an unprecedented epimerization on the cladinose sugar occurs. Its structure was thoroughly investigated using NMR spectroscopy and compared to the natural epimer, revealing how the change in configuration of one single stereocenter (out of 16) profoundly diminished the antimicrobial activity through spatial manipulation of ribosome binding epitopes. At the same time, the anti-inflammatory properties of parent macrolide were retained, as demonstrated by inhibition of LPS- and cigarette-smoke-induced pulmonary inflammation. Not surprisingly, the compound has promising developable properties including good oral bioavailability and a half-life that supports once-daily dosing. This novel anti-inflammatory candidate has significant potential to fill the gap in existing anti-inflammatory agents and broaden treatment possibilities