Macrolides – more than antibiotics

Makrolidni antibiotici zauzimaju važno mjesto u liječenju zaraznih bolesti radi relativno širokog spektra antimikrobnog djelovanja i neškodljivosti. Upravo je rasprostranjena primjena dovela do kliničkih zapažanja o učincima makrolida koja se ne mogu objasniti direktnim antibiotskim djelovanjem. Naime, postoje brojna izvješća o djelotvornosti makrolidnih antibiotika u liječenju kroničnih upalnih bolesti poput difuznog panbronhiolitisa, cistične fibroze, bronhiolitis obliterans sindroma, itd. Rezultati detaljnih kliničkih i pretkliničkih istraživanja pokazuju da makrolidni antibiotici imaju imunomodulatorna svojstva, dok se u osnovi dijela takvih učinaka nalazi i inhibicija proizvodnje faktora virulencije Pseudomonas aeruginosa i nastanka biofilma. Posljedice imunomodulatornog djelovanja makrolida vidljive su i pri liječenju zaraznih bolesti poput izvanbolnički stečene pneumonije i sepse, a očituju se kroz veću stopu preživljenja i kraći boravak u bolnici. Na kliničarima je da prepoznaju potencijal imunomodulacije uzrokovane makrolidima, dok znanstvenici koji se bave otkrivanjem novih lijekova trebaju usmjeriti svoje snage u pravcu otkrića novih imunomodulatornih makrolida koji neće 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 oslobađanje interleukina-1β u miševa 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 μg/ear) to exert anti-inflammatory effects, similar to those of dexamethasone (50 μg/ear), was confirmed by the inhibition by all three agents of ear swelling and interleukin- 1β concentration in the ear tissue of PMA-treated mice, supporting this clinically relevant treatment mode.Literaturni podaci pokazuju da odgovarajući makrolidni antibiotici, poput azitromicina i klaritromicina, osim protubakterijskih učinaka posjeduju i protuupalna i imunomodulacijska svojstva koja se očituju njihovim nakupljanjem u upalnim stanicama i sprječavanjem oslobađanja proupalnih citokina. Dosadašnja istraživanja pokazuju da davanje navedenih makrolida u miševa, prije izazivanja upale, umanjuje neposrednu upalnu reakciju kože. Međutim, 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 površinu uške miševa 30 minuta nakon izazivanja neposredne upale kože s forbol 12-miristat 13-acetatom (PMA), svojim protuupalnim djelovanjem umanjuju Th1 upalni odgovor. Protuupalni učinci azitromicina i klaritromicina (500 μg / uški) bili su podjednaki protuupalnom djelovanju deksametazona (50 μg / uški), u smislu smanjenja otekline uške i koncentracije interleukina-1β u tkivu uške miševa obrađivanih s PMA om, što ide u prilog klinički relevantnom načinu liječenja

Imunobiologija crijevne suznice: od lokalne imunosti i mikrobioma do zglobne upale

Sagledavajući evolucijski razvoj kralježnjaka i njihovu koevoluciju s vlastitom crijevnom mikrobiotom i okolišem, postaje jasno važno mjesto imunološkog sustava pridruženog sluznicama u razvoju ukupnog imunološkog sustava jedinke i jačanju obrambenog sustava organizma. Koncept limfatičkog tkiva pridruženog sluznici crijeva u širem smislu predstavlja strukturu i funkciju urođene i stečene, humoralne i celularne imunosti pridružene sluznici u procesiranju luminalnih antigena. Taj koncept uključuje integritet sluzničke barijere, sloj sluzi, očuvani epitelni sloj i uske veze između stanica, lučenje antimikrobnih peptida, obrasce prepoznavanja antigena, uključivši mikrobne i one nastale oštećenjem tkiva, obrasce stvaranja signala i puteve prijenosa signala, mehanizme humoralne i celularne imunosti, citokinsku mrežu i lokalni citokinski okoliš, interakciju urođenih limfoidnih stanica s pomagačkim, izvršnim i regulacijskim limfocitima T, interakciju s ostalim stanicama strome te metaboličku i imunološku interakciju s vlastitim mikrobiomom. Rezultati brojnih istraživanja zabilježili su etiopatogenetsku povezanost između crijevne i zglobne upale, tvrdeći kako se u patogenetskom kolopletu isprepliću činitelji naslijeđa, promijenjena imunološka reakcija te činitelji okoliša, onog vanjskog i unutarnjeg pod kojim razumijevamo crijevnu mikrobiotu. Opravdano je ustvrditi kako za sve skupine navedenih reumatoloških bolesti postoji, kako za koji entitet, više ili manje dokaza o povezanosti s crijevnom upalom, odnosno patološkom imunološkom 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 količina podataka mogli bi izdvojiti fenotipski različite skupine bolesnika s reumatoidnim artritisom i spondiloartropatijama, uz dijagnostičke i terapijske implikacije. Prvenstveno u svjetlu pretpostavke da gensko naslijeđe, imunološka reakcija i crijevna disbioza na različit način doprinose nastanku bolesti u različitih skupina bolesnika, odnosno u individualnom bolesniku. Primjenom načela translacijske medicine u istraživanju, dijagnostici i terapiji crijevne i zglobne upale činimo značajan korak naprijed ka preciznoj i personaliziranoj medicini

Eksperimentalne konvulzije u štakora: učinci blokatora kanala kalcija na biokemijske pokazatelje oštećenja moždanih stanica : doktorska disertacija

Sažetak disertacije "Eksperimentalne konvulzije u štakora: učinci blokatora kanala kalcija na biokemijske pokazatelje oštećenja moždanih stanica" nije dostupan

Unprecedented Epimerization of an Azithromycin Analogue: Synthesis, Structure and Biological Activity of 2′-Dehydroxy-5″-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 Barton–McCombie 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

Correlation of ex vivo cytokine secretion profiles with scoring indices in ulcerative colitis

Background: In ulcerative colitis, the complexity of mucosal cytokine secretion profiles and how they correlate with endoscopic and clinical scores is still unclear. Methods: In this study, we collected fresh biopsies from UC patients to investigate which cytokines are produced in ex vivo culture conditions, a platform increasingly used for testing of novel drugs. Then, we correlated cytokine production with several scoring indices commonly used to assess the severity of the disease. Results: Increased levels of IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNFα and IFNɣ were produced by biopsies of UC patients compared to non-IBD controls. Our results show a better correlation of cytokine levels with Mayo Endoscopic Subscore (MES) and Mayo score, than the more complex Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Out of 10 measured cytokines, eight correlated with MES, six with Mayo score and only three with UCEIS, due to the partial increase in cytokine secretion observed in donors with UCEIS = 7–8. When we analysed individual subscores within the UCEIS, Vascular Network subscore showed a correlation similar to MES (7/10 cytokines), while Bleeding as well as Erosions and Ulcers subscores correlated with only 3/10 cytokines, similarly to the total UCEIS. Conclusions: Our findings suggest that choosing biopsies from donors with MES = 2–3 and UCEIS = 2–6 from areas with no bleeding and no superficial and/or deep ulcers could enable a deeper insight into the cytokine profile of the inflamed tissue and represent a better tool for studying potential therapeutic targets and evaluation of novel therapies

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 17β-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