Utjecaj tvrdokorne infekcije bakterijom helicobacter pylori na izraženost bcl-2 u upalnim stanicama želučane sluznice

Chronic Helicobacter (H.) pylori infection is an etiological factor related to gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The expression of bcl-2 protein significantly decreases as the grade of MALT lymphoma advances. The aim of this study was to evaluate bcl-2 expression in inflammatory cells in lamina propria in gastric biopsy samples collected from two groups of patients with chronic gastritis divided on the basis of the success or failure of H. pylori eradication. Sixty-five patients with chronic gastritis were divided into two groups of 45 and 20 patients according to their therapeutic response. The gastric mucosa samples were analyzed histologically in both groups of patients before and after standard therapy (for eradicated, after one therapeutic cycle; and for non-eradicated, after three therapeutic cycles) for H. pylori density, urease activity and bcl-2 expression. In the eradicated group of patients, H. pylori eradication was accompanied by significantly lower grades of bacterial colonization and lower urease activity in the corpus and antrum. Bcl-2 expression in inflammatory cells showed no statistically significant changes in either patient group at either location. There was no between-group difference in bcl-2 expression either. In conclusion, persistent long-lasting H. pylori infection is associated with higher grades of bacterial colonization and higher urease activity but not with bcl-2 expression in inflammatory cells.Kronična infekcija bakterijom Helicobacter (H.) pylori je etiološki čimbenik želučanog adenokarcinoma i limfoma limfoidnog tkiva povezanog sa sluznicom (MALT limfoma). Izraženost proteina bcl-2 značajno se smanjuje s napredovanjem stupnja MALT limfoma. Cilj ove studije bio je procijeniti izraženost bcl-2 u upalnim stanicama lamine proprije u uzorcima dobivenim želučanom biopsijom u dvjema skupinama bolesnika s kroničnim gastritisom podijeljenim prema uspješnoj ili neuspješnoj eradikaciji H. pylori. Ukupno je 65 bolesnika s kroničnim gastritisom podijeljeno u dvije skupine od po 45 i 20 bolesnika prema terapijskom odgovoru. U objema skupinama su uzorci želučane sluznice analizirani histološki prije i nakon standardne terapije (kod onih s uspješnom eradikacijom nakon jednog terapijskog ciklusa, a u onih s neuspješnom eradikacijom nakon tri terapijska ciklusa) na gustoću H. pylori, aktivnost ureaze i izraženost bcl-2. Eradikacija H. pylori u skupini bolesnika s uspješnom eradikacijom bila je praćena značajno nižim stupnjem bakterijske kolonizacije i nižom aktivnošću ureaze u korpusu i antrumu. Izraženost bcl-2 nije se statistički značajno promijenila ni na jednoj lokaciji ni u jednoj skupini bolesnika. Isto tako, nije bilo nikakve razlike među dvjema skupinama bolesnika u izraženosti bcl-2. Zaključuje se kako je dugotrajna ustrajna infekcija bakterijom H. pylori povezana s višim stupnjem bakterijske kolonizacije i višom aktivnošću ureaze, ali nije povezana s izraženošću bcl-2 u upalnim stanicama

Design, Synthesis, and in Vitro Activity of Novel 2′-<i>O</i>-Substituted 15-Membered Azalides

Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2′-<i>O</i>-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2′. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for <i>P. falciparum</i> parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents

Synthesis, structure-activity relationship, and antimalarial activity of ureas and thioureas of 15-membered azalides

Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N''-substituted 9a-(N'-carbamoyl-β-aminoethyl), 9a-(N'-thiocarbamoyl-β-aminoethyl), 9a-[N'-(β-cyanoethyl)-N'-(carbamoyl-β-aminoethyl)], 9a-[N'-(β-cyanoethyl)-N'-(thiocarbamoyl-β-aminoethyl)], 9a-{N'-[β-(ethoxycarbonyl)ethyl]-N'(carbamoyl-β-aminoethyl)}, and 9a-[N'-(β-amidoethyl)-N'-(carbamoyl-β-aminoethyl)] of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugars on the macrocyclic ring and aromatic moiety on 9a-position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides

Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis

A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides

Background and purpose: Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low. ----- Experimental approach: Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model. ----- Key results: Novel fast-acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine-resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half-lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti-plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow-acting azithromycin. ----- Conclusion and implications: The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy

A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides

Background and purpose: Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low. ----- Experimental approach: Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model. ----- Key results: Novel fast-acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine-resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half-lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti-plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow-acting azithromycin. ----- Conclusion and implications: The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy