Crohnova choroba a ulcerózní kolitida jsou chronická, zánětlivá střevní onemocnění medikamentózně a chirurgicky nevy- léčitelná. V posledních 20 letech došlo k dramatickému vývoji především léčby medikamentózní. V biologické léčbě byly zavedeny nové preparáty s mechanismem účinku cíleným na molekuly s klíčovým postavením v patogenezi idiopatických střevních zánětů.

Crohn's disease and ulcerative colitis are chronic, inflammatory bowel disease medically and surgically incurable. In the last 20 years, there has been a dramatic development, especially of medicamentous treatment. In biological therapy, new agents have been introduced with a mechanism of action targeted on molecules of key role in the pathogenesis of inflammatory bowel disease.

• MeSH
• biologická terapie metody   MeSH
• biosimilární léčivé přípravky terapeutické užití   MeSH
• Crohnova nemoc farmakoterapie   MeSH
• idiopatické střevní záněty * farmakoterapie   MeSH
• individualizovaná medicína MeSH
• inhibitory interleukinu terapeutické užití   MeSH
• inhibitory Janus kinas aplikace a dávkování   terapeutické užití   MeSH
• inhibitory TNF aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• molekuly buněčné adheze antagonisté a inhibitory   MeSH
• receptory sfingosin-1-fosfátu antagonisté a inhibitory   MeSH
• ulcerózní kolitida farmakoterapie   MeSH
• Check Tag
• lidé MeSH

BACKGROUND AND AIMS: Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II. METHODS: TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator's discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed. RESULTS: Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262]. CONCLUSIONS: Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

• MeSH
• C-reaktivní protein analýza   MeSH
• dospělí MeSH
• gastrointestinální endoskopie metody   statistika a číselné údaje   MeSH
• gastrointestinální látky aplikace a dávkování   škodlivé účinky   MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   škodlivé účinky   MeSH
• imunologická odpověď na dávku MeSH
• leukocytární L1-antigenní komplex analýza   MeSH
• lidé MeSH
• molekuly buněčné adheze antagonisté a inhibitory   MeSH
• monitorování léčiv * metody   statistika a číselné údaje   MeSH
• mukoproteiny antagonisté a inhibitory   MeSH
• ulcerózní kolitida * diagnóza   farmakoterapie   imunologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

The C-type lectin DC-SIGN expressed on immature dendritic cells is a promising target for antiviral drug development. Previously, we have demonstrated that mono- and divalent C-glycosides based on d-manno and l-fuco configurations are promising DC-SIGN ligands. Here, we described the convergent synthesis of C-glycoside dendrimers decorated with 4, 6, 9, and 12 α-l-fucopyranosyl units and with 9 and 12 α-d-mannopyranosyl units. Their affinity against DC-SIGN was assessed by surface plasmon resonance (SPR) assays. For comparison, parent O-glycosidic dendrimers were synthesized and tested, as well. A clear increase of both affinity and multivalency effect was observed for C-glycomimetics of both types (mannose and fucose). However, when dodecavalent C-glycosidic dendrimers were compared, there was no difference in affinity regarding the sugar unit (l-fuco, IC50 17 μM; d-manno, IC50 12 μM). For the rest of glycodendrimers with l-fucose or d-mannose attached by the O- or C-glycosidic linkage, C-glycosidic dendrimers were significantly more active. These results show that in addition to the expected physiological stability, the biological activity of C-glycoside mimetics is higher in comparison to the corresponding O-glycosides and therefore these glycomimetic multivalent systems represent potentially promising candidates for targeting DC-SIGN.

• MeSH
• biomimetické materiály chemie   farmakologie   MeSH
• fukosa chemie   MeSH
• inhibiční koncentrace 50 MeSH
• lektiny typu C antagonisté a inhibitory   MeSH
• mannosa chemie   MeSH
• molekuly buněčné adheze antagonisté a inhibitory   MeSH
• receptory buněčného povrchu antagonisté a inhibitory   MeSH
• Publikační typ
• časopisecké články MeSH

Mast cells and basophils (MCs/Bs) play a crucial role in type I allergy, as well as in innate and adaptive immune responses. These cells mediate their actions through soluble mediators, some of which are targeted therapeutically by, for example, H1- and H2-antihistamines or cysteinyl leukotriene receptor antagonists. Recently, considerable progress has been made in developing new drugs that target additional MC/B mediators or receptors, such as serine proteinases, histamine 4-receptor, 5-lipoxygenase-activating protein, 15-lipoxygenase-1, prostaglandin D2, and proinflammatory cytokines. Mediator production can be abrogated by the use of inhibitors directed against key intracellular enzymes, some of which have been used in clinical trials (eg, inhibitors of spleen tyrosine kinase, phosphatidylinositol 3-kinase, Bruton tyrosine kinase, and the protein tyrosine kinase KIT). Reduced MC/B function can also be achieved by enhancing Src homology 2 domain-containing inositol 5' phosphatase 1 activity or by blocking sphingosine-1-phosphate. Therapeutic interventions in mast cell-associated diseases potentially include drugs that either block ion channels and adhesion molecules or antagonize antiapoptotic effects on B-cell lymphoma 2 family members. MCs/Bs express high-affinity IgE receptors, and blocking their interactions with IgE has been a prime goal in antiallergic therapy. Surface-activating receptors, such as CD48 and thymic stromal lymphopoietin receptors, as well as inhibitory receptors, such as CD300a, FcγRIIb, and endocannabinoid receptors, hold promising therapeutic possibilities based on preclinical studies. The inhibition of activating receptors might help prevent allergic reactions from developing, although most of the candidate drugs are not sufficiently cell specific. In this review recent advances in the development of novel therapeutics toward different molecules of MCs/Bs are presented.

• MeSH
• alergie imunologie   terapie   MeSH
• antialergika farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• bazofily imunologie   MeSH
• cílená molekulární terapie MeSH
• degranulace buněk účinky léků   MeSH
• imunoterapie metody   trendy   MeSH
• iontové kanály antagonisté a inhibitory   MeSH
• lidé MeSH
• mastocyty imunologie   MeSH
• molekuly buněčné adheze antagonisté a inhibitory   MeSH
• receptory IgE antagonisté a inhibitory   MeSH
• receptory kanabinoidní metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Příčinou maligního ascitu mohou být různé solidní nádory. Nejčastěji se vyskytuje při metastatickém karcinomu ovaria, žaludku, karcinomu prsu, endometriálním karcinomu, karcinomu tlustého střeva a pankreatu. Primární léčbou maligního ascitu je chemoterapie. Při rekurentním ascitu je však často neúčinná. Catumaxomab (Removab) je trojfunkční monoklonální bispecifická protilátka, která je zaměřená proti adhezní molekule epitelových buněk (EpCAM – epithelial cell adhesion molecule) a antigenu CD3. Je složená z myší protilátky IgG2a a potkaní protilátky IgG2b a reprezentuje novou podtřídu protilátek. V multicentrické klinické studii II./III. fáze bylo u nemocných léčených catumaxomabem delší přežívání bez nutnosti paracentézy (ovariální karcinom 52 vs. 11 dní, non-ovariální karcinom 37 vs. 11 dní, p < 0,0001). Nejvýznamnějšími nežádoucími účinky byly příznaky způsobené SIRS (syndrom systémové zánětlivé odpovědi).

Malignant ascites can be caused by a number of solid tumours. It is most commonly found in association with metastatic ovarian and stomach cancers, breast cancer, endometrial cancer, and colon and pancreas cancers. Primary treatment of malignant ascites is chemotherapy, but it is frequently ineffective in recurrent ascites. Catumaxomab (Removab) is a three- -functional monoclonal bispecific antibody targeting the epithelial cell adhesion molecule (EpCAM) and CD3 antigen. It is composed of mouse IgG2 and rat IgG2b antibodies and represents a new antibody subclass. A multicentre clinical phase II/III trial in patients treated with catumaxomab showed extended survival without the necessity of paracentesis (ovarian cancer 52 vs. 11 days, non-ovarian cancer 37 vs. 11 days, p < 0.0001). The most significant adverse effects were symptoms due by SIRS (systemic inflammatory response syndrome).

• Klíčová slova
• punkce ascitu,
• MeSH
• ascites terapie   MeSH
• biologická terapie metody   MeSH
• hodnocení léčiv statistika a číselné údaje   MeSH
• karcinom terapie   MeSH
• klinické zkoušky jako téma statistika a číselné údaje   MeSH
• lidé MeSH
• molekuly buněčné adheze antagonisté a inhibitory   MeSH
• paracentéza využití   MeSH
• protilátky bispecifické farmakologie   škodlivé účinky   terapeutické užití   MeSH
• výběr pacientů MeSH
• Check Tag
• lidé MeSH

Several lines of evidence suggest that in mice the activation of SMAD2/3 signaling by oocyte secreted factors, together with epidermal growth factor receptor (EGFR) activation, is essential to induce cumulus expansion. Here we show that inhibition of EGFR kinase in follicle stimulating hormone (FSH)-stimulated porcine oocyte-cumulus cell complex (OCCs) strongly decreases hyaluronan (HA) synthesis and its retention in the matrix, as well as progesterone synthesis. Although porcine cumulus cells undergo expansion independently of oocytes, we use biochemical and gene expression analyses to show that they do require activation of SMAD2/3 for optimal stimulation of HA synthesis and proteins involved in the organization of this polymer in the expanded matrix. Furthermore, FSH-induced progesterone synthesis by porcine cumulus cells was increased by blocking SMAD2/3 activation. In conclusion, these results support the hypothesis that an FSH-EGF autocrine loop is active in porcine OCCs, and provide the first evidence that the SMAD2/3 signaling pathway is induced by paracrine/autocrine factors in porcine cumulus cells and is involved in the control of both cumulus expansion and steroidogenesis.

• MeSH
• benzamidy farmakologie   MeSH
• C-reaktivní protein metabolismus   MeSH
• chinazoliny farmakologie   MeSH
• dioxoly farmakologie   MeSH
• epidermální růstový faktor metabolismus   MeSH
• erbB receptory antagonisté a inhibitory   metabolismus   MeSH
• folikuly stimulující hormon metabolismus   MeSH
• glukuronosyltransferasa antagonisté a inhibitory   metabolismus   MeSH
• isochinoliny farmakologie   MeSH
• kumulární buňky metabolismus   MeSH
• kyselina hyaluronová biosyntéza   MeSH
• meióza účinky léků   MeSH
• molekuly buněčné adheze antagonisté a inhibitory   metabolismus   MeSH
• myši MeSH
• oocyty enzymologie   fyziologie   MeSH
• prasata MeSH
• progesteron biosyntéza   MeSH
• protein Smad2 antagonisté a inhibitory   metabolismus   MeSH
• protein Smad3 antagonisté a inhibitory   metabolismus   MeSH
• pyridiny farmakologie   MeSH
• pyrroly farmakologie   MeSH
• sérový amyloidový protein metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• tyrphostiny farmakologie   MeSH
• vývojová regulace genové exprese účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: The aberrant expression of myeloid antigens on acute lymphoblastic leukemia (ALL) cells is a well-documented phenomenon. So far, there have been no reports of a functional consequence of this aberrant expression. The granulocytic marker carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6, CD66c) is a GPI-anchored molecule that is reported to be the most frequently aberrantly expressed myeloid marker in ALL with a strong correlation with genotype. MATERIALS AND METHODS: We mimicked CEACAM6 signaling in ALL cells by cross-linking with anti-CEACAM6 antibody. Next, we measured a response to CEACAM6 signaling by integrin subunits expression, integrin ligand binding, phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2), Akt, and p38 mitogen-activated protein kinase (MAPK) and apoptosis by flow cytometry. RESULTS: Following CEACAM6 cross-linking in ALL cells, we detected Erk1/2, Akt, and p38 MAPK phosphorylation and integrin upregulation, as well as enhanced binding of integrin ligands (vascular cell adhesion molecule-1 [VCAM-1] and intercellular cell adhesion molecule-1 [ICAM-1]). However, CEACAM6 signaling resulted in an increase in apoptosis, unlike other GPI-anchored molecules, such as CD24. CONCLUSION: The present study is the first to demonstrate the functional consequences of CEACAM6 cross-linking in B-cell precursor ALL cells.

• MeSH
• antigeny nádorové imunologie   metabolismus   MeSH
• apoptóza MeSH
• CD antigeny imunologie   metabolismus   MeSH
• fosforylace účinky léků   imunologie   MeSH
• GPI-vázané proteiny MeSH
• imunologický capping MeSH
• integriny imunologie   metabolismus   MeSH
• lidé MeSH
• MAP kinasový signální systém MeSH
• mezibuněčná adhezivní molekula-1 imunologie   metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 3 imunologie   metabolismus   MeSH
• mitogenem aktivované proteinkinasy p38 imunologie   metabolismus   MeSH
• molekuly buněčné adheze antagonisté a inhibitory   imunologie   metabolismus   MeSH
• nádorové buněčné linie MeSH
• onkogenní protein v-akt imunologie   metabolismus   MeSH
• pre-B-buněčná leukemie imunologie   metabolismus   MeSH
• protilátky nádorové imunologie   farmakologie   MeSH
• regulace genové exprese u leukemie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• biologické modely MeSH
• cévní endotel patologie   účinky léků   zranění   MeSH
• finanční podpora výzkumu jako téma MeSH
• glykosaminoglykany farmakologie   MeSH
• králíci MeSH
• molekuly buněčné adheze antagonisté a inhibitory   MeSH
• pentoxifylin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

• Klíčová slova
• REOPRO (CENTOCOR, INC, MALVERN, PENNSYLVANIA),
• MeSH
• balónková koronární angioplastika metody   trendy   MeSH
• biomedicínský výzkum MeSH
• dospělí MeSH
• inhibitory agregace trombocytů imunologie   krev   terapeutické užití   MeSH
• ischemická choroba srdeční farmakoterapie   chirurgie   MeSH
• lidé MeSH
• molekuly buněčné adheze antagonisté a inhibitory   fyziologie   účinky léků   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• randomizované kontrolované studie MeSH