ACT-1014-6470 is an orally available complement factor 5a receptor 1 antagonist and a novel treatment option in auto-inflammatory diseases. The in vitro inhibition potential of ACT-1014-6470 on cytochrome P450 isozymes (CYPs) and its effect on the pharmacokinetics (PK) of the CYP2C19 and CYP3A4 substrates omeprazole and midazolam, respectively, in humans were assessed. In vitro assays were conducted with isoform-specific substrates in human liver microsomes. In an open-label, two-period, fixed-sequence cocktail study, single doses of 20 mg omeprazole and 2 mg midazolam were administered concomitantly to 20 healthy male subjects alone (treatment A) and after a single dose of 100 mg ACT-1014-6470 (treatment B) under fed conditions. Safety and PK assessments were performed. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of noncompartmental PK parameters of treatment B versus treatment A were calculated. In vitro, no time-dependent inhibition was observed and the lowest inhibition constant of 4.3 μM ACT-1014-6470 was recorded for CYP2C19. In humans, GMRs (90% CI) of omeprazole PK were 1.9 (1.5-2.5) for maximum plasma concentration (Cmax ) and 1.9 (1.5-2.3) for area under the plasma concentration-time curve from 0 to 12 h (AUC0-12 h ). Midazolam PK showed GMRs (90% CI) of 1.1 (1.1-1.2) for Cmax and 1.5 (1.4-1.6) for AUC0-24 h . All treatments were well-tolerated. In line with in vitro results and regulatory risk factor calculation, the increased exposure to omeprazole and midazolam in humans after concomitant administration with a single dose of 100 mg ACT-1014-6470 reflected a weak inhibition of CYP2C19 and CYP3A4.

• MeSH
• cytochrom P-450 CYP3A * MeSH
• cytochrom P450 CYP2C19 MeSH
• faktor Va * MeSH
• lékové interakce MeSH
• lidé MeSH
• midazolam farmakokinetika   MeSH
• omeprazol farmakokinetika   MeSH
• systém (enzymů) cytochromů P-450 MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• beta-2-mikroglobulin analýza   MeSH
• celulosa analogy a deriváty   MeSH
• chronické selhání ledvin krev   terapie   MeSH
• dialýza ledvin přístrojové vybavení   MeSH
• dospělí MeSH
• hemodialyzační roztoky analýza   MeSH
• komplement C5a analýza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membrány umělé MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• srovnávací studie MeSH

A disturbing interaction of PAN membranes and the bradykinin generation system particularly in the presence of angiotensin converting enzyme inhibitors has been described. A modified new membrane, SPAN (special PAN), was produced by varying the polymer components in type and composition, in particular by a reduction in Na-Methallylsulfonate. Although the SPAN membrane successfully averted the bradykinin generating ability of PAN, it was important to determine whether such a modification did not lead to a loss of the satisfactory biocompatibility profile characteristic of the parent membrane. For this purpose, we conducted the present clinical study in nine patients comparing 3 membranes; (i) a polysulphone membrane (F60S); (ii) PAN; and (iii) SPAN, to examine the clinical biocompatibility profile and performance of the new membrane. A small increase in C5a with F60S and SPAN was found which is in the range expected for highly biocompatible synthetic membranes. The three dialysers had a similar inert profile for terminal complement complex arterial values, and had similar venous values. A minimal nonsignificant decline in white cell count was observed at 15 min for all dialysers, but otherwise WBC counts were unchanged. Platelet counts were unchanged throughout treatment for the three dialysers. Arterial and venous thrombin-anti-thrombin complex values were similar for all three dialysers. F60S and SPAN dialysers had similar urea clearances.(ABSTRACT TRUNCATED AT 250 WORDS)

• MeSH
• beta-2-mikroglobulin metabolismus   MeSH
• biokompatibilní materiály chemie   terapeutické užití   MeSH
• chronické selhání ledvin metabolismus   terapie   MeSH
• dialýza ledvin * přístrojové vybavení   MeSH
• dospělí MeSH
• komplement C5a metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membranolytický komplex metabolismus   MeSH
• membrány umělé * MeSH
• mladiství MeSH
• močovina metabolismus   MeSH
• počet leukocytů MeSH
• senioři MeSH
• trombin metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• senioři MeSH
• Publikační typ
• klinické zkoušky MeSH
• randomizované kontrolované studie MeSH

INTRODUCTION: ANCA-associated vasculitis (AAV) is a rare but potentially life-threatening disease. Currently used induction treatment (cyclophosphamide or rituximab with high-dose corticosteroids) has significantly improved outcome of AAV, but is associated with high toxicity. Alternative complement pathway activation was shown to play a role in the pathogenesis of AAV, thus providing rationale for the use of avacopan, a selective inhibitor of C5a receptor, in the treatment of AAV. Areas covered: Pharmacokinetic and pharmocodynamic properties of avacopan, clinical efficacy and safety and tolerability of avacopan in so far performed clinical trials in patients with AAV are reviewed and discussed. Expert opinion: Avacopan was shown to have at least similar efficacy compared to high dose corticosteroids in patients with active AAV with renal involvement, while there were no major safety issues reported. Replacement of corticosteroids should decrease the corticosteroid-related toxicity and improve long-term outcome of patients with AAV even though this still needs to be confirmed in a larger trial. Data on long-term outcome of avacopan-treated patients are currently lacking and will be eagerly awaited. In the future, avacopan could replace corticosteroids not only in the induction phase, but also in the maintenance treatment of AAV.

• MeSH
• ANCA-asociované vaskulitidy farmakoterapie   patofyziologie   MeSH
• aniliny škodlivé účinky   farmakologie   terapeutické užití   MeSH
• glukokortikoidy aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• imunologické faktory aplikace a dávkování   terapeutické užití   MeSH
• kyseliny nipekotinové škodlivé účinky   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• receptor pro anafylatoxin C5a antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• srovnávací studie MeSH

• MeSH
• aktivace neutrofilů imunologie   MeSH
• imunitní systém - jevy imunologie   MeSH
• infekce spojené se zdravotní péčí * imunologie   komplikace   mortalita   MeSH
• komplement C5a sekrece   MeSH
• kritický stav * mortalita   MeSH
• lidé MeSH
• multiorgánové selhání * etiologie   imunologie   MeSH
• nemoci imunitního systému etiologie   komplikace   mortalita   MeSH
• neutrofily imunologie   MeSH
• péče o pacienty v kritickém stavu MeSH
• zánět * etiologie   imunologie   komplikace   MeSH
• Check Tag
• lidé MeSH

INTRODUCTION: ANCA-associated vasculitis (AAV) is a rare, life-threatening disease which may result in serious pulmonary and kidney damage. Cyclophosphamide or rituximab and high-dose glucocorticoids significantly improved patient outcomes, but at the expense of severe complications. Moreover, many patients still relapse and bear a significant burden of both disease- and treatment-related complications. Alternative complement pathway and C5a receptor signaling were demonstrated to play an important role in AAV pathogenesis. Avacopan is selective C5a receptor inhibitor successfully tested in renal AAV as glucocorticoid-sparing agent. AREAS COVERED: Pharmacokinetic/pharmacodynamic properties, clinical efficacy and safety of avacopan, available clinical trials and real-world experience with avacopan. EXPERT OPINION: In the phase 3 trial avacopan was shown to be non-inferior at six and superior at 12 months compared to high-dose glucocorticoids and either cyclophosphamide or rituximab in patients with active AAV. Treatment with avacopan was well tolerated and associated with improved quality of life. In patients with severe renal AAV, renal function improved more in avacopan-treated than in high-dose glucocorticoid-treated patients. Avacopan could thus replace high-dose glucocorticoids to avoid glucocorticoid-related toxicity and to improve long term renal outcome. As avacopan is CYP 3A4 inhibitor and substrate, drug-drug interactions must be considered during the treatment.

• MeSH
• ANCA-asociované vaskulitidy * farmakoterapie   MeSH
• aniliny MeSH
• cyklofosfamid aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• glukokortikoidy * aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• imunosupresiva aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• kvalita života * MeSH
• kyseliny nipekotinové MeSH
• lidé MeSH
• receptor pro anafylatoxin C5a antagonisté a inhibitory   MeSH
• rituximab škodlivé účinky   aplikace a dávkování   farmakologie   MeSH
• stupeň závažnosti nemoci MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• srovnávací studie MeSH

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

• MeSH
• ANCA-asociované vaskulitidy farmakoterapie   MeSH
• aniliny škodlivé účinky   terapeutické užití   MeSH
• cyklofosfamid terapeutické užití   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• glukokortikoidy aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• kombinovaná farmakoterapie škodlivé účinky   MeSH
• kyseliny nipekotinové škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prednison aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• receptor pro anafylatoxin C5a antagonisté a inhibitory   MeSH
• rituximab terapeutické užití   MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

• Klíčová slova
• studie CLEAR, avacopan,
• MeSH
• ANCA-asociované vaskulitidy * farmakoterapie   MeSH
• aniliny škodlivé účinky   terapeutické užití   MeSH
• cyklofosfamid terapeutické užití   MeSH
• dvojitá slepá metoda MeSH
• glukokortikoidy škodlivé účinky   terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• kyseliny nipekotinové škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• prednison škodlivé účinky   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• receptor pro anafylatoxin C5a antagonisté a inhibitory   MeSH
• rituximab terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Genome methylation profiles define naïve-like (n-CLL), memory-like (m-CLL), and intermediate (i-CLL) subsets of chronic lymphocytic leukaemia (CLL). The profiles can be easily determined by the analysis of the five-CpG signature. m-CLL, i-CLL, and n-CLL with the good, intermediate, and poor prognoses, respectively, differ by the somatic hypermutation status of the immunoglobulin heavy chain variable gene (IGHV), a widely used prognostic predictor in CLL. We have previously shown that the expression of WNT5A, encoding a ROR1 ligand, distinguishes patients with the worse outcome within the prognostically favourable IGHV-mutated subgroup. To analyse the mechanisms controlling WNT5A expression, we investigated the methylation status of 54 CpG sites within the WNT5A promoter and its relation to the WNT5A gene expression. In a cohort of 59 CLL patients balanced for combinations of IGHV and WNT5A statuses, we identified three promoter CpG sites whose methylation level correlated with the WNT5A expression within the IGHV-mutated subgroup. Further, we complemented our data with the methylation status of the five-CpG signature. IGHV-mutated/WNT5A-negative and IGHV-mutated/WNT5A-positive cases overlapped with m‐CLL and i‐CLL methylation subgroups, respectively, while most IGHV‐unmutated samples were assigned to n-CLL. Median methylation levels of all the three CpG sites in the WNT5A promoter were lowest in i-CLL. Finally, a detailed analysis of m-CLL and i-CLL showed that undetectable WNT5A expression predicts longer treatment-free survival with higher statistical significance than the classification according to the five-CpG signature. To conclude, a favourable m-CLL subgroup is associated with mutated IGHV and undetectable WNT5A expression due to its promoter methylation.

• MeSH
• chronická lymfatická leukemie * genetika   MeSH
• lidé MeSH
• ligandy MeSH
• metylace DNA MeSH
• mutace MeSH
• prognóza MeSH
• promotorové oblasti (genetika) MeSH
• protein Wnt 5a genetika   metabolismus   MeSH
• těžké řetězce imunoglobulinů genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• časná přecitlivělost MeSH
• cefaloridin farmakologie   MeSH
• chemické jevy MeSH
• chemie MeSH
• chloramfenikol aplikace a dávkování   krev   MeSH
• erytrocyty imunologie   MeSH
• Freundovo adjuvans aplikace a dávkování   MeSH
• hemaglutinační testy MeSH
• imunodifuze MeSH
• imunoelektroforéza MeSH
• komplement fixační testy MeSH
• kožní testy MeSH
• králíci MeSH
• morčata MeSH
• ovce imunologie   MeSH
• oxytetracyklin farmakologie   MeSH
• peniciliny farmakologie   MeSH
• protilátky analýza   MeSH
• tvorba protilátek MeSH
• zkřížené reakce MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• morčata MeSH
• zvířata MeSH