PURPOSE: We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial. PATIENTS AND METHODS: Patients received induction with obinutuzumab (G) or rituximab (R) plus bendamustine, or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or cyclophosphamide, vincristine, prednisone (CVP) chemotherapy, followed by maintenance with the same antibody in responders. MRD status was assessed at predefined time points (mid-induction [MI], end of induction [EOI], and at 4-6 monthly intervals during maintenance and follow-up). Patients with evaluable biomarker data at diagnosis were included in the survival analysis. RESULTS: MRD positivity was associated with inferior progression-free survival (PFS) at MI (hazard ratio [HR], 3.03 [95% CI, 2.07 to 4.45]; P < .0001) and EOI (HR, 2.25 [95% CI, 1.53 to 3.32]; P < .0001). MRD response was higher after G- versus R-chemotherapy at MI (94.2% v 88.9%; P = .013) and at EOI (93.1% v 86.7%; P = .0077). Late responders (MI-positive/EOI-negative) had a significantly poorer PFS than early responders (MI-negative/EOI-negative; HR, 3.11 [95% CI, 1.75 to 5.52]; P = .00011). The smallest proportion of MRD positivity was observed in patients receiving bendamustine at MI (4.8% v 16.0% in those receiving CHOP; P < .0001). G appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the G-chemo groups. During the maintenance period, more patients treated with R than with G were MRD-positive (R-CHOP, 20.7% v G-CHOP, 7.0%; R-CVP, 21.7% v G-CVP, 9.4%). Throughout maintenance, MRD positivity was associated with clinical relapse. CONCLUSION: MRD status can determine outcome after induction and during maintenance, and MRD negativity is a prerequisite for long-term disease control in FL. The higher MRD responses after G- versus R-based treatment confirm more effective tumor cell clearance.
- MeSH
- bendamustin hydrochlorid MeSH
- cyklofosfamid MeSH
- doxorubicin MeSH
- folikulární lymfom * MeSH
- galium * terapeutické užití MeSH
- lidé MeSH
- prednison MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- reziduální nádor farmakoterapie MeSH
- rituximab MeSH
- vinkristin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Klíčová slova
- milvexian, žaludeční polypy,
- MeSH
- cévní mozková příhoda * farmakoterapie prevence a kontrola MeSH
- gabapentin farmakologie terapeutické užití MeSH
- genetické markery MeSH
- inhibitory protonové pumpy * škodlivé účinky MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- pánevní bolest * farmakoterapie MeSH
- polypy etiologie MeSH
- pyrimidiny farmakologie terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- triazoly farmakologie terapeutické užití MeSH
- žaludek patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
BACKGROUND: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis. METHODS: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated). FINDINGS: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment. INTERPRETATION: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis. FUNDING: Merck.
- MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- hydroxybutyráty * MeSH
- inhibitory proteinkinas terapeutické užití škodlivé účinky MeSH
- krotonáty * terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nitrily * terapeutické užití MeSH
- piperidiny MeSH
- proteinkinasa BTK antagonisté a inhibitory MeSH
- pyrimidiny * terapeutické užití MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie MeSH
- toluidiny * terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
- MeSH
- adiponektin metabolismus krev MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa * metabolismus MeSH
- faktor 2 související s NF-E2 metabolismus MeSH
- folikuly stimulující hormon krev MeSH
- GABA metabolismus MeSH
- hormon uvolňující gonadotropiny metabolismus MeSH
- hypothalamus * metabolismus účinky léků patologie MeSH
- inzulinová rezistence MeSH
- krysa rodu rattus MeSH
- leptin krev metabolismus MeSH
- letrozol farmakologie MeSH
- luteinizační hormon krev MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar * MeSH
- pyroptóza * účinky léků MeSH
- syndrom polycystických ovarií * chemicky indukované metabolismus farmakoterapie patologie MeSH
- testosteron krev MeSH
- triglyceridy krev metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- analgetika MeSH
- anestetika lokální aplikace a dávkování terapeutické užití MeSH
- gabapentin aplikace a dávkování terapeutické užití MeSH
- kvalita života MeSH
- lidé MeSH
- lidokain aplikace a dávkování terapeutické užití MeSH
- postherpetická neuralgie * diagnóza farmakoterapie prevence a kontrola MeSH
- senioři MeSH
- transdermální náplast MeSH
- vakcína proti pásovému oparu MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- syndrom bolestiplných dolních končetin a pohyblivých prstců,
- MeSH
- bolest diagnóza patologie MeSH
- dolní končetina * patologie MeSH
- dospělí MeSH
- gabapentin terapeutické užití MeSH
- lidé MeSH
- nemoci nervového systému * diagnóza MeSH
- pohybové poruchy MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
AIMS: Patients with heart failure (HF) display metabolic alterations, including heightened ketogenesis, resulting in increased beta-hydroxybutyrate (β-OHB) formation. We aimed to investigate the determinants and prognostic impact of circulating β-OHB levels in patients with advanced HF and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 867 patients with advanced HFrEF (age 57 ± 11 years, 83% male, 45% diabetic, 60% New York Heart Association class III), underwent clinical and echocardiographic examination, circulating metabolite assessment, and right heart catheterization (n = 383). The median β-OHB level was 64 (interquartile range [IQR] 33-161) μmol/L (normal 0-74 μmol/L). β-OHB levels correlated with increased markers of lipolysis (free fatty acids [FFA]), higher natriuretic peptides, worse pulmonary haemodynamics, and lower humoral regulators of ketogenesis (insulin/glucagon ratio). During a median follow-up of 1126 (IQR 410-1781) days, there were 512 composite events, including 324 deaths, 81 left ventricular assist device implantations and 107 urgent cardiac transplantations. In univariable Cox regression, increased β-OHB levels (T3 vs. T1: hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13-1.72, p = 0.002) and elevated FFA levels (T3 vs. T1: HR 1.39, 95% CI 1.09-1.79, p = 0.008) were both predictors of a worse prognosis. In multivariable Cox analysis evaluating the simultaneous associations of FFA and β-OHB levels with outcomes, only FFA levels remained significantly associated with adverse outcomes. CONCLUSIONS: In patients with advanced HFrEF, increased plasma β-OHB correlate with FFA levels, worse right ventricular function, greater neurohormonal activation and other markers of HF severity. The association between plasma β-OHB and adverse outcomes is eliminated after accounting for FFA levels, suggesting that increased β-OHB is a consequence reflecting heightened lipolytic state, rather than a cause of worsening HF.
- MeSH
- biologické markery * krev MeSH
- echokardiografie MeSH
- kyselina 3-hydroxymáselná * krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- prognóza MeSH
- senioři MeSH
- srdeční katetrizace MeSH
- srdeční selhání * krev patofyziologie MeSH
- tepový objem * fyziologie MeSH
- transplantace srdce MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
This study aimed to investigate the concentration of pregabalin in the plasma of chicks to determine its pharmacokinetic parameters. Pregabalin (300 mg/kg) was administered orally to 42 clinically healthy Ross chicks as part of a randomized controlled study. Blood samples were collected from the jugular vein at 0.5, 1, 2, 4, 8, and 24 h after drug administration from six chicks per each time. The concentrations of pregabalin in the plasma samples were determined using a quantitative HPLC assay, and pharmacokinetic parameters were calculated using the PKSolver program. Pharmacokinetic parameters were determined using a noncom-partmental model. The concentrations of pregabalin were 133.80 ± 2.35, 183.20 ± 3.91, 295.60 ± 2.82, 248.40 ± 7.60, 219.00 ± 2.72 and 154.00 ± 5.50 μg/ml at the times 0.5, 1, 2, 4, 8, and 24 h respectively. The pharmacokinetics parameters were t1/2β 29 h, Tmax 2 h, Cmax 295 μg, Kel 0.023 h-1, MRT 43h, Vd 1.127 L/h/kg, Cl 0.026 L/h/kg and AUC0-∞ 11420.31 μg.h/ml. This study concluded that pregabalin has a long elimination half-life and poor clearance from the animal body, which is reflected in the prolonged impact of its action.
V článku autor referuje o novinkách u fibromyalgie jak z hlediska patofyziologie a diagnostiky, tak z hlediska hodnocení klinické manifestace i léčby. Za největší změnu lze pokládat současnou interpretaci patofyziologických mechanismů v mozku (nociplastická bolest), které jsou příčinou klinické manifestace příznaků, zejména rozsáhlých bolestí svalů a vazů. V klinické diagnostice bylo největší změnou opuštění vyšetřování tzv. citlivých bodů a použití novějších diagnostických kritérií. V medikamentózní léčbě se věnujeme zejména použití pregabalinu, duloxetinu a milnacipranu, jejich optimálnímu dávkování a nežádoucím účinkům. Mnoho významných odborníků se domnívá, že fibromylagie patří do rukou neurologů, a to nejen mechanismem vzniku, ale i používanými léky.
The article discusses new developments in fibromyalgia disease in terms of diagnosis, evaluation of clinical manifestation and treatment. The most important change is the elucidation of the pathophysiological mechanisms in the brain (nociplastic pain) that underlie the clinical manifestation of the symptoms, especially the widespread muscle and ligament pain. In clinical diagnosis, the biggest change has been the abandonment of the investigation of the so-called tender points and the use of newer diagnostic criteria. In drug therapy, we are particularly concerned with the use of pregabalin, duloxetine and milnacipran, their optimal dosage and side effects. Many eminent experts believe that the disease belongs in the hands of neurologists, not only in terms of the mechanism of origin, but also in terms of the treatment used, neurologists are best qualified to do so.
