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Pokročilé inoperabiiní choiangiokarcinomy patří mezi chemorezistentní nádory s mediánem přežití kolem 6 měsíců. Až u 50 % nemocných mohou být přítomny fúze v genu pro receptor fibroblastového růstového faktoru 2 (fibroblast growth factor receptor 2, FGFR2). Pemigatinib je malá cílená molekula registrovaná pro terapii pokročilých cholangiokarcinomů s fúzním genem FGFR2. Kazuistika popisuje první zkušenosti s léčbou tímto novým léčivým přípravkem.

Advanced inoperable cholangiocarcinomas are among the chemoresistant tumors with a median survival of about 6 months. Fusions in the fibroblast growth factor receptor 2 (FGFR2) gene may be present in up to 50% of patients. Pemigatinib is a small targeting molecule registered for the treatment of advanced cholangiocarcinomas with the FGFR2 fusion gene. The case report describes the first experience with treatment with this new drug.

Klíčová slova
pemigatinib,
MeSH
adherence a compliance při léčbě MeSH
cholangiokarcinom diagnóza terapie MeSH
diagnostické zobrazování MeSH
lidé MeSH
morfoliny terapeutické užití MeSH
nádory žlučových cest diagnóza terapie MeSH
onkogenní fúze MeSH
počítačová rentgenová tomografie MeSH
příčina smrti MeSH
pyrimidiny terapeutické užití MeSH
pyrroly terapeutické užití MeSH
receptory fibroblastových růstových faktorů MeSH
senioři MeSH
Check Tag
lidé MeSH
mužské pohlaví MeSH
senioři MeSH
Publikační typ
kazuistiky MeSH

Článek

Tofacitinib in combination with methotrexate in patients with rheumatoid arthritis: patient-reported outcomes from the 24-month Phase 3 ORAL Scan study

Clinical and Experimental Rheumatology. 2020 ; 38 (5) : 848-857. [pub] 20191219

Clin Exp Rheumatol
ISSN 0392-856X
Medvik
Zdroj

OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we present data from the completed Phase 3 randomised controlled trial (RCT) ORAL Scan (NCT00847613), which evaluated the impact of tofacitinib on patient-reported outcomes (PROs) through 24 months in patients with active RA and inadequate responses to methotrexate (MTX-IR). METHODS: Patients were randomised 4:4:1:1 to receive tofacitinib 5 or 10 mg twice daily (BID), or placebo advanced to tofacitinib 5 or 10 mg, plus background MTX. Patients receiving placebo advanced to tofacitinib at month 3 (non-responders) or month 6 (remaining patients). Mean changes from baseline in PROs, assessed at months 1-24, included Health Assessment Questionnaire-Disability Index, Patient Global Assessment of disease activity (visual analogue scale [VAS]), Patient Assessment of Arthritis Pain (VAS), health-related quality of life (Short Form-36 version 2), Functional Assessment of Chronic Illness Therapy-Fatigue and Medical Outcomes Study-Sleep. RESULTS: Overall, 539/797 (67.6%) patients completed 24 months' treatment. At month 3, tofacitinib-treated patients reported signi cant (p<0.05) mean changes from baseline versus placebo across all PROs, and significantly more patients reported improvements ≥ minimum clinically important differences versus placebo. Improvements in PROs with tofacitinib were sustained to month 24. Following advancement to tofacitinib, placebo-treated patients generally reported changes of similar magnitude to tofacitinib-treated patients. CONCLUSIONS: Patients with RA and MTX-IR receiving tofacitinib 5 or 10 mg BID plus MTX reported significant and clinically meaningful improvements in PROs versus placebo at month 3, which were sustained through 24 months.

MeSH
antirevmatika * terapeutické užití MeSH
dvojitá slepá metoda MeSH
hodnocení výsledků péče pacientem MeSH
kombinovaná farmakoterapie MeSH
lidé MeSH
methotrexát terapeutické užití MeSH
piperidiny MeSH
pyrimidiny MeSH
pyrroly terapeutické užití MeSH
revmatoidní artritida * diagnostické zobrazování farmakoterapie MeSH
výsledek terapie MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH

Článek

Gastrointestinální stromální nádor - novinky v léčbě
[Gastrointestinal stromal tumour: advances in treatment]

Linke, Zdeněk
Autor Autorita Onkologická klinika FN Motol, Praha

Onkologie (Olomouc, Print). 2020 ; 14 (5) : 226-232.

ISSN 1802-4475
Medvik
Zdroj

V indikaci metastatického GIST zůstávají standardem preparáty imatinib, sunitinib, regorafenib. Avapritinib (nový TK-inhibitor) je nově schválen v indikaci 1. linie metastatického GIST s mutací PDGFR D842, ale neprokázal superioritu oproti regorafenibu v celé populace GIST. Mezi další zajímavé tyrosinkinázové inhibitory patří kabozantinib, pazopanib, ripretinib. Data o efektivitě BRAF blokátorů a imunoterapii anti-PD-1 preparáty jsou zatím velmi omezená. Znovunasazení imatinibu po selhání předchozí léčby imatunibem, sunitinibem a regorafenibem se zdá být efektní jen minimálně. Doporučený standard 3leté adjuvantní léčby imatinibemu pacientů po resekci GIST vysokého rizika nezměnily ani výsledky studie PERSIST s aplikovaným imatinibem v adjuvantní indikaci po dobu 5 let.

Imatinib, sunitinib, and regorafenib have remained the standard therapy for metastatic GIST. Avapritinib (a novel TK inhibitor) has been newly approved as the first-line treatment of metastatic GIST with a PDGFR D842 mutation, but has not been shown to be superior compared with regorafenib in the entire GIST population. Other interesting tyrosine kinase inhibitors include cabozantinib, pazopanib, and ripretinib. Data on the efficacy of BRAF inhibitors and immunotherapy with anti-PD-1 drugs have been limited so far. Repeated administration of imatinib after failure of previous treatment with imatinib, sunitinib, and regorafenib appears to have a minimum effect only. The recommended standard of 3-year adjuvant therapy with imatinib in patients after high-risk GIST resection has remained unchanged by the results of the PERSIST clinical trial with a 5-year administration of adjuvant imatinib.

Článek

Aktuální farmakoterapeutické přístupy u pacientů s ulcerózní kolitidou
[Current pharmacotherapeutic practice in patients with ulcerative colitis]

Mikoviny Kajzrlíková, Ivana, 1982-
Autor Autorita Beskydské Gastrocentrum, Interní oddělení, Nemocnice ve Frýdku-Místku

Farmakoterapeutická revue. 2020 ; 5 (2) : 174-179.

ISSN 2533-6878
Medvik
Zdroj

Uicerózní koLitida je chronické zánětLivé onemocnění, které postihuje tlusté střevo. Rozsah onemocnění je variabilní, kontinuálně od rekta orálně. Jedná se o celoživotní nemoc, na jejímž vzniku se podílejí faktory genetické i vlivy vnějšího prostředí. Charakteristické je střídání období klidu a vzplanutí nemoci. Vzhledem k nejasné etioLogii kauzální Léčba není známa, dostupné přípravky působí útlumem zánětu. Konvenční Léčba zahrnuje aminosaLicyLáty, kortikosteroidy a imunosupresiva. V současné době jsou k dispozici četné přípravky bioLogické Léčby působící na různých místech zánětLivé kaskády, do skupiny monokLonáLních protiLátek patří infliximab, adaLimumab, goLimumab, vedoLizumab a ustekinumab. Novější přípravky, takzvané maLé moLekuLy, představuje tofacitinib.

Ulcerative colitis is a chronic inflammatory condition that causes continuous mucosal inflammation of the colon, it affects the rectum and to a variable extent the colon in a continuous fashion. It is a lifelong disease arising from an interaction between genetic and environmental factors, and is characterized by a relapsing and remitting course. Its precise aetiology is unknown, therefore medical therapy is targeted to attenuation of the inflammation. Conventional therapy is represented by 5-aminosalicylic acid, corticosteroids and immunosuppressants. Nowadays, various biologics are available, the group of monoclonal antibodies comprises infliximab, adalimumab, golimumab, vedolizumab and ustekinumab. Novel drugs, so called small molecules, are represented by tofacitinib.

Článek

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Theranostics. 2020 ; 10 (12) : 5259-5275. [pub] 20200406

ISSN 1838-7640
Medvik
Zdroj

Purpose: Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive and metastatic disease, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Hence, developing effective targeted therapy using potent proteasome inhibitor is required. Methods: We evaluated anti-cancer activity of a potent proteasome inhibitor, marizomib, in vitro using breast cancer lines and in vivo using 4T1.2 murine syngeneic model, MDA-MB-231 xenografts, and patient-derived tumor xenografts. Global proteome profiling, western blots, and RT-qPCR were used to investigate the mechanism of action for marizomib. Effect of marizomib on lung and brain metastasis was evaluated using syngeneic 4T1BR4 murine TNBC model in vivo. Results: We show that marizomib inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, we show that marizomib is a dual inhibitor of proteasome and oxidative phosphorylation (OXPHOS) in TNBCs. Marizomib reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of genes involved in the epithelial-to-mesenchymal transition. We demonstrate that marizomib-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and combined inhibition of glycolysis with marizomib leads to a synergistic anti-cancer activity. Conclusions: Our data provide a strong rationale for a clinical evaluation of marizomib in primary and metastatic TNBC patients.

Článek

Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four-Month, Phase III Study

Arthritis & rheumatology. 2019 ; 71 (6) : 878-891. [pub] 20190424

Arthritis Rheumatol
ISSN 2326-5205
Medvik
Zdroj

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here. METHODS: Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression. RESULTS: Overall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported. CONCLUSION: Our findings indicate that clinical and radiographic treatment effects are sustained in months 12-24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.

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