Biological evaluation, molecular docking, and sar studies of novel 2-(2,4-dihydroxyphenyl)- 1H- benzimidazole analogues

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong $IC_{50}$ 5-0.2 $\mu$ M AChE and moderate ($IC_{50}$ 5-0.2 M) BuChE inhibition in vitro. Some compounds were e ective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure–activity relationships were discussed. The compounds inhibited also in vitro self-induced A$\beta$ (1-42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine

Vesicular Contact Reaction May Progress into Erythema Multiforme

No abstract availabl

Avelumab use in Merkel cell carcinoma treatment

Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. It was the first immunotherapy to be approved for the treatment of MCC. In March 2017, the FDA granted accelerated approval to avelumab for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) irrespective of prior therapy. In July 2017, the European Medicines Agency (EMA) recommended the approval of avelumab as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (mMCC). Approvals were based on the efficacy and safety demonstrated in JAVELIN Merkel 200 (NCT02155647), a multi-center, open-label, single-arm, phase II clinical trial [1]. Part A of the study consisted of patients treated in the second line with metastatic, chemotherapy-refractory MCC. Part B consisted of systemic treatment-naive patients who received avelumab as first-line treatment for metastatic or distally recurrent MCC. In the first line the ORR is 39.7%. Durable responses lasting at least 6 months were observed and the majority of responses are observed earlywith the median time to response of 6.1 week. PFS rate at 6 months and at 12 months are 41% and 31%, respectively. Median OS is 20.3 months. The OS rate at 1 year is 60%

Avelumab use in Merkel cell carcinoma treatment

Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. It was the first immunotherapy to be approved for the treatment of MCC. In March 2017, the FDA granted accelerated approval to avelumab for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) –irrespective of prior therapy. In July 2017, the European Medicines Agency (EMA) recommended the approval of avelumab as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (mMCC). Approvals were based on the efficacy and safety demonstrated in JAVELIN Merkel 200 (NCT02155647), a multi-center, open-label, single-arm, phase II clinical trial [1]. Part A of the study consisted of patients treated in the second line with metastatic, chemotherapy-refractory MCC. Part B consisted of systemic treatment-naive patients who received avelumab as a first-line treatment for metastatic or distally recurrent MCC. In the first line the ORR is 39.7%. Durable responses lasting at least 6 months were observed and the majority of responses are observed early with the median time to response of 6.1 week. PFS rate at 6 and 12 months are 41% and 31%, respectively. Median OS is 20.3 months. The OS rate at 1 year is 60%

Clear cell sarcoma

Clear cell sarcoma (CCS), also referred as to melanoma of soft tissues, is a rare malignant tumour of soft tissues. This tumour harbors the characteristic features of soft tissue sarcoma (STS) and is a slowly growing, painless tumour, which then acquires an aggressive course. CCS is characterized by a translocation t(12; 22)(q13; q12), which in addition to the diagnostic implications may be important for targeted treatment in the future. CCS occurs mainly on the limbs, most often shin (in feet and ankle area) in the tendons and aponeurosis, often at a young age. CCS is characterized by high potential to develop metastases in regional lymph nodes (about 30% of cases). In the diagnostic process one should consider performing a sentinel node biopsy with possible subsequent radical lymphadenectomy in the case of metastases detection. Treatment of localized disease is limited to radical local excision with complementary radiotherapy. Due to the resistance to classical chemotherapy and the presence of characteristic molecular abnormalities, trials of molecular targeted therapies in this group of cancers are ongoing. In clinical trials, MET inhibitors, tyrosine kinase inhibitors (TKI) — sunitinib and pazopanib were evaluated. CCS was also one of the subtypes of tumours evaluated in the CREATE clinical trial with crizotinib

Mięsak jasnokomórkowy

Mięsak jasnokomórkowy (CCS), zwany również czerniakiem tkanek miękkich, to rzadki nowotwór złośliwy tkanek miękkich. Nowotwór ten ma charakterystyczne cechy mięsaka tkanek miękkich (MTM) w postaci wolno rosnącego, niebolesnego guza, który następnie nabiera agresywnego przebiegu, CCS charakteryzuje translokacja t(12;22) (q13;q12), co oprócz implikacji diagnostycznych może mieć w przyszłości znaczenie dla leczenia celowanego. Mięsak jasnokomórkowy występuje głównie na kończynach, najczęściej dolnych (stopy, okolica kostek), w okolicy ścięgien i rozcięgien, często u osób w młodym wieku. Cechuje się znaczną zdolnością do tworzenia przerzutów do regionalnych węzłów chłonnych (ok. 30% przypadków). W postępowaniu diagnostycznym należy uwzględnić wykonanie biopsji węzła wartowniczego z ewentualną następową radykalną limfadenektomią w przypadku stwierdzenia przerzutów. Leczenie postaci zlokalizowanych ogranicza się do radykalnego miejscowego wycięcia z uzupełniającą radioterapią. W związku z opornością na klasyczną chemioterapię i obecnością charakterystycznych zaburzeń molekularnych trwają obecnie badania nad zastosowaniem leczenia celowanego molekularnie w tej grupie nowotworów. W badaniach klinicznych oceniano skuteczność inhibitorów MET, inhibitorów kinaz tyrozynowych (TKI) — sunitynibu i pazopanibu. Mięsak jasnokomórkowy był także jednym z podtypów nowotworów ocenianych w ramach badania klinicznego CREATE z zastosowaniem kryzotynibu

Valsartan in the treatment of primary hypertension : Polish multicenter, randomised studies

Wstęp Celem pracy jest ocena skuteczności hipotensyjnej i tolerancji walsartanu u pacjentów z łagodnym i umiarkowanym nadciśnieniem tętniczym pierwotnym. Metody Badaniami objęto 93 pacjentów (34K/60M), w wieku 18-80 lat (śr. 50 lat) z nadciśnieniem pierwotnym pochodzących z 6 ośrodków klinicznych w Polsce, u których przy końcu 2-tygodniowego stosowania placebo wartości ciśnienia rozkurczowego (DBP — diastolic blood pressure) mieściły się w granicach 95-115 mm Hg. Walsartan (Diovan®, Novartis) stosowano w jednorazowej dawce dobowej 80 mg przez 8 tygodni, z możliwością dodania hydrochlorotiazydu w dawce 12,5 mg/dobę po 4 tygodniach leczenia pacjentom, u których DBP nie spadło poniżej 95 mm Hg. Ciśnienie mierzono co 2 tygodnie metodą tradycyjną (standaryzowane manometry rtęciowe). Po okresie stosowania placebo (PA), po 4 i 8 tygodniach leczenia aktywnego u pacjentów wykonywano całodobową rejestrację ciśnienia tętniczego (ABPM) aparatem Spacelab 90121. Wyniki W dwóch 4-tygodniowych okresach badania uzyskano istotne statystycznie obniżenie ciśnienia tętniczego w porównaniu z okresem po PA. Ciśnienie skurczowe (SBP — systolic blood pressure) po 8 tygodniach leczenia obniżyło się ze 156 ± 14,8 mm Hg do 136 ± 15 mm Hg — mierzone metodą standardową oraz ze 144 ± 15,3 mm Hg do 134 ± 14,3 mm Hg — w rejestracji dobowej. Ciśnienie rozkurczowe obniżyło się odpowiednio z 103 ± 4,4 mm Hg do 89 ± 8,9 mm Hg — mierzone metodą standardową oraz z 98 ± 12,2 do 90 ± 12,9 mm Hg — w zapisie dobowym ABPM. U 61 osób poddanych monoterapii (Diovan®) po 8 tygodniach leczenia SBP średnio obniżyło się o 20 mm Hg, a DBP o 16 mm Hg — mierzone metodą standardową, a w zapisie dobowym ABPM odpowiednio o 9 i 8 mm Hg. U 32 pacjentów wymagających leczenia skojarzonego SBP po 8 tygodniach leczenia obniżyło się o 21 mm Hg, zaś DBP o 13 mm Hg — mierzone metodą standardową, a w zapisie dobowym odpowiednio o 12 i 9 mm Hg. Działania niepożądane w postaci bólów i zawrotów głowy, osłabienia i zgagi obserwowano u 6 pacjentów stosujących Diovan® i u 8 chorych leczonych metodą skojarzoną. Powyższe dolegliwości były umiarkowane i ustępowały w trakcie dalszego leczenia. Wnioski Walsartan jest skutecznym i dobrze tolerowanym lekiem hipotensyjnym zarówno w monoterapii, jak i w leczeniu skojarzonym z hydrochlorotiazydem.Background The aim of the study was the evaluation of valsartan’s efficacy and tolerance in patients with mild and moderate essential hypertension. Material and Methods The research carried out in six medical centres in Poland included 93 patients (60 male, 34 female), aged 18–80 (mean age: 50), with primary hypertension, whose diastolic blood pressure (DBP) at the end of a two-week placebo treatment ranged 95–115 mm Hg. Valsartan (Diovan®, Novartis) was administered as a single daily dose of 80 mg for 8 weeks. In case of patients whose DBP did not come down below 95 mm Hg after 4 weeks, a daily dose of 12,5 mg hydrochlorothiazide was added to the treatment. Blood pressure was measured with the traditional method (standardised mercurial manometers) every 2 weeks. After the period of placebo administration (PA), and after 4 and 8 weeks of treatment, 24-hour ambulatory blood pressure measurements (APBM) were performed with a Spacelab 90121 recorder. Results In both 4-week treatment periods, statistically significant reduction of blood pressure, as compared to the period of PA, was observed. After 8 weeks of treatment, systolic blood pressure (SBP) decreased from 156 ± ± 14,8 mm Hg to 136 ± 15 mm Hg (standard measurement), and from 144 ± 15,3 mm Hg to 134 ± 14,3 mm Hg (ABPM). DBP decreased respectively from 103 ± ± 4,4 mm Hg to 89 ± 8,9 mm Hg (standard method) and from 98 ± 12,2 to 90 ± 12,9 mm Hg in ABPM. After 8 weeks, in 61 patients who underwent only valsartan treatment, SBP decreased by 20 mm Hg on average, and DBP decreased by 16 mm Hg in standard method, and in ABPM by 9 and 8 mm Hg, respectively. After 8 weeks, in 32 patients who required combination treatment, SBP decreased by 21 mm Hg on average, and DBP decreased by 13 mm Hg in standard method, and in ABPM by 12 and 9 mm Hg, respectively. Side effects in form of headache, vertigo, general weakness and pyrosis were observed in 6 patients taking valsartan and in 8 in the combination treatment group. The side effects were moderate and withdrew as the treatment continued. Conclusion Valsartan is an effective and well tolerated antihypertensive drug, both when administered in monotherapy and in combination with hydrochlorothiazide