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41.
Thamer A. Alsubi Mohamed W. Attwa Ahmed H. Bakheit Hany W. Darwish Hatem A. Abuelizz Adnan A. Kadi 《RSC advances》2020,10(38):22668
Ribociclib (RBC, Kisqali®) is a highly selective CDK4/6 inhibitor that has been approved for breast cancer therapy. Initially, prediction of susceptible sites of metabolism and reactivity pathways were performed by the StarDrop WhichP450™ module and the Xenosite web predictor tool, respectively. Later, in vitro metabolites and adducts of RBC were characterized from rat liver microsomes using LC-MS/MS. Subsequently, in silico data was used as a guide for the in vitro work. Finally, in silico toxicity assessment of RBC metabolites was carried out using DEREK software and structural modification was proposed to reduce their side effects and to validate the bioactivation pathway theory using the StarDrop DEREK module. In vitro phase I metabolic profiling of RBC was performed utilizing rat liver microsomes (RLMs). Generation of reactive metabolites was investigated using potassium cyanide (KCN) as a trapping nucleophile for the transient and reactive iminium intermediates to form a stable cyano adduct that can be identified and characterized using mass spectrometry. Nine phase I metabolites and one cyano adduct of RBC were characterized. The proposed metabolic pathways involved in generation of these metabolites are hydroxylation, oxidation and reduction. The reactive intermediate generation mechanism of RBC may provide an explanation of its adverse reactions. Aryl piperazine is considered a structural alert for toxicity as proposed by the DEREK report. We propose that the generation of only one reactive metabolite of RBC in a very small concentration is due to the decreased reactivity of the piperazine ring compared to previous reports of similar drugs. Docking analysis was performed for RBC and its proposed derivatives at the active site of the human CDK6 enzyme. Methyl-RBC exhibited the best ADMET and docking analysis and fewer side effects compared to RBC and fluoro-RBC. Further drug discovery studies can be conducted taking into account this concept allowing the development of new drugs with enhanced safety profiles that were confirmed by using StarDrop software. To the best of our knowledge, this is the first literature report of RBCin vitro metabolic profiling and structural characterization and toxicological properties of the generated metabolites.Nine phase I metabolites and one product of KCN trapping of RBC were characterized. Aryl piperazine is considered a structural alert for toxicity as proposed by the DEREK report. Methyl-RBC exhibited less toxicity and more binding affinity to CDK6. 相似文献
42.
Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two‐center experience
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43.
Rashad Al-Salahi Moustapha E. Moustapha Hatem A. Abuelizz Abdulrahman I. Alharthi Khalid A. Alburikan Ismail T. Ibrahim Mohamed Marzouk Mohamed A. Motaleb 《Saudi Pharmaceutical Journal》2018,26(8):1120-1126
3-Benzyl-2-((3-methoxybenzyl)thio)benzo[g]quinazolin-4(3H)-one was previously synthesized and proved by physicochemical analyses (HRMS, 1H and 13C NMR). The target compound was examined for its radioactivity and the results showed that benzo[g]quinazoline was successfully labeled with radioactive iodine using NBS via an electrophilic substitution reaction. The reaction parameters that affected the labeling yield such as concentration, pH and time were studied to optimize the labeling conditions. The radiochemical yield was 91.2?±?1.22% and the in vitro studies showed that the target compound was stable for up to 24?h. The thyroid was among the other organs in which the uptake of 125I-benzoquinazoline has increased significantly over the time up to 4.1%. The tumor uptake was 6.95%. Radiochemical and metabolic stability of the benzoquinazoline in vivo/in vitro and biodistribution studies provide some insights about the requirements for developing more potent radiopharmaceutical for targeting the tumor cells. 相似文献
44.
Hatem A. Elmezayen Hirohisa Okabe Yoshifumi Baba Toshihiko Yusa Rumi Itoyama Yosuke Nakao Takanobu Yamao Naoki Umzaki Masayo Tsukamoto Yuki Kitano Tatsunori Miyata Kota Arima Hiromitsu Hayashi Katsunori Imai Akira Chikamoto Yo-ichi Yamashita Hideo Baba 《Surgery today》2020,50(6):569-576
Programmed death ligand 1 (PD-L1) is a key target for the treatment of several malignancies. The present study was conducted to clarify the role of serum PD-L1 in hepatocellular carcinoma (HCC). Serum PD-L1 (sPD-L1) was examined by an enzyme-linked immunosorbent assay in 153 patients with HCC who underwent curative hepatectomy at Kumamoto University in 2011–2016. The expression of PD-L1 in tissue (tPD-L1) was investigated by immunohistochemistry. The clinical roles of the PD-L1 expression in both serum and tissue were examined. The sPD-L1 was significantly elevated in HCC patients compared to patients without any malignant or inflammatory disease (234 vs. 93 pg/mL, p < 0.0001). The percentage of the tPD-L1-positive area (%tPD-L1) in the background liver was significantly higher than in the tumor (1.52% vs. 0.48%, p < 0.0001). The %tPD-L1 in the background liver but not in the tumor was significantly correlated with the sPD-L1 level (p = 0.0079). The sPD-L1, %tPD-L1 in the tumor, and %tPD-L1 in the background liver were not correlated with the overall survival after surgery. PD-L1-expressing cells in the background liver, but not in the tumor tissue, appeared to contribute to the sPD-L1 level. The sPD-L1 level may thus not indicate the tumor burden in patients with HCC. 相似文献
45.
Hatem G. Said AbdulRahman A. Babaqi Aly Mohamadean Ahmed H. Khater Mohamed H. Sobhy 《International orthopaedics》2014,38(5):1063-1066
Purpose
The proximal part of the long head of the biceps muscle has become a recognized cause of significant shoulder pain. Tenodesis of the long head of the biceps has been advocated as a treatment for pain resulting from biceps tendonopathy, biceps instability, and biceps tendon tears. All of these pathologies may be encountered during rotator cuff, SLAP or Bankart surgery, or in isolation. Several techniques have been described for this tenodesis, including various arthroscopic and subpectoral methods.Methods
We present a modified bone bridge technique of Mazzocca et al., for subpectoral biceps tenodesis. In this technique we tenodese the tendon through two bone tunnels back over the muscle itself without implants.Results
Application of this technique on 30 patients (ages 25–48 years) with short-term follow-up of 12–18 months showed statistically significant improvement (P value < 0.05) of the mean Constant and Oxford shoulder scores (pre-operative mean scores were 39.03 and 21.3, respectively, while postoperative mean scores were 76.43 and 44.8, respectively).Conclusion
This technique has potential advantages as it allows the possibility of adjusting the tension of the biceps tendon before final suturing, in addition to quicker soft tissue healing. 相似文献46.
F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy
Bruno Le Grand Robert Letienne Elisabeth Dupont-Passelaigue Frédérique Lantoine-Adam Frédéric Longo Monique David-Dufilho Georghia Michael Kunihiro Nishida Daniel Catheline Philippe Legrand Stéphane Hatem Stanley Nattel 《Naunyn-Schmiedeberg's archives of pharmacology》2014,387(7):667-677
Atrial fibrillation (AF) is a common complication of heart failure. The aim of the present study was to investigate the effects of a new pure docosahexaenoic acid derivative called F 16915 in experimental models of heart failure-induced atria dysfunction. The atrial dysfunction-induced AF was investigated (1) in a dog model of tachypacing-induced congestive heart failure and (2) in a rat model of heart failure induced by occlusion of left descending coronary artery and 2 months reperfusion. F 16915 (5 g/day for 4 weeks) significantly reduced the mean duration of AF induced by burst pacing in the dog model (989?±?111 s in the vehicle group to 79?±?59 s with F 16915, P?<?0.01). This dose of F 16915 also significantly reduced the incidence of sustained AF (5/5 dogs in the vehicle group versus 1/5 with F 16915, P?<?0.05). In the rat model, the percentage of shortening fraction in the F 16915 group (100 mg/kg p.o. daily) was significantly restored after 2 months (32.6?±?7.4 %, n?=?9 vs 17.6?±?3.4 %, n?=?9 in the vehicle group, P?<?0.01). F 16915 also reduced the de-phosphorylation of connexin43 from atria tissue. The present results show that treatment with F 16915 reduced the heart dilation, resynchronized the gap junction activity, and reduced the AF duration in models of heart failure. Thus, F 16915 constitutes a promising new drug as upstream therapy for the treatment of AF in patients with heart failure. 相似文献
47.
48.
Naim Alkhouri Michael Berk Lisa Yerian Rocio Lopez Yoon-Mi Chung Renliang Zhang Thomas M. McIntyre Ariel E. Feldstein Stanley L. Hazen 《Digestive diseases and sciences》2014,59(7):1617-1624
Background and Aim
Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). By employing a highly sensitive liquid chromatography–tandem mass spectrometry (LC/MS/MS) approach we recently were able to define the circulating profile of bioactive lipid peroxidation products characteristic of patients with nonalcoholic steatohepatitis (NASH) and developed the OxNASH score for NASH diagnosis. The aims of this study were to assess the utility of OxNASH as a predictor of NASH and study the association between OxNASH and specific histologic features of NAFLD.Methods
Our cohort consisted of 122 patients undergoing liver biopsy for clinical suspicion of NAFLD. The NAFLD activity score (NAS) was calculated for each patient. Levels of fatty acid oxidation products were quantified using stable isotope dilution LC/MS/MS, and OxNASH was calculated.Results
The mean age of our patients was 49.3 (±11.6) years, and the mean body mass index was 31.5 (±4.8) kg/m2. The majority of patients were Caucasian (82 %) and 48 % were female. OxNASH correlated with NAS and with the individual histologic features of NAFLD, namely, steatosis, inflammation, and ballooning (P < 0.05), with the strongest association being with inflammation [rho (ρ) 0.40, 95 % confidence interval 0.23, 0.57, P < 0.001]. There was also a correlation between the stage of fibrosis and OxNASH (P = 0.001). These associations remained statistically significant after adjustment for multiple confounders.Conclusions
Based on our results, in adult patients with NAFLD, OxNASH correlates with histologic features of NASH and appears to be a promising noninvasive marker. 相似文献49.
Yasser Emad Ashraf Anbar Ihab Abo-Elyoun Nashwa El-Shaarawy Hadeel Al-Hanafi Hatem Darwish Mona Gamil Johannes J. Rasker 《Clinical rheumatology》2014,33(6):791-797
This study aimed to determine the frequency of rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) antibodies in a cohort of patients with palindromic rheumatism (PR) and to find determinants for progression to rheumatoid arthritis (RA). All new cases of PR (n?=?90) were included prospectively and followed up for 1 year, and a comparison group of RA cases (n?=?70) was also included. At study entry in all patients in both groups, RF and anti-CCP antibodies were tested, and the findings were compared and correlated. In the PR group at presentation, RF was positive in 30 patients (33.3 %) and, in the RA group, in 45 patients (64.3 %). Anti-CCP antibodies were positive in 35 patients (38.9 %) with PR and in 58 patients (82.9 %) with RA. In the PR group, positive correlations were observed between RF and C-reactive protein (CRP) (p?=?0.036), while anti-CCP positively correlated with disease duration (p?=?0.015) and CRP (p?<?0.001). At 1-year follow-up, 25 cases (27.5 %) had progressed to RA, 3 (3.3 %) cases had developed systemic lupus, 43 cases had responded to hydroxychloroquine with complete remission, five cases had developed other rheumatic diseases, and 14 cases had progressed to undifferentiated arthritis. After regression analysis, the involvement of hand joints and positive anti-CCP were the only predictors that determined progression into RA within a year (p?<?0.001 and p?=?0.02, respectively). Early hand joint involvement and positive anti-CCP at disease onset are good predictors for progression to RA in this domain. 相似文献
50.