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Hend Kothayer Samy M. Ibrahim Moustafa K. Soltan Samar Rezq Shireen S. Mahmoud 《Drug development research》2019,80(3):343-352
In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED50) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED50 values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABAA binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.
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Hit, Lead & Candidate Discovery |
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aVR sign as a risk factor for life-threatening arrhythmic events in patients with Brugada syndrome 总被引:2,自引:0,他引:2
BACKGROUND: Risk stratification in Brugada syndrome (BS) is controversial, especially in asymptomatic individuals. OBJECTIVE: The aim of this study was to evaluate the significance of lead aVR in patients with BS. METHODS: Twenty-four patients with the electrocardiogram pattern of BS (24 male, mean age 32.1 +/- 13.6 years) and 24 healthy age- and gender-matched controls were studied. RESULTS: Thirteen patients were symptomatic. The R-wave amplitude or R/q ratio in lead aVR was significantly greater in patients experiencing a recurrence compared with those who did not. The aVR sign was defined as R wave >/= 0.3 mV or R/q >/= 0.75 in lead aVR. Most of the recurrences (78%) were in patients with present aVR sign; 84% of BS patients with present aVR sign had events during follow-up. In contrast, only 27% of BS patients with absent aVR sign had events during follow-up. CONCLUSION: Our study shows significant correlation between a prominent R wave in lead aVR (aVR sign) and risk for development of arrhythmic events in BS. In the presence of BS, prominent R wave in lead aVR may reflect more right ventricular conduction delay and subsequently more electrical heterogeneity, which in turn is responsible for a higher risk of arrhythmia. 相似文献
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Clemens Aigner Peter Jaksch Samy Mazhar Kriztina Czebe Gabriel Marta Sharokh Taghavi Georg Lang Walter Klepetko 《European journal of cardio-thoracic surgery》2004,25(2):184-187
OBJECTIVES: The use of OKT3 for treatment of advanced high-grade acute rejection episodes eventually can result in cytokine release and consecutive pulmonary edema. Temporary extracorporeal membrane oxygenation (ECMO) bridging can be used to overcome this crucial period before the beneficial effects of OKT3 can be observed. METHODS: We summarize our experience with three patients, who underwent lung transplantation and presented with severe acute rejection episodes. OKT3 had to be initiated due to insufficient response to standard rejection therapy with corticosteroids. Upon initiation of OKT3 treatment, a massive life-threatening deterioration of lung function in spite of heavily invasive respirator treatment was seen and temporary ECMO support was imperative to support graft function. Results of this treatment were retrospectively reviewed. RESULTS: In all cases femoro-femoral veno-arterial ECMO was used for support of the impaired graft and after a period of 4-5 days led to a massive improvement of graft function. In the further course two patients could be discharged from hospital and are still alive 30 and 36 months, respectively, after the described incident. One patient died 4 months later due to liver failure. CONCLUSIONS: We conclude that the use of ECMO support in patients experiencing significant side effects from OKT3 therapy is a useful and effective therapeutic tool to overcome the initial critical period until the lung has sufficiently recovered. 相似文献
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Cloud point temperatures (Tcp) and crystallization temperatures (Tl/s) were measured at different constant shear rates for the ternary system tetrahydronaphthalene/poly(ethylene oxide)/oligo(dimethyl siloxane‐b‐ethylene oxide) using a rheo‐optical device and in the case of Tl/s additionally a viscometer. This system enables for the first time a joint investigation of both transitions with a given mixture. Shear favors the homogeneous liquid state and the formation of crystals. Tcp (liquid/liquid demixing, UCST) shifts to lower and Tl/s (liquid/solid, segregation of PEO) to higher temperatures by several degrees as the shear rate, , is increased up to 500 s?1. The normalized shift in Tcp fits well into previous results for high molecular weight blends, oligomer mixtures, polymer solutions in single solvents and low molecular weight mixtures. A phase separated near critical blend was examined 1 K below its Tcp by means of a shear cell (Linkam) in the quiescent state and under shear with respect to its morphology. Upon an increase in one observes a transition from the co‐continuous structures existing in the quiescent state via deformed and oriented particles to string like morphologies. Finally, at sufficiently high shear rates the mixture becomes homogeneous and structures can no longer be seen under the microscope. The morphologies developing after the secession of shear are pointing to pronounced influences of the flow history of the system on the final structure of two phase blends.
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We previously conducted a study of 88 cases of prostate cancer in an attempt to identify potential prognostic biomarkers that can distinguish aggressive cases that must be treated immediately. Prostate cancer is a serious disease affecting men worldwide and compromises the quality of life of its patients. Biomarkers studied included chromosome 7 trisomy, chromosome 8 trisomy, and HER-2/neu oncogene amplification. These biomarkers were initially studied because trisomy 8 and oncogene amplification of the HER-2/neu gene have been reported in many other cancers, including those studied in this laboratory. In view of the fact that HER-2/neu amplification was not found to play a prominent role in the group of prostate cancer specimens that we studied, an exploration of other biomarkers was felt to be warranted. Thus, we began a pilot study of c-myc oncogene copy number in prostate cancer using the same protocol for fluorescent in situ hybridization and a direct-labeled SpectrumOrange LSI c-myc probe (Vysis, Inc., Downers Grove, IL) on formalin-fixed, paraffin-embedded tissue. From a total of 36 cases of prostate cancers successfully analyzed, we found 11 (31%) tumors exhibiting 3 or more positive signals for c-myc in 15% or more of the cells. Of these, only 7 tumors (19% of the total cases studied) had >/=3 signals in 20% or more of the cells. No case had >/=3 signals in 25% or more of the cells. Compared to other molecular probes tested, the c-myc signals were more faint and the quality of the preparation was less optimal than other tumor specimens that we previously studied. Based on the information available thus far, we conclude that an increased copy number in c-myc oncogene copy number was not a prominent finding in our cohort of prostate cancer patients. 相似文献
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