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1.
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.
相似文献
Hit, Lead & Candidate Discovery |
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Sarraf S Tejada R Abawi M Oberst M Dennis T Simon KC Blancato J 《Cancer Genetics and Cytogenetics》2005,161(1):63-69
Cell lines derived from tumors contain numerous chromosomal aberrations and are the focus of study in tumor evolution. The ovarian teratocarcinoma cell line PA-1 demonstrates a single chromosomal aberration: a reciprocal t(15;20)(p11.2;q11.2). A complete molecular genetic analysis was undertaken to characterize this cell line. The PA-1 cell line was studied with fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), bacterial artificial chromosome (BAC) microarray, and Western blotting. Amplification of 20q is frequently implicated in both breast and ovarian cancer; this region contains a number of oncogenes including MDM2, ZNF217, and the ovarian tumor marker WFDC2 (alias HE4). FISH revealed gene amplification of AIB1 (now known as NCOA3) but not STK15 (now known as AURKA). Immunoblot analysis demonstrated 3.6-fold overexpression of the AIB1 protein product, but no elevation of the STK15. BAC cancer gene microarray analysis showed gene amplification of > or =1.20 for five oncogenes. The presence of a consistent single change in PA-1, the t(15;20)(p11.2;q11.2), suggests that the aberration is significant with respect to the transformation status of the cell line. This translocation appears to cause overexpression of AIB1 (and perhaps other proteins), which may provide an immortalizing effect on this cell line. 相似文献
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Xiaoyu Wang Mingzhen Zhang Regina R. Woloshun Yang Yu Jennifer K. Lee Shireen R. L. Flores Didier Merlin James F. Collins 《Nutrients》2021,13(5)
Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH. 相似文献
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Gildasio S. De Oliveira Paul C. Fitzgerald Shireen Ahmad R. Jay Marcus Robert J. McCarthy 《Journal of clinical anesthesia》2013,25(8):651-658
Study ObjectiveTo compare time to awakening and upper airway morbidity between desflurane and sevoflurane using a Laryngeal Mask Airway (LMA) and a balanced anesthetic regimen inclusive of opioids.DesignRandomized, double-blinded, placebo-controlled clinical trial.SettingAmbulatory surgery unit of a university hospital.Patients80 subjects receiving general anesthesia for outpatient gynecological surgery using a LMA.InterventionsDesflurane/fentanyl or sevoflurane/fentanyl were used for anesthetic maintenance.MeasurementsPatients were randomly assigned to receive desflurane or sevoflurane. The primary outcome was time to awakening as determined by an observer who was blinded to study group allocation. Secondary outcomes included the frequency of sore throat, cough, and pain perioperatively and at 2 and 24 hours postoperatively. Quality of recovery (QoR; via QoR-40 questionnaire) at 24 hours also was determined.Main ResultsThe median (IQR) time to eye opening following desflurane was 6.8 (5.0 - 9.8) minutes versus 11.8 (8.8 - 14.6) minutes following sevoflurane (P < 0.001), or a difference of 5.0 (99% CI 2.3 - 6.8) minutes. The median difference in response to verbal commands was 5.3 (99% CI 2.4 - 7.1) minutes. The frequency of cough, laryngospasm, sore throat, and hoarseness did not differ between groups. Quality of recovery at 24 hours was better in the desflurane group: difference in medians 6 (99% CI 0 – 12; P = 0.003).ConclusionsDesflurane retains faster awakening properties than does sevoflurane when used in combination with fentanyl as part of anesthetic maintenance in outpatient surgery with a LMA. The balanced anesthetic maintenance regimen seems to reduce the potential airway reactivity properties of desflurane. 相似文献
7.
Upper gastrointestinal bleeding from peptic ulcers is common. Advances in prognostication, therapeutic endoscopy, and medical
management have evolved rapidly. Patients most likely to rebleed after therapy can now be identified and monitored more closely,
and patients with ulcers of low risk for rebleeding can be managed on an outpatient basis. High-risk patients include those
with ulcers containing a visible vessel or who are actively bleeding. Endoscopic therapy is mandatory in high-risk patients
and involves at least two hemostatic techniques. Second-look endoscopy and repeated hemostasis should be performed promptly
in patients who rebleed. Adjunctive treatment includes intravenous proton pump inhibitor administered in high doses for the
first 72 hours after endoscopic therapy. Further studies are needed to determine the optimal combination of hemostatic techniques
to better target patients who are at risk for ulcer rebleeding. 相似文献
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Phillip L. Pearl Robert McCarter Colleen L. McGavin Yuezhou Yu Fabian Sandoval Stacey Trzcinski Shireen M. Atabaki Tammy Tsuchida John van den Anker Jianping He Pavel Klein 《Epilepsia》2013,54(9):e135-e137
Posttraumatic seizures develop in up to 20% of children following severe traumatic brain injury (TBI). Children ages 6–17 years with one or more risk factors for the development of posttraumatic epilepsy, including presence of intracranial hemorrhage, depressed skull fracture, penetrating injury, or occurrence of posttraumatic seizure were recruited into this phase II study. Treatment subjects received levetiracetam 55 mg/kg/day, b.i.d., for 30 days, starting within 8 h postinjury. The recruitment goal was 20 treated patients. Twenty patients who presented within 8–24 h post‐TBI and otherwise met eligibility criteria were recruited for observation. Follow‐up was for 2 years. Forty‐five patients screened within 8 h of head injury met eligibility criteria and 20 were recruited into the treatment arm. The most common risk factor present for pediatric inclusion following TBI was an immediate seizure. Medication compliance was 95%. No patients died; 19 of 20 treatment patients were retained and one observation patient was lost to follow‐up. The most common severe adverse events in treatment subjects were headache, fatigue, drowsiness, and irritability. There was no higher incidence of infection, mood changes, or behavior problems among treatment subjects compared to observation subjects. Only 1 (2.5%) of 40 subjects developed posttraumatic epilepsy (defined as seizures >7 days after trauma). This study demonstrates the feasibility of a pediatric posttraumatic epilepsy prevention study in an at‐risk traumatic brain injury population. Levetiracetam was safe and well tolerated in this population. This study sets the stage for implementation of a prospective study to prevent posttraumatic epilepsy in an at‐risk population. 相似文献