Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and VEGFR-2.

EGFR and VEGFR-2 are involved in pathological disorders and the progression of different kinds of tumors, the combined blockade of EGFR and VEGFR signaling pathways appears to be an attractive approach to cancer therapy. In this work, a series of 4-anilinoquinazoline derivatives containing substituted diaryl urea or glycine methyl ester moiety were designed and identified as EGFR and VEGFR-2 dual inhibitors. Compounds 19i, 19j and 19l exhibited the most potent inhibitory activities against EGFR (IC50 = 1 nM, 78 nM and 51 nM, respectively) and VEGFR-2 (IC50 = 79 nM, 14 nM and 14 nM, respectively), they showed good antiproliferative activities as well. Molecular docking established the interaction of 19i with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors.

Determination of Sertraline in Human Plasma by UPLC-MS/MS and its Application to a Pharmacokinetic Study.

A sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS-MS) method was developed to determine sertraline in human plasma. Sample preparation was accomplished through a simple liquid-liquid extraction with ethyl acetate. Chromatographic separation was carried out on an Acquity UPLC BEH C18 column using a gradient mobile phase system composed of acetonitrile and 1% formic acid in water at a flow rate of 0.40 mL/min. Mass spectrometric analysis was performed using a XEVO TQD mass spectrometer coupled with an electrospray ionization source in the positive ion mode. The multiple reaction monitoring transitions of m/z 306.3 → 275.2 and 326.2 → 291.1 were used to quantify for sertraline and midazolam (internal standard), respectively. The linearity of this method was found to be within the concentration range of 1.0-100.0 ng/mL with a lower limit of quantification of 1.0 ng/mL. Only 2.0 min was needed for an analytical run. This fully validated method was successfully applied to the pharmacokinetic study after an oral administration of 100 mg sertraline to 20 Chinese healthy male volunteers.

[Effects of nonnutritive sucking on gastric emptying and gastroesophageal reflux in premature infants].

OBJECTIVE: Although nonnutritive sucking (NNS) during tube feeding has some benefits on the physiology and development of premature infants, the effect on gastrointestinal function remains controversial. The aim of the study was to evaluate the effects of NNS on the gastric emptying and gastroesophageal reflux (GER) in premature infants. METHODS: Thirty eight healthy appropriate-for-gestational-age premature infants (birth weight ranged from 1050 g to 1790 g, gestational age ranged from 28 weeks to 35 weeks) accepting intermittent nasogastric feeding (INGF) were randomized into NNS group and N-NNS group according to INGF with and without NNS and fed with the same milk formula. Group NNS (n = 18) received oral stimulation by means of a pacifier immediately before feeding, during feeding and then after feeding for 5 min. Group N-NNS (n = 20) served as control and received INGF alone. The following data were collected and recorded, the fluid intake (including both intravenous and oral), milk intake, caloric intake, time of caloric intake reaching 418.4 kJ/(kg x d) by enteral feeding and relevant condition to feeding. Gastric emptying was measured when oral intake reaching above 8 ml/kg while concurrently measuring 24 hour esophageal pH. Real time ultrasonic images of the gastric antrum were obtained and the antral cross sectional area (ACSA) was measured and the half emptying time (50% DeltaACSA) was calculated. Using 24-hour intraesophageal pH monitoring for evaluation of GER, the five parameters of esophageal pH were recorded: number of reflux episodes during 24 hours, reflux index, number of episodes lasting > 5 min, the duration of longest episode and the total time of pH < 4.0. RESULTS: Within two weeks after feeding, there was no significant difference in the fluid intake, caloric intake between the two groups (P > 0.05). Gastric emptying was measured on day 13.26, milk intake had no difference between the two groups and there was no difference in prefeed ACSA. The half gastric emptying time in NNS group was significantly shorter than that in N-NNS group [(58.33 +/- 22.94) min vs. (73.75 +/- 17.76) min, P < 0.05]. Thirty-two of the 38 infants developed GER, the morbidity was 84.2%; the number of reflux episodes during 24 hours was significantly fewer in NNS group than that in N-NNS group [9 (2 - 31) vs. 14 (5 - 31), P < 0.05]; the total time pH < 4.0 and reflux index was lower in NNS than that in N-NNS, but the difference was not statistically significant. The time of reaching 418.4 kJ/(kg x d) by enteral feeding in NNS group was significantly shorter than that in N-NNS group [(12.36 +/- 4.29) d vs. (15.50 +/- 4.58) d, P < 0.05]. The incidence of feeding intolerance such as vomiting and abdominal distension was lower in NNS group than that in N-NNS group, but the difference was not statistically significant (P > 0.05). However, the morbidity of gastric residue in NNS was significantly lower than that in N-NNS (16.7% vs 50.0%, respectively, P < 0.05). CONCLUSION: NNS used during intermittent nasogastric tube feeding is an easy and safe intervention. NNS can improve gastric emptying and decrease the number of reflux episodes, has a positive improving effect on the development of gastrointestinal motility, is beneficial to premature infants for establishing postnatal enteral nutrition.

[Effects of intermittent nasogastric feeding with nonnutritive sucking on nutrient and gastrointestinal tract transit time in premature infants].

OBJECTIVE: To evaluate the effects of nonnutritive sucking (NNS) on the nutrient intake, physical growth, feeding-related complications and whole gastrointestinal transit time (WGTT) in premature infants. METHODS: Thirty eight healthy appropriate for gestational age premature infants (birth weights ranged from 1 050 g to 1 790 g) accepting intermittent nasogastric feeding (INGF) were randomized into NNS group and N-NNS group according to INGF with and without NNS and fed with the same milk formula. The following data were collected and recorded, the physical growth parameters (e.g, body weight, length and head circumference) and the birth-weight regaining time, the fluid intake (including both intravenous and oral), caloric intake, time of reaching 418.4 kJ/(kg.d) by enteral feeding, time of putting nasogastric tube, stool frequency and characters, and relevant complications. WGTT were monitored. RESULTS: The birth-weight regaining time in NNS group was significantly shorter than that in N-NNS group [(8.8 +/- 3.7) d vs (11.1 +/- 3.0) d, P < 0.05]. Within two weeks after feeding, there was no significant difference in the increase of body weight, length and head circumference between the two groups (P > 0.05). The time of reaching 418.4 kJ/(kg.d) by enteral feeding in NNS group was significantly shorter than that in N-NNS group [(12.3 +/- 5.1) d vs (15.7 +/- 5.2) d, P < 0.05]; the times of putting nasogastric tube were respectively (13 +/- 10) d and (17 +/- 12) d, but the difference was not significant (P > 0.05). The morbidity of such complications as vomiting and abdominal distension was lower in NNS group than that in N-NNS group, but the difference was not statistically significant (P > 0.05). However, the morbidity of gastric residue in NNS was significantly lower than that in N-NNS (P < 0.05). WGTT of the second week in NNS group was significantly shorter than that in N-NNS [(33 +/- 13) h vs (45 +/- 20) h, P < 0.05]. Stool frequencies of the second week in NNS group were significantly more than those in N-NNS group [(2.26 +/- 0.17) times/d vs (1.79 +/- 0.58) times/d, P < 0.05]. However, there were no significantly differences in WGTT and stool frequencies of the first week between the two groups (P > 0.05). CONCLUSION: NNS was recommended as a beneficial intervention for premature infants during intermittent nasogastric tube feeding.