Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor.

A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido[3,4-d]pyrimidine, and pyrido[3,2-d]pyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme). However the pyrido[3,2-d]pyrimidine analogues were 2-6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were generally less potent overall toward inhibition of heregulin-stimulated autophosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds showed better activity when given orally than intraperitoneally. All showed significant tumor growth inhibition (stasis) over a dose range. The poor aqueous solubility of the compounds was a drawback, requiring formulation as fine particulate emulsions.     

Preoperative ketorolac increases bleeding after tonsillectomy in children

Purpose

To compare the incidence of vomiting following codeine or ketorolac for tonsillectomy in children.

Methods

We had planned to enrol 240 patients, aged 2–12 yr undergoing elective tonsillectomy into a randomized, single-blind study in University Children’s Hospital. The study was terminated, after 64 patients because interim analysis of the data by a blinded non-study scientist concluded that the patients were at undue risk of excessive perioperative bleeding. After induction of anaesthesia by inhalation with N₂O/halothane or with propofol 2.5?3.5 mg· kg^?1 iv, the children were administered 150 μg· kg^?1 ondansetron and 50 μg · kg^?1 midazolam. Maintenance of anaesthesia was with N₂O and halothane in O₂. Subjects were administered either 1.5 mg · kg^?1 codeine im or 1 mg· kg^?1 ketorolac iv before the commencement of surgery. Intraoperative blood loss was measured with a Baxter Medi-Vac® Universal Critical Measurement Unit. Postoperative management of vomiting and pain was standardized. Vomiting was recorded for 24 hr after anaesthesia. Data were compared with ANOVA, Chi-Square analysis and Fisher Exact Test.

Results

Thirty-five subjects received ketorolac. Demographic data were similar. The incidence of vomiting during the postoperative period was 31% in the codeine-group and 40% in the ketorolac-group. Intraoperative blood losses was 1.3 ± 0.8 ml · kg^?1 after codeine and 2.2 ± 1.9 ml · kg^?1 after ketorolac (mean ± SD) P < 0.05. Five ketorolac-treated patients had bleeding which led to unscheduled admission to hospital, P < 0.05, Exact Test.

Conclusion

Preoperative ketorolac increases perioperative bleeding among children undergoing tonsillectomy without beneficial effects.     

Genetic analysis of resistance to total bromodeoxyuridine substitution in mammalian cell hybrids

Somatic cell hybrids derived from the fusion of Chinese hamster ovary cells (CHO) and mutant Syrian hamster melanoma cells (2E) were tested for their ability to grow with all of the thymidine (dThd) in their DNA replaced with 5-bromo-2-deoxyuridine (BrdU), a phenotypic capability of the 2E cells but not of the CHO cells. Under these conditions, the 2E cells survived and grew, all of the hybrid clones survived and grew to varying degrees, and the CHO cells did not survive at all. When 2E cells were tested, they were also found to be resistant to the toxic effects of BrdU substitution and white light irradiation, relative to CHO cells. Thus, when the DNAs of 2E and CHO cells were equally (50%) substituted with BrdU, and the two cell lines irradiated with identical doses of white light, the survival of CHO cells was reduced to <1% of that of unirradiated cells, while 40% of the 2E cells survived. The 2E × CHO hybrid clones were found to survive at values from 10% to 40% under these identical conditions. Thus, the phenotypic characteristics of 2E cells involving total substitution and resistance to the toxic effects of BrdU substitution and white light irradiation appear to be expressed in a codominant fashion in somatic cell hybrids.     

Assessing the Efficiency of HIV Prevention around the World: Methods of the PANCEA Project

Objective. To develop data collection methods suitable to obtain data to assess the costs, cost-efficiency, and cost-effectiveness of eight types of HIV prevention programs in five countries.
Data Sources/Study Setting. Primary data collection from prevention programs for 2002–2003 and prior years, in Uganda, South Africa, India, Mexico, and Russia.
Study Design. This study consisted of a retrospective review of HIV prevention programs covering one to several years of data. Key variables include services delivered (outputs), quality indicators, and costs.
Data Collection/Extraction Methods. Data were collected by trained in-country teams during week-long site visits, by reviewing service and financial records and interviewing program managers and clients.
Principal Findings. Preliminary data suggest that the unit cost of HIV prevention programs may be both higher and more variable than previous studies suggest.
Conclusions. A mix of standard data collection methods can be successfully implemented across different HIV prevention program types and countries. These methods can provide comprehensive services and cost data, which may carry valuable information for the allocation of HIV prevention resources.     

Understanding Youth Athlete Motivation,Training, and Activity Progression During and After the COVID-19 Sports Interruption

BackgroundCOVID-19 restrictions created a period of disrupted sports participation for youth athletes. The physical conditioning, sports training habits, and patterns of sports activity resumption upon returning to normal sports activity are currently unknown.Purpose/HypothesisThis study aimed to determine the extent to which youth athletes maintained their training levels during the early stages of the COVID-19 pandemic and understand the strategies that enhanced motivation and adherence to a training regimen while in isolation. A secondary aim was to analyze how youth athletes returned to activity and identify injuries associated with prolonged sports interruption.Study DesignObservational / Survey StudyMethodsA survey designed to determine activity changes, type of organized instruction, and athlete preferences for training support were distributed by email using snowball sampling methodology to athletes 14-21 years old who were involved in competitive sports when pandemic restrictions were enacted. As sports activities resumed, a follow-up survey was distributed to the same respondents to identify feelings of preparedness, training habits, and injuries.ResultsOf the155 subjects (mean age 16.1 ± 2 years, 64.5% female) that completed the initial survey, 98% reported a stoppage of in-person sports participation and 70% decreased their exercise/training volume, with 41% (n=63) reporting > 50% reduction. Most athletes (86%) received instruction from coaches, with written workouts (70%) being most common; however, most athletes (70%) preferred instructor-led, group training sessions. Of the 43 subjects that completed the follow-up survey (34% response rate), there was an increase in athletic exposures compared to mid-pandemic levels, and 25% reported sustaining a sports-related injury shortly after resuming sports activities.ConclusionsPandemic-related sports restrictions resulted in a significant reduction in youth athlete training and conditioning. Coaches attempted to maintain training via the use of written workouts; however, athletes preferred instructor-led, group training sessions. There was a rapid resumption of sports activities, which may have contributed to the high rate of injuries in this study.Level of Evidence3