Syntheses of a radiolabelled CXCR2 antagonist AZD5069 and its major human metabolite.

The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group.

The synthesis of [(14) C]AZD5122. Incorporation of an IV (14) C-microtracer dose into a first in human study to determine the absolute oral bioavailability of AZD5122.

AZD5122, N-(2-(2,3-difluorobenzylthio)-6-((2R,3R)-3,4-dihydroxybutan-2-ylamino)pyrimidin-4-yl)azetidine-1-sulfonamide was under investigation as a potential chemokine receptor CXCR2 antagonist for the treatment for inflammatory diseases. To gain a better understanding of the human pharmacokinetic profile, an exploratory phase I IV microtracer study was conducted using carbon-14 radiolabelled AZD5122. [(14) C]AZD5122 was carbon-14 labelled in the pyrimidine ring in five steps in an overall radiochemical yield of 19% from [(14) C]thiourea. The absolute oral bioavailability of AZD5122 was assessed in healthy subjects by an oral administration of AZD5122, followed by a concomitant intravenous [(14) C]AZD5122 microdose.

A short expedient synthesis of [(14)C]Ticlopidine.

To support the development of a reactive metabolite strategy, the preparation of several radiolabelled compounds such as [(14)C] Ticlopidine was required. In this report, we describe a facile and rapid synthesis of [(14)C] Ticlopidine starting from [(14)C] carbon dioxide. The compound was radiolabelled in the 2-chloromethyl portion of the molecule with a specific activity of 53.4 mCi/mmol and with a radiochemical purity of 98.5%. Storage stability was best as the hydrochloride salt in an ethanol solution.

Waiting for the pain to get worse: characteristics of a pediatric population with acute dental pain.

PURPOSE: The purpose of this study was to examine how acute dental pain in children is managed. METHODS: A prospective 18-item cross-sectional survey was administered to 300 parent-child dyads seeking care at a large urban tertiary care hospital emergency walk-in dental clinic. RESULTS: The children's mean age was 8 years, 6 months (±3 years, 2 months). The mean duration of pain was 17.7 days. Seventy-six percent of children had been treated with at least 1 dose of over-the-counter pain medication. Acetaminophen was most commonly used (40%), followed by ibuprofen (37%). Regression analysis revealed child age to be significantly correlated with over 40% of pain management behaviors. Younger children were less likely to have received over-the-counter analgesia for dental pain (P<.05). CONCLUSION: Parents delayed seeking dental care for over 2 weeks. Acute dental pain was most commonly managed with acetaminophen. Seeking dental care was delayed more often for older children.

Fatigue and health in a seafaring population.

BACKGROUND: Occupational fatigue is relatively common within the general population and has been linked to reduced performance, injury and longer term ill-health. Despite growing acknowledgement of this problem in the maritime sector, little research has been conducted into the risk factors, prevalence and consequences of seafarers' fatigue. AIMS: To examine the prevalence of fatigue among seafarers, identify potential risk factors and assess possible links with poor performance and ill-health. METHODS: Cross-sectional questionnaire survey of seafarers working in the offshore oil support, short-sea and deep-sea shipping industries. A number of tools were used including the fatigue subscale of the profile of fatigue-related symptoms, the Cognitive Failures Questionnaire, the General Health Questionnaire and the SF36 General Health scale. RESULTS: In all, 1855 questionnaires were completed giving an overall response rate of 20%. Fatigue symptoms were associated with a range of occupational and environmental factors, many unique to seafaring. Reporting a greater number of risk factors was associated with greater fatigue [e.g. OR = 2.53 (1.90-3.35) for those with three or four risk factors and OR = 9.54 (6.95-13.09) for those with five or more risk factors]. There was also a strong link between fatigue and poorer cognitive and health outcomes, with fatigue the most important of a number of risk factors, accounting for 10-14% of the variance. CONCLUSIONS: Seafarers' fatigue could impact on safety within the industry and may be linked to longer term individual ill-health. It can only be addressed by considering how multiple factors combine to contribute to fatigue.

Patterns of fatigue among seafarers during a tour of duty.

BACKGROUND: Work-related fatigue is associated with sickness absence and mental and physical health problems, and may increase the risk of accidents and injuries at work. Relatively little is known about fatigue among seafarers, particularly during a tour of duty. The aim of this study was to describe the pattern of day to day fatigue among seafarers during a tour at sea. METHODS: Participants from the offshore support, short sea and coastal, and deep sea sectors of the UK shipping industry completed daily diaries. Information about sleep and fatigue was collected each day on waking and retiring. RESULTS: Fatigue on waking was a more sensitive measure of cumulative occupational fatigue than fatigue on retiring. Fatigue on waking increased between the start and end of tour. This increase took place in particular during the first week at sea, and was most apparent among those on shorter tours of duty. CONCLUSIONS: Day to day changes in fatigue are measurable, and may vary among particular sub-groups of seafarers. Used among larger groups, such a diary method could help identify times and activities associated with the greatest risk.