The effect of NIDCR R25 grant support on the curriculum and culture of a research non-intensive dental school.

Our objective was to evaluate changes in curriculum and culture within a research non-intensive dental school after implementation of programs supported by the NIH-NIDCR R25 Oral Health Research Curriculum Grant. We designed new curricular elements to foster an appreciation of research/discovery, an interest in academic/research careers, and application of biomedical/clinical advances to patient care. Funding was utilized to develop, implement, and assess a dedicated curricular track of continuous student research/scholarly activity throughout the four years of dental education. This track represented mandatory hours of didactic time exposing students to topics not traditionally included in dental curricula. Additionally, students were provided with customized flexible schedules to participate in elective "hands-on" mentored research/scholarly experiences at local, national, and international sites, including linkages to certificate, MS, and PhD programs. Funding was also used to support a wide array of faculty development activities that provided skill sets required to deliver integrated biomedical/clinical content, research-oriented evidence-based approaches to dental education, and translational case-based teaching methods emphasizing the application of new science/technologies to patient care. We measured changes in student, faculty, and institutional profiles/attitudes using traditional benchmarks, surveys, and focus groups. Comparisons were made between baseline data prior to R25 program initiation and data collected after years 3-4 of program implementation. Significant increases were demonstrated in: (1) student participation in research/scholarship, attendance at national meetings, research awards, publication of manuscripts, pursuit of advanced training/degrees, and expressions of interest in academic/research careers; (2) faculty participation in development activities, publication of manuscripts, and mentoring of students; and (3) increased institutional credibility within the university, supportive infrastructure for research/scholarship, and cultural expectations for academic excellence. Thus, we believe that the R25 programming changed the culture of our dental school, creating a supportive environment for research/scholarship, increasing academic productivity, and altering the attitudes of faculty/students.

Lack of secondary hyperalgesia and central sensitization in an acute sheep model.

BACKGROUND AND OBJECTIVES: We aimed to determine the following in an experimental acute pain model in sheep: (1) whether multimodal analgesia with intravenous fentanyl and ketorolac was more effective than fentanyl alone; (2) whether secondary hyperalgesia (central sensitization) occurred in adjacent (foreleg) dermatomes after thoracic surgery; (3) whether ketorolac used preemptively influenced the development of secondary hyperalgesia after surgery. METHODS: Changes in primary nociception were measured by increases to tolerated pressure, applied to the foreleg by a blunt pin, before foreleg withdrawal occurred. Changes to breath-to-breath interval and estimated end-tidal CO2 were used as indices of respiratory effects. Study 1 (n = 6) compared the paired responses to acute nociception after ketorolac (90 mg) or saline (control) pretreatment, followed by fentanyl (graded, 0 mg to 1.5 mg). Study 2 (n = 6) used a cross-over of ketorolac (90 mg) or saline (control) 24 hours and 1 hour, respectively, before a standardized thoracotomy incision, followed by antinociceptive testing with ketorolac (90 mg) and fentanyl (0.6 mg) daily over 4 days. RESULTS: In study 1, fentanyl produced naloxone-antagonizable antinociception and respiratory depression. Ketorolac did not affect fentanyl antinociception, except for prolonging antinociception at the highest dose; it did not affect the respiratory effects. In study 2, preemptive ketorolac had no effect on the postoperative antinociceptive or respiratory effects of fentanyl. The pharmacokinetics of fentanyl were unaltered by ketorolac. CONCLUSIONS: The results obtained in this acute pain model found no significant evidence of a fentanyl-ketorolac interaction, of central sensitization as shown by secondary hyperalgesia, or of a preemptive analgesic effect.

Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep.

UNLABELLED: Commercially available bupivacaine is an equimolar mixture of R(+)- and S(-)-bupivacaine. S(-)-bupivacaine (i.e., levobupivacaine) is currently undergoing preclinical evaluation. Cross-over studies with i.v. levobupivacaine and bupivacaine were conducted in two groups of seven conscious sheep. Doses were chosen to avoid convulsions (smaller dose 6.25-37.5 mg/min) or to be potentially toxic (larger dose 75-200 mg/3 min). In subconvulsive doses, both drugs produced similar time- and dose-dependent depression of left ventricular systolic contractility (dP/dt(max)). Convulsions occurred consistently with > or = 75 mg of bupivacaine and > or = 100 mg of levobupivacaine, producing an abrupt reversal of dP/dt(max) depression. Subconvulsive doses produced minor cardiovascular effects on heart rate and blood pressure, whereas both were increased by convulsions. Cardiac output and myocardial blood flow were decreased with larger doses of both drugs. Doses > 75 mg of bupivacaine or > 100 mg of levobupivacaine induced QRS widening and ventricular arrhythmias, but significantly fewer and less deleterious arrhythmias were induced by levobupivacaine. Three animals died after 150, 150, and 200 mg of bupivacaine from the sudden onset of ventricular fibrillation. These doses of levobupivacaine produced nonfatal arrhythmias that automatically returned to sinus rhythm. We conclude that levobupivacaine could offer a greater margin of clinical safety than bupivacaine. IMPLICATIONS: Levobupivacaine comprises 50% of commercially available bupivacaine and is being considered for use in its own right. Local anesthetics can cause toxicity to the cardiovascular and central nervous systems. As a part of a preclinical evaluation of levobupivacaine, this study compared the toxic effects of levobupivacaine and bupivacaine in sheep.

Systemic and regional pharmacokinetics of levobupivacaine and bupivacaine enantiomers in sheep.

UNLABELLED: Commercially available bupivacaine is an equimolar mixture of R(+)- and S(-)-bupivacaine. S(-)-bupivacaine (levobupivacaine) is the subject of current clinical evaluation. We conducted partial cross-over systemic and regional pharmacokinetic studies of i.v. bupivacaine (12.5-200 mg) and levobupivacaine (6.25-200 mg) in ewes. Enantiospecific analysis of blood drug concentration-time data and of regional myocardial and brain drug mass balance data indicated that (a) there was a higher mean total body clearance of R(+)-bupivacaine than of S(-)-bupivacaine (as previously reported); (b) there were no differences in the systemic pharmacokinetics of S(-)-bupivacaine whether administered alone or as a component of bupivacaine; (c) there was no evidence of dose-dependent pharmacokinetics with either enantiomer; (d) for both enantiomers, mean calculated myocardial tissue concentrations of 1%-4% dose occurred between 3 and 5 min. Mean brain concentrations of 0.2%-1% dose occurred between 2 and 4 min after the administration of bupivacaine but between 4 and 5 min after the administration of levobupivacaine. There was no evidence that systemic toxicity induced by these local anesthetics significantly modified their pharmacokinetics, and there was no evidence of an enantiomer-enantiomer pharmacokinetic interaction for bupivacaine. IMPLICATIONS: Levobupivacaine comprises 50% of commercially available bupivacaine and is being considered for use in its own right. As a part of its preclinical evaluation, this study considered whether levobupivacaine behaved kinetically in the body in the same way as when administered as a component of bupivacaine.