Paediatric population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in cystic fibrosis and bone marrow transplant patients

Objectives: The aim of the study was to characterise the population pharmacokinetics (popPK) properties of itraconazole (ITRA) and its active metabolite hydroxy-ITRA in a representative paediatric population of cystic fibrosis (CF) and bone marrow transplant (BMT) patients. The goals were to determine the relative bioavailability between the two oral formulations, and to explore improved dosage regimens in these patients. Methods: All paediatric patients with CF taking oral ITRA for the treatment of allergic bronchopulmonary aspergillosis and patients undergoing BMT who were taking ITRA for prophylaxis of any fungal infection were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. ITRA and hydroxy-ITRA plasma concentrations were measured by HPLC[1]. A nonlinear mixed-effect modelling approach (NONMEM 5.1.1) was used to describe the PK of ITRA and hydroxy-ITRA simultaneously. Simulations were used to assess dosing strategies in these patients. Results: Forty-nine patients (29CF, 20 BMT) were recruited to the study who provided 227 blood samples for the population analysis. A 1-compartment model with 1st order absorption and elimination best described ITRA kinetics, with 1st order conversion to hydroxy-ITRA. For ITRA, the apparent clearance (ClItra/F) and volume of distribution (Vitra/F) was 35.5L/h and 672L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h-1 and for the oral solution formulation it was 0.959 h-1. The capsule comparative bioavailability (vs. solution) was 0.55. For hydroxy-ITRA, the apparent volume of distribution and clearance were 10.6 L and 5.28 L/h, respectively. Of several screened covariates only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. Conclusion: The developed popPK model adequately described the pharmacokinetics of ITRA and hydroxy-ITRA in paediatric patients with CF and patients undergoing BMT. High inter-patient variability confirmed previous data in CF[2], leukaemia and BMT[3] patients. From the population model, simulations showed the standard dose (5 mg/kg/day) needs to be doubled for the solution formulation and even 4 times more given of the capsules to achieve an adequate target therapeutic trough plasma concentration of 0.5 mg/L[4] in these patients.

Further evidence of linkage at 7p22 with familial hyperaldosteronism type II and exclusion of genetic defects in the RBAK coding regions

Once thought rare, primary aldosteronism (PAL) is now reported to be responsible for 5–10% of hypertension. Unlike familial hyperaldosteronism type I (FH-I), FH-II is not glucocorticoidremediable and not associated with the hybrid CYP11B1/CYP11B2 gene mutation. At least five times more common than FH-I, FH-II is clinically indistinguishable from apparently sporadic PAL, suggesting an even higher incidence. Studies performed in collaboration with C Stratakis (NIH, Bethesda) on our largest Australian family (eight affected members) demonstrated linkage at chromosome 7p22. Linkage at this region was also found in a South American family (DNA provided by MI New, Mount Sinai School of Medicine, New York) and in a second Australian family. The combined multipoint LOD score for these 3 families is 4.61 (q = 0) with markers D7S462 and D7S517, providing strong support for this locus harbouring mutations responsible for FH-II. A newly identified recombination event in our largest Australian family has narrowed the region of linkage by 1.8 Mb, permitting exclusion of approximately half the genes residing in the originally reported 5 Mb linked locus. Candidate genes that are involved in cell cycle control are of interest as adrenal hyperplasia and adrenal adenomas are common in FH-II patients. A novel candidate gene in this linked region produces the retinoblastoma-associated Kruppel-associated box protein (RBaK) which interacts with the retinoblastoma gene product to repress the expression of genes activated by members of the E2F family of transcription factors.

The rural medicine rotation: Increasing rural recruitment through quality undergraduate rural experiences

TITLE: The Rural Medicine Rotation: Increasing Rural Recruitment through Quality Undergraduate Rural Experiences Eley Diann, University of Queensland, School of Medicine, Rural Clinical Division, Toowoomba 4350, Queensland Australia Baker Peter, University of Queensland, School of Medicine Rural, Clinical Division, Toowoomba 4350, Queensland Australia Chater Bruce, University of Queensland, Chair, Clinical School Management Committee, School of Medicine Rural Clinical Division, Queensland Australia CONTEXT: While rural background and rural exposure during medical training increases the likelihood of rural recruitment (Wilkinson, 2003), the quality and content of that exposure is the key to altering undergraduatesâ?? perceptions of rural practice. The Rural Clinical Division at University of Queensland (UQ) runs the Rural Medicine Rotation (RMR) within the School of Medicine. The RMR is one of five eight week clinical rotations in Year three and is compulsory for all students. The RMR provides the opportunity to learn from a wide range of health professionals and clinical exposure is not restricted to general practice but also includes remote area nursing, Indigenous health care, allied health professionals and medical specialists. Week 1 involves preparation for their rural placement with workshops and seminars and Week 8 consolidates their placement and includes case and project presentations and a summative assessment. Weeks 2-7 are spent living and working as part of the health team in different rural communities. SETTING: Rural communities in and around Queensland including locations such as Arnham Land, Thursday Island, Mt. Isa and Alice Springs METHOD: All aspects of the RMR are evaluated with surveys using both qualitative and quantitative free response questions, completed by all students at the end of the Week 8. RESULTS: Overall the RMR is evaluated highly and narratives offered by students show that the RMR provides a positive rural experience. The overall impact of the RMR for students in 2004 ranked 3.45 on a scale of 1 to 4 (1 = lowest and 4 = highest), and is exemplified by the following quote; â??I enjoyed my placement so much I am now considering rural medicine something I definitely had not considered beforeâ??. OUTCOME: The positive impact of the RMR on studentâ??s perceptions of rural medicine is encouraging and can help achieve the overall aim of increasing recruitment of the rural workforce in Australia.

Medical error:a discussion of the medical construction of error and suggestions for reforms of medical education to decrease error

Introduction: There is a growing public perception that serious medical error is commonplace and largely tolerated by the medical profession. The Government and medical establishment's response to this perceived epidemic of error has included tighter controls over practising doctors and individual stick-and-carrot reforms of medical practice. Discussion: This paper critically reviews the literature on medical error, professional socialization and medical student education, and suggests that common themes such as uncertainty, necessary fallibility, exclusivity of professional judgement and extensive use of medical networks find their genesis, in part, in aspects of medical education and socialization into medicine. The nature and comparative failure of recent reforms of medical practice and the tension between the individualistic nature of the reforms and the collegiate nature of the medical profession are discussed. Conclusion: A more theoretically informed and longitudinal approach to decreasing medical error might be to address the genesis of medical thinking about error through reforms to the aspects of medical education and professional socialization that help to create and perpetuate the existence of avoidable error, and reinforce medical collusion concerning error. Further changes in the curriculum to emphasize team working, communication skills, evidence-based practice and strategies for managing uncertainty are therefore potentially key components in helping tomorrow's doctors to discuss, cope with and commit fewer medical errors.

College of Medicine Faculty

List of Florida International University College of Medicine faculty

Florida International University School of Medicine Initiative: Board of Governors Presentation Draft

Annotated draft of a presentation for the Board of Governors on the Florida International University School of Medicine Initiative. Presentation provides an overview of the proposed outcomes resulting from the establishmend of a School of Medicine at Florida International University and the impact on the physician shortage and health care in South Florida.

School of Medicine Initiative, Proposal for A Program in Allopathic Medicine

Review copy of Florida International University School of Medicine Initiative: Proposal for a Program in Allopathic Medicine. Submitted to Florida International University Board of Trustees on September 19, 2004.

The commercial bark harvest of the African cherry (Prunus africana) on Mount Oku, Cameroon: Effects on traditional uses and population dynamics

Bark extracts of the African cherry (Prunus africana) are used to treat benign prostatic hyperplasia. This study examined the effects of commercial bark harvest on population dynamics in the Kilum-Ijim Forest Preserve on Mount Oku, Cameroon and on traditional uses. P. africana is valued for its timber and as fuel although its greatest value is as a traditional medicine for human and animal ailments. Harvest has depleted the resource and has eroded traditional forest protection practices. I constructed matrix models to examine the effects of bark harvest on population structure and on population dynamics in harvested and unharvested populations. Harvesting simulations examined the effect on the population growth rate (λ) with differing levels of mortality of harvest-sized and large trees and differing harvest frequencies. Size class frequencies for the entire forest decreased in a reverse j-shaped curve, indicating adequate recruitment in the absence of harvest. Individual plots showed differences from the overall forest data, suggesting effects of natural and man-made perturbations, particularly due to bark harvest. One plot (harvested in the 1980s) showed a temporal difference in λ and fluctuated around one, due to alternating high and low fruiting years; other unharvested plots showed smaller temporal differences. Harvested plots (harvested illegally in 1997) had values of λ less than one and showed small temporal differences. The control plot also showed λ less than one, due to poor recruitment in the closed canopy forest. The value of λ for the combined data was 0.9931 suggesting a slightly declining population. The elasticity matrix for the combined data indicated the population growth rate was most sensitive to the survival of the large reproductive trees (42.5% of the elasticity). In perturbation analyses, reducing the survival of the large trees caused the largest reductions in λ. Simulations involving harvesting frequency indicated λ returns to pre-harvest conditions if trees are re-harvested after 10–15 years, but only if the large trees are left unharvested. Management scenarios suggest harvest can be sustainable if seedlings and small saplings are planted in the forest and actively managed, although large-scale plantations may be the only feasible option to meet market demand. ^