Severity of coeliac disease and clinical management study when using a non-metabolised medication: a phase I pharmacokinetic study.

OBJECTIVE: The non-metabolised antihistamine fexofenadine has oral absorption resulting from transporter activity. Uptake by enterocyte organic anion transporting polypeptides and efflux by an ATP-binding cassette transporter (P-glycoprotein) are primary determinants. Coeliac disease-mediated lesions to the small intestinal mucosa may alter oral absorption of the drug probe, fexofenadine. DESIGN: A phase I, open-label, single-dose, pharmacokinetic study SETTING: London, Ontario, Canada PARTICIPANTS: Patients with coeliac disease (n=41) with positive serology and healthy individuals (n=48). MAIN OUTCOME MEASURES: Patients with coeliac disease-duodenal histology and oral fexofenadine pharmacokinetics within a 3-week period. Healthy individuals-oral fexofenadine pharmacokinetics with water and grapefruit juice. RESULTS: Patients with coeliac disease were stratified by disease severity: Group A (n=15, normal), B+C (n=14, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=12, moderate to severe villous blunting). Patients with coeliac disease in groups A, B+C and D and healthy individuals receiving water had similar fexofenadine AUC0-8 (2038±304, 2259±367, 2128±410, 1954±138 ng.h/mL; p>0.05; mean±SEM) and Cmax (440±73, 513±96, 523±104, 453±32 ng/mL; p>0.05), respectively. These four groups all had higher fexofenadine AUC0-8 (1063±59; p<0.01) and Cmax (253±18; p<0.05) compared with those for healthy individuals receiving grapefruit juice. Coeliac groups had a positive linear trend between disease severity and fexofenadine Tmax (2.0±0.3, 2.7±0.4, 3.1±0.5 hours; p<0.05). CONCLUSIONS: Coeliac disease severity based on duodenal histopathology did not affect oral fexofenadine bioavailability. Increased Tmax suggested absorption distal to the duodenum (jejunum + ileum), where histology seems more normal which may be the key determinant. Patients with coeliac disease may not require consideration for alternative clinical drug management for a number of non-metabolised and transport-mediated medications.

Severity of coeliac disease and clinical management study when using a CYP3A4 metabolised medication: a phase I pharmacokinetic study.

OBJECTIVE: Severity of coeliac disease depends in part on the extent of small intestinal mucosa injury. Patients with the most abnormal pathology have loss of duodenal villi CYP3A4, a drug-metabolising enzyme that inactivates many drugs. These patients are hypothesised to have greater systemic concentrations of felodipine, a drug which normally has low oral bioavailability secondary to intestinal CYP3A4-mediated metabolism. It serves as a representative for a class containing many medications. DESIGN: A phase I, open-label, single-dose, pharmacokinetic study. SETTING: London, Ontario, Canada. PARTICIPANTS: Patients with coeliac disease (n=47) with positive serology and healthy individuals (n=68). MAIN OUTCOME MEASURES: Patients with coeliac disease-upper gastrointestinal endoscopy and oral felodipine pharmacokinetics study within a 3-week period. Healthy individuals-oral felodipine pharmacokinetics study with water and grapefruit juice. RESULTS: Coeliac stratification categories: Group A (n=15, normal), B+C (n=16, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=16, moderate/severe villous blunting). Groups A, B+C and D had linear trends of increasing felodipine AUC0-8; mean±SEM, 14.4±2.1, 17.6±2.8, 25.7±5.0; p<0.05) and Cmax (3.5±0.5, 4.0±0.6, 6.4±1.1; p<0.02), respectively. Healthy subjects receiving water had lower felodipine AUC0-8 (11.9±0.9 vs 26.9±0.9, p=0.0001) and Cmax (2.9±0.2 vs 7.7±0.2, p=0.0001) relative to those receiving grapefruit juice. CONCLUSIONS: Increased felodipine concentrations in patients with coeliac disease were most probably secondary to decreased small intestinal CYP3A4 expression. Patients with severe coeliac disease and healthy individuals with grapefruit juice had equivalently enhanced effect. Thus, patients with severe coeliac disease would probably experience similarly altered drug response, including overdose toxicity, from many important medications known to be metabolised by CYP3A4. Patients with coeliac disease with severe disease should be considered for other clinical drug management, particularly when there is the potential for serious drug toxicity.

Discerning applicants' interests in rural medicine: a textual analysis of admission essays.

BACKGROUND: Despite efforts to construct targeted medical school admission processes using applicant-level correlates of future practice location, accurately gauging applicants' interests in rural medicine remains an imperfect science. This study explores the usefulness of textual analysis to identify rural-oriented themes and values underlying applicants' open-ended responses to admission essays. METHODS: The study population consisted of 75 applicants to the Rural Physician Leadership Program (RPLP) at the University of Kentucky College of Medicine. Using WordStat, a proprietary text analysis program, applicants' American Medical College Application Service personal statement and an admission essay written at the time of interview were searched for predefined keywords and phrases reflecting rural medical values. From these text searches, derived scores were then examined relative to interviewers' subjective ratings of applicants' overall acceptability for admission to the RPLP program and likelihood of practicing in a rural area. RESULTS: The two interviewer-assigned ratings of likelihood of rural practice and overall acceptability were significantly related. A statistically significant relationship was also found between the rural medical values scores and estimated likelihood of rural practice. However, there was no association between rural medical values scores and subjective ratings of applicant acceptability. CONCLUSIONS: That applicants' rural values in admission essays were not related to interviewers' overall acceptability ratings indicates that other factors played a role in the interviewers' assessments of applicants' acceptability for admission.

Effect of CKD and dialysis modality on exposure to drugs cleared by nonrenal mechanisms.

BACKGROUND: Patients with kidney disease frequently experience adverse effects from medication exposure, even when drugs are cleared by nonrenal pathways. Although many studies suggest that nonrenal drug clearance is decreased in chronic kidney disease (CKD), there remains a paucity of in vivo studies in patients with varying degrees of decreased kidney function and those comparing the impact of dialysis modality (eg, hemodialysis [HD] and peritoneal dialysis [PD]). STUDY DESIGN: We performed in vivo clinical pharmacokinetic studies of midazolam, a nonrenally cleared specific probe for CYP3A4, and fexofenadine, a nonspecific probe for hepatic and intestinal transporters. SETTING & PARTICIPANTS: Healthy controls (n=8), patients with non-dialysis-dependent (NDD)-CKD (n=8), and patients receiving HD (n=10) or PD (n=8). OUTCOMES: Exposure to midazolam and fexofenadine were quantified using area under the curve (AUC). Comprehensive pharmacokinetic parameters also were calculated for both probes. RESULTS: Midazolam AUC was significantly higher in the HD group (382.8 h·ng/mL) than in the healthy-control (63.0 h·ng/mL; P<0.001), NDD-CKD (84.5 h·ng/mL; P=0.002), and PD (47.4 h·ng/mL; P<0.001) groups. Fexofenadine AUC was significantly higher in each of the NDD-CKD (2,950 h·ng/mL; P=0.003), HD (2,327 h·ng/mL; P=0.01), and PD (2,095 h·ng/mL; P=0.04) groups compared with healthy controls (1,008 h·ng/mL). LIMITATIONS: Small study groups had different proportions of diabetic patients, early stages of CKD not available. CONCLUSIONS: Our data suggest that selection of dialysis modality is a major determinant of exposure to the CYP3A4 probe midazolam. Exposure to the intestinal and hepatic transporter probe fexofenadine is altered in patients with NDD-CKD and PD and HD patients. Thus, drug development and licensing of nonrenally cleared drugs should include evaluation in these 3 patient groups, with these results included in approved product information labeling. This reinforces the critical need for more in vivo studies of humans that evaluate the exposure to drugs cleared by these pathways.

Ciprofloxacin and rifampin have opposite effects on levothyroxine absorption.

BACKGROUND: Levothyroxine (L-T4) absorption varies between individuals, and can be affected by various concomitantly administered drugs. Case reports have indicated an association between cotreatment with ciprofloxacin or rifampin and hypothyroidism in patients on a stable L-T4 dose. METHODS: The effects of two antibiotics on T4 absorption were prospectively assessed in a double-blind, randomized, crossover fashion. Eight healthy volunteers received 1000 µg L-T4 combined with placebo, ciprofloxacin 750 mg, or rifampin 600 mg as single doses. We measured total plasma thyroxine (T4) concentrations over a 6-hour period after dosing using liquid chromatography-tandem mass spectrometry. For each study arm, areas under the T4 plasma concentration-time curve (T4 AUCs) were compared. RESULTS: Coadministration of ciprofloxacin significantly decreased the T4 AUC by 39% (p = 0.035), while, surprisingly, rifampin significantly increased T4 AUC by 25% (p = 0.003). CONCLUSION: Intestinal absorption of L-T4 is differentially affected by acute coadministration of ciprofloxacin or rifampin. Mechanistic studies focused on intestinal and possibly hepatic thyroid hormone transporters are required to explain the observed drug interactions with L-T4.

Effect of short-term proton pump inhibitor treatment and its discontinuation on chromogranin A in healthy subjects.

CONTEXT: Chromogranin A (CgA) is used as a generic tumor marker for neuroendocrine tumors. Proton pump inhibitors (PPI) are known to increase CgA, but it is not clear to what extent, and there is little information on how long PPI need to be discontinued before the effect of PPI has disappeared. Furthermore, is it not known whether this PPI effect is dependent on the CgA assay used. OBJECTIVE: The aim of the study was to determine the effect of 7-d treatment with a PPI and its discontinuation on CgA in serum and plasma comparing four CgA assays. DESIGN AND PARTICIPANTS: Seventeen healthy subjects took lansoprazole 30 mg at bedtime for 7 d, and blood samples for CgA were obtained at baseline, d 7 of PPI use, and 1, 2, 4, and 7 d after discontinuation of the PPI. In all samples, CgA was measured using the following assays: Alpco (serum and plasma), Cis-Bio (serum and plasma), DAKO, and Cis-Bio radioisotope assay. RESULTS: When using the same assay, CgA was higher in plasma than in serum. Treatment with a PPI for 1 wk resulted in a significant (about 2.5-fold) increase in CgA with significant interindividual variation. After discontinuation of PPI, serum CgA gradually declined, with a half-life of 4-5 d. CONCLUSION: Short-term PPI use results in a significant increase of CgA in serum and plasma, an effect that is largely independent of the assay used. PPI need to be discontinued for 2 wk to fully eliminate their effect on CgA. This effect of PPI needs to be considered when interpreting results of CgA measurements.

Increasing the medical school applicant pool: a key to training more rural physicians.

CONTEXT: Workforce studies show shortages of physicians in many areas of the United States. These shortages are especially severe in states such as Kentucky with many rural counties and are predicted to worsen in the future unless there are changes throughout our educational system to build aspirations and prepare students for medical school education. PURPOSE: To examine rural-urban differences and community characteristics of applicants and matriculants to Kentucky's two allopathic medical schools and influences on the educational aspirations of young students who wish to become physicians. METHODS: The number of Kentucky applicants and matriculants to allopathic medical schools was obtained from the Association of American Medical College's data warehouse for the period from 2002-2006. A continuous, multidimensional measure was used to classify counties by degree of rurality. Socio-demographic variables were selected for the counties of residence for applicants and matriculants. Model variables were tested in a least squares multiple regression model for their ability to explain patterns among Kentucky's 120 counties in the number of both resident applicants and matriculants to medical school. Data from a survey of middle school participants in summer health camps were analyzed to help identify important influences on young students aspiring to a career as a health professional, especially becoming a physician, and how these might be supported to increase the supply of rural medical school applicants. FINDINGS: The low number of rural applicants to medical school was highly correlated with the relative rurality of their county of residence, a low physician-to-population ratio and a low number of total primary care physicians. The percentage of county residents having a bachelor's degree level of education or higher had a positive impact on the application rate. Respondents became interested in health careers at age 15 or younger, and parents and grandparents, teachers, and close associates stimulated their aspirations, with teachers being the most influential. CONCLUSIONS: Prospective students respond to their perception of need for physicians. Rural students are influenced by those who are more highly educated. To overcome the shortage of physicians in rural communities efforts must be made to increase the aspirations for medical education of prospective students from rural counties.

The impact of health on Kentucky's economy.

All states are strongly committed to economic development policies and activities as participants in national and global competition. However, a sometimes overlooked and perhaps under appreciated influence on economic development is the health of a state's citizens. This study focuses on how the health status of Kentucky profoundly influences its economy, workforce, productivity, and general quality of life. If Kentucky's economy is to improve significantly, as compared to other states, significant improvements in the health status of its citizens must be achieved in the near future and sustained over time. In an era of growing concern about rising health insurance costs and maintaining a reliable and productive workforce, employers are increasingly likely to locate in communities where measures of health status are strongly positive. The latest report from the United Health Foundation indicates that in 2007 Kentucky had the 8th worst health status in the nation based on a set of risk factors and outcomes. These risk factors include personal behaviors, community and environment, and public health policies that culminate in key health outcomes related to quality of life and longevity. While it is a serious challenge, our research demonstrates that many of these risk factors can be lowered through relatively low cost and effective interventions that produce substantial improvements in health and Kentucky's rank. Health education is very effective when it begins early in life and continues to emphasize the importance of healthy behaviors, such as not smoking, healthy diets and exercise, and weight control. Preventive health services that identify and treat diseases and conditions that lead to premature death increase both longevity and economic growth through lower treatment costs for chronic diseases and an increase in human capital. Policy changes, such as primary enforcement of motor vehicle seat belt use and encouragement of the use of safety equipment at work, also saves lives and contributes to economic development. Kentucky has already implemented many programs to begin the necessary transformation to a healthier Commonwealth. Creation of additional programs and expansion of those successful ones in place are keys to producing both significant health change and economic growth.

Physician computer skills: a prerequisite to the future in healthcare services.

Physicians in Kentucky have been slow to endorse and implement electronic medical records and other forms of information technology (IT), although this technology is available to them. Information was ob tained from medical relicensure data for all licensed Kentucky physicians and through two sample surveys to assess the use of IT in Kentucky medicine. Sixty-eight percent of licensed physicians recorded an e-mail address on their annual relicensure application, but more physicians were knowledgeable about IT than indicated by this relicensure response. A recorded e-mail address was more likely for younger physicians, physicians in hospital-based specialties, and those in larger medical specialty or academic physician groups. Those entering an email address were more likely to use IT for e-mail, word-processing, searching medical literature, and even consulting with other physicians. Only 10% of physicians with an e-mail address and 4.5% ofj those who did not list an e-mail address used e-mail to communicate with patients. Physicians entering an e-mail address were also more likely to employ an electronic medical record in their practice. Increased use of IT in medical practices is likely only if it can be associated with an increase in reimbursement or an improvement in quality of care.