Interpretation of Cytochrome P-450 Inhibition and Induction Effects From Clinical Data: Current Standards and Recommendations for Implementation.

Agents that modify cytochrome P-450 (CYP) enzyme activity are characterized as strong, moderate, or weak inhibitors or inducers based on the magnitude of their impact on substrate exposure in clinical studies. Criteria for these classifications are simple and semiquantitative. However, assignment of a given agent to a CYP inhibitor or inducer category is often complicated by limitations of the published data, inconsistent study findings, and other factors. CYP inhibitor and inducer categories are commonly used as a basis for differentiating drug interaction management recommendations. For example, product labeling for a CYP substrate may recommend avoidance in combination with strong inhibitors and dose reduction in combination with moderate inhibitors. When such recommendations exist, ambiguity or variability in placement of inhibitors or inducers into categories can introduce potentially harmful variations in clinical drug interaction management. Failure to adequately reflect the drug interaction potential of an agent by under-categorizing it (e.g., calling it weak when data point to moderate effects), for example, may lead clinicians to respond inadequately to real risks, or to ignore potential interactions altogether. Over-categorization may lead to actions such as over-adjustment of substrate doses or unnecessary avoidance of optimal treatments. This review describes the current criteria for assignment of CYP inhibitor and inducer categories, summarizes common circumstances leading to ambiguous or variable CYP inhibitor and inducer categorizations, and proposes an approach to data interpretation and application of current criteria under uncertainty. When applied to > 1,000 CYP reviews, the approach described has identified a clear categorization in almost all cases.

Evaluation of clinical research knowledge and interest among pharmacy residents: survey design and validation.

PURPOSE: The development and validation of a survey to describe the research knowledge, attitudes, and skills of pharmacy practice residents are described. SUMMARY: A survey was drafted to determine if pharmacy practice residency experience and the American Society of Health-System Pharmacists (ASHP)-required project improve the residents' objectively and subjectively assessed research knowledge, to determine if the residency experience and the ASHP-required project affect the residents' attitudes regarding research as a component of their future professional practice, and to subjectively assess the effect of the residency experience and the ASHP-required project on other essential skills, such as problem solving, critical thinking, and time management. An initial questionnaire was developed and underwent content validation testing by clinical pharmacists and faculty, residents, and research fellows. Following content validation, the questionnaire underwent construct validity testing (for discriminative validity and responsiveness) in students, residents, and clinical pharmacists and faculty. Reliability was tested in a subgroup of subjects who completed the questionnaire twice within two to four weeks. From the content validation phase, average scores for individual questions ranged from 1.00 to 2.00. Discriminative validity testing of the revised questionnaire demonstrated the instrument's ability to discriminate between groups expected to differ. Effect-size and mean-knowledge score differences indicated high levels of responsiveness, signifying the instrument's ability to detect change over time or after an intervention. CONCLUSION: A survey questionnaire developed to measure research knowledge and interest among pharmacy practice residents demonstrated its validity and reliability with significant sensitivity and responsiveness.

Use of laryngeal mask airway in flexible bronchoscopy in infants and children.

In the past two decades, flexible bronchoscopy (FB) has gained increasing popularity among pediatric pulmonologists. The objective of this study was to review our experience with pediatric flexible bronchoscopy over the past 15 years, with special focus on route of bronchoscopy. This is a retrospective study. We reviewed our pediatric FB procedures performed at the University of Michigan, Mott Children's Hospital, from 1988-2003. The study included 1,947 procedures in 1,548 patients, with a mean of 1.3 procedures/patient. The male:female ratio was 1.66:1, and age was 4.9 +/- 5.6 years (mean +/- SD). Patients <2 years of age represented 46.6% of the study population. The laryngeal mask airway (LMA) was the most common route for flexible bronchoscopy in children 2 years of age and above. Complication rates were lower with the use of the LMA (1.9%) compared to the nasal route (3.5%). Stridor was the most common indication in the age group <2 years (20.8%), while persistent pulmonary infiltrates were more common in the older age groups (32.2-37%). Laryngomalacia was the most common finding in patients with stridor (31.5%), while inflammatory changes were more common with other indications. Procedure-related complications were reported in 2.3% of procedures. Bronchoalveolar lavage (BAL) samples were obtained and analyzed in 51.2% of FB procedures (n=1,000), of which 19.4% yielded positive microbiology cultures. In conclusion, FB is a safe procedure in pediatrics. Children less than 7 years of age represent the majority of FB subjects. The LMA offered a lower rate of procedure-related complications when compared to the nasal route or endotracheal tube. It also reduced procedure time and anesthesia time.

Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacantha).

Hawthorn, an herbal supplement, is currently being evaluated for the treatment of heart failure. The flavonoid components of hawthorn may be responsible for hawthorn's beneficial effects in the treatment of heart failure. However, these components may also affect P-glycoprotein function and cause interactions with drugs that are P-glycoprotein substrates, such as digoxin, which is also used to treat heart failure. Therefore, the purpose of this study was to determine the effect of hawthorn on digoxin pharmacokinetic parameters. A randomized, crossover trial with 8 healthy volunteers was performed evaluating digoxin 0.25 mg alone (D) for 10 days and digoxin 0.25 mg with Crataegus special extract WS 1442 (hawthorn leaves with flowers; Dr. Willmar Schwabe Pharmaceuticals) 450 mg twice daily (D + H) for 21 days. Pharmacokinetic studies were performed for 72 hours. There were no statistically significant differences in any measured pharmacokinetic parameters. The AUC0-infinity, Cmax-Cmin, Cmin, and renal clearance for the D group were 79 +/- 26 mcg.h/L, 1.4 +/- 0.7 mcg/L, 0.84 +/- 0.2 mcg/L, and 74 +/- 10 mL/min versus 73 +/- 20 mcg.h/L, 1.1 +/- 0.1 mcg/L, 0.65 +/- 0.2 mcg/L, and 81 +/- 22 mL/min for the D + H group, respectively (p > 0.05). Following 3 weeks of concomitant therapy, hawthorn did not significantly alter the pharmacokinetic parameters for digoxin. This suggests that both hawthorn and digoxin, in the doses and dosage form studied, may be coadministered safely.

Single plasma concentrations of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam do not predict midazolam clearance in healthy subjects.

The 30-minute ratio of 1'-hydroxymidazolam:midazolam plasma concentrations has been used as a measure of midazolam clearance in liver transplant patients. This study determined if a single concentration of 1'-hydroxymidazolam or the ratio of 1'-hydroxymidazolam:midazolam could be used to predict midazolam clearance in healthy subjects. Plasma midazolam and 1'-hydroxymidazolam concentrations from three previous studies were used for analyses. Data obtained predose and at 5, 30, 60, 120, 240, 300, and 360 minutes following intravenous doses of midazolam in 61 adults were divided and used to derive and validate equations to predict midazolam clearance. Equations were derived using linear regression and then validated by comparing predicted to observed clearance. Only one equation was related to midazolam clearance as afunction of 1'-hydroxymidazolam, but it did not predict midazolam clearance (r = 0.29, p = 0.31). Single sampling of 1'-hydroxymidazolam or 1'-hydroxymidazolam:midazolam plasma concentrations cannot be used to predict midazolam clearance in healthy adults.

Limited sampling strategy to predict AUC of the CYP3A phenotyping probe midazolam in adults: application to various assay techniques.

Midazolam clearance is used to phenotype hepatic CYP3A activity but requires multiple plasma samples following a single intravenous dose. The authors evaluated the use of a limited sampling scheme, using different assay techniques to determine the reproducibility of such a strategy in estimating midazolam AUC. Seventy-three healthy adults received midazolam as a single intravenous bolus dose. At least eight plasma samples were collected from each subject and were assayed using either LC/MS/MS or electron capture gas chromatography. Eleven subjects were randomly selected for the training set using stepwise linear regression to determine relationships between midazolam plasma concentrations and AUC. Validation of the predictive equations was done using the remaining 62 subjects. Mean percent error (MPE), mean absolute error (MAE), and root mean square error (RMSE) were calculated to determine bias and precision. Based on the training set, five models were generated with coefficients of determination ranging from 0.87 to 0.95. Validation showed that MPE, MAE, and RMSE values were acceptable for three of the models. Intrasubject reproducibility was good. In addition, training set datafrom one institution were able to predict data from the other two institutions using other assay techniques. Minimized plasma sampling mayprovide a simpler method for estimating midazolam AUC for CYP3A phenotyping. A limited sampling strategy is more convenient and cost-effective than standard sampling strategies and is applicable to more than one assay technique.

The use of high resolution computerized tomography (HRCT) of the chest in evaluating the effect of tobramycin solution for inhalation in cystic fibrosis lung disease.

OBJECTIVES: To compare the usefulness of HRCT of the chest versus spirometric measures (PFTs) in evaluating the effect of tobramycin solution for inhalation (TSI) in cystic fibrosis (CF). METHODS: Thirty-two CF patients with mostly mild lung disease age > or = 6 years, were enrolled in a double-blind, placebo-controlled pilot study. Patients were chronically colonized with Pseudomonas aeruginosa for at least 6 months prior to and at enrollment. If patients were on TSI, they were taken off for at least 3 months prior to enrollment. Duration was 6 months; 31 subjects completed the study. HRCT and PFTs were evaluated at baseline, after 28 days of treatment and at the end of the study. Study medication was administered as 5 ml nebulized treatment twice a day for 28 days followed by 28 days off (one cycle). Study consisted of three cycles. Two radiologists scored all films using a validated system. A total HRCT score consists of the sum of subscores: linear opacities, hyperinflation, nodular opacities, peribronchial thickening, mucous plugging, and bronchiectasis; each subscore could range from 0 to 80, with potential total scores varying from 0 to 480. The percent of the maximum possible HRCT score was then calculated and used for all comparisons. RESULTS: Using two tailed paired t-test, the percent maximum HRCT score decreased by 1.4 +/- 2.6% (mean +/- SD) (P = 0.049) and 0.3 +/- 2.8% (P = 0.63) for the TSI group and decreased by 0.1 +/- 1.5% (P = 0.74) and increased by 0.6 +/- 1.8% (P = 0.23) for the placebo group between visits 1 and 2, and visits 1 and 3, respectively. The data were then analyzed using a mixed model utilizing changes in scores over the durations of the study for each group. The change of HRCT score for the TSI group was -0.24/day (P = 0.02) and -0.03/day (P = 0.22), and for the control group the change was -0.01 (P = 0.93) and 0.02 (P = 0.29) between visits 1 and 2, and visits 1 and 3 respectively. FEF(25-75)% and FEV(1)% changes were not statistically significant using both analyses. CONCLUSION: HRCT seems to be more sensitive in detecting treatment effect than PFT in CF patients with mild lung disease, especially following the first treatment period (visit 2). Total HRCT score showed some improvement at the end of the study, though not statistically significant. This is probably due to obtaining the HRCT an average of 30 days after completion of the TSI treatment, and selection of study population with mostly mild lung disease. This could indicate that the most significant improvement in the total HRCT score in this patient population occurs after the first treatment period with TSI.

Identifying barriers to treatment adherence and related attitudinal patterns in adolescents with cystic fibrosis.

INTRODUCTION: The treatment of cystic fibrosis (CF) is directed toward correction of organ dysfunction and relief of symptoms resulting from the disease. Lack of adherence to daily treatment regimens may have substantial short-term and long-term effects on patients with CF. In this study, we attempted to identify barriers to treatment adherence which could be predicted by objective measures and explore ways to improve adherence in adolescents with CF. METHODS: A questionnaire was given to patients 12.0-20.9 years of age, designed with focus on specific barriers to adhering to treatment plan and related attitudinal patterns. Observational and analytical results were collected. RESULTS: We obtained questionnaires and objective health data for 60 respondents. The most commonly identified barriers to adherence were forgetting or losing medications (32/60) and being too busy (23/60). Attitudinal patterns that played a significant role for nonadherence included unintentional forgetting (40/60), feeling that following CF treatments resulted in less freedom in their lives (30/60), and believing it is acceptable to miss a treatment every few days (18/60) or to miss treatments when busy (18/60). DISCUSSION: There were a few statistically significant differences of adherence patterns between demographic subgroups in our study. Males were more likely to agree that it is acceptable to miss doses if they are made up with extra doses later (24% vs. 3%, P = 0.04). Patients who perceived themselves to be less healthy agreed more to statements of limited freedom, nonsympathetic medical providers, and difficulty adhering during times of decreased symptoms. This highlights an unexpected risk: as CF progresses and patients perceive themselves to be less healthy, they may become less likely to be adherent during the periods they are feeling the best, while at the same time becoming less likely to perceive empathy from their physicians. CONCLUSIONS: Survey results describe a variety of beliefs and attitudinal patterns which contribute to nonadherence in CF treatment, especially relating to time management. While patients largely understood the importance of treatments to their health, predictors of risky behaviors could lead to targeted interventions by CF centers to address these challenges and improve adherence.

Effect of pharmacy practice residency training on residents' knowledge of and interest in clinical research.

PURPOSE: The effect of pharmacy practice residency training on subjectively and objectively assessed research knowledge, skills, and interests of residents was studied. METHODS: A preintervention versus post-intervention design was used. Residency year 2004- 05 residents were administered a validated Web-based survey at the beginning of residency and again at the end of residency. The survey collected resident responses to questions regarding resident and residency characteristics, subjective assessments of specific professional skills and research skills and knowledge, and objective assessments of basic research knowledge. For residents who completed beginning and end of residency surveys, results were linked when possible to allow for paired and unpaired statistical analyses. RESULTS: Totals of 346 (33.2% response rate) and 222 (21.3% response rate) surveys were completed at the beginning and the end of the residency, respectively, with 129 respondents completing both. Statistically significant improvements were observed for the total and paired population in subjectively assessed research-related skills and abilities and general professional skills. Subjectively assessed understanding of specific statistical tests revealed a significant improvement. Total population analysis and paired population analysis revealed no changes in objectively assessed research-related knowledge from the beginning of the residency to the end of the residency. CONCLUSION: Although there was improvement from the beginning to the end of residency in subjectively assessed research-related skills and abilities and in self-assessed understanding of most statistical tests, the end of residency objectively assessed research-related knowledge scores were unchanged. Residents' expectations that the residency would increase research knowledge, skills, and desire for research involvement were unmet. These results suggest that training based on residency program standards may not increase residents' interest or provide them with the skills necessary to participate in clinical research.

Impact of patient financial incentives on participation and outcomes in a statin pill-splitting program.

OBJECTIVES: To examine willingness to participate in a pill-splitting program and the impact of pill splitting on patients' adherence and lipid control. STUDY DESIGN: Nested randomized trial. METHODS: A total of 200 patients who used statins and were candidates for a pill-splitting regimen were identified from a large university-based health plan. Sixty-three percent of study participants were female, 41% were nonwhite, and 94% had at least some college education. Patients were surveyed regarding their willingness to split pills, and 111 consented to participate in a 6-month trial in which half were randomized to receive a financial incentive to split pills: a 50% reduction in their per-refill copayment. Data on patients' statin refills and lipid control were obtained from billing and medical records. RESULTS: Compared with patients unwilling to participate in the program, those agreeing to split pills were more likely to be female and white. After 6 months, most patients in the trial (89%) were willing to continue pill splitting for a 50% copayment reduction. Patients reported few problems with pill splitting and had no noticeable change in their adherence. The financial-incentive group and the control group did not differ significantly with respect to their low-density lipoprotein cholesterol levels after pill splitting: -2.0 mg/dL and -1.2 mg/dL, respectively. CONCLUSIONS: Most patients indicated that at least a 50% copayment reduction would be required to enroll in a pill-splitting program after the study ended. However, in this relatively educated population, financial incentives did not influence patients' adherence, satisfaction, or health outcomes.

Adherence to treatment in children and adolescent patients with cystic fibrosis.

PURPOSE: The purpose of this study was to monitor medication adherence in cystic fibrosis (CF) patients and its correlation with disease severity and patient age. METHODS: Children less than 12 years of age (group 1) and adolescents 12 years of age and older (group 2) were recruited from the University of Michigan CF Center. The study duration was 3 months. A total of 22 patients per group were enrolled. Adherence to ADEKs, an oral multivitamin, and dornase alfa, a nebulized mucolytic medication, was monitored. Adherence to ADEKs was monitored by using the Medication Event Monitoring System (MEMS) SmartCaps (APREX, AARDx, Inc., Union City, California). Dornase alfa adherence rate was monitored by counting empty medication vials. RESULTS: Thirty-three patients completed the study, 15 patients in group 1 and 18 patients in group 2. The overall mean adherence rates for ADEKs and dornase alfa were (+/- SD) 63.6% +/- 24.0% and 66.5% +/- 31.2%, respectively. The median ADEKs and dornase alfa adherence rate for group 1 was 84.6% and 79.1%, respectively (p = .08); and for group 2 was 56.7% vs. 78.4%, respectively (p = .07). There was a trend toward significance, suggesting that the adherence rate for ADEKs was higher than for dornase alfa (p = .08) in group 1. Group 2 showed a trend toward adherence to dornase alfa than to ADEKs (p = .07). There was a trend for ADEKs adherence between groups 1 and 2 (p = .09), but not for dornase alfa (p = .93). CONCLUSION: Parental supervision and disease severity are likely to play a major role in adherence to medical management. Partnership with patients and families about the treatment plan might be important for improving adherence rate. The MEMS SmartCaps is an electronic monitoring technology that should be used to measure drug adherence objectively both in further larger clinical trials and in the outpatient setting.

Vardenafil treatment for erectile dysfunction.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, and adverse effects of vardenafil in the treatment of erectile dysfunction (ED). DATA SOURCES: Literature searches were performed using the MEDLINE database (referenced citations through December 2002), and the references of all identified articles were scanned for additional publications of interest. Unpublished information provided by the manufacturer and proceedings of professional meetings were also evaluated. STUDY SELECTION AND DATA EXTRACTION: All available studies were utilized to obtain information regarding pharmacology. Only human studies were used to gather pharmacokinetic, drug interaction, efficacy, and safety data. DATA SYNTHESIS: Vardenafil is a potent and selective inhibitor of the phosphodiesterase 5 (PDE5) enzyme that has been shown to improve erectile function in several populations of men with ED. Vardenafil has a rapid onset of action, is hepatically metabolized, and has a half-life of 4-6 hours. Clinical trials in otherwise healthy men with ED, men with ED and diabetes, and men with ED and a history of prostatectomy have demonstrated vardenafil's efficacy. Adverse effects appear to be relatively mild in intensity and dose dependent, with 22-61% of subjects reporting adverse effects. CONCLUSIONS: Vardenafil is a safe and effective oral agent for the treatment of ED. Its greater potency and PDE5 selectivity compared with sildenafil appear to confer a lower risk of vision-related adverse effects, but other clinical consequences of these differences are currently unclear.

Effect of tablet splitting on serum cholesterol concentrations.

OBJECTIVE: To evaluate the effects of tablet splitting on low-density lipoprotein (LDL) cholesterol and total cholesterol values in patients taking simvastatin and atorvastatin. DESIGN: A retrospective chart review of total cholesterol and LDL cholesterol values of patients instructed to split simvastatin or atorvastatin between January 1999 and November 2000. SETTING: Veterans Affairs Medical Center in Huntington, WV. PATIENTS: Patients were included if they were taking simvastatin or atorvastatin with regular lipid management and follow-up laboratory results. Patients were required to remain on the same milligram-per-day dose at least 6-8 weeks before and after tablet-splitting initiation and have cholesterol values drawn at least 6 weeks after initiation of both whole-tablet and half-tablet dosing. Patients were excluded if they had a triglyceride level > 400 mg/dL or were noncompliant on the basis of pharmacy records and provider notes. MEASUREMENT OUTCOMES: The primary end points were changes in total cholesterol and LDL cholesterol values before and after the patient was switched to half-tablet therapy. RESULTS: The overall results for this review demonstrated no statistically significant increase in total cholesterol and LDL cholesterol concentrations. Total cholesterol and LDL cholesterol values actually decreased from presplitting to postsplitting, p = 0.017 and p = 0.003, respectively. CONCLUSIONS: The investigation showed that half-tablet dosing was as effective as whole-tablet dosing. The program will be continued as a part of quality patient care at the Huntington Veterans Affairs Medical Center.

The potential role of HMG-CoA reductase inhibitors in pediatric nephrotic syndrome.

OBJECTIVE: To evaluate the safety and efficacy of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as a potential treatment option for the dyslipidemia associated with childhood nephrotic syndrome. DATA SOURCES: Searches of MEDLINE (1966-April 2004), Cochrane Library, International Pharmaceutical Abstracts (1977-April 2004), and an extensive manual review of journals were performed using the key search terms nephrotic syndrome, familial hypercholesterolemia, dyslipidemia, and HMG-CoA reductase inhibitor. STUDY SELECTION AND DATA EXTRACTION: Two prospective uncontrolled studies evaluating the safety and efficacy of statin therapy in pediatric nephrotic syndrome were included. DATA SYNTHESIS: While an extensive amount of data is available in adult nephrotic syndrome in which statin therapy decreases total plasma cholesterol 22-39%, low-density lipoprotein cholesterol (LDL-C) 27-47%, and total plasma triglycerides 13-38%, only 2 small uncontrolled studies have been conducted evaluating the utility of these agents in pediatric nephrotic syndrome. These studies indicate that statins are capable of safely reducing total cholesterol up to 42%, LDL-C up to 46%, and triglyceride levels up to 44%. CONCLUSIONS: Lowering cholesterol levels during childhood may reduce the risk for atherosclerotic changes and may thus be of benefit in certain patients with nephrotic syndrome. Statins have demonstrated short-term safety and efficacy in the pediatric nephrotic syndrome population. Implementing pharmacologic therapy with statins in children with nephrotic syndrome must be done with care until controlled studies are conducted in this population.

Accuracy of the avosure PT pro system compared with a hospital laboratory standard.

OBJECTIVE: To compare international normalized ratio (INR) values obtained using the AvoSure PT Pro point-of-care (POC) system with those obtained using a standard laboratory method. METHODS: Forty-one INR values obtained from the POC system were compared with those obtained from a standard laboratory method. The POC method was evaluated for both laboratory and clinical agreement. To evaluate laboratory agreement, various analyses were used, including mean-squared prediction error (MSE) and mean prediction error (ME), Bland-Altman analysis, correlation, and paired t-test comparing group INR means. For clinical accuracy, discrepant pairs were identified and evaluated to determine whether dosage adjustments would have been needed based on values obtained. RESULTS: The POC system demonstrated modest precision (MSE = 0.147, 95% CI 0.065 to 0.228) and relatively little bias (ME = 0.090, 95% CI -0.025 to 0.205). Bland-Altman analysis also suggested good agreement at average INRs from 2.0 to 3.0. At average INR values >3.0, the POC system consistently overestimated INR. Values obtained with the POC system were significantly correlated with those obtained from the hospital laboratory (r = 0.77; p < 0.001). Similarly, mean +/- SD POC INR did not differ significantly from the laboratory-determined INR (2.45+/-0.59 vs. 2.37+/-0.48, respectively; p = 0.176). Regarding clinical accuracy, the values clinically agreed in 85.4% of the cases. CONCLUSIONS: The AvoSure PT Pro POC system appears to be useful for INR values within the 2.0-3.0 range, but values outside of this range should probably be confirmed with a standard laboratory method.