Impact of prostate cancer on sexual relationships: a longitudinal perspective on intimate partners' experiences.

INTRODUCTION: In this prospective study of localized prostate cancer patients and their partners, we analyzed how partner issues evolve over time, focusing on satisfaction with care, influence of cancer treatment, and its impact on relationship with patient, cancer worry, and personal activities. AIMS: Our study aims were twofold: (i) to determine whether the impact of treatment on patients and partners moderate over time and (ii) if receiving surgery (i.e., radical prostatectomy) influences partner issues more than other treatments. METHODS: Patients newly diagnosed with localized prostate cancer and their female partners were recruited from three states to complete surveys by mail at three time points over 12 months. MAIN OUTCOME MEASURES: The four primary outcomes assessed in the partner analysis included satisfaction with treatment, cancer worry, and the influence of cancer and its treatment on their relationship (both general relationship and sexual relationship). RESULTS: This analysis included 88 patient-partner pairs. At 6 months, partners reported that cancer had a negative impact on their sexual relationship (39%--somewhat negative and 12%--very negative). At 12 months, this proportion increased substantially (42%--somewhat negative and 29%--very negative). Partners were significantly more likely to report that their sexual relationship was worse when the patient reported having surgery (P = 0.0045, odds ratio = 9.8025, 95% confidence interval 2.076-46.296). A minority of partners reported significant negative impacts in other areas involving their personal activities (16% at 6 months and 25% at 12 months) or work life (6% at 6 months, which increased to 12% at 12 months). CONCLUSION: From partners' perspectives, prostate cancer therapy has negative impact on sexual relationships and appears to worsen over time.

Accurate targeting of daily intravenous busulfan with 8-hour blood sampling in hospitalized adult hematopoietic cell transplant recipients.

Daily intravenous (i.v.) busulfan is increasingly being used in hematopoietic cell transplantation (HCT) conditioning regimens. Intravenous busulfan doses administered at the traditional frequency of every 6 hours can be targeted ((T)Bu) to a patient-specific concentration at steady state (C(ss)) using therapeutic drug monitoring (TDM). In this report, we describe our experiences with TDM of daily i.v. busulfan in an adult population, with the specific aims of (1) evaluating covariates associated with busulfan clearance, and (2) assessing the feasibility of TDM for outpatient administration of daily (T)Bu with pharmacokinetic sampling over 6 hours. A retrospective pharmacokinetic analysis was conducted in 87 adults receiving daily (T)Bu as part of cyclophosphamide followed by (T)BU (CY/(T)BU), fludarabine monophosphate (fludarabine) followed by (T)BU, or (T)BU concurrent with fludarabine conditioning. The desired C(ss) was achieved in 85% of patients receiving daily i.v. busulfan. Busulfan clearance was not associated with sex or age, but was associated with the day of dosing and conditioning regimen (P = .0016). In patients receiving CY/(T)BU, no differences in clearance were found between dosing days (P > .36); however, clearance decreased significantly in patients receiving fludarabine-based regimens (P = .0016). Busulfan clearance and C(ss) estimates from pharmacokinetic sampling over 8, 11, or 24 hours were comparable (P > .4). However, pharmacokinetic modeling of individual patient concentration-time data over 6 hours could not reliably estimate busulfan clearance or C(ss).

Measures of adherence to oral hypoglycemic agents at the primary care clinic level: the role of risk adjustment.

BACKGROUND: Prior research found that in the Veterans Affairs health care system (VA), the proportion of patients adherent to oral hypoglycemic agents varies from 50% to 80% across primary care clinics. This study examined whether variation in patient and facility characteristics determined those differences. METHODS: Retrospective cohort study of 444,418 VA primary care patients with diabetes treated in 559 clinics in fiscal year (FY) 2006-2007. Patients' adherence to each oral hypoglycemic agent was computed for the first 3 months of FY2007, and averaged across agents to produce an adherence score for the patient's overall regimen. Patients with an adherence score over 0.8 were defined as adherent. Risk adjustment used hierarchical logistic regression accounting for patient factors and facility effects by clustering patients within clinics and clinics within parent VA medical centers. We then assessed the influence of risk adjustment using observed-to-expected (O/E) ratios computed for each clinic. RESULTS: The mean unadjusted proportion of adherent patients in clinics was 0.715 (interdecile range 0.559-0.826). The percent variation in patient's likelihood of being adherent explained at the patient, clinic, and parent VA medical center levels was 2.94%, 0.27%, and 0.76%, respectively. The mean clinic-level observed-to-expected ratio was 1.001 (interdecile range 0.975-1.027). CONCLUSIONS: The variation in the proportion of patients adherent across clinics remained large after risk adjustment. As patient and facility effects explained only 4% of the variance in adherence, comparing clinics based on unadjusted scores is a reasonable starting point unless more predictive patient, provider, and facility factors are identified.

Complementary and alternative medicine use among newly diagnosed prostate cancer patients.

PURPOSE: We surveyed prostate cancer patients about complementary and alternative medicine (CAM) use and evaluated patient factors that correlated with CAM use 6 months following diagnosis. METHODS: The Prostate CAncer Therapy Selection study was a prospective, observational multi-site study of men's treatment decision-making process after a diagnosis of local stage prostate cancer. Recruitment occurred in community urology practices in Washington State, hospital-based urology clinics affiliated with the University of Southern California, and Kaiser Permanente in Northern California. Eligible study participants included men over age 21 diagnosed with local stage prostate cancer between May 1, 2005 and December 31, 2006. RESULTS: Fifty-two percent of survey respondents (379) reported using one or more types of CAM. Of the patients, 51% used one CAM method, 26% used two methods, and 23% used three or more methods. The most commonly reported category was mind-body therapies (65%). Only 43% of patients discussed their CAM use with a health professional; of those, 20% informed their primary care physician and 30% told the doctor managing their prostate cancer care. Less than half thought the CAM they used was "very helpful", but a majority thought it was somewhat helpful for their condition. CONCLUSIONS: Further research is needed to characterize the goals prostate cancer patients have for CAM, whether the treatments met those goals, and how this translates into the perceived helpfulness of these therapies. The implications of patients not discussing CAM use with health professionals at the time of prostate cancer treatment need further studies.

Predicting costs of care in heart failure patients.

BACKGROUND: Identifying heart failure patients most likely to suffer poor outcomes is an essential part of delivering interventions to those most likely to benefit. We sought a comprehensive account of heart failure events and their cumulative economic burden by examining patient characteristics that predict increased cost or poor outcomes. METHODS: We collected electronic medical data from members of a large HMO who had a heart failure diagnosis and an echocardiogram from 1999-2004, and followed them for one year. We examined the role of demographics, clinical and laboratory findings, comorbid disease and whether the heart failure was incident, as well as mortality. We used regression methods appropriate for censored cost data. RESULTS: Of the 4,696 patients, 8% were incident. Several diseases were associated with significantly higher and economically relevant cost changes, including atrial fibrillation (15% higher), coronary artery disease (14% higher), chronic lung disease (29% higher), depression (36% higher), diabetes (38% higher) and hyperlipidemia (21% higher). Some factors were associated with costs in a counterintuitive fashion (i.e. lower costs in the presence of the factor) including age, ejection fraction and anemia. But anemia and ejection fraction were also associated with a higher death rate. CONCLUSIONS: Close control of factors that are independently associated with higher cost or poor outcomes may be important for disease management. Analysis of costs in a disease like heart failure that has a high death rate underscores the need for economic methods to consider how mortality should best be considered in costing studies.

Association between alcohol screening results and hospitalizations for trauma in Veterans Affairs outpatients.

BACKGROUND: Alcohol consumption is a risk factor for traumatic injury, but it is unknown whether responses to alcohol screening questionnaires administered routinely in primary care are associated with subsequent hospitalization for traumatic injury. OBJECTIVE: We evaluated the association between alcohol screening scores and the risk for subsequent hospitalizations for trauma among Veterans Affairs (VA) general medicine patients. METHOD: This study included VA outpatients (n = 32,623) at seven sites who returned mailed surveys (1997-1999). Alcohol Use Disorders Identification Test Consumption (AUDIT-C) scores grouped patients into six drinking categories representing nondrinkers, screen-negative drinkers, and drinkers who screened positive for mild, moderate, severe, and very severe alcohol misuse (scores 0, 1-3, 4-5, 6-7, 8-9, 10-12, respectively). VA administrative and Medicare data identified primary discharge diagnoses for trauma. Cox proportional hazard models were used to estimate the risk of trauma-related hospitalization for each drinking group adjusted for demographics, smoking, and comorbidity. RESULTS: Compared with screen-negative drinkers, patients with severe and very severe alcohol misuse (AUDIT-C 8-9 and ≥10) were at significantly increased risk for trauma-related hospitalization over the follow-up period (adjusted hazard ratios AUDIT-C: 8-9 2.06, 95% confidence interval (CI) 1.31- 3.24 and AUDIT-C≥10 2.13, 95% CI 1.32-3.42). CONCLUSIONS: Patients with severe and very severe alcohol misuse had a twofold increased risk of hospital admission for trauma compared to drinkers without alcohol misuse. SCIENTIFIC SIGNIFICANCE: Alcohol screening scores could be used to provide feedback to patients regarding risk of trauma-related hospitalization. Findings could be used by providers during brief alcohol-related interventions with patients with alcohol misuse.

Health insurer policies toward risk-stratified colorectal cancer screening: a survey of health plan medical directors.

OBJECTIVES: We sought to determine whether health insurance coverage of colorectal cancer (CRC) screening varied based on risk. BACKGROUND: Population-wide screening guidelines for cancer often incorporate risk information, with modified screening recommendations for those at higher risk due to family history or other factors. METHODS: In a nationwide Internet- and mail-based survey of health insurance plan medical directors, respondents were asked about their organization's policies towards coverage of CRC screening for persons at average and higher risk of CRC. Additional questions asked about whether the insurer had a definition of increased risk, and coverage of genetic testing for familial CRC syndromes. RESULTS: Survey invitations were sent to 1158 medical directors; 133 (11%) completed the survey. All plans covered screening for average and high-risk persons. The onset of screening was earlier and intervals were more frequent for higher risk compared to average risk persons, with most respondents stating coverage was determined by "physician discretion." While 75% had a definition of high risk, only 55% covered genetic testing. CONCLUSIONS: Most insurers offer enhanced coverage of CRC screening, most commonly following the discretion of the physician. Whether this coverage results in earlier, more frequent, or more complete screening of higher risk persons remains uncertain.

Alcohol screening and risk of postoperative complications in male VA patients undergoing major non-cardiac surgery.

BACKGROUND: Patients who misuse alcohol are at increased risk for surgical complications. Four weeks of preoperative abstinence decreases the risk of complications, but practical approaches for early preoperative identification of alcohol misuse are needed. OBJECTIVE: To evaluate whether results of alcohol screening with the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) questionnaire-up to a year before surgery-were associated with the risk of postoperative complications. DESIGN: This is a cohort study. SETTING AND PARTICIPANTS: Male Veterans Affairs (VA) patients were eligible if they had major noncardiac surgery assessed by the VA's Surgical Quality Improvement Program (VASQIP) in fiscal years 2004-2006, and completed the AUDIT-C alcohol screening questionnaire (0-12 points) on a mailed survey within 1 year before surgery. MAIN OUTCOME MEASURE: One or more postoperative complication(s) within 30 days of surgery based on VASQIP nurse medical record reviews. RESULTS: Among 9,176 eligible men, 16.3% screened positive for alcohol misuse with AUDIT-C scores ≥ 5, and 7.8% had postoperative complications. Patients with AUDIT-C scores ≥ 5 were at significantly increased risk for postoperative complications, compared to patients who drank less. In analyses adjusted for age, smoking, and days from screening to surgery, the estimated prevalence of postoperative complications increased from 5.6% (95% CI 4.8-6.6%) in patients with AUDIT-C scores 1-4, to 7.9% (6.3-9.7%) in patients with AUDIT-Cs 5-8, 9.7% (6.6-14.1%) in patients with AUDIT-Cs 9-10 and 14.0% (8.9-21.3%) in patients with AUDIT-Cs 11-12. In fully-adjusted analyses that included preoperative covariates potentially in the causal pathway between alcohol misuse and complications, the estimated prevalence of postoperative complications increased significantly from 4.8% (4.1-5.7%) in patients with AUDIT-C scores 1-4, to 6.9% (5.5-8.7%) in patients with AUDIT-Cs 5-8 and 7.5% (5.0-11.3%) among those with AUDIT-Cs 9-10. CONCLUSIONS: AUDIT-C scores of 5 or more up to a year before surgery were associated with increased postoperative complications.

Provider and partner interactions in the treatment decision-making process for newly diagnosed localized prostate cancer.

OBJECTIVE: • To evaluate the degree to which the partners of prostate cancer patients participate in the shared decision-making process with the patients' providers during the time between diagnosis and initiating treatment. PATIENTS AND METHODS: • We recruited patients with newly diagnosed local-stage prostate cancer and their partners to complete take-home surveys after biopsy but before initiating treatment at urology practices in three states. • We asked partners to describe their roles in the decision-making process, including participation in clinic visits, and perceptions of encouragement from providers to participate in the treatment decision-making process. We also asked partners to rate their satisfaction with the patients' providers. RESULTS: • Family members of 80% of newly diagnosed patients agreed to participate; most (93%) were partners (i.e. spouses or significant others). Most partners (93%) had direct contact with the patients' physicians. • Among the partners who had contact with providers, most (67%) were very satisfied with the patients' providers and 80% indicated that the doctor encouraged them to participate in the treatment decision. Overall, 91% of partners reported very frequent discussions with their loved one about the pending treatment decision, and 69% reported that their role was to help the patient make a decision. • In multivariate models, provider encouragement of partner participation was associated with higher partner satisfaction (odds ratio 3.4, 95% CI 1.4-8.4) and an increased likelihood of partners reporting very frequent discussions with their loved one (odds ratio 6.1, 95% CI 1.3-27.7). CONCLUSIONS: • Partners often attended clinic visits and were very involved in discussions about treatment options with both loved ones and providers. • Provider encouragement of participation by partners greatly facilitates shared decision-making between patients and partners.

Patient preferences and urologist recommendations among local-stage prostate cancer patients who present for initial consultation and second opinions.

OBJECTIVES: This study describes urologist recommendations for treatment among local-stage prostate cancer patients presenting for initial management consultations versus second opinions. We hypothesized that urologists present a wider range of management recommendations and are less likely to consider the patient preference during the initial consultation. METHODS: Newly diagnosed local-stage prostate cancer patients and their urologists participated in a survey at urology practices in three states. The urologist's survey included questions about the patient's clinical status, treatments discussed and recommended, and factors that influenced the urologist's recommendations. RESULTS: Of the 238 eligible patients, 95 men presented for an initial consultation, and 143 men presented for a second opinion. In multivariate analysis, urologists recommended 0.52 more treatments (standard error 0.19, P<0.001) during an initial consultation as opposed to a second opinion. The proportion recommending surgery increased from 71-91% (initial consultation versus second opinion setting). Among initial consultations, 59% had low-risk disease, and urologists' recommendations included surgery (80%), external radiation (38%), brachytherapy (seeds) (52%), and active surveillance (25%). Of the 54% with low-risk disease in a second opinion consultation, urologists' recommendations included surgery (90%), external radiation (16%), brachytherapy (14%), and active surveillance (16%). CONCLUSIONS: In second opinion settings urologists discussed fewer treatment options and recommended surgery more often. These findings also applied to men with low-risk prostate cancer.

Health care use and primary prophylaxis with colony-stimulating factors.

OBJECTIVES: We examined health care use in conjunction with primary prophylaxis use of colony stimulating factors (CSF) during patients' initial course of chemotherapy. METHODS: This retrospective cohort study identified adults aged 25 years and older with a diagnosis of breast, colorectal, or nonsmall cell lung cancer between 2002 and 2005 from the Western Washington Surveillance Epidemiology and End Results Puget Sound registry. We linked these records to health insurance claims from four payers representing 75% of those insured in the state. Claims records were used to determine chemotherapy regimen type, CSF use, febrile neutropenia occurrences, and supportive care. Chemotherapy regimens were categorized as conferring high, intermediate, or low risk of myelosuppression according to the National Comprehensive Cancer Network guidelines. CSF use was described as primary prophylaxis, other, or none. Antibiotics and antifungal and antiviral agents per National Comprehensive Cancer Network guidelines for supportive care for cancer infection were categorized using Healthcare Common Procedure Coding System and National Drug Code assignments. RESULTS: Use of CSF as primary prophylaxis is not significantly associated with a reduction in antibiotic use or inpatient or outpatient visits. Primary prophylactic CSF use was associated with less use of antiviral drugs. CONCLUSIONS: CSF use is not associated with a reduction in health care use, with the exception of antiviral drug use. Given the expense associated with CSF use, pragmatic trials and additional research are needed to further assess the affects of CSF on health care use.

Unanticipated and underappreciated outcomes during management of local stage prostate cancer: a prospective survey.

PURPOSE: Due to the complexity of factors that must be considered when choosing a therapy for prostate cancer, we hypothesized that many men will find that certain factors such as side effects gain or lose importance after therapy relative to their expectations before therapy. MATERIALS AND METHODS: We conducted a prospective survey of men deciding on a therapy for local stage prostate cancer in 3 geographic regions. Men were asked to rate the importance of 11 personal factors before starting therapy and again 6 months after therapy. RESULTS: Among 448 eligible men completing the most common treatment options, overall satisfaction with treatment choice was high across all therapies. While most men changed rankings of importance in at least 1 of the 11 factors, the majority of pre-post evaluations were highly consistent. In adjusted analyses the 2 factors that emerged as significantly underappreciated for all major prostate cancer treatments were 1) the impact of treatment on usual daily activities, and 2) the recommendations of friends and relatives who were affected with prostate cancer. CONCLUSIONS: Initial patient expectations of the importance of the majority of factors related to prostate cancer treatment are generally accurate. Better counseling may improve the accuracy of patient expectations of the personal burden of treatment, and their evaluation of the advice of affected friends and relatives.

Outcomes predicted by phosphorous in chronic kidney disease: a retrospective CKD-inception cohort study.

BACKGROUND: The impact of secondary hyperparathyroidism on morbidity and mortality among patients with chronic kidney disease (CKD) is unclear. METHODS: We conducted a retrospective cohort study to investigate the relationship between CKD and serum phosphorous. Through clinical databases at a large health maintenance organization, we identified a dynamic CKD inception cohort between 1997 and 2004, with stage 3-5 kidney disease with subsequent phosphorous measurement; the patients were followed up for up to 5 years for outcomes of mortality, cardiovascular mortality, cardiovascular hospitalizations and renal replacement therapy (RRT; dialysis or transplant). Survival analysis with time-varying covariables for phosphorous and renal function estimated the relationship between phosphorous level and outcomes, adjusting for potential confounding variables. RESULTS: A total of 930 patients with complete data were included in our analysis; they had a higher disease burden than excluded patients. Phosphorous did not predict overall or cardiovascular mortality, or cardiovascular hospitalizations. The rate of RRT increased significantly with the level of phosphorous, even when controlling for renal function. CONCLUSIONS: Contrary to some previous reports, we did not find evidence of increased mortality with phosphorous, but did find that increased levels of phosphorous are related to excess rates of RRT. Our work does not suggest that controlling phosphorous will lower the risk of RRT; our work motivates randomized controlled trials to investigate the clinical value of such interventions.

Discontinuation of radiation treatment among medicaid-enrolled women with local and regional stage breast cancer.

For women with nonmetastatic breast cancer, radiation therapy is recommended as a necessary component of the breast conserving surgery (BCS) treatment option. The degree to which Medicaid-enrolled women complete recommended radiation therapy protocols is not known. We evaluate radiation treatment completion rates for Medicaid enrollees aged 18-64 diagnosed with breast cancer. We determine clinical and socio-demographic factors associated with not starting treatment, and with interruptions or not completing radiation treatment. Using data from the Washington State Cancer Registry linked to Medicaid enrollment and claims records, we identified Medicaid enrollees diagnosed with breast cancer from 1997 to 2003 who received BCS. Among the 402 women who met inclusion criteria, 105 (26%) did not receive any radiation. Factors significantly associated with not receiving radiation included in situ disease and non-English as a primary language. Among those who received at least one radiation treatment, 65 (22%) failed to complete therapy and 71 (24%) patients had at least one 5 to 30 day gap in treatment. We found no significant predictors of interruptions in treatment or early discontinuation. A substantial proportion of Medicaid-insured women who are eligible for radiation therapy following BCS either fail to receive any treatment, experience significant interruptions during therapy, or do not complete a minimum course of treatment. More effort is needed to ensure this vulnerable population receives adequate radiation following BCS.

Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the Children's Oncology Group.

Cyclophosphamide-based regimens are front-line treatment for numerous pediatric malignancies; however, current dosing methods result in considerable interpatient variability in tumor response and toxicity. In this pediatric population, the authors' objectives were (1) to quantify and explain the pharmacokinetic variability of cyclophosphamide and 2 of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM), and (2) to apply a population pharmacokinetic model to describe the disposition of cyclophosphamide and these metabolites. A total of 196 blood samples were obtained from 22 children with neuroblastoma receiving intravenous cyclophosphamide (400 mg/m2/d) and topotecan. Blood samples were quantitated for concentrations of cyclophosphamide, HCY, and CEPM using liquid chromatography-mass spectrometry and analyzed using nonlinear mixed-effects modeling with the NONMEM software system. After model building was complete, the area under the concentration-time curve (AUC) was computed using NONMEM. Cyclophosphamide elimination was described by noninducible and inducible routes, with the latter producing HCY. Glomerular filtration rate was a covariate for the fractional elimination of HCY and its conversion to CEPM. Considerable interpatient variability was observed in the AUC of cyclophosphamide, HCY, and CEPM. These results represent a critical first step in developing pharmacokinetic-linked pharmacodynamic studies in children receiving cyclophosphamide to determine the clinical relevance of the pharmacokinetic variability in cyclophosphamide and its metabolites.

Sensitivity of administrative claims to identify incident cases of lung cancer: a comparison of 3 health plans.

BACKGROUND: Administrative claims are readily available, but their usefulness for identifying persons with non-small cell lung cancer (NSCLC) is relatively unknown, particularly for younger persons and those enrolled in Medicaid. OBJECTIVES: To determine the sensitivity of ICD-9-CM codes for identifying persons with NSCLC. METHODS: This was a retrospective analysis of insurance claims records linked to the Surveillance, Epidemiology, and End Results (SEER) cancer registry for the time period January 1, 2002, through December 31, 2005. Persons included in the sample were identified with NSCLC using SEER morphology and histology codes and were enrolled in a commercial health plan, Medicaid, or Medicare fee-for-service health plans in Washington State. The outcome measure was sensitivity, defined as the percentage of SEER-identified patients who were accurately identified as NSCLC cases using ICD-9-CM diagnoses (162.2, 162.3, 162.4, 162.5, 162.8, 162.9, or 231.2) recorded in any claim field in administrative claims data. We examined the influence of varying the number and timing of administrative codes in relation to the SEER cancer diagnosis date. In multivariate models, we examined the influence of age, sex, and comorbidity on sensitivity. RESULTS: The sensitivity of 1 medical claim including at least 1 ICD-9-CM code for identifying NSCLC within 60 days of diagnosis as documented in the SEER registry was 51.1% for Medicaid, 87.7% for Medicare, and 99.4% for commercial plan members. Sensitivity can improve at the expense of identifying a portion of patients who are 3 or more months from their true diagnosis date. In multivariate models, age, race, and noncancer comorbidity but not gender significantly influenced sensitivity. CONCLUSIONS: Administrative claims are sensitive for identifying patients with new NSCLC in the commercial and Medicare plans. For Medicaid patients, linkage with cancer registry records is needed to conduct studies using administrative claims.

Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.

The influence of CYP3A5 expression on the extent of hepatic CYP3A inhibition is substrate-dependent: an in vitro-in vivo evaluation.

Despite several studies suggesting that CYP3A5 expression can influence the extent of hepatic CYP3A-mediated inhibition, a systematic in vitro-in vivo evaluation of this potential clinically important issue has not been reported. Using representative probes from two distinct CYP3A substrate subgroups (midazolam, erythromycin), the inhibitory potency of fluconazole was evaluated in pooled human liver microsomes (HLM) with a low or high specific CYP3A5 content, in recombinant CYP3A enzymes (rCYP3A), and in healthy volunteers lacking or carrying the CYP3A5(*)1 allele. Fluconazole was a slightly more potent inhibitor of CYP3A activity in CYP3A5-HLM than in CYP3A5+ HLM with midazolam (K(i) of 15 and 25 microM, respectively) but not with erythromycin (IC(50) of 70 and 54 microM, respectively). In comparison, fluconazole was a much more potent inhibitor of rCYP3A4 than rCYP3A5 with both midazolam (K(i) of 7.7 and 54 microM, respectively) and erythromycin (IC(50) of 100 and 350 microM, respectively). As predicted from HLM, with i.v. midazolam, the average (+/- S.D.) in vivo K(i) (K(i,iv)) was significantly higher in CYP3A5(*)1 carriers (24 +/- 17 and 17 +/- 8 microM for homozygous and heterozygous groups, respectively) than in noncarriers (13 +/- 6 microM) (p = 0.02). With the erythromycin breath test, the average K(i,iv) was not different between homozygous CYP3A5(*)1 carriers (30 +/- 12 microM) and noncarriers (58 +/- 53 microM). In conclusion, the effect of CYP3A5 on hepatic CYP3A-mediated inhibitory drug-drug interactions is substrate-dependent, and HLM, rather than rCYP3A, are the preferred in vitro system for predicting these interactions in vivo.

The association between alcohol consumption and risk of COPD exacerbation in a veteran population.

BACKGROUND: Alcohol has been associated with COPD-related mortality but has not yet been demonstrated to be an independent risk factor for COPD exacerbation. Our objective was to evaluate the association between alcohol consumption and the subsequent risk of COPD exacerbation. METHODS: A prospective cohort study of general medicine outpatients seen at one of seven Veterans Affairs (VA) medical centers who returned health screening questionnaires. Three screening questionnaires, AUDIT-C (0 to 12 points), CAGE (0 to 4 points), and a single item about the frequency of drinking six or more drinks on an occasion (binge drinking), were used to classify alcohol consumption. The main outcome, COPD exacerbation, was based on primary VA discharge diagnosis (International Classification of Diseases, Ninth Revision) or outpatient diagnosis of COPD accompanied by prescriptions for either antibiotics or prednisone within 2 days. RESULTS: Among the 30,503 patients followed up for a median of 3.35 years, those patients with AUDIT-C scores > or = 6, CAGE scores > or = 2, or who reported binge drinking at least weekly were at an increased risk of COPD exacerbation in age-adjusted analysis. Adjusted hazard ratios were 1.4 (95% confidence interval [CI], 1.1 to 1.7) for AUDIT-C score > or = 6, 1.4 (95% CI, 1.3 to 1.5) for CAGE score > or = 2, and 1.6 (95% CI, 1.2 to 2.2) for those who reported binge drinking daily or almost daily. However, with adjustment for measures of tobacco use, the association between alcohol consumption and increased risk of COPD exacerbation was no longer evident. CONCLUSIONS: Alcohol consumption, whether quantified by AUDIT-C, CAGE score, or binge drinking, was not associated with an increased risk of COPD exacerbation independent of tobacco use.

Clinical and demographic characteristics help explain variations in pain at the end of life.

The natural history of pain at the end of life is not well understood. The purpose of this study was to estimate the association between clinical and demographic characteristics and pain in persons who received hospice care in the United States. Data for this study were obtained from a national provider of hospice pharmacy services and included information about the hospice and person receiving hospice care, including geographic location, primary diagnoses, pain intensity, and opioid analgesic use. The data were collected from 2000 to 2004. Worst pain intensity during the previous 24 hours was assessed by the hospice nurse using a 0-10 numeric rating scale (0=none, 10=worst) at an average of 4.1 times per person during hospice care. Regression models were constructed to explain last and average pain scores using data from persons with at least two pain intensity scores. Hospice services were provided to 51,578 persons with at least two pain intensity scores. Of this cohort, 52% were female, 87.5% were Caucasian, and 66.4% had a primary diagnosis of cancer. The mean age at discharge or death was 73.8 years. Patient characteristics accounted for nearly one-third and nearly one-half of the variability in last and average pain scores, respectively. Severe pain on admission and frequency of pain reports were associated with less intense pain. Clinical and demographic characteristics contributed to identifying persons who had severe pain during their hospice admission. These data contribute to understanding pain in persons at the end of life.