The effect of pharmacogenetic profiling with a clinical decision support tool on healthcare resource utilization and estimated costs in the elderly exposed to polypharmacy.

OBJECTIVE: To compare healthcare resource utilization (HRU) and clinical decision-making for elderly patients based on cytochrome P450 (CYP) pharmacogenetic testing and the use of a comprehensive medication management clinical decision support tool (CDST), to a cohort of similar non-tested patients. METHODS: An observational study compared a prospective cohort of patients ≥65 years subjected to pharmacogenetic testing to a propensity score (PS) matched historical cohort of untested patients in a claims database. Patients had a prescribed medication or dose change of at least one of 61 oral drugs or combinations of ≥3 drugs at enrollment. Four-month HRU outcomes examined included hospitalizations, emergency department (ED) and outpatient visits and provider acceptance of test recommendations. Costs were estimated using national data sources. RESULTS: There were 205 tested patients PS matched to 820 untested patients. Hospitalization rate was 9.8% in the tested group vs. 16.1% in the untested group (RR = 0.61, 95% CI = 0.39-0.95, p = 0.027), ED visit rate was 4.4% in the tested group vs. 15.4% in the untested group (RR = 0.29, 95% CI = 0.15-0.55, p = 0.0002) and outpatient visit rate was 71.7% in the tested group vs. 36.5% in the untested group (RR = 1.97, 95% CI = 1.74-2.23, p < 0.0001). The rate of overall HRU was 72.2% in the tested group vs. 49.0% in the untested group (RR = 1.47, 95% CI = 1.32-1.64, p < 0.0001). Potential cost savings were estimated at $218 (mean) in the tested group. The provider majority (95%) considered the test helpful and 46% followed CDST provided recommendations. CONCLUSION: Patients CYP DNA tested and treated according to the personalized prescribing system had a significant decrease in hospitalizations and emergency department visits, resulting in potential cost savings. Providers had a high satisfaction rate with the clinical utility of the system and followed recommendations when appropriate.

Consideration of international generic distribution policies on patient outcomes in the United States and Germany.

Generic substitution of narrow therapeutic index drugs can have unintended consequences. Generic switching is often driven by cost incentives, regulations and supply, but may raise concerns about equal bioavailability, therapeutic equivalence and about possible confusion for the patient. Integrated systems of care with active management of patient behaviors, including adherence, may minimize the impact of switching. This article is intended to present policy drivers and potential consequences of generic switching and the role of pharmacist education in minimizing patient risk using warfarin and the pharmaceutical distribution systems of the United States and Germany as examples.

Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain.

BACKGROUND: Opioids are used increasingly in the management of moderate-to-severe chronic non-cancer pain (CNCP). Opioid-induced bowel disorders (OBD) markedly impact health-related quality of life (HRQoL) and frequently limit medically indicated opioid pharmacotherapy. We assessed the risk factors, and effect of OBD on HRQoL in CNCP patients. We also estimated the likely prevalence of narcotic bowel syndrome (NBS). These effects have been reported in cancer patients but not in CNCP previously. METHODS: Ambulatory CNCP patients (n = 146) taking regularly scheduled opioids were invited to complete the Bowel-Disease-Questionnaire and a pain-sensitive HRQoL instrument. The Rome-II criteria were used to define bowel disorders. Narcotic bowel syndrome was defined as presence of daily severe to very-severe abdominal pain of more than 3 months duration requiring more than 100 mg of morphine equivalent per day. KEY RESULTS: Ninety-eight patients (69%) returned the survey. Respondents had taken opioids for 10 days to 10 years (median 365 days) at a median daily dose of 127.5 mg morphine-equivalent (range 7.5-600 mg). Constipation prevalence was 46.9% (95% CI 36.8-57.3), nausea 27% (95% CI 17.2-35.3), vomiting 9% (95% CI 17.2-35.3), and gastro-esophageal reflux disease 33% (95% CI 23.5-42.9). Chronic abdominal pain was reported by 58.2% (95% CI 53.2-73.9) and 6.4%, (95% CI 2.4-13.5) fulfilled the criteria of NBS. Prevalence of constipation increased with duration of treatment. Health-related quality of life was low in patients with chronic abdominal pain. CONCLUSION & INFERENCES: Bowel disorders including chronic abdominal pain and NBS are common in patients taking opioids for CNCP. Decreased HRQoL in patients with CNCP is driven by chronic abdominal pain.

Estimation of the cost savings resulting from the use of ursodiol for the prevention of gallstones in obese patients undergoing rapid weight reduction.

BACKGROUND: Morbidly obese patients enrolled in a rapid weight reduction program are at a high risk of developing gallstones. Two multicenter, placebo-controlled, randomized, double-blind trials have demonstrated that the prophylactic use of ursodiol in males and females 18 to 70 years of age is effective for the prevention of gallstone formation in this patient population. This study examines the cost consequences associated with the prophylactic use of ursodiol. METHODS: A medical decision analysis model for the prophylactic administration of ursodiol in morbidly obese patients undergoing rapid weight reduction by either gastric bypass surgery or very-low-calorie-diet, was developed through the use of data from two clinical trials and review of the related literature. The expert opinion of clinicians from the fields of internal medicine, gastroenterology and surgery were solicited. Financial data for the charges associated with cholecystectomies, physician fees and ursodiol were obtained from current financial databases. RESULTS: The model demonstrates that the prophylactic administration of ursodiol, in morbidly obese patients undergoing rapid weight reduction, results in cost savings. Sensitivity analysis was performed to illustrate that the cost savings achieved by the prophylactic use of ursodiol were valid over a realistic range of charges and assumptions. CONCLUSION: The decision model may allow health care decision makers to apply their own data to the model to determine the cost savings obtainable through the prophylactic use of ursodiol in patients undergoing rapid weight reduction.

Radiosynthesis of 6-[C-11]-D-glucose.

Availability of 6-[C-11]-D-glucose will permit positron emission tomography (PET) investigations of glucose utilization derived from the pentose shunt which supports biosynthesis in tissues. The first radiosynthesis of 6-[C-11]-D-glucose is described. As much as 1 mCi of 6-[C-11]-D-glucose, sufficient for animal studies, is obtained from [C-11]CO2 after 100 min with a 16% radiochemical yield (EOB). The radiosynthesis has many attractive features. The method uses [C-11]CH3I and combines a Wittig reaction and a stereoselective OsO4 catalyzed alkene hydroxylation. The OsO4 hydroxylation of the [C-11]-labeled alkene (9) is accomplished in less than 10 min with high stereoselectivity (94:6) in favor of the 6-[C-11]-D-gluco-isomer. HPLC purification (C-18) of the protected labeled sugar removes the undesired 6-[C-11]-L-ido-sugar at an early stage and avoids the use of an expensive low-capacity ion-exchange HPLC column. OsO4, a highly toxic reagent, is removed in the process by adsorption and inactivation on polymer-bound triphenylphosphine.

Characterization of iodovinylmisonidazole as a marker for myocardial hypoxia.

Misonidazole and related compounds are metabolically trapped in viable cells as a function of reduced cellular pO2. [18F]fluoromisonidazole has been used to detect hypoxia in the heart and in tumors noninvasively with positron emission tomography. The purpose of this study was to characterize the uptake of the iodinated misonidazole congener iodovinylmisonidazole (IVM) in ischemic myocardium. In six open chest dogs (Group 1), the left anterior descending (LAD) coronary artery was partially occluded and in four dogs (Group 2), demand ischemia was produced by the combination of atrial pacing and catecholamine infusion in the presence of a LAD stenosis. [131I]IVM (5-15 microCi/kg, i.v.) was given following the onset of ischemia. Tracer deposition was measured by postmortem tissue sampling 4 hr postinjection and compared to microsphere myocardial blood flow (MBF) measurements made at baseline and at 2 hr postinjection. In Group 1, regional IVM deposition in heart samples within the ischemic area was inversely related to MBF with maximum tissue:blood ratios of 3.2. For a given level of reduced blood flow, IVM uptake was higher in the subendocardium indicating a greater vulnerability of the subendocardium to reductions in oxygen delivery. In Group 2, enhanced IVM deposition was detected as a result of demand ischemia, even in some regions where absolute flow was normal or increased from baseline, indicating that flow per se is not the principal determinant of tracer uptake. We conclude that IVM is a promising marker for myocardial hypoxia with potential clinical application using gamma camera imaging.

Synthesis of an (iodovinyl)misonidazole derivative for hypoxia imaging.

Nitroimidazoles undergo a bioreduction in viable hypoxic tissue, resulting in trapping within these tissues, as demonstrated by misonidazole. A radioiodinated analogue of misonidazole (IVM, (E)-5-(2-Nitroimidazolyl)-4-hydroxy-1-iodopent-1-ene, 3) has been synthesized by halodestannylation, for evaluation as an imaging agent for hypoxia. A key step in the synthetic sequence involves the use of the Lewis acid BF3.Et2O to promote the nucleophilic ring opening of glycidyl tosylate with (E)-1-lithio-2-(tributylstannyl)ethylene. Direct comparison of IVM versus F-MISO (2) another misonidazole type hypoxic cell marker, in several in vitro cell culture studies, indicates that IVM behaves in analogous fashion to F-MISO and has promise as a hypoxia imaging agent for SPECT.