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Study Objective: Numerous medications interact at serotonin (5-hydroxytryptamine [5-HT]) receptors directly or through off-target interactions, causing mild to severe serotonergic adverse drug events (ADEs), particularly among older adults. Our objective was to develop a novel molecular-based toxicity scoring system to assess serotonergic burden resulting from concurrently administered drugs. Quantitative methods to assess serotonergic burden may provide a useful clinical tool for improving pharmacotherapy., Design: Retrospective cohort study., Data Sources: PharMetrics Legacy health claims database (January 2001-December 2013) and ChEMBL bioactivity database., Patients: A 2-serotonergic drug exposure cohort (78,172 patients) and a 3-serotonergic drug exposure cohort (19,900 patients) were generated, and population-level statistics were collected. Nonexposure cohorts were created for each drug exposure cohort and matched in a 4:1 ratio for age, sex, and length of enrollment., Measurements and Main Results: Eight 5-HT medications were screened against multiple bioactivity databases to identify their off-target interactions at 5-HT receptors and serotonin reuptake transporter protein. A computational serotonin burden score (SBS) was derived from the receptor-specific interaction propensities reported from the comprehensive bioactivity screen. Linear regression was used to characterize associations between SBSs and combined total ADE incidence rate detected by International Classification of Diseases, Ninth Revision, Clinical Modification, diagnosis codes. A significantly greater incidence of 17 potential 5-HT-related ADEs was seen in exposed serotonergic drug cohorts (p<0.05). A positive correlation between SBS and overall ADE incidence rate in the 2-serotonergic drug exposure cohort (R 2  = 0.69, p<0.34) and 3-drug cohort (R 2  = 0.85, p<0.01) was observed. When both drug cohorts were combined, total drug SBSs strongly correlated with the composite 5-HT adverse event rate (R 2  = 0.92, p<0.0001). Despite an increasing burden of illness, these data suggest that drug combinations with higher SBSs are associated with a higher rate of potential serotonergic ADEs., Conclusion: In this test of concept, positive associations between SBSs and serotonin-related ADEs suggest that it may offer a pharmacologic-based foundation for developing risk assessment tools to assist in optimizing pharmacotherapy., (© 2019 Pharmacotherapy Publications, Inc.)

Study Objective: Serotonergic adverse drug events (ADEs) are caused by enhanced intrasynaptic concentrations of 5-hydroxytryptamine (5-HT). No systematic process currently exists for evaluating cumulative 5-HT and off-target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) by using a molecular bioinformatics, polypharmacologic approach for assessment of the participation of individual 5-HT drugs in serotonin syndrome (SS) reports., Data Sources: Publicly available databases including the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data., Design: An in-house bioinformatics TargetSearch program ( http://dxulab.org/software) was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes and serotonin reuptake transporter protein (SERT). In addition, off-target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define seven polypharmacological drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS by using the Sternbach and Hunter criteria., Measurements and Main Results: A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug's total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple-receptor interactions had a disproportionately higher number of SS cases using both the Hunter criteria (mean PRR 1.72, 95% CI 1.05-2.39) and Sternbach (mean PRR 1.54, 95% CI 1.29-1.79). 5-Hydroxytryptamine agonists were associated with a significantly lower proportion of SS cases using the Hunter and Sternbach criteria, respectively (mean PRR 0.49, 95% CI 0.17-0.81 and mean PRR 0.49, 95% CI 0.15-0.83). Drugs with disproportionately higher participation in SS vary considerably between the two diagnostic criteria., Conclusion: The SEBM model suggests a possible polypharmacological role in SS. Although further research is needed, off-target receptor activity may help explain differences in severity of toxicity and clinical presentation., (© 2018 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals, Inc. on behalf of Pharmacotherapy Publications, Inc.)

In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2) unadjusted odds ratio (UOR) scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS); (3) adjusted odds ratio (AOR) re-scoring by removing the effect of cofounding factors (age, gender, reporting year); (4) logistic regression (LR) coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: -2.68; p-value<0.01). The discovery is supported by clinical reports that patients fully recovered from MCP-induced TD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Anticholinergic (AC) adverse drug events (ADEs) are caused by inhibition of muscarinic receptors as a result of designated or off-target drug-receptor interactions. In practice, AC toxicity is assessed primarily based on clinician experience. The goal of this study was to evaluate a novel concept of integrating big pharmacological and healthcare data to assess clinical AC toxicity risks., Methods: AC toxicity scores (ATSs) were computed using drug-receptor inhibitions identified through pharmacological data screening. A longitudinal retrospective cohort study using medical claims data was performed to quantify AC clinical risks. ATS was compared with two previously reported toxicity measures. A quantitative structure-activity relationship (QSAR) model was established for rapid assessment and prediction of AC clinical risks., Results: A total of 25 common medications, and 575,228 exposed and unexposed patients were analyzed. Our data indicated that ATS is more consistent with the trend of AC outcomes than other toxicity methods. Incorporating drug pharmacokinetic parameters to ATS yielded a QSAR model with excellent correlation to AC incident rate ( R 2 = 0.83) and predictive performance (cross validation Q 2 = 0.64). Good correlation and predictive performance ( R 2 = 0.68/ Q 2 = 0.29) were also obtained for an M2 receptor-specific QSAR model and tachycardia, an M2 receptor-specific ADE., Conclusions: Albeit using a small medication sample size, our pilot data demonstrated the potential and feasibility of a new computational AC toxicity scoring approach driven by underlying pharmacology and big data analytics. Follow-up work is under way to further develop the ATS scoring approach and clinical toxicity predictive model using a large number of medications and clinical parameters., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: In late 2007, the Food and Drug Administration (FDA) held public hearings exploring the establishment of a new behind-the-counter (BTC) drug program. However, little is known about the views of pharmacists regarding such a program., Objective: To assess the overall perceptions of Idaho's practicing pharmacists about the creation of a formal BTC drug program, the appropriateness of including certain drug categories, specific barriers to its adoption, and the impact of the new program on access to medicines., Methods: A survey of practicing pharmacists in Idaho was conducted by mail, utilizing anonymous responses. Key questions exploring the views of pharmacists about the new BTC drug program utilized 5-point Likert scales. Data were also collected on respondent characteristics., Results: A total of 357 practicing pharmacists in Idaho (31% response rate) returned the mail survey; 84% of pharmacists agreed that the FDA should be exploring an expanded BTC program, and 88% of pharmacists agreed that this program would improve access to some prescription-only products and convenience for patients. Almost 71% of pharmacists reported a personal willingness to both initiate and monitor certain BTC drug therapies. When focusing on specific drug categories for BTC status, the highest support was for selected agents within smoking cessation therapies (85%), nasal corticosteroids for allergies (81%), and vaccines (75%). Pharmacists who reported low barriers to the adoption of a new BTC program were significantly more likely to support this program than were those reporting high barriers. Only 39% of pharmacists agreed that adequate facilities were currently available for private evaluation and counseling of BTC patients., Conclusions: Pharmacists in a statewide survey of perceptions regarding a new BTC drug program overwhelmingly believe that patients would benefit. Pharmacists strongly support the development of the new program, and more than two thirds indicate that they would likely participate, given the necessary supporting institutional framework. Perceived barriers are related to willingness to participate and likely can be minimized through education and provision of private consulting areas.

Background: It has been estimated that more than $8 billion is spent annually on the management of breast cancer in the United States. The taxane chemotherapeutic agents are cornerstones in the treatment of breast cancer, yet no study has assessed whether the choice of a taxane affects the economic outcomes of metastatic breast cancer treatment., Objective: To determine if differences exist in the medical cost of care in patients receiving taxane-based chemotherapy for metastatic breast cancer, and to compare the use of ancillary medications (for neutropenia, anemia, and nausea and vomiting) and their associated costs among taxanes., Method: We identified women with metastatic breast cancer based on diagnosis codes and the women's previous adjuvant chemotherapeutic regimens. Paid medical insurance claims were captured for the 24-month study period, from January 1, 2006, through December 31, 2007. The groups were determined according to the specific taxane administered. Total medical costs were captured from the date of first taxane administration to the end of data availability. Outpatient pharmacy costs were not available. A multivariate analysis was used to evaluate the total medical costs in each group. Median total medical costs per patient per month during the study period were adjusted using a multiple regression analysis. Utilization and cost of medications administered in the office or hospital for chemotherapy-induced adverse effects were captured and adjusted with Tobit models., Results: Of the 2245 study participants, 1035 received docetaxel, 997 received generic paclitaxel, and 213 received nab-paclitaxel. On average, patients in the nab-paclitaxel group received more doses (9.6) than those in the generic paclitaxel (6.0) or docetaxel (4.8) groups. The multivariate analysis was robust, explaining 72% of the variability in total medical costs across the 3 taxane groups. Median per-patient per-month total medical costs for study participants were within approximately $800 of each other among the groups. Generic paclitaxel had the lowest total medical costs. The total costs for docetaxel and nab-paclitaxel were not significantly different. Nab-paclitaxel had the lowest utilization and lowest costs associated with colony-stimulating factors. The proportion of patients receiving erythropoiesis-stimulating agents was not significantly different among the 3 drugs, but the costs for these agents were significantly lower in patients receiving nab-paclitaxel than in those receiving docetaxel. Antiemetic use was highest in the docetaxel group, but the costs for antiemetics were not different among the 3 taxane groups., Conclusion: The differences in total medical costs among the 3 taxanes were modest. Total medical costs were lowest for patients receiving generic paclitaxel and comparable between the docetaxel and nab-paclitaxel groups. Patients taking nab-paclitaxel received more doses than patients taking the other taxanes. Nab-paclitaxel was associated with lower utilization and costs for colony-stimulating factors compared with generic paclitaxel and docetaxel.

Objectives: To evaluate early predictors of advanced pharmacy practice experience (APPE) performance using either timed pharmaceutical care plan (TPCP) reports of 4 case histories or traditional lecture-based pharmacotherapy course examinations., Methods: Statistical process control (SPC) methods were used to identify a group of third-year pharmacy students "at risk" for poor APPE performance (defined as an APPE grade point average of < 3.0). Examination scores from an integrated lecture-based pharmacotherapy sequence were used for comparison., Results: TPCP scores but not lecture-based examination scores successfully identified 6 of 10 students who ultimately performed poorly in their APPEs., Conclusion: Adaptation of SPC methods to assess student performance during problem-based learning (PBL) case reports is a useful technique for identifying students "at risk" for poor APPE performance.

Objective: To estimate frequencies of potential errors involving similarly named drugs using a retrospective claims database and measure the association between frequencies of potential errors and two measures of drug name similarity, edit distance (minimum number of insertions, substitutions, or deletions of characters required to change a given word into another target word) and normalized edit distance (proportion of letters that must be changed to commute one word to another, and ranges from 0 to 1, with 0 indicating identical words, and 1 indicating a pair of words with no common letters)., Design: Retrospective database analysis., Setting: Idaho Medicaid claims data from 1993 to 2000., Patients: Not applicable., Intervention: Potential errors were detected using adjacent claims generated by dispensing of one drug followed by dispensing of the other drug with a similar name. In all, four potential error criteria were developed: two for detecting potential refill errors and two for detecting potential initial errors. A total of 10 drug pairs were randomly selected from the Idaho Medicaid claims database for each value of edit distance, which ranged from 1 to 30 (n = 300)., Main Outcome Measures: Frequencies of potential medication errors in claims sequences for initial and refill claims, edit distance, and normalized edit distance., Results: Of 300 drug pairs studied, 106 (35.33%) were involved in at least one potential error. A total of 1,138 dispensing episodes satisfied the criteria for potential errors. Frequencies of potential errors per drug pair were negatively associated with edit distance (r = -0.133, P < .05) and normalized edit distance (r = -0.226, P < .01). Frequencies of potential initial errors also were negatively associated with edit distance (r = -0.126, P < .05) and normalized edit distance (r = -0.222, P < .01). Potential refill errors also had negative association with edit distance (r = -0.134, P < .05) and normalized edit distance (r = -0.226, P < .01)., Conclusion: Error criteria were successfully applied to a retrospective claims database to detect potential initial and refill errors that involved similarly named drugs.

Background: Assimilation of vitamin B(12) from dietary sources requires gastric acid. By decreasing acid production, the proton pump inhibitors (PPIs) and histamine(2) (H(2))-blockers may reduce vitamin B(12) absorption., Objective: To determine whether chronic acid suppression therapy is associated with the initiation of vitamin B(12) supplementation, we conducted a retrospective case-control study using a state-wide Medicaid population., Methods: Case patients were identified as those who initiated vitamin B(12) supplementation during the study period. Four control patients were age- and gender-matched to each case. Patients (n = 109 844) with a paid claim between September 27, 1995, and September 27, 1997, were eligible for inclusion. Chronic acid suppression therapy was defined as treatment with H(2)-blockers or PPIs for >/=10 of the 12 months prior to the first vitamin B(12) injection. Comparisons were made between the case and control groups regarding exposure to chronic acid suppression therapy., Results: One hundred twenty-five cases were matched to 500 controls. Twenty-three patients (18.4%) had been exposed to chronic acid suppression therapy compared with 55 (11.0%) of the control group (p = 0.025; OR 1.82; 95% CI 1.08 to 3.09)., Conclusions: Initiation of vitamin B(12) supplementation was associated with chronic gastric acid suppression therapy.

Objective: To compare the healing of stage II decubitus ulcers with topically applied phenytoin sodium with two other standard topical treatment procedures in a long-term care setting; and to assess the extent of systemic absorption after topical application in the phenytoin group., Methods: Forty-seven nursing home patients with stage II decubitus ulcers were chosen for this study. The patients were matched for age, gender, and size and severity of wounds, and randomly assigned to each treatment group. Clinical assessment of decubitus ulcers was performed at the beginning of treatment and at each dressing change. Ulcers were examined for the presence of healthy granulation tissue, reduction in surface dimensions, and time to healing. Two phenytoin sodium plasma concentrations were to be obtained on all patients in the phenytoin group., Results: Topical phenytoin therapy resulted in a shorter time to complete healing and formation of granulation tissue when compared with DuoDerm dressings or triple antibiotic ointment applications (p < or = 0.05). The mean +/- SD time to healing in the phenytoin group was 35.3 +/- 14.3 days compared with 51.8 +/- 19.6 and 53.8 +/- 8.5 days for the DuoDerm and triple antibiotic ointment groups, respectively. Healthy granulation tissue in the phenytoin group appeared within two to seven days in all subjects. Patients in the standard treatment groups required six to 21 days to produce new granulation tissue. Serum phenytoin sodium concentrations were nondetectable. No patient withdrew from the study secondary to adverse treatment effects., Conclusions: Both the phenytoin and standard treatment groups showed progress over the study period. However, the phenytoin group demonstrated more rapid results in all aspects of ulcer healing.

Objective: To evaluate the impact of including community pharmacists in strategies to alter excessive prescribing of antiulcer medications (AUMs) in a statewide drug utilization review (DUR) program. Mailing educational materials to physicians is a common intervention strategy of retrospective DUR programs. However, pharmacists are typically left out of this process, ignoring a possibly influential healthcare provider., Methodology: Patients without gastroesophageal reflux disease who received > or = 1.0 normalized therapeutic equivalents (e.g., 1.0 NTE = ranitidine 300 mg/d or omeprazole 20 mg/d) for five of six prior months were included. The pharmacists and physicians of these patients were divided into one of three geographically distinct groups: group 1 physicians received mailed materials only (pharmacists were not contacted); group 2 physicians and pharmacists received mailed materials only; and group 3 physicians and pharmacists received mailed materials, and the pharmacists were contacted by phone. Mean NTE and AUM costs were analyzed six months before and six months following the intervention., Results: One hundred thirty-eight, 329, and 248 patients were included in G1, G2, and G3, respectively. There was a 12.4%, 8.0%, and 14.0% reduction in NTE for G1, G2, and G3, respectively. G1 AUM cost decreased 7.7% ($7710); G2 decreased 6.8% ($14 037); G3 decreased 20.5% ($26722). The total decrease in AUM cost for the entire cohort from before to after the intervention was $48469 (p < 0.05) in the six months following the intervention., Conclusions: A follow-up phone call to pharmacists in a statewide DUR intervention enhances the effectiveness of DUR interventions under the conditions studied. Enlisting the support of community pharmacists may improve the cost savings of these interventions.

Eight methods for estimating creatinine clearance (CLcr) were compared in 65 men with serum creatinine concentrations (SCr) less than or equal to 1.5 mg/dL (group 1) and 65 men with SCr greater than 1.5 mg/dL (group 2). All patients had SCr values that did not fluctuate by more than +/- 10% for two weeks before and two weeks after measurement of CLcr. For each patient, predictions of CLcr by each of eight currently used formulas were compared with measured CLcr values; both regression analysis and predictive error analysis were used. Group 1 patients ranged in age from 32 to 64 years (mean, 53), weighed from 48 to 105 kg (mean, 73), and were from 63 to 79 inches in height (mean, 69). Group 2 patients ranged from 26 to 63 years of age (mean, 53), weighed from 34 to 141 kg (mean, 80), and were from 63 to 76 inches in height (mean, 70). Measured CLcr values ranged from 29.8 to 197 mL/min in group 1 and from 2.8 to 118 mL/min in group 2. Ranges of SCr values were 0.7-1.5 mg/dL (mean, 1.1) in group 1 and 1.6-7.1 mg/dL (mean, 2.8) in group 2; the formula of Cockcroft and Gault, which uses age, body weight, and SCr, had the highest correlation and the greatest accuracy in group 1, whereas the formula of Jelliffe, which uses body surface area and SCr, had the highest correlation and the greatest accuracy in group 2. Estimation of creatinine clearance can be improved by identification and use of the formula that is best suited to a specific patient population.

In a randomized, double-blind, dose-ranging trial, the acute antihypertensive effects of 7.5, 15, 30, 45, 60, 90, and 120 mg single daily doses of urapidil were compared with those of placebo in 10 patients with essential hypertension. Patients were randomized to either urapidil or placebo, such that each active drug day was followed by a placebo washout day. Blood pressure and heart rate responses were measured in the supine position, immediately upon standing, and after 3 to 5 minutes of standing for each dose. A variable but significant reduction in systolic and diastolic blood pressures that lasted from 4.5 to 8 hours was observed primarily at the 60, 90, and 120 mg doses (P less than 0.05). The maximum reduction in diastolic blood pressure occurred in the standing position at 3 to 5 hours after dosing. When urapidil was compared with placebo, a change from the supine to the standing positions produced a significantly larger reduction in systolic and diastolic blood pressures (P less than 0.05) but no significant change in heart rate. This suggests an acute blood pressure lowering effect of urapidil that occurs predominantly in the standing position and that does not significantly increase heart rate.

The increasing use of the calcium-entry blockers has led to an enhanced potential for drug interactions with a variety of different drugs. Interactions with cardiovascular agents are of great concern because of the consequences of synergistic negative dromotropism or inotropism. We therefore assessed the concomitant use of calcium-entry blockers and cardiac glycosides, beta-blockers, antiarrhythmic agents, and other chemical types of calcium-entry blockers from a standpoint of clinical relevance. We also evaluated reported drug interactions with H2-receptor antagonists, anticonvulsants, lithium carbonate, general anesthetics, cytostatic drugs, rifampin, and sulfinpyrazone with regard to clinical implications, along with the modification of calcium-entry blocker dose for concurrent social drug use, such as cigarette smoking and ethanol intake. Although a myriad of potential drug interactions exists for these agents, combination therapy is still a reasonable alternative if doses are adjusted appropriately.

The impact of home infusion therapies on the pharmaceutical services drug budget of the Colorado Medicaid program was evaluated retrospectively. Pharmacy billing claims and prior authorization forms for home infusion therapies submitted to the Colorado Department of Social Services during a 26-month period were reviewed to determine the costs of the drug or hydration solutions and ancillary products necessary for the preparation and administration of the solutions. A dispensing fee of +3.40 per dose was figured into calculations of total costs of home infusion therapies, and an estimated cost of +100-+150 per day for follow-up care was added. Equivalent costs of hospitalization were calculated using an average per diem charge of +315. A total of 61 patients received 1361 days of home infusion therapy during the study period. The majority of patients received home antimicrobial therapy; 752 days of hospitalization theoretically were avoided because of home administration of antimicrobial agents, which translates into a cost savings of +76,716-+114,316. Patients also received home parenteral nutrition therapy, analgesic therapy, and rehydration therapy that yielded cost savings of +48,374-+78,824 but in some cases resulted in higher costs than hospitalization would have. Home infusion therapies increased pharmaceutical services costs by +99,475, representing an important shift of costs from the hospital services budget to the pharmaceutical services budget. Home infusion therapies generally incur lower costs than would be incurred during an equivalent hospital stay. The Colorado Medicaid budget should be adjusted to compensate for the shift of costs from hospital to pharmaceutical services.

The extent of medication use and drug information preferences was surveyed randomly from patients at six different pharmacy health care systems. Following verbal consultation, each patient was given one or more modified United States Pharmacopoeia drug information leaflets corresponding to the verbal information and a self-addressed, stamped questionnaire to complete. Chi-square analysis was performed on 317 responses with overwhelming acceptance (96 percent) of the medication information provided. Although a majority of respondents (62 percent) preferred a combination of both written and oral information, specific information preferences (oral, written, or both) were significantly related to educational level, pharmacy attended, and prescription status. Nearly 45 percent of the respondents indicated the information was responsible for changing their medication use. Subjects who were elderly, taking cardiovascular medications, or getting refill prescriptions were significantly less likely to change as a result of the information provided. Although 65 percent of the respondents were unwilling to pay an additional fee for the service, females and those who were 45-54 years and over 65 years old were significantly more willing to pay for the information. In addition, the willingness to pay tended to increase as the number of daily medications taken increased. Consideration of socioeconomic and prescription variables may help define subgroups with specific information preferences and counseling activities that may be directly reimbursable.