Randy C. Hatton

Emerging roles for pharmacists in clinical implementation of pharmacogenomics.

Pharmacists are uniquely qualified to play essential roles in the clinical implementation of pharmacogenomics. However, specific responsibilities and resources needed for these roles have not been defined. We describe roles for pharmacists that emerged in the clinical implementation of genotype‐guided clopidogrel therapy in the University of Florida Health Personalized Medicine Program, summarize preliminary program results, and discuss education, training, and resources needed to support such programs. Planning for University of Florida Health Personalized Medicine Program began in summer 2011 under leadership of a pharmacist, with clinical launch in June 2012 of a clopidogrel‐CYP2C19 pilot project aimed at tailoring antiplatelet therapies for patients undergoing percutaneous coronary intervention and stent placement. More than 1000 patients were genotyped in the pilot project in year 1. Essential pharmacist roles and responsibilities that developed and/or emerged required expertise in pharmacy informatics (development of clinical decision support in the electronic medical record), medication safety, medication‐use policies and processes, development of group and individual educational strategies, literature analysis, drug information, database management, patient care in targeted areas, logistical issues in genetic testing and follow‐up, research and ethical issues, and clinical precepting. In the first 2 years of the program (1 year planning and 1 year postimplementation), a total of 14 different pharmacists were directly and indirectly involved, with effort levels ranging from a few hours per month, to 25–30% effort for the director and associate director, to nearly full‐time for residents. Clinical pharmacists are well positioned to implement clinical pharmacogenomics programs, with expertise in pharmacokinetics, pharmacogenomics, informatics, and patient care. Education, training, and practice‐based resources are needed to support these roles and to facilitate the development of financially sustainable pharmacist‐led clinical pharmacogenomics practice models.

Antiepileptic Hypersensitivity Syndrome in Children

OBJECTIVE: To assess clinical features and outcomes of childhood antiepileptic hypersensitivity syndrome (AHS). AHS is an idiosyncratic reaction to aromatic anticonvulsants that can result in severe multiorgan dysfunction and death. METHODS: Children with suspected AHS (fever, rash, lymphadenopathy, liver dysfunction) were identified by an in-house computerized adverse drug event reporting system. The medical charts of children with suspected AHS were reviewed. A MEDLINE search (from 1966 to October 1999) was performed using the term antiepileptic hypersensitivity syndrome. RESULTS: Fourteen of 36 children who experienced a rash, urticaria, pruritus, fever, or hepatotoxicity associated with aromatic anticonvulsants met the criteria for AHS (mean age 10.4 ± 6.5 y; males to females 8:6, white to African-American to biracial 10:3:1). Eight patients were receiving phenytoin, six carbamazepine, and four phenobarbital alone or in combination. The mean time from exposure to development of symptoms was 23.0 ± 14.8 days. In addition to rash and fever (present in all patients by definition), other common features of AHS were lymphocytosis (71.4%), elevated erythrocyte sedimentation rate (64.3%), elevated aminotransferases (64.3%), lymphadenopathy (57.1%), eosinophilia (42.8%), coagulopathy (42.8%), leukocytosis (35.7%), leukopenia (35.7%), hyperbilirubinemia (35.7%), and nephritis (7.1%). All children recovered except one, who died from complications of liver failure. Clinical outcome was similar between children who received systemic steroid therapy (n = 5) and those who did not. Antiepileptics producing AHS were discontinued in all patients. CONCLUSIONS: AHS can be fatal in children if not promptly recognized. Fever, rash, and hepatotoxicity should serve as presumptive evidence for AHS, which requires immediate discontinuation of an offending anticonvulsant.

Efficacy and Safety of Oral Phenylephrine: Systematic Review and Meta-Analysis

Background: Oral phenylephrine is used as a decongestant, yet there has been no previously published systematic review supporting its efficacy and safety. Objective: To assess the efficacy and safety of oral phenylephrine as a nonprescription decongestant. Methods: MEDLINE, the Cochrane Central Registry of Controlled Trials, EMBASE International Pharmaceutical Abstracts, and the Federal Register were searched for-English and non–English-language studies published through January 2007 that measured the effects of oral phenylephrine on nasal airway resistance (NAR) in patients with nasal congestion. The retrieved studies were supplemented with information from our personal files and by hand searches of the references in any of the studies. Additionally, a Web of Science Search was conducted using the Cited Reference function for all published clinical trials identified. Studies included in the analysis were randomized, placebo-controlled trials; studies of combination products were excluded. Two investigators independently extracted data on NAR, self-reported decongestant effects, and cardiovascular effects (ie, heart rate, blood pressure) from each of the included studies. Meta-analyses were performed for NAR and cardiovascular effects using a random effects model. Subjective decongestant effects were summarized. Results: Based on 8 unpublished studies that included 138 patients, phenylephrine 10 mg did not affect NAR more than placebo; the mean maximal difference in relative change from baseline between phenylephrine and placebo was 10.1% (95% CI −3.8% to 23.9%). Eight unpublished studies on phenylephrine 25 mg showed a significant reduction of maximal NAR compared with placebo of 27.6% (95% CI 17.5% to 37.7%). There was significant heterogeneity among the studies included in this analysis, which was partially attributable to different laboratories and methods used. Patient-re ported decongestion was not consistently better for any phenylephrine dose compared with placebo, and NAR was a more sensitive measurement of efficacy. Phenylephrine showed no consistent effect on heart rate or blood pressure for doses of 25 mg or less. Conclusions: There is insufficient evidence that oral phenylephrine is effective for nonprescription use as a decongestant. The Food and Drug Administration should require additional studies to show the safety and efficacy of phenylephrine.

Removal of iron dextran by hemodialysis: An in vitro study

Intravenous iron dextran is frequently prescribed for iron-deficient hemodialysis patients, a practice that has increased during the erythropoietin era. Whether iron dextran is removed by hemodialysis has been a concern, especially for high permeability membranes. The purpose of this in vitro study was to measure iron dextran clearance by nine different hemodialyzers (Fresenius F3, F8, and F80B; Baxter CF25, CA150, CA210, and CT190; Toray BK2.1P; and Hospal Filtral 16) representing six types of membranes (polysulfone, cuprophane, cellulose acetate, cellulose triacetate, polymethylmethacrylate, and polyacrylonitrile) and including membranes considered high efficiency and high flux. Clearances were assessed using a closed-loop, fixed-volume reservoir model. Absolute drug removal also was determined over the 30-minute experiments. Iron dextran clearance did not exceed 25 mL/min, and clearances also were minimal after a single automated reuse with glutaraldehyde sterilant. A maximum of 8% of iron dextran was removed during the experiment. We conclude that iron dextran clearance by the nine hemodialyzers studied was small or too low to be detected in this sensitive in vitro dialysis system and that adjusting dosing schedules is not needed.

Discontinuation rates of Helicobacter pylori treatment regimens: a meta-analysis.

We conducted a meta‐analysis to determine what factors in treatment regimens for Helicobacter pylori are associated with increased discontinuation rates. Studies were selected from the 1990–1996 MEDLINE data base, and references in published articles and reviews were obtained. Each article was uniformally abstracted for factors that could potentially affect dropout rates. Drug regimens with high numbers of doses per day had highest dropout rates (p=0.0001). The total dropout rate was lowest for regimens containing a proton pump inhibitor (OR = 0.75, CI 0.57, 0.98). The rate was high in regimens containing a bismuth compound due to side effects (OR = 2.79, CI 1.78, 4.36). The main finding was that drug regimens for eradication of H. pylori that have a high number of doses per day result in higher discontinuation rates than regimens with fewer doses per day.

Bismuth Subgallate–Epinephrine Paste in Adenotonsillectomies

OBJECTIVE: To evaluate the role of bismuth subgallate–epinephrine (BSE) paste as a hemostatic in adenotonsillectomies. DATA SOURCES: MEDLINE (January 1966–October 1999) and Current Contents (January 1997–October 1999) were searched, using bismuth subgallate, adenoidectomy, tonsillectomy, and adenotonsillectomy as search terms. A citation search was performed using Science Citation Index (January 1977–October 1999). DATA SYNTHESIS: Adenotonsillectomies are common procedures; although there are few complications, hemorrhage is a concern. Bismuth subgallate has historically been used as an astringent and hemostatic. An evaluation of studies of bismuth subgallate and BSE paste was conducted. CONCLUSIONS: There is minimal evidence to support this practice, but data suggest that epinephrine may be the active ingredient in BSE paste. BSE paste is inexpensive, poses little risk, and may decrease postoperative bleeding; therefore, it may be a reasonable hemostatic agent.

Evaluation of Contraindicated Drug-Drug Interaction Alerts in a Hospital Setting

Background: Risks associated with contraindicated drug-drug interaction alerts (CDDIAs) should always outweigh benefits. Misclassified CDDIAs should be eliminated. Objective: To review CDDIAs and determine if they are contraindicated according to Food and Drug Administration-approved product labeling and if there are circumstances in which contraindicated interactions are acceptable. Methods: A cross-sectional observational and quality improvement study was conducted over two 1 -year periods. The 20 most common CDDIAs from May 2007 to May 2008 and all CDDIAs from April 2008 to April 2009 were collected at a large teaching hospital. Horizon Meds Manager used First DataBank as the knowledge base for decision support. Interactions were deemed truly contraindicated if listed in the contraindications section of the labeling of at least one of the interacting drugs. Alerts were grouped by drug and pharmacologic class to evaluate the evidence supporting the relevance of these interactions. An expert panel determined when an alert was misclassified. A medical advisory committee determined whether a contraindicated drug-drug combination was acceptable. Results: Twelve (60%) of the most common 20 contraindicated interaction pairs from 2007 to 2008 were inappropriately classified. Half of the alerts were not truly contraindicated. The 8 truly contraindicated drug-drug pairs were ketorolac and other nonsteroidal antiinflammatory drugs or oral solid potassium products and anticholinergics. Half of these interactions were subsequently deemed acceptable under specific circumstances. Similar results were found in the second year, with only 55.1% of all CDDIAs being truly contraindicated despite eliminating some of the alerts that were misclassified in the first year. Nearly three fourths of legitimate CDDIAs were deemed acceptable under specific circumstances, Conclusions: Most contraindicated drug-drug interaction alerts from a commercial knowledge base were inappropriately categorized and could be downgraded. Some contraindicated drug combinations are permissible under specific circumstances. Alerts suggesting that certain drugs should never be used together, but their use together is sometimes acceptable, contribute to alert fatigue.

Carisoprodol: A marginally effective skeletal muscle relaxant with serious abuse potential

This review examines literature on the efficacy and abuse potential of carisoprodol, makes recommendations for use of this agent in the hospital setting, and outlines applicable federal and state regulations. A Medline search using key words and MeSH terms was conducted. In addition, International Pharmaceutical Abstracts (1970–2002), Current Contents (1996–2002), Cochrane Database of Systematic Reviews (1999–2002), and Psych Info (1872–2002) were searched for relevant literature. Articles cited in the bibliographies produced by these searches were included in the review. A Web of Science search was conducted for all citations found in all the searches. Pain is a common physical symptom in patients with musculoskeletal problems, and pharmacologic therapy is often combined with nonpharmacologic measures to treat the pain etiology and symptomatology. Skeletal muscle relaxants (SMRs) and nonsteroidal anti-inflammatory drugs (NSAIDs) represent the most common drug therapy choices in patients with mild-to-moderate somatic pain. Carisoprodol (Soma) is an SMR that has a poorly defined mechanism of action and a high potential for abuse. This literature review produced little evidence to support the use of carisoprodol in pain control. The research also showed that patients with a history of previous substance abuse are more likely to abuse this drug; thus carisoprodol does not meet safety and efficacy standards and should be removed from the market. At the very least, states should reschedule carisoprodol as a schedule IV controlled substance to minimize chronic misuse and abuse. If carisprodol is listed in hospital formularies, it should be handled as a controlled substance regardless of its federal status. Alternative sedatives (eg, phenobarbital) should be used to manage patients experiencing carisoprodol withdrawal symptoms.

Use of Nifedipine in the Hypertensive Diseases of Pregnancy

OBJECTIVE: To review the available data about the use of nifedipine to treat hypertension in pregnancy. DATA SOURCES: All English language cases and studies published after 1984 and indexed in MEDLINE, Excerpta Medica, and BIOSIS PREVIEWS under the headings nifedipine, hypertension in pregnancy, uteroplacental blood flow, maternal/fetal hemodynamics, preeclampsia, and pregnancy outcome. MAIN OUTCOME MEASURES: The primary outcome indicators included the safety and antihypertensive efficacy of nifedipine in pregnancy; the effects of nifedipine on maternal/fetal hemodynamics; and the effect, if any, of nifedipine on perinatal outcome. CONCLUSIONS: Traditional drug therapy choices for hypertension in pregnancy continue to be hydralazine for acute reduction of blood pressure and methyldopa for the management of chronic hypertension. Current data indicate that nifedipine is an appropriate second-line antihypertensive medication in pregnancy, but more clinical trials are needed before it can be considered an appropriate choice for initial therapy. As do other antihypertensive agents, nifedipine provides maternal benefit by lowering blood pressure and reducing the risk of cerebral hemorrhage and end-organ damage. However, perinatal benefit of nifedipine remains to be established.

Evaluation of Online Drug References for Identifying Over-the-Counter Solid Oral Dosage Forms

OBJECTIVE To evaluate six drug references for their usefulness in identifying over-the-counter (OTC) solid oral dosage forms (SODFs). DESIGN Retrospective evaluation of a convenience sample of requests for product identification. SETTING Drug information center that accepts information requests from health care providers and law enforcement officials throughout the state in which it is located. PARTICIPANTS Researchers. INTERVENTIONS Using a convenience sample of 68 nonprescription drugs and 41 dietary supplements obtained from the drug information centers question and answer database, researchers sought to identify the SODFs using six drug-identification online databases. MAIN OUTCOME MEASURE Likelihood of identifying a SODF with a given reference, reported as the percentage identified and the corresponding 95% confidence interval. RESULTS Overall, 88.2% of nonprescription drugs could be identified using all six references. The highest percentage of nonprescription drugs (77.9%) were identified using Identidex, followed by Ident-A-Drug (67.6%), Drug Identifier (45.6%), RxList (39.7%), Lexi-Drug ID (33.8%), and Clinical Pharmacology (17.6%). Using Ident-A-Drug and RxList together led to the identification of two fewer nonprescription drugs than did Identidex at approximately 5% of the cost. Only 15 (37.5%) of the dietary supplements had an identifying imprint on the dosage form, and 7 (46.6%) of the imprinted products were identified. But overall, only 17.1% (7 of 41) of dietary supplements could be identified, as none of the products without imprints could be positively identified. CONCLUSION Using these six online references, nonprescription drugs could be identified more frequently than could dietary supplements. The lack of imprints on many dietary supplements is an impediment to identification of these products.