BACKGROUND:

The complexity of clinical pharmacy services usually leads to an inconsistent or even poor description of their interventions in scientific reports. To ensure comparability and reproducibility of the evidence, an in-depth description of pharmacist interventions is required.

OBJECTIVE:

To validate a new tool called DEPICT (Descriptive Elements of Pharmacist Intervention Characterization Tool) to characterize clinical pharmacy services.

METHODS:

We developed a 3-phase study. First, to create a theoretical framework, an overview of systematic reviews was performed in PubMed between 2000 and 2010. Then, an in-depth analysis of the included studies was carried out to identify a list of components in order to create the instrument. Finally, 2 independent raters separately applied the tool to a random sample of 28 randomized clinical trials extracted from the systematic reviews. Interrater agreement was evaluated using PABAK (prevalence-adjusted bias-adjusted κ) coefficient or intraclass correlation coefficient (ICC).

RESULTS:

We included 49 systematic reviews in our overview. Analysis of these studies resulted in 58 intervention components, with 57 dichotomous variables and 1 discrete variable. These items resulted in a preliminary version of the instrument. The reliability analysis showed that 8 binary items of this version had a PABAK less than or equal to 0.60. These items were then excluded or modified, resulting in a final version of the tool, with 54 items organized into 12 domains. DEPICT showed an average PABAK of 0.85 (95% CI 0.81 to 0.88) and an ICC of 1.0. Twenty items presented a PABAK value between 0.61 and 0.80 (substantial agreement) and 33 had a value between 0.81 and 1.0 (almost perfect agreement).

CONCLUSIONS:

DEPICT is a reproducible instrument for describing the components of pharmacist interventions performed as part of clinical pharmacy services. It allows retrospective analysis of published studies and can be used as a reference guide to report pharmacist interventions in future studies.

OBJECTIVE:

To describe a practical solution for addressing body weight when using the Cockcroft-Gault equation to determine drug dosing.

DATA SOURCES:

A literature search was conducted using PubMed MEDLINE (1980-April 2013) using creatinine clearance, Cockcroft and Gault, Cockcroft-Gault, body weight, and obesity as search terms. Reference citations from publications reviewed were included.STUDY SELECTION AND

DATA EXTRACTION:

All English-language articles identified by the search were reviewed. Studies comparing the accuracy and bias of the Cockcroft-Gault equation using a variety of body weight designations in adult populations were included in the analysis.

DATA SYNTHESIS:

Study

RESULTS:

We propose the use of a CrCl range for drug dosing purposes, with the lower boundary defined by using IBW in the Cockcroft-Gault equation and the upper boundary by using TBW.

OBJECTIVE:

To review the place in therapy of mirabegron, a new oral β3-adrenergic receptor agonist, for the treatment of overactive bladder (OAB).

DATA SOURCES:

A literature search of MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations Databases (1996-April 2013) was conducted using the key words mirabegron, receptor, adrenergic, beta-3; adrenergic beta-3 receptor; beta-3 receptor, and overactive bladder; urinary bladder; overactive. All published articles regarding mirabegron were included. References of selected articles, data from poster presentations, and abstract publications were additionally reviewed.STUDY SELECTION AND

DATA EXTRACTION:

Available English-language data from reviews, abstracts, presentations, and clinical trials of mirabegron in humans were reviewed; relevant clinical data were selected and included.

DATA SYNTHESIS:

Mirabegron is the newest option for treatment of OAB with symptoms of urge incontinence. As a β3-receptor agonist, it reduces bladder muscle contractions. In two 12-week, randomized, double-blind, placebo-controlled Phase 3 studies, mirabegron significantly reduced the number of incontinence episodes per 24 hours from baseline (-1.47, -1.63, and -1.13; p < 0.05; and -1.57, -1.46, and -1.17; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). Micturitions per 24 hours were also reduced from baseline (-1.66, -1.75, and -1.05; p < 0.05; and -1.93, -1.77, and -1.34; p < 0.05; all values for mirabegron 50 mg, 100 mg, and placebo). A 12-month trial found mirabegron to have a safety and efficacy profile similar to that of tolterodine.

CONCLUSIONS:

Treatment of OAB initially includes lifestyle and nonpharmacologic intervention; for patients with persistent symptoms despite these treatments, drug therapy represents a next-step approach for symptom control. Mirabegron alleviates symptoms of OAB while having a mechanism of action that provides an alternative for patients who are intolerant of or who have contraindications to anticholinergic agents. The place in therapy of mirabegron relative to anticholinergics in the treatment of urge incontinence has not yet been established.

OBJECTIVE:

To evaluate everolimus drug-drug and drug-food interactions, with an emphasis on patients with cancer.

DATA SOURCES:

Literature was accessed through PubMed (1990-March 2013) using Boolean combinations of the terms drug interactions, herb-drug interactions, food-drug interactions, everolimus, antineoplastic agents, hormonal, and breast neoplasms. In addition, reference citations from publications and the prescribing information for everolimus were reviewed.STUDY SELECTION AND

DATA EXTRACTION:

All articles published in English, including human, animal, and in vitro studies, identified from the

DATA SOURCES:

Patients with cancer are at increased risk for drug interactions because of the multiple medications they are prescribed to treat their disease and comorbid conditions. Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is indicated for the treatment in adults with progressive neuroendocrine tumors of pancreatic origin that are unresectable, locally advanced, or metastatic; adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; and, recently, postmenopausal women with advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. As its use increases among patients with cancer, clinicians must be knowledgeable about potential drug and/or food/nutrient interactions and the mechanisms by which these interactions occur, to mitigate and prevent unwanted reactions and ensure patient safety.

CONCLUSIONS:

Everolimus is a widely used oral mTOR inhibitor that has the potential for drug interactions that may affect therapeutic outcomes, produce toxicities, or both. This article provides a review of evidence-based literature, along with the prescribing information, to educate clinicians on the significance of these drug interactions and their impact on management with everolimus.

OBJECTIVE:

To report a case of cholestatic jaundice as a result of combination herbal and designer supplement use.

CASE SUMMARY:

A 50-year-old Hispanic male presented to the hospital with a 1-week history of significant painless jaundice; total bilirubin on admission was 29.4 mg/dL. He reported use of both herbal (creatine and whey protein) and designer (Incredible Bulk and Spartan 45) supplements concurrently for approximately 2 months. Upon admission, all supplements were discontinued and multiple laboratory and diagnostic tests were ordered. On day 6 of his hospital admission, a liver biopsy was performed, the

RESULTS:

Anabolic-androgenic steroids are capable of causing hepatotoxicity, and multiple cases reported in the literature support this. A case report described hepatotoxicity secondary to both creatine and whey protein consumption, and several reports have described liver damage secondary to designer supplement use. To our knowledge, this is the first case to describe hepatotoxicity as a result of combination herbal and designer supplement use. The Roussel Uclaf Causality Assessment Method (RUCAM) score for drug-induced hepatotoxicity indicated a highly probable correlation between the use of combination supplements and cholestatic jaundice.

CONCLUSIONS:

Health care professionals need to be aware of complications associated with designer supplement use and should be able to identify patients who would benefit from education on herbal and designer supplement use.

OBJECTIVE:

To report on a patient who was successfully rechallenged with clozapine after perforation of the large intestine and pulmonary embolism post operatively, and provide a literature review on clozapine rechallenge.

CASE SUMMARY:

A 46-year-old Japanese man with treatment-resistant schizophrenia developed constipation and slight abdominal discomfort while taking clozapine 275 mg/day. He developed appendicitis, leading to perforation of the large intestine. During the postsurgery period, a partial embolism of the pulmonary artery was revealed. The patient's constipation was relieved when clozapine was discontinued, but other antipsychotics failed to control his delusions well. After thorough

DISCUSSION:

Clozapine is a gold standard medication in treatment-resistant schizophrenia but is associated with various adverse effects, some of which are life-threatening. Reintroduction of clozapine after severe adverse drug effects when other medications are not effective almost always poses a clinical dilemma for mental health professionals. A PubMed search (to January 25, 2013) using the key words clozapine and rechallenge found 50 articles. There were only sporadic positive case reports regarding the rechallenge after clozapine-related serious gastrointestinal problems.

CONCLUSIONS:

From the currently available evidence, most psychiatrists appear to avoid reintroduction of clozapine. However, the evidence is too weak to draw a definitive conclusion about reintroduction of this drug. Reintroduction of clozapine after initial adverse effects in patients with treatment-resistant schizophrenia may warrant case-by-case judgment, but needs to be further investigated.

OBJECTIVE:

To report what we believe to be the first case of severe hypothyroidism with reduced drug metabolism and transport activity.

CASE SUMMARY:

A 32-year-old African American woman with a history of treatment-resistant lupus nephritis and concurrent hypothyroidism was participating in a clinical study to evaluate cyclophosphamide pharmacokinetics in patients with glomerulo-nephritis due to lupus nephritis and small-vessel vasculitis. Thyroid-stimulating hormone levels ranged from 60 to 300 μIU/mL, despite high doses of thyroid replacement hormone (levothyroxine 400 μg twice weekly). The pharmacokinetics of the probe drug cocktail (flurbiprofen/fexofenadine) were altered, with formation clearance of flurbiprofen (CYP2C9 function) lower in our patient versus the average value in our study cohort, suggesting a reduction in activity. The area under the concentration-time curve from 0 to 24 hours for fexofenadine (transporter function) was 2-fold higher in our patient compared to that of other study patients. Pharmacokinetic data showed markedly decreased cyclophosphamide clearance and exposure to 4-hydroxycyclophosphamide, as well as a reduced metabolic ratio of 4-hydroxycyclophosphamide to cyclophosphamide.

DISCUSSION:

Previous cases of altered pharmacokinetics and toxicity of medications in patients with mild to moderate thyroid dysfunction have been published. Our case evaluated the impact of a severe form of hypothyroidism on cyclophosphamide pharmacokinetics and probe drug metabolism and transport. If changes were not demonstrated at the extreme spectrum of hypothyroidism, there would be little concern for changes in patients with less severe disease. Profound hypothyroidism likely contributed to the patient's poor response to cyclophosphamide treatment through its influence on CYP isoenzymes responsible for the activation to 4-hydroxycyclophosphamide and possibly through reduced transport function.

CONCLUSIONS:

Clinicians should monitor for significant hypothyroidism in patients who are prescribed drugs (eg, cyclophosphamide) that require metabolic conversion to form active therapeutic moieties.

BACKGROUND:

The use of intravenous bicarbonate in diabetic ketoacidosis (DKA) may be considered for patients with a pH less than 6.9 according to the American Diabetes Association. The impact of this therapy on resolution of acidosis in patients with DKA is unclear.

OBJECTIVE:

To determine whether the use of intravenous bicarbonate therapy was associated with improved outcomes in patients with severe DKA who were seen in the emergency department.

METHODS:

This review was conducted from 2007 to 2011 in the emergency department of a tertiary teaching hospital. Adults diagnosed with DKA with an initial pH less than 7.0 were included. Patients were stratified into 2 groups based on receipt of intravenous bicarbonate. The primary study outcome was time to resolution of acidosis, defined as return to pH greater than 7.2. Secondary outcomes included length of stay; continuous infusion insulin use; and intravenous fluid, potassium, and insulin requirements within the first 24 hours of hospital admission, beginning upon admittance to the emergency department. We also conducted a subgroup analysis of patients with an initial pH less than 6.9.

RESULTS:

There was no significant difference in time to resolution of acidosis (8 hours vs 8 hours; p = 0.7) or time to hospital discharge (68 hours vs 61 hours; p = 0.3) between patients who received intravenous bicarbonate (n = 44) compared with those who did not (n = 42). The median dose of intravenous bicarbonate was 100 mEq (100-150) for patients who received intravenous bicarbonate. Insulin and fluid requirements in the first 24 hours were significantly higher in patients who received intravenous bicarbonate compared with those who did not (100 units vs 86 units; p = 0.04 and 7.6 L vs 7.2 L; p = 0.01, respectively). There was no significant difference in hours of continuous insulin infusion (27 hours vs 26 hours; p = 0.09) or potassium requirements in the first 24 hours of hospital stay (135 mEq vs 120 mEq; p = 0.84).

CONCLUSIONS:

Intravenous bicarbonate therapy did not decrease time to resolution of acidosis or time to hospital discharge for patients with DKA with an initial pH less than 7.0.

OBJECTIVE:

To evaluate the efficacy and safety of aclidinium bromide, a novel, long-acting inhaled muscarinic receptor antagonist approved by the Food and Drug Administration (FDA) in July 2012, as a treatment in the management of moderate to severe chronic obstructive pulmonary disease (COPD).

DATA SOURCES:

Literature was identified through PubMed/MEDLINE (2000-March 2013) and International Pharmaceutical Abstracts using the search terms aclidinium, COPD, chronic bronchitis, emphysema, anticholinergic, and muscarinic antagonist. In addition, US government websites, including fda.gov and clinicaltrials.gov, were reviewed for pertinent information. Forest Laboratories, Inc provided previously unpublished clinical trial data. All reference citations from identified publications were reviewed for possible inclusion.STUDY SELECTION AND

DATA EXTRACTION:

All identified Phase 1, 2a, 2b, and 3 studies evaluating the safety and efficacy of aclidinium bromide were reviewed.

DATA SYNTHESIS:

Once- and twice-daily aclidinium bromide was assessed for efficacy and safety in patients with moderate to severe COPD. In comparison to placebo, aclidinium significantly improves trough and peak forced expiratory volume in 1 second (FEV1). Significant increases in trough and peak FEV1 were sustainable for up to 64 weeks. In addition to improvement in trough and peak FEV1, twice-daily aclidinium 400 μg induced clinically meaningful improvements in the health status of patients with moderate to severe COPD. Aclidinium was generally well tolerated, with headache, cough, diarrhea, and nasopharyngitis the most common treatment-related adverse effects noted in clinical trials. Aclidinium did not demonstrate a difference in the incidence of systemic anticholinergic-associated adverse effects in comparison to placebo or active comparator.

CONCLUSIONS:

Aclidinium bromide is a novel, inhaled, long-acting anticholinergic that, when administered at the FDA-approved dose, safely produces clinically and statistically significant bronchodilation and improves health status in patients with moderate to severe COPD. Long-term clinical trials assessing the efficacy and safety of aclidinium are warranted.