Geoffrey C. Wall

Oral versus Topical NSAIDs in Rheumatic Diseases A Comparison

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs worldwide and are responsible for approximately one-quarter of all adverse drug reaction reports. NSAIDs are widely prescribed for patients with rheumatic disease — a population at increased risk for serious gastrointestinal (GI) complications. Topical administration of NSAIDs offers the advantage of local, enhanced drug delivery to affected tissues with a reduced incidence of systemic adverse effects, such as peptic ulcer disease and GI haemorrhage.NSAIDs administered topically penetrate slowly and in small quantities into the systemic circulation; bioavailability and maximal plasma NSAID concentration after topical application are generally less than 5 and 15%, respectively, compared with equivalent oral administration. Product formulation may have a dramatic impact, not only on absorption rates but also on penetration depth. Compared with oral administration, topical application leads to relatively high NSAID concentrations in the dermis. Concentrations achieved in the muscle tissue below the site of application are variable, but are at least equivalent to that obtained with oral administration. NSAIDs applied topically do reach the synovial fluid, but the extent and mechanism (topical penetration versus distribution via the systemic circulation) remain to be determined. In addition, marked interindividual variability was noted in all studies; percutaneous absorption may be strongly influenced by individual skin properties.In general, interpretation of clinical studies measuring efficacy of topical NSAIDs in rheumatic disease states is difficult because of a remarkably high placebo response rate, use of rescue paracetamol (acetaminophen), and significant variability in percutaneous absorption and response rates between patients. Overall efficacy rates attributable to topical NSAIDs in patients with rheumatic disorders ranged from 18 to 92% of treated patients. Topically applied NSAIDs have a superior safety profile to oral formulations. Adverse effects secondary to topical NSAID application occur in approximately 10 to 15% of patients and are primarily cutaneous in nature (rash and pruritus at site of application). GI adverse drug reactions are rare with topically applied NSAIDs, compared with a 15% incidence reported for oral NSAIDs. Available clinical studies suggest, but do not document, equivalent efficacy of topical over oral NSAIDs in rheumatic diseases.

Comment: Drug-Drug Interaction Between Clopidogrel and the Proton Pump Inhibitors

Objective: To evaluate the interaction between clopidogrel and proton pump inhibitors (PPIs). Data Sources: Literature retrieval was accessed through PubMed (1980–January 2009), abstracts from 2008 American Heart Association and 2009 Society of Cardiovascular Angiography and Interventions Scientific Sessions, and media press releases using the terms clopidogrel, proton pump inhibitors, cytochrome 2C19, genetic cytochrome P450 polymorphisms, and drug interaction. In addition, reference citations from publications identified in the search were reviewed. Study Selection and Data Extraction: Relevant original research articles and review articles were evaluated. Articles were selected if they were published in English and focused on any of the key words or appeared to have substantial content addressing the drug interaction. Data Synthesis: Recent attention has been placed on a potential interaction observed between clopidogrel and the widely used PPIs. Preliminary evidence suggests that omeprazole interacts with clopidogrel, reducing clopidogrels antiplatelet effects as measured by various laboratory tests. Most data indicate that the interaction involves the competitive inhibition of the CYP2C19 isoenzyme. The interaction appears to be clinically significant, as several retrospective analyses have shown an increase in adverse cardiovascular outcomes when PPIs and clopidogrel are used concomitantly. However, this may not be a class effect. Conclusions: Available data suggest that omeprazole is the PPI most likely to have a significant interaction with clopidogrel. Further studies are needed to determine that an interaction between the other PPIs and clopidogrel does not exist. In situations in which both clopidogrel and a PPI are indicated, pantoprazole should be used since it is the PPI least likely to interact with clopidogrel.

Oral Aloe Vera–Induced Hepatitis

Objective: To report a case of possible oral aloe vera-induced hepatitis. Case Summary: A 73-year-old female was admitted to the hospital for acute hepatitis. Extensive laboratory testing did not reveal the cause of the patients disease. She was asked multiple times whether she was taking any home medications, which she initially denied. It was only after an extensive medication history done by a clinical pharmacist that the patient admitted to using oral aloe vera capsules for constipation. Upon discontinuation of the oral aloe vera, liver markers of hepatotoxicity returned to normal levels. Discussion: Herbal medications pose an increasing problem in patient safety, as the different types of these products and the number of patients who use them continue to grow. In the US, these products are not subject to the same regulatory scrutiny as prescription medications; thus, safety information can be difficult to obtain. In particular, hepatic toxicity due to herbal agents is poorly described in the medical literature. Aloe vera, often used topically for minor burns, can also be used orally as a laxative or an “anti-aging” agent. According to the Naranjo probability scale, the hepatotoxicity in this case was possibly related to ingestion of oral aloe vera. Additionally, using the Roussel Uclaf Causality Assessment Method for determining drug hepatotoxicity, the patients symptoms were scored as probably caused by oral aloe vera. The more conservative designation was used in our report. Conclusions: With the widespread use of oral aloe vera and other herbal products, clinicians faced with a case of acute hepatitis that is not readily diagnosed should question patients about herbal use.

Effects of antidepressants in patients with irritable bowel syndrome and comorbid depression

BACKGROUND Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that affects up to 15% of community dwelling individuals. Psychiatric comorbidities, particularly symptoms of major depressive disorder (MDD), occur in up to 90% of patients with IBS. OBJECTIVE This article reviews the available literature on the use of antidepressants for both IBS and psychiatric depressive symptoms in patients with IBS. METHODS MEDLINE and International Pharmaceutical Abstracts (both, 1980-May 2010) were searched for English-language publications that involved antidepressant treatment of MDD in patients with IBS. The search terms were depression, irritable, bowel, treatment, and functional. The reference lists of key articles were searched for additional pertinent articles. Randomized controlled trials published in the past 10 years were given priority. RESULTS Of 46 articles identified by the literature search, 11 were included in the review: 4 studies of selective serotonin reuptake inhibitors (SSRIs), 4 of tricyclic antidepressants (TCAs), 1 comparing an SSRI and a TCA, 1 of the serotonin-norepinephrine reuptake inhibitor duloxetine, and a case report involving the tetracyclic antidepressant mirtazapine. Most of the identified studies excluded patients with a diagnosis of depression and/or anxiety. No controlled studies were identified in which the primary outcome was objective assessment of MDD symptoms in patients with IBS. Two of the SSRI studies, one of citalopram and the other of paroxetine, reported approximately 50% improvement in IBS symptoms (both studies, P = 0.01); the study of paroxetine reported a 30% improvement in scores on the Beck Depression Inventory (P = 0.01). The 2 studies of fluoxetine found no statistically significant benefit on IBS symptoms. TCAs were reported to have benefits on IBS symptoms, predominantly diarrhea. Only one of the TCA studies examined and found a significant improvement in depressive symptoms with desipramine 150 mg/d (P = 0.025). Both the open-label study of duloxetine and the case report involving mirtazapine found improvements in IBS and psychiatric symptoms. CONCLUSIONS The evidence for the benefit of antidepressant treatment in patients with IBS and comorbid depression was limited and contradictory. Some anti-depressants may help symptoms of IBS, although whether the same drugs and doses are associated with improvements in concomitant depressive symptoms remains to be elucidated.

Pediatric Constipation Therapy Using Guidelines and Polyethylene Glycol 3350

OBJECTIVE To review current guidelines on the treatment of functional constipation in pediatric patients, with an emphasis on the role of polyethylene glycol 3350 (PEG 3350). DATA SOURCES Primary medical literature published in English was identified by MEDLINE search (1980—May 2003). STUDY SELECTION AND DATA EXTRACTION Recently published treatment guidelines relating to pediatric functional constipation and its pharmacotherapy are assessed and compared. Published trials evaluating PEG 3350 in pediatric subjects are discussed and their results applied to the clinical role and use of this new agent. DATA SYNTHESIS Constipation is a common disorder among children. A number of factors may play a role. A variety of medications are commonly used for this disorder, although few treatments have undergone evaluation by controlled clinical trials. Consensus guidelines recommend either osmotic laxatives, mineral oil, or their combination for maintenance treatment in concert with patient and parental education and behavioral training. PEG 3350 solution (MiraLax) has been shown in recent clinical studies to be an effective maintenance treatment for pediatric constipation. CONCLUSIONS PEG 3350 is an effective and well-tolerated treatment choice for pediatric constipation, especially as an adjunct to education and behavioral training. PEG 3350 is an option for children with constipation who have failed or are intolerant of other pharmacotherapies. THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-04-016-H01

Verapamil Toxicity Resulting from a Probable Interaction with Telithromycin

OBJECTIVE: To report a case of hypotension and bradyarrhythmia caused by verapamil toxicity in a patient prescribed telithromycin. CASE SUMMARY: A 76-year-old white woman receiving verapamil 180 mg/day for hypertension experienced a sudden onset of shortness of breath and weakness and was found to be profoundly hypotensive and bradycardic, with a systolic blood pressure of 50–60 mm Hg and a heart rate of 30 beats/min. She had been taking telithromycin 800 mg/day for 2 days previously for acute sinusitis. The patient was treated with crystalloids, vasopressors, and transvenous pacing. Approximately 72 hours after admission, her blood pressure and heart rate rapidly returned to normal, and she was discharged several days later. DISCUSSION: Telithromycin is a known substrate of the CYP3A4 system, and several pharmacokinetic interactions can occur by displacement of other drugs from this system. Verapamil is metabolized through several cytochrome P450 isoenzyme systems. Although there are no previous reports of an interaction between these drugs, other possible causes for the patients symptoms were excluded and the diagnosis of a probable interaction between verapamil and telithromycin leading to verapamil toxicity was made. CONCLUSIONS: Telithromycin is a ketolide antibiotic approved for treatment of respiratory tract infections and acute sinusitis. The potential for clinically significant drug interactions should be considered before using this agent, especially in patients taking other drugs that are metabolized through the CYP3A system. Caution should be exercised when considering the use of this antibiotic in patients receiving verapamil.

A Faculty-Led Mock Residency Interview Exercise for Fourth-Year Doctor of Pharmacy Students:

Purpose: To determine whether a faculty-led mock-interview activity enhanced pharmacy student preparation for the residency interview process and increased match rates. Methods: Twenty-eight doctor of pharmacy students volunteered for a 40-minute mock-interview session with 2-person faculty teams. A standard roster of 12 interview questions was derived from published literature and the faculty members’ experience. Feedback on the student’s interview performance was provided verbally during the session. Following the interview, students were given a 2-part survey instrument. The first part of the survey was administered immediately following the mock-interview session and the second part was administered after the standard date for residency program results (known as “Match Day”). Participant match rates were compared to American Society of Health-System Pharmacists (ASHP) national rates. Results: 82.5% (23 of 27) of students in the mock-interview group matched a postgraduate year 1 (PGY1) program. Compared to national rates (61.9%), more students in our surveyed mock-interview group matched a PGY1 residency (P = .015; odds ratio [OR] 3.546, 95% CI 1.161-12.116). Conclusions: Higher match rates were seen in the students completing the mock residency interview compared to ASHP national rates. In general, students completing the mock interview found the process helpful and felt better prepared for their residency interviews.

Gastroparesis-Associated Refractory Nausea Treated with Aprepitant

Objective: To report a case of refractory nausea in a patient with idiopathic gastroparesis successfully treated with aprepitant. Case Summary: A 41-year-old female with idiopathic gastroparesis demonstrated by a delayed gastric emptying time experienced significant nausea, vomiting, and abdominal pain. This resulted in numerous hospital admissions and regular outpatient intravenous fluid administration. Over a 3-year period the patient had been treated with numerous agents for nausea and vomiting, including metocfopramide 10 mg 3 times daily, ondansetron 8 mg 2 times daily, and promethazine (various doses from 12.5 to 25 mg orally up to 3 times daily). No treatment tried was either tolerated or effective. As a last option before considering gastric pacing the patient was started on aprepitant 40 mg daily. The patient had a dramatic response to aprepitant and reported that her nausea had decreased significantly after 48 hours of starting the medication (2 doses). She was able to tolerate oral feeding and her need for outpatient intravenous hydration abated. Over the course of 2 months while using aprepitant her gastroparesis symptoms continued to improve. She reported no adverse effects attributable to aprepitant. After the first 2 months of aprepitant treatment, the patient was unable to continue the medication due to cost. Although her symptoms did worsen after discontinuation, they did not return to their initial severity. At 4 months after the trial of aprepitant, she continued to have improved symptoms. She claimed not to have daily nausea or vomiting, but still required high-dose promethazine and occasional outpatient intravenous fluids. At that point, she had gained 7.2 kg from the time that she had started aprepitant. Discussion: Aprepitant, a neurokinin-1 receptor antagonist, is approved in the US for nausea and vomiting associated with surgery and cancer chemotherapy. To our knowledge, this is the second reported case of its use in gastroparesis-induced nausea. Our patient reported relief of nausea and vomiting despite existing evidence showing that aprepitant has no significant effect on accelerating gastric emptying. Despite its acquisition cost, our patient avoided hospital admission and the administration of intravenous hydration, suggesting aprepitant may be cost-effective in this case. Conclusions: Aprepitant may have some utility in treating refractory nausea caused by gastroparesis. This case suggests that the drugs antiemetic effect may be successfully used in areas not approved by the Food and Drug Administration. A controlled trial examining aprepitant in patients with such challenging clinical conditions may be warranted.

Pharmacotherapy of xerostomia in primary Sjögren's syndrome

We reviewed the current literature concerning the treatment of dry mouth in patients with primary Sjögrens syndrome (SJS). Computerized MEDLINE search engines were used with the terms Sjögren, xerostomia, dry mouth, and treatment. References from key articles were searched, and all pertinent articles were procured and reviewed. Primary SJS is an uncommon but serious disorder. Dry mouth caused by SJS can lead to dental erosion, dysphagia, oral infections, and discomfort. Preventing these complications is of paramount importance. Pharmacotherapy is limited to topical saliva substitutes, which are considered first, followed by muscarinic stimulators such as pilocarpine or cevimeline, if required. Immunosuppressive therapy is being investigated. Patients should have regular oral and dental examinations to detect complications. Satisfaction with the efficacy and tolerability of treatment should be monitored frequently. The clinician may have to use a trial‐and‐error approach to determine a successful regimen.

Evaluation of total-dose iron sucrose infusions in patients with iron deficiency anemia

PURPOSE The safety and efficacy of a total-dose iron sucrose infusion protocol used in a large, tertiary care teaching hospital were studied. METHODS Nondialysis-dependent patients ages 18 years or older who received > or =250 mg of iron sucrose as a single i.v. infusion between January 2005 and January 2007 were eligible for study inclusion. The protocol for total-dose iron sucrose infusion was the same for all patients. The total dose of iron sucrose for each patient was calculated using an equation that included the desired hemoglobin (Hb) value, observed Hb level, ideal body weight, and sex. The calculated dose was divided into portions, rounded to the nearest 250 mg, and administered over four hours every other day. Outcomes measured included Hb, transferrin saturation, and serum ferritin values. RESULTS A total of 26 patients met the inclusion criteria. The mean +/- S.D. Hb concentration before total-dose iron sucrose infusion was 9.37 +/- 0.9 g/dL, and the mean +/- S.D. corpuscular volume was 75 +/- 7.1 mum(3). The mean +/- S.D. postinfusion Hb concentration for 19 patients for whom follow-up Hb levels were available was 11.4 +/- 1.2 g/dL, significantly higher than the 9.45 +/- 0.8 g/dL measured before the first infusion (p = 0.03). No significant adverse effects were reported in 47 of 49 infusions, with 2 patients experiencing mild nausea. CONCLUSION A treatment protocol consisting of alternate-day total-dose iron sucrose infusions was well tolerated and appeared to be effective in improving Hb concentrations in patients with iron deficiency anemia and without chronic kidney disease.