Julie A. Murphy

Levetiracetam Use in Pregnancy

Objective: To review data evaluating levetiracetam management of epilepsy during pregnancy. Data Sources: A literature search of PubMed (1966–June 2009) was performed using the terms pregnancy, epilepsy, levetiracetam, and anticonvulsants. Bibliographies of all articles retrieved were reviewed to identify additional relevant articles. Study Selection and Data Extraction: All studies including humans and published in English with data describing levetiracetam management during pregnancy were included. Data Synthesis: The pharmacokinetic studies included in this review demonstrate that the clearance of levetiracetam increases during pregnancy, particularly during the third trimester, which subsequently leads to decreased serum levetiracetam concentrations. The increase in clearance is most likely due to an increase in renal blood flow. The teratogenic studies included in this review included a total of 147 patients. Of these patients, 2% experienced a major congenital malformation (MCM) and 4.8% experienced a minor anomaly. All of the patients who had either an MCM or a minor anomaly were receiving antiepileptic drug (AED) polytherapy. It was unknown whether 10.9% of the 147 patients discussed were receiving levetiracetam monotherapy or AED polytherapy. None of the published literature assessed adherence to AED therapy. Folic acid supplementation was addressed in only one of the case series presented. Conclusions: If levetiracetam is used during pregnancy, women should receive adequate amounts of folic acid (0.4–5 mg/day) and serum concentrations of levetiracetam should be determined before conception if possible and during each trimester, especially during the middle of the third trimester, to assess therapeutic concentrations. The dose may need to be increased during the third trimester to provide concentrations consistent with those before conception. Patients should be informed that there appears to be a small chance of malformations with levetiracetam, but that the data are limited.

Lacosamide: An Adjunctive Agent for Partial-Onset Seizures and Potential Therapy for Neuropathic Pain:

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of lacosamide, a new agent for use as adjunctive treatment in partial-onset seizures and a potential agent for treatment of neuropathic pain. Data Sources: A MEDLINE search (1966–July 2009) was conducted using the key words lacosamide, harkoseride, SPM-927, ADD-234037, epilepsy, anticonvulsant, and neuropathic pain. Bibliographies of all articles retrieved were also reviewed. Study Selection and Data Extraction: All studies including humans and published in English with data describing lacosamide for the adjunctive treatment of partial-onset seizures and for treatment of neuropathic pain were reviewed. Data Synthesis: Lacosamide is a functionalized amino acid molecule that selectively enhances the slow inactivation of voltage-gated sodium channels and interacts with the collapsin-response mediator protein-2. With its bioavailability of approximately 100%, minimal protein binding, and few drug–drug interactions, lacosamide has a favorable pharmacokinetic profile. Recent data suggest that lacosamide may have a role as adjunctive treatment of partial-onset seizures. Open-label studies showed a 14-47% reduction in seizure frequency, while placebo-controlled trials demonstrated a 26-40% reduction in seizure frequency. The 50% responder rates ranged from 32.7% to 41.2% with varying doses of lacosamide. Although lacosamide use is not approved by the Food and Drug Administration for treatment of neuropathic pain, studies demonstrated reductions of 2.01–3.60 in pain scale scores. The most common adverse effects, occurring in greater than 10% of subjects in the clinical trials, include arthralgia, ataxia, blurred vision, diplopia, dizziness, fatigue, headache, injection site pain (only in intravenous studies), nausea, tremor, upper respiratory tract infection, and vomiting. Conclusions: Lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures. Its exact role in the treatment of neuropathic pain needs to be determined.

Retigabine (ezogabine) as add-on therapy for partial-onset seizures: an update for clinicians

Objective: The present study reviewed the pharmacology, pharmacokinetics, efficacy, and safety of retigabine (ezogabine), a potential agent for use as adjunctive treatment in refractory partial-onset seizures. Methods: A MEDLINE search (1966–May 2011) was conducted using the key words retigabine, ezogabine, D-23129, epilepsy, and anticonvulsant. Bibliographies of all articles retrieved were also reviewed. All studies including humans and published in English with data describing retigabine for the adjunctive treatment of partial-onset seizures were reviewed. Results: Retigabine has been shown to interact with the KCNQ2/KCNQ3 subunits of the potassium channels, GABAA receptors, and weakly block sodium and calcium channels. Retigabine is 50–60% bioavailable, metabolized by N-glucuronidation and N-acetylation, 80% protein bound, and has few drug–drug interactions. Recent data suggest that retigabine may have a role as adjunctive treatment for refractory partial-onset seizures. Placebo-controlled trials demonstrated a 23.4–44.3% reduction in seizure frequency with 50% responder rates ranging from 23.2% to 47.0% with varying doses of retigabine. The most common adverse effects, occurring in greater than 10% of subjects in the clinical trials, include abnormal gait, confusion, dizziness, fatigue, headache, nausea, somnolence, speech disorder, tremor, urinary tract infection, and blurred vision. Conclusions: Retigabine is a promising agent for adjunctive treatment of refractory partial-onset seizures.

Vortioxetine for the Treatment of Depression

Objective: To evaluate the clinical literature and potential clinical role of vortioxetine (Brintellix) for the treatment of major depressive disorder (MDD). Data Sources: A MEDLINE search (1966-February 2014) was conducted using the search terms vortioxetine, Lu AA21004, and depression. Bibliographies of all articles retrieved were also reviewed. All references included were published between 1999 and 2014. Study Selection/Data Extraction: All studies that included humans and were published in English, with data describing vortioxetine for the treatment of MDD, were reviewed. Data Synthesis: Vortioxetine is a novel multimodal antidepressant agent, which inhibits the 5-HT transporter protein, acts as a 5-HT3 antagonist, 5-HT1A receptor agonist, 5-HT7 receptor antagonist, and a partial agonist of the 5-HT1B receptor. It has been studied in 10 short-term (6-8 weeks), 1 relapse-prevention, and 3 long-term extension trials. Vortioxetine demonstrated efficacy in reducing Montgomery-Asberg Depression Rating Scale or Hamilton Rating Scale for Depression scores in 6 of the short-term trials. The proportion of individuals who responded to treatment and achieved remission increased over time in all 3 long-term trials. The most common adverse effects, consistently reported by >10% of individuals in the clinical trials include nausea and headache. Conclusions: Vortioxetine is an effective agent for the treatment of MDD, but it does not have any clear advantages over other available treatment options.

Lacosamide and epilepsy.

We will review all available studies on the use of lacosamide in the treatment of partial‐onset seizures. The available evidence includes two open‐label studies and three randomized controlled trials evaluating the safety and efficacy of oral lacosamide. One open‐label study and one randomized controlled trial evaluating the safety and tolerability of intravenous lacosamide was also identified. Lacosamide was found to be efficacious with significant reduction in seizure frequency dosed 400–600 mg daily. Moreover, its adverse drug effects were mild and infrequently reported in the literature. Findings suggest that lacosamide is an effective agent for adjunctive treatment of refractory partial‐onset seizures.

Evaluation of education on the appropriate use of vitamin k in warfarin reversal in adult inpatients.

Purpose Vitamin K (phytonadione) is a commonly used first-line reversal agent for vitamin K antagonist (VKA) therapy in patients presenting with a supratherapeutic international normalized ratio (INR) with or without significant bleeding or in patients with a therapeutic INR in need of surgery. The purpose of this study was to determine the impact of education on the appropriate use of vitamin K for VKA reversal. Methods Data were collected on patients admitted to a community teaching hospital during February 2010 (pre-education group). These data were analyzed to determine the most common guideline deviations in vitamin K use. Following this analysis, pharmacist education took place in the form of in-service presentations; a protocol, including a guideline-based dosing table, was developed to assist pharmacists in evaluating vitamin K therapy. Data were then collected on patients admitted during February 2011 (post-education group). Results Forty patients and 47 vitamin K administrations were included in the pre-education group, and 34 patients and 49 vitamin K administrations were included in the post-education group. The number of patients with appropriate vitamin K administrations improved after pharmacist education (25% pre-education vs 55.8% post-education; P = .01). Whereas 27.6% of individual vitamin K administrations were appropriate in the pre-education group, this increased to 63.2% in the post-education group (P = .04). Conclusion Education techniques on the appropriate use of vitamin K for VKA reversal significantly improved compliance with standards of care for proper use of vitamin K. Additional education sessions are necessary to further increase compliance with standards of care and subsequently optimize patient care.

Managing the residency scramble.

The American Society of Health-System Pharmacists Resident Matching Program offered 1951 postgraduate year 1 (PGY1) pharmacy residency positions for the 2010–2011 residency year to 2915 participating PGY1 applicants.[1][1] After results for the match were released, 1801 applicants matched with an

Potential short-term use of oral cladribine in treatment of relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system. The clinical course of MS varies among patients. Currently, interferon (IFN) products, including IFN β-1a administered intramuscularly or subcutaneously and IFN β-1b subcutaneously, glatiramer acetate, natalizumab, and mitoxantrone are approved disease-modifying therapies for the treatment of relapsing-remitting MS. Cladribine, also known as 2-chlorodeoxyadenosine, is a synthetic adenosine deaminase-resistant purine nucleoside analog that preferentially depletes lymphocyte subpopulations. This sustained effect on lymphocytes is advantageous for patients with MS. CLARITY (CLAdRIbine Tablets Treating MS OrallY), a Phase III trial, has demonstrated that short-term oral cladribine decreases relapse rates and risk of disability progression in comparison with placebo. Cladribine was well tolerated in the study, with the most common adverse effects being headache, nausea, upper respiratory tract infections, and lymphocytopenia. An ongoing study is evaluating the efficacy and safety of the combination of oral cladribine and IFN-β products. A further ongoing study is examining the use of oral cladribine in clinically isolated syndrome and time to conversion to MS. Although the results of CLARITY are promising, the exact role of oral cladribine may be better defined with the completion of ongoing studies.

Evidence Based Review of Pharmacotherapy for Opioid-Induced Constipation in Noncancer Pain:

Objective: To summarize and evaluate the existing literature regarding medications to treat opioid-induced constipation (OIC) in patients with chronic noncancer pain (CNCP). Data Sources: PubMed, EMBASE, and Web of Science were searched using the following terms: constipation, opioid, chronic, pain, noncancer, nonmalignant, methylnaltrexone, alvimopan, lubiprostone, naloxegol, and naldemedine. Study Selection and Data Extraction: The search was limited to randomized controlled trials reporting human outcomes. Data extracted included the following: study design, population, intervention, control, outcomes related to OIC and safety, and potential biases assessed using Cochrane Collaboration’s Risk of Bias Assessment Tool. Data Synthesis: After assessment, 16 of the 190 studies were included: methylnaltrexone (n = 4), naloxegol (n = 3), naldemedine (n = 2), lubiprostone (n = 3), and alvimopan (n = 4). Lubiprostone was the only nonperipherally acting µ-opioid receptor antagonist included. Only 1 study (naloxegol) used “usual care” (nonstudy laxative) rather than placebo as a comparator. Placebo-controlled trials demonstrated benefit for methylnaltrexone, naloxegol, naldemedine, and lubiprostone, with conflicting evidence for alvimopan. No data suggest that one agent is better than another. Overall risk of bias across all studies was low to moderate. Conclusions: With risk of bias determined to be low to moderate, published data to date suggest that methylnaltrexone, naloxegol, and naldemedine may be appropriate to treat OIC in patients with CNCP.

ACE Inhibitor-Induced Angioedema of the Small Bowel: A Case Report and Review of the Literature:

Angiotensin-converting enzyme (ACE) inhibitors are known to cause angioedema. Most ACE inhibitor-induced angioedema cases describe swelling in the periorbital region, tongue, and pharynx. We describe a case of a 62-year-old female with presumed angioedema of the small bowel after more than a 2-year history of lisinopril use (with no recent changes in her dose of 40 mg orally twice daily). The patient presented with nausea and intermittent left middle and upper quadrant abdominal pain and denied history of angioedema or swelling with any medications or any history of abdominal pain. On physical examination, bowel sounds, liver, and spleen were normal. Laboratory tests revealed leukocytosis (15 400 per mm3) and normal complement 1 esterase inhibitor levels. Abdominal computed tomography (CT) showed segmental small bowel thickening and edema with ascites and surrounding inflammatory changes. There was no lymphadenopathy, obstruction, or ileus. Two days after discontinuation of the lisinopril, the patient reported improvement in symptoms. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the development of angioedema of the small bowel and the lisinopril therapy. This case highlights the unique manner in which ACE inhibitor-induced angioedema may present. A review of published cases of ACE inhibitor-induced angioedema of the small bowel is provided.