2 pharmacy and wellness review november 2010

Volume one, Issue two November 2010

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Review

A New Horizon: Emergency Department Pharmacy Practice Amanda C. McDavid, fifth-year pharmacy student from Burke, Va.

A Review of Rivaroxaban, an Oral Anticoagulant

Lindsey A. Hallman, fifth-year pharmacy student from Olmsted Falls, Ohio; Chad A. Rounds, fifth-year pharmacy student from Fort Wayne, Ind.; Rebecca A. Carey, sixth-year pharmacy student from Trenton, Mich.; Nicole R. Hume, sixth-year pharmacy student from London, Ohio; Ryan W. Naseman, sixth-year pharmacy student from Anna, Ohio; Karen L. Kier, PSPh ’82, Ph.D., MSc., RPL

An Update on Exenatide and Liraglutide for Type 2 Diabetes Mellitus

Sarah M. Webb, fifth-year pharmacy student from Edison, Ohio; Lacey A. Shumate, fifth-year pharmacy student from Bucyrus, Ohio; Ashley M. Overy, fifth-year pharmacy student from Grafton, Ohio; Ashley E. Lehnert, sixth-year pharmacy student from Ashtabula, Ohio; Monica A. Weisenberger, sixth-year pharmacy student from Columbus, Ohio; David R. Bright, assistant professor of pharmacy practice; Whitney N. Detillion, sixth-year pharmacy student from Portsmouth, Ohio

Use of Gastric Bypass Surgery for the Treatment of Type 2 Diabetes Mellitus

Editorial Board: Editor-in-chief Maggie Allen Managing Editor Lyndsi Kill Content Editor Kate Klyczek Lead Editors Whitney Detillion Ryan Naseman

Kaitlin A. Sanders, fifth-year pharmacy student from Kendallville, Ind.; Jenna L. Schaffner, fifth-year pharmacy student from North Canton, Ohio; Leslie M. Hart, sixth-year pharmacy student from Cooperstown, Pa.; Whitney N. Detillion, sixth-year pharmacy student from Portsmouth, Ohio; Anne Gentry, PharmD

Formatting Editor Emily Miller

Preparing for the Genomic Age: Thiopurine S-Methytransferase Polymorphism

Web site Editor Christine Allen

Hilary Stewart, fifth-year pharmacy student from Centerburg, Ohio; Lisa Berni, fifth-year pharmacy student from Dennison, Ohio; Tyler Bulcher, sixth-year pharmacy student from Powell, Ohio; Joel Rittenhouse, sixth-year pharmacy student from Portland, Ind.; Ryan W. Naseman, sixth-year pharmacy student from Anna, Ohio

Prescription Drug Abuse: The Pharmacist’s Occupational Hazard

Brieann J. Miller, fifth-year pharmacy student from Fairfield, Ohio; Cynthia C. Nguyen, sixth-year pharmacy student from Troy, Ohio; Joshua P. Stevens, sixth-year pharmacy student from Milan, Ohio; Nicholas J. Edmonds, fifth-year pharmacy student from North Olmsted, Ohio; Ryan W. Naseman, sixth-year pharmacy student from Anna, Ohio; Michael M. Milks, BSPh ’76, Ph.D., R.Ph., professor of pharmacology Charles J. Broussard R.Ph., M.Ed.

A Novel Approach to Treating Alzheimer’s Disease

Circulation Editor Christopher D. Westrick

Faculty Advisors: Dr. Anne F. Gentry, PharmD Dr. Kelly M. Shields, PharmD Dr. Karen L. Kier, BSPh ’82, Ph.D., R.Ph., BCPS

Kristen Quertinmont, fifth-year pharmacy student from Carmel, Ind.; Breanne Rizzo, pharmacy student from Columbus, Ohio; Caitlin Swann, fifth-year pharmacy student from Strongsville, Ohio; Lindsay Coram, sixth-year pharmacy student from Eastlake, Ohio; Mary Klein, sixth-year pharmacy student from Mount Cory, Ohio; Whitney Detillion, sixth-year pharmacy student from Portsmouth, Ohio

The Importance of Early Diagnosis and Treatment of Postpartum Depression

Sarah E. Drake, fifth-year pharmacy student from Fairfield, Ohio; Alison L. Huet, fifth-year pharmacy student from New Kensington, Pa.; Tana M. Peterman, fifth-year pharmacy student from Jacksonville, N.C.; Jamie L. Drees, sixth-year pharmacy student from Canal Winchester, Ohio; Robert D. Raiff, sixth-year pharmacy student from Westlake, Ohio

Osteoarthritis: Natural Supplements for Joint Health

Katherine Salay, fifth-year pharmacy student from Brecksville, Ohio; Kimberly Gathers, fifth-year pharmacy student from Mercer, Pa.; Lindsey McClish, fifth-year pharmacy student from Bellville, Ohio; Lisa Vranekovic, sixth-year pharmacy student from Mentor, Ohio; Kristin Seaman, sixth-year pharmacy student from Shiloh, Ohio; Ryan W. Naseman, sixth-year pharmacy student from Anna, Ohio

Good Publication Practice Guidelines: Integrity, Completeness, Transparency, Accountability and Responsibility Anne Gentry, PharmD Assistant director of the Drug Information Center Advisor for The Pharmacy and Wellness Review In this second issue of The Pharmacy and Wellness Review, under the direction of Editor-in-Chief Maggie Allen, a sixth-year pharmacy student from Olean, N.Y., a select group of Ohio Northern University pharmacy students display their research and professional-writing skills.

Through participation on The Pharmacy and Wellness Review staff and editorial board, ONU pharmacy students learn the importance of author responsibility in the interpretation and communication of medical research. Just as they will experience in practice someday, their work is the product of collaboration with other individuals.

The International Society for Medical Publication Professionals has developed the Good Publication Practice (GPP2) Guidelines to assist individuals and organizations in maintaining ethical practices and complying with current industry requirements.1 These guidelines apply to peer-reviewed journal articles and presentations at scientific meetings.

The Pharmacy and Wellness Review endorses and utilizes these guidelines for our publication.

GPP2 checklist for articles and presentations1 Integrity • Accurate, objective, balanced writing • Full access to data for authors and contributors • Absence of duplicative publications • Honest attribution of authorship Completeness • Clear description of research hypotheses • Reporting the detail required to ensure unbiased presentation • Complete and honest reference to related work • Use of unique trial identifiers • Discussion of limitations of study design and findings • Making public or publishing results regardless of outcome Transparency • Making clear sources of funding • Disclosure of potential conflicts of interest • Acknowledging individuals who have made significant contributions, including, but not limited to, those made by authors, and by description of these contributions • Recognizing the contributions of research sponsors Accountability • Being accountable for the work and, in the case of authors and presenters, taking public responsibility for the work • Assigning a guarantor Responsibility • Making public or publishing results in a timely manner • Respecting intellectual property • Respecting the responsibilities of contributing individuals and organizations for good publication practice Reference: Graf C, Battisti WP, Bridges D, et al for the International Society for Medical Publication Professionals. Good publication practice for communicating company-sponsored medical research: the GPP2 guidelines. BMJ 2009;339:b4330.

Pharmacy Practice

A New Horizon: Emergency Department Pharmacy Practice Amanda C. McDavid, fifth-year pharmacy student from Burke, Va.

With an estimated 3.8 million preventable adverse events each year, the emergency department (ED) has the highest rate of preventable adverse drug events (ADEs) of all hospital areas. In fact, the rate of medication errors resulting in harm to ED patients is more than double that of inpatients.1 Despite this striking data, emergency departments are among the least likely of all hospital settings to have a dedicated clinical pharmacist on the patient care team. In 2008, a mere 9.3 percent of hospitals had a formal policy requiring pharmacist review of ED medications before administration, and even fewer (6.8 percent) had decentralized pharmacists in the department.2 A variety of factors contribute to the error-prone nature of the emergency department. Although recent years have seen an increase in ED visits overall, the number of EDs in the United States has declined, leading to overcrowding.3 Additionally, providers must contend with a wide range of diseases and medications – usually with minimal to no patient history – in an often chaotic environment, treating multiple patients simultaneously. These items, combined with the fast pace and intense pressure of the ED, form a recipe for error. That risk is further compounded by the lack of pharmacist review.

Introduction of clinical pharmacy services to intensive care units and internal medicine teams has reduced preventable ADEs by a substantial 66 percent and 78 percent, respectively.4 Pharmacists have the potential to similarly decrease ADEs and improve patient outcomes in the emergency department by a variety of means. These include traditional roles, such as involvement in resuscitation teams and management of drug inventory, along with more novel methods, such as provision of specialized clinical and ambulatory care services.4 The pharmacist’s double-check is especially vital to ED staff in the context of codes, cardiac alerts and traumas, in which critical decisions are made with limited time. Pharmacists have been members of resuscitation teams since the 1970s.4 In addition to formal pharmacy education and post-graduate residencies, additional training in Advanced Cardiac Life Support, Pediatric Advanced Life Support, Hazmat Life Support, and others prepare the pharmacist to function effectively as part of resuscitation and critical care teams. The emergency pharmacist (EPh) anticipates, suggests, and prepares appropriate medications and doses for these critical patients. This allows for other staff to attend to tasks such as blood draws and intravenous line placement. The pharmacist also may assist with ventilation and cardiopulmonary resuscitation as needed.5 Consultation services are another valuable contribution the EPh makes to the patient care team. The EPh can recommend appropriate therapy for patients with renal or hepatic impairment, provide toxicology information for overdoses and poisonings, guide appropriate antibiotic selection, and participate in medical rounds. They promote adherence to National

Quality Indicators and encourage the use of evidence-based medicine.4 The physical presence of the pharmacist on the unit encourages communication, collaboration and trust between providers, allowing for optimal utilization of consultation services.5 Emergency departments with established EPh programs have reported promising results. In addition to cost savings, a perception of increased quality of care and medication safety among physicians and nurses has been described.1 Following implementation of clinical pharmacy services in one ED, a survey showed that 96 percent of the ED staff felt that the EPh was an integral part of the team, 85 percent felt the EPh should double-check all high-risk meds, and 99 percent of the staff felt the EPh improves the quality of care, including 100 percent of ED physicians.6 In 2009, 6.8 percent of EDs report having an emergency pharmacist on staff, an increase from 3.4 percent two years previously.2 Hospitals are headed in the right direction, but substantial room for improvement remains. With the support of organizations, including the American Society of Health-System Pharmacists, the Institute of Medicine, and the Agency for Healthcare Research and Quality, incorporation of emergency pharmacists into ED teams is bound to continue.4,6 Emergency pharmacists may reduce overall hospital costs, avoid medication errors, and improve patient outcomes.

The author wishes to acknowledge the assistance of Kyle Weant and Stephanie Baker of UK HealthCare for their review of the content of this article. Their expertise and guidance is very much appreciated.

1. Fairbanks, RJ. The Emergency Pharmacist: Safety Measure in Emergency Medicine. Justification Summary Document. Dec 2007. The Emergency Pharmacist Research Center. Available at www.emergencypharmacist.org/doc/toolkit%20page/Justification-REVISED.pdf 2. Pederson CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration-2008. Am J Health-Syst Pharm 2009; 66:926-46.

3. Hays, DP. Clinical Pharmacy Services in the Emergency Department.

Presented at American Society of Health-System Pharmacists Mid-Year Clinical Meeting, Anaheim, CA; Dec 2006. www.emergencypharmacist. org/doc/DPH_final.pdf 4. American Society of Health-System Pharmacists. ASHP statement on pharmacy services to the emergency department. Am J Health-Syst Pharm 2008; 65:2380–3.

5. Cohen V. Safe and Effective Medication Use in the Emergency Department. American Society of Health-System Pharmacists. Bethesda, MD 2009.

6. Fairbanks RJ, Hildebrand JM, Kolstee KE, Schneider SM, Shah MN. Medical and nursing staff value and utilize clinical pharmacists in the Emergency Department. Emerg Med J 2007; 24:716-719.

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A Review of Rivaroxaban, an Oral Anticoagulant Lindsey A. Hallman, fifth-year pharmacy student from Olmsted Falls, Ohio; Chad A. Rounds, fifth-year pharmacy student from Fort Wayne, Ind.; Rebecca A. Carey, sixth-year pharmacy student from Trenton, Mich.; Nicole R. Hume, sixth-year pharmacy student from London, Ohio; Ryan W. Naseman, sixth-year pharmacy student from Anna, Ohio; Karen L. Kier, PSPh ’82, Ph.D., MSc., RPL

Background In post-operative patients, limited mobility can lead to increased morbidity and mortality due to venous thromboembolism (VTE), which is a life-threatening complication consisting of either deep vein thrombosis (DVT) or pulmonary embolism (PE). Prophylaxis with anticoagulants is often recommended for this patient group for this reason.1-3 In general surgery patients without prophylaxis, DVT incidence is approximately 25 percent.3 Patients undergoing more mobility-limiting procedures, such as total hip or knee replacement surgery or hip fracture surgery, DVT rates are at rates of up to 35-60 percent. With regard to PE, prevalence varies greatly depending on the site of surgery but overall is an important consideration due to the high potential for patient harm. Without prophylaxis, general surgery patients have a PE incidence of 1.6 percent, with 0.9 percent fatality. With an increase in procedure complexity, PE incidence can go as high as 3.6-12.9 percent, such as in hip fracture surgery.1-4

The effectiveness of anticoagulation prophylaxis often is weighed against the safety risks and administration issues of available treatments, and these issues can leave physicians looking for better options.

As addressed in the previous issue of The Pharmacy and Wellness Review, development of new anticoagulation agents for prophylaxis of VTE has been underway as drug companies aim to create orally available agents that target the clotting cascade in specific ways to avoid undesired coagulation while minimizing patient bleeding risk.5 The goal of these new therapeutic agents is to ease patient administration and increase tolerability while being as effective or better than currently available agents in prevention of VTE. Specific targets for therapy include Factors IIa and Xa. Select anticoagulants showing promise in the pipeline include dabigatran, a direct thrombin (Factor IIa) inhibitor, which was discussed in a previous issue of The Pharmacy and Wellness Review (May 2010), and rivaroxaban, a direct Factor Xa inhibitor.

Dabigatran was recently given approval by the Food and Drug Administration (FDA). Rivaroxaban has been granted approval for use in both the European Union and Canada since September 2008.6 Rivaroxaban was submitted in July 2008 for U.S. FDA approval. It was approved by the FDA advisory committee but was denied by the FDA with a need for more information, which the manufacturer, Bayer, is preparing.3, 5, 6 Rivaroxaban is a competitive, selective and reversible Factor Xa inhibitor. The bioavailability is greater than 80 percent and is not affected by food, leading to a half-life of approximately nine hours, which may be prolonged in the elderly.7 Renal excretion accounts for two-thirds of elimination, while the rest is eliminated in the feces via P-glycoprotein and some hepatic metabolism by the CYP450 enzyme system. It is possible that inhibition of CYP3A4 could cause an increase in plasma levels. Rivaroxaban has a contraindication in renal failure (CrCl <30 ml/ min) due to lack of evidence. Early dose-finding studies in hip or knee replacement found rivaroxaban did not have a true dose-response relationship with regards to efficacy, but bleeding risk did increase

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proportionally with increases in dosage. The optimal dose was found to be between 5 and 20 mg, and rivaroxaban is available as a 10 mg tablet in countries where it is approved.

Efficacy Several trials concluded efficacy exists for regular clinical use of rivaroxaban in patients. The RECORD 1 and 4 trials had a primary efficacy composite endpoint of any DVT (proximal or distal), confirmed non-fatal PE, and all cause mortality during treatment.8,9 The RECORD 4 trial had 366 patients eligible for the efficacy analysis with symptomatic DVT during follow-up confirmed by venography or ultra-sound.9 Using the composite data, 44.3 percent of patients on enoxaparin 40 mg daily had some complication included in the composite endpoint. The 10 mg twice-daily dose of rivaroxaban did considerably better, with only 23.3 percent of patients having a complication (p=0.29). The 5 mg twice-daily rivaroxaban dose had similar efficacy to enoxaparin, with 40.4 percent having complications. Major VTE occurred in patients ranging from rates of 0-6.7 percent with various doses of rivaroxaban versus 4.3 percent with enoxaparin. All rivaroxaban dose-range groups investigated had efficacy similar to twice-daily enoxaparin beginning the day after surgery.

Alternatively, RECORD 1 compared 10 mg rivaroxaban to 40 mg enoxaparin in patients receiving VTE prophylaxis after hip arthroplasty and found rivaroxaban to be more efficacious than enoxaparin.8 At the end of the trial, 69 percent of 4,541 patients were included in the superiority analysis, with venography required for inclusion. The primary composite endpoint of complications occurred in 1.1 percent in the rivaroxaban group and 3.7 percent in the enoxaparin group (p < 0.001), with major VTE occurring in 0.2 percent of the rivaroxaban group contrasted with 2 percent of enoxaparin patients. Major bleeding was observed in 0.3 percent of the rivaroxaban group versus 0.1 percent with enoxaparin.

Another study, RECORD 2, looked at an extended duration of rivaroxaban versus short-term enoxaparin use for prevention of VTE after hip arthroplasty.10 This study used a modified intention-to-treat analysis for the primary efficacy of 864 patients in the rivaroxaban group and 869 patients in the enoxaparin group. The primary endpoint occurred in 2 percent of the rivaroxaban group and 9.3 percent in the enoxaparin group. The incidence of bleeding was similar in both groups (6.6 percent for rivaroxaban versus 5.5 percent with enoxaparin). Extended thromboprophylaxis was concluded to be more effective with rivaroxaban than short-term enoxaparin.

A trial independent of the RECORD series, known as the Einstein Study, was a randomized, dose-ranging, double-blind, open-labeled study that compared rivaroxaban to low molecular weight heparin (LMWH) and vitamin K antagonist (VKA) therapy per hospital protocol until an INR of 2-3 was reached in patients with acute symptomatic DVTs.11 Of the 543 patients in the study, 449 were eligible to be included in the per-protocol

November 2010

A Review of Rivaroxaban, an Oral Anticoagulant analysis. With a primary efficacy composite outcome of symptomatic recurrent DVT, symptomatic fatal/nonfatal PE and asymptomatic deterioration in negative thrombotic effects, rivaroxaban was found to be more efficacious than LMWH/VKA. The LMWH/VKA group had 9 percent of patients experience the primary efficacy endpoint compared to 5.4-6.6 percent of rivaroxaban patients. With the 5-20 mg rivaroxaban range deemed to be efficacious, the 20 mg dose was found to be most effective in preventing DVT recurrences.

Safety The phase II ATLAS trial was a double-blind, open-label, with block randomization of 1:1:1 placebo:rivaroxaban (doses 5-20 mg) once daily:rivaroxaban (2.5-10 mg) twice daily with at least 225 patients per tier.6 The study called for liver function tests to take place once a month during the study. The safety endpoint consisted of clinically significant bleeding requiring assistance, such as lab tests or surgery. Liver function tests revealed no significant difference in the rate of alanine aminotransferase greater than three times the upper limit of normal in patients given rivaroxaban compared with placebo (3.7 percent versus 4.5 percent, respectively). Clinically significant bleeding occurred in a dose-dependent manner compared to placebo.12 Rivaroxaban was compared to enoxaparin in a randomized, doubleblind/dummy study, active-comparator-controlled, multi-national study in 873 patients undergoing hip replacement surgery that received prophylaxis of VTE between six and eight hours post-operation.13 The primary safety outcome was the incidence of major bleeding, which ranged from 0.7 percent with the 10 mg rivaroxaban dose to 5.1 percent with the 40 mg dose. The study determined no significant difference in incidence of major post-operation bleeding between rivaroxaban and enoxaparin.

A total of 845 patients was used in the safety population data, which determined a significant dose-response relationship (p=0.0391).13 In RECORD 1 when dosing rivaroxaban, the occurrence of major VTE decreased while the risk of major bleeding increased compared to enoxaparin, suggesting the patient’s status should be considered when selecting therapy.10 A challenge in the approval process for rivaroxaban is the lack of power for safety outcomes in the studies. Post-marketing pharmacovigilance should provide more data on the safety of rivaroxaban.

Place in therapy Based on safety and efficacy data, rivaroxaban has evidence that it could be an effective treatment in VTE prophylaxis in post-surgical patients. Further studies, including post-marketing surveillance, could help to reinforce this evidence. There are no currently published studies looking into efficacy and safety of rivaroxaban in comparison to warfarin in VTE. The ROCKET-AF trial looking at rivaroxaban in atrial fibrillation versus warfarin is currently ongoing, and results will help to further determine rivaroxaban’s usefulness long-term.11

Cardiology

Although rivaroxaban has been shown to be clinically useful in patients, some concern was raised over the degree of benefit over enoxaparin in the RECORD trial series results due to inherent trial/design issues.

Specifically, Van Thiel raised awareness in an editorial that enoxaparin dosing was inconsistent with recommendations in the United States and that less-than-optimum duration and dosing prevented maximum enoxaparin benefit in comparison to rivaroxaban.15 Lack of power for differences in major bleeding, as well as some questionable safety evaluations compared to current recommendations, also weakened the findings of this extensive study. While these points are justified, the trial program did demonstrate promising results for rivaroxaban as an alternative agent for VTE prophylaxis. With varying international standards for prophylaxis and new CHEST guidelines, which were published after the trials had been conducted, the issues do not seem to limit rivaroxaban therapy for consideration. Slated to finish in fall 2010, the ROCKET-AF trial will provide results detailing the clinical comparison of rivaroxaban to warfarin.11 The FDA Advisory Panel has requested more data of Bayer, rivaroxaban’s manufacturer, which is not likely to be submitted until late 2010 or early 2011, meaning FDA approval will be delayed until 2011 at the earliest.16 References: 1. Haines ST, Witt DM, Nutescu EA. Venous Thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors.

Pharmacotherapy: A Pathophysiologic Approach. 7th Ed. New York: McGraw-Hill Companies, Inc.; 2008. p331-68.

2. Majerus PW, Tollefsen DM. Blood Coagulation and Anticoagulant, Thrombotic, and Anti-platelet Drugs. In: Brunton LL, Lazo JS, Parker KL. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th Ed. New York: McGraw-Hill, Companies, Inc.; 2006. p1467-88.

3. Geerts WH, Heit JA, Clagett GP, Pineo GF, Colwell CW, Anderson FA, et al. Prevention of venous thromboembolism. Chest. 2001 Jan;119(1 suppl):132S-175S. 4. Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ, and the American College of Chest Physicians. Antithrombotic and thrombolytic therapy: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008 Jun;133(6 suppl):110S112S. 5. Hallman LA, Rounds CA, Carey RA, Hume NR, Naseman R, Kier KL, Spicer J. A review of dabigatran, an oral anticoagulant. Pharmacy and Wellness Review. May 2010;1(1):1-3.6. Xarelto. (n.d.). Retrieved Feb. 1, 2010, from Bayer Schering Pharma AG website:http://xarelto.com/scripts/ pages/en/index.php.

7. Karthikeyan,G, Eikelboom, JW, Hirsh J. New oral anticoagulants: Not quite there yet. Pol Arch Med Wewn. 2009 Jan-Feb;119(1-2):53-8.

8. Turpie AG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007 Jun; 27(6):1238-47.

9. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar Ak, et al for the RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun;358(26):2765-2775.

10. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al for the RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.

Lancet. 2008 Jul;372(9632):31-39.

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A Review of Rivaroxaban, an Oral Anticoagulant

11. Buller HR, Lensing AW, Prins MH, Agnelli G, Cohen A, Gallus AS, et al. on behalf of the Einstein-DVT Dose-Ranging Study investigators. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study.

Blood. 2008 Sep;112(6):2242-7.

12. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009 Jul;374:29-38.

13. Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al.

A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation. 2006 Nov;114(22):2374-81.

14. Becker R, Berkowitz SD, Breihardt G, Califf RM, Fox K, Hacke W, et al. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010 Mar;159(3):340-347.

15. Van Thiel D, Kalodiki E, Wahi R, Litinas E, Haque W, Rao G. Interpretation of benefit-risk of enoxaparin as comparator in the RECORD program: rivaroxaban oral tablets (10 milligrams) for use in prophylaxis in deep vein thrombosis and pulmonary embolism in patients undergoing hip or knee replacement surgery. Clin Appl Thromb Hemost.

2009;15:389-394.

16. Morozov A. (2010, March 2). Bayerâ&#x20AC;&#x2122;s 4Q show recovery. In Morning Star [News Article]. Retrieved April 24, 2010, from Toronto Star website: http://torontostar.morningstar.ca/globalhome/industry/news. asp?articleid=328029.

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Diabetes

An Update on Exenatide and Liraglutide for Type II Diabetes Mellitus Sarah M. Webb, fifth-year pharmacy student from Edison, Ohio; Lacey A. Shumate, fifth-year pharmacy student from Bucyrus, Ohio; Ashley M. Overy, fifth-year pharmacy student from Grafton, Ohio; Ashley E. Lehnert, sixth-year pharmacy student from Ashtabula, Ohio; Monica A. Weisenberger, sixth-year pharmacy student from Columbus, Ohio; David R. Bright, assistant professor of pharmacy practice; Whitney N. Detillion, sixth-year pharmacy student from Portsmouth, Ohio

Intro Incretin hormones, such as gastric inhibitory peptide and glucagon-like peptide-1 (GLP-1), are produced in the intestines, and their combined effects are known as the incretin effect.1 Glucagon-like peptide 1 (GLP-1) stimulates glucose-dependent insulin secretion, inhibits postprandial glucagon secretion, and slows gastric emptying, thus reducing appetite.

Endogenous GLP-1 is degraded rapidly by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in an extremely short half-life. Newer treatments, such as exenatide, liraglutide and exenatide long-acting release (LAR), have been developed as medications that exert GLP-1 activity and yet resist DPP-4 inactivation. Exenatide was approved by the FDA in 2005 as an adjunct therapy for type 2 diabetes mellitus (T2DM). It was the first incretin mimetic to demonstrate a decrease in hemoglobin A1C (HbA1c) via glycemic control (average 1 percent reduction) and a significant decrease in body weight (1.6 – 5.3 kg reduction).2,3 Liraglutide is the newest GLP-1 mimetic to be approved for T2DM, gaining approval in early 2010.1 Unlike exenatide, which needs to be dosed twice daily, liraglutide is designed for once-daily dosing. A long-acting exenatide product, Bydureon® (exenatide LAR), is currently being developed for once-weekly dosing. With the recent approval of liraglutide and the possable approval of exenatide LAR, practitioners may find it valuable to assess how each GLP-1 agent will fit into therapy for T2DM. Exenatide The use of exenatide has widely been compared to the use of long-acting insulin for T2DM that is uncontrolled after initial therapies. Although long-acting insulin may offer a greater decrease in HbA1c than exenatide, it causes weight gain, an unwanted effect in T2DM patients.4 Over the past five years, exenatide has established a role within T2DM therapy, but long-term adverse events have also been noted with therapy.

Like other new treatments for T2DM, the adverse drug reaction (ADR) profile of exenatide has been a cause for concern as long-term treatment data becomes available. The most common ADRs associated with exenatide treatment are nausea, vomiting, diarrhea and hypoglycemia.5 However, most of these ADRs occur in combination therapy with other T2DM medications and can be controlled through monitoring therapy. 5 In addition to minor adverse reactions with exenatide, as of Jan. 1, 2010, the FDA has received 36 post-marketing reports of acute pancreatitis, including six cases of hemorrhagic or necrotizing pancreatitis and two deaths.2 However, it is important to note that 90 percent of these patients had confounding factors for pancreatitis (obesity, hyperlipidemia, hypertriglyceridemia, alcohol use).

Thirty additional cases were subsequently reviewed by the FDA, none of which resulted in fatality. Initial symptoms began at an average of 34 days after starting exenatide treatment, and abdominal pain was the most common symptom, occurring in 23 of the 30 patients. Symptoms subsided for 22 of the 23 patients after exenatide was discontinued; however, reexposure caused a recurrence of symptoms in most patients.

Because of the controversy regarding the issue of pancreatitis with the use of exenatide, the manufacturer has recently made an addition to the package insert pertaining to patient monitoring.6 The warning recognizes that patients should be monitored for symptoms of pancreatitis when treatment is started on the medication or if the dose is increased. If symptoms are consistent for diagnosis of pancreatitis, treatment should be discontinued immediately and the patient should be appropriately managed. These patients are then ineligible for any future treatment with exenatide.

The FDA also has received 78 cases of altered renal function in patients receiving exenatide treatment (62 acute, 16 renal insufficiency).7 Initial symptoms occurred three days to two years after initiation of exenatide treatment in patients who were 23-83 years old. Fourteen of these patients had a past medical history of chronic kidney disease, a contraindication for exenatide treatment, and 95 percent had at least one risk factor for altered kidney function, such as cardiac insufficiency, hypertension, pancreatitis, rhabdomyolysis or urinary tract infection.

Several patients were also at increased risk due to the use of antiretrovirals, antihypertensives, diuretics or NSAIDs. Four deaths were reported, and 91 percent of the treated patients required hospitalization. Symptoms improved in half of the patients after discontinuation of exenatide, while 18 patients required dialysis and two required a renal transplant.

A precautionary statement has since been added to the labeling for exenatide about treatment in patients with low creatinine clearance (<50 mL/min).5 Practitioners should continue to evaluate renal function prior to exenatide treatment and throughout the progression of T2DM in individual patients.

In late 2009, the FDA granted approval to use exenatide monotherapy in T2DM patients. The indication was granted after a study showed improved glucose control and weight loss in a 24-week, randomized, double-blind, placebo-controlled trial with 203 patients completing the study.8 Patients were randomized to 5 mcg twice-daily or 10 mcg twice-daily dosing, with the primary endpoint of decreased HbA1c and secondary endpoints of fasting serum glucose, postprandial glucose and weight. Results from the study showed a statistically significant decrease in mean postprandial glucose (5 mcg -17.5 mg/dL; 10 mcg -18.7 mg/dL; placebo -5.2 mg/dL; p <0.001). Adverse events were similar between monotherapy and adjunct therapy, with nausea being the most common.

The effectiveness of monotherapy compared to adjunct therapy has not yet been studied.

Exenatide Long-acting Release (LAR) Amylin Pharmaceuticals, Eli Lilly, and Alkermes have developed a long-acting exenatide product, Bydureon® (exenatide LAR), which is a once-weekly form of Byetta. Recently, the FDA denied approval due to clarifications needed on labeling, risk evaluation and mitigation strategy (REMS), and the manufacturing process. At the time this article was written, Bydureon was still not FDA-approved, but the following two studies demonstrate its potential in the treatment of T2DM.

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Diabetes

An Update on Exenatide and Liraglutide for Type II Diabetes Mellitus

A 30-week, randomized, non-inferiority, comparator-controlled, open-label trial was performed comparing exenatide LAR 2 mg once-weekly to 10 mcg exenatide twice-daily to assess safety, efficacy, tolerability and non-inferiority of the long-acting product. This product was considered to be non-inferior if HbA1c change was <0.4 percent at week 30. A total of 295 weightstable patients with T2DM were included in this study. Subjects were either naïve to anti-diabetic treatment or were receiving one or more anti-diabetic agents, including metformin, sulfonylureas, thiazolidinediones or a combination, for at least two months prior to the trial. Patients were randomized into two groups, both receiving 5 mcg exenatide twice daily for three days, then either 2 mg exenatide LAR for 30 weeks or 5 mcg exenatide twice daily for 28 days followed by 10 mcg exenatide for the remainder of the 30week study. Results showed that, by week 10, the once-weekly group had a significant decrease in HbA1c, 1.9, compared to the twice-daily group, 1.5 (p=0.0023) despite patient background. The once-weekly group also had 77 percent of patients achieve HbA1c of ≤7 percent compared to 61 percent in the twice-daily group (p=0.0039). The twice-daily group had 35 percent of patients with a baseline HbA1c of ≥9 percent achieve a final HbA1c of ≤7 percent, while the once-weekly group had 65 percent of patients achieve this level (p=0.02). Bodyweight decreased in both the exenatide and exenatide LAR groups (-3.6 kg and -3.7 kg, respectively, p=0.89). Fasting plasma glucose levels significantly decreased in the once-weekly group versus the twice-daily group (-41.4 mg/dL and -25.2 mg/dL), respectively, p<0.0001). In addition, the Diabetes Treatment Satisfaction Questionnaire (DTSQ) showed a significant increase in satisfaction in the once-weekly group. Adverse events for the once-weekly group were mild and included nausea (26.4 percent) and injection site pruritus (17.6 percent) and were significantly lower than the twice-daily group. No major hypoglycemic events, occurrences of pancreatitis or significant abnormalities were found.

Overall, both exenatide and exenatide LAR decreased HbA1c. Significant reduction in HbA1c values due to continuous exposure to exenatide indicate that glycemic control provided by the once-weekly formulation is not inferior to the twice-daily formulation.12 A 52-week, randomized, multi-center, open-labeled trial was performed to evaluate the effects of exenatide twice daily and exenatide once weekly on treatment satisfaction and quality of life. Patient-reported outcome instruments included DTSQ and the Impact of Weight on Quality Of Life (IWQOLLite), which were given at baseline and weeks 30 and 52. A total of 295 patients were included – 148 in the 2 mg exenatide once-weekly and 147 in the 10 mcg twice-daily during weeks 1-30, then 2 mg weekly for weeks 30-52.

Results of the DTSQ scores showed that at week 52, treatment satisfaction improved in the once-weekly group. However, the IWQOL-Lite showed a significant increase in satisfaction in both groups (p<0.001), but there was no difference between them. After the twice-daily group switched to once-weekly exenatide, improvement was seen for treatment satisfaction, convenience, flexibility and continuance. In this group, the IWQOL-Lite also showed significant improvement in physical function and public distress. Overall, the weekly group had improved satisfaction with treatment convenience, flexibility and public distress. All comparisons were shown to be statistically significant with p<0.05. In addition, there was no difference in adverse events between the groups. Overall, the once-weekly form had improvement in satisfaction, convenience and flexibility. This could be a result of ease of use, less frequent administration, and greater improvement in glucose control with perceived hyperglycemia. The willingness to continue treatment could possibly improve adherence and, thus, the outcome and control of T2DM.13 6

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Liraglutide Recently approved by the FDA, liraglutide is authorized for use in T2DM as monotherapy or in combination with other anti-diabetic medications, such as metformin, thiazolidinediones or sulfonylureas.1 The approval was delayed due to possible risk of medullary thyroid cancer, though malignant tumors were only evident in animal trials. Novo Nordisk, the manufacturer of liraglutide, funded the Liraglutide Effect and Action in Diabetes (LEAD 1-6) studies to establish the safety and efficacy of liraglutide. LEAD trials 1, 2, 4 and 5 primarily focused on combination therapy with liraglutide and one or more oral antidiabetic medication, whereas LEAD-3 focused on monotherapy, and LEAD-6 compared liraglutide with exenatide.

The LEAD-3 trial is a double-blinded, randomized trial performed to evaluate and compare the efficacy of liraglutide 1.2 mg and 1.8 mg once daily with oral glimepiride 8 mg once daily as monotherapy for T2DM.9 A total of 746 participants with early T2DM were enrolled for the 52-week trial.

Participants were 18-80 years old, had an HbA1c between 7-11 percent, had a BMI of ≤40 kg/m2, and had not used insulin or corticosteroids in the previous three months. Participants were placed into one of three treatment groups: 1.2 mg liraglutide (n=251), 1.8 mg liraglutide (n=247), or 8 mg glimepiride (n=248). At the completion of the trial, HbA1c was reduced more significantly in both liraglutide therapies than glimepiride (Table 1). Greater decreases in HbA1c were seen in patients previously treated with lifestyle modifications only as compared to those patients who had received oral anti-diabetic medications preceding the trial. Significantly more patients achieved the American Diabetes Association HbA1c target of less than 7 percent in the liraglutide therapies as compared to glimepiride (table 1). No major hypoglycemia occurred, though minor hypoglycemia occurred in all three groups. Nausea was more prevalent in liraglutide groups but decreased after four weeks. The LEAD-3 trial was extended another 52 weeks with 440 patients entering the extra year of treatment.10 After the extension period was completed, mean reductions in HbA1c and those reaching the target goal were significantly greater with liraglutide 1.2 mg and 1.8 mg than glimepiride (table 1). Treatment with liraglutide is shown to be effective and safe as monotherapy and produces significant greater reductions in HbA1c and FPG as compared with glimepiride.

The LEAD-6 trial is a 26-week randomized trial that compares the safety and efficacy of liraglutide with exenatide in T2DM patients not adequately controlled on metformin alone (n=127), a sulfonylurea alone (n=45), or metformin plus a sulfonylurea (n=292).11 The 464 participants were 18-80 years old, HbA1c between 7-11 percent, had a BMI of ≤45 kg/m2, and had no previous insulin or exenatide. The patients continued on their treatment and were randomly chosen to receive either 1.8 mg liraglutide once daily (n=233) or 10 mcg exenatide twice daily (n=231). After 26 weeks, more patients reached target HbA1c levels of <7 percent and had significantly improved glycemic control with liraglutide than exenatide (table 1). Both liraglutide and exenatide groups had similar weight reductions (table 1).

The incidence of nausea was initially similar in both groups but was less persistent in the liraglutide group (p<0.0001). Treatment satisfaction was measured using the Diabetes Treatment Satisfaction Questionnaire. Overall, treatment satisfaction was significantly better with liraglutide (n=161) than with exenatide (n=143) (p=0.0004).

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An Update on Exenatide and Liraglutide for Type II Diabetes Mellitus

Diabetes

Table 1. Efficacy of liraglutide (LIRA) as monotherapy in the treatment of T2DM. Results from two LEAD trials. LEAD-3 compared LIRA against glimepiride (GLIM) for efficacy as monotherapy. LEAD-6 compared the efficacy of LIRA to exenatide (EXEN).9, 10, 11 Study

LEAD-3 (Mono) LEAD-3 (Mono extension) LEAD-6 (Vs. EXEN)

Therapy

LIRA 1.2mg LIRA 1.8mg GLIM 8mg LIRA 1.2mg LIRA 1.8mg GLIM 8mg LIRA 1.8mg EXEN 10mcg

No. of pts 251 247 248 149 154 137 233 231

Mean HbA1c (%)

Mean FPG (mg/dL)

Baseline

Baseline

8.3 8.3 8.4 8.1 8.1 8.0 8.2 8.1

Change

-0.84 -1.14 -0.51 -1.1 -1.4 -0.6 -1.12 -0.79

167.4 171 171 --* --176.4 171

Change

-15.1 -26.8 -5.2 -23.4 -27 -5.4 -29 -10.8

Pts at ADA target HbA1c (%) 43 51 28 53 58 37 54 43

Body Wt (kg) Baseline

92.5 92.8 93.4 ---93.1 93

Change

-1.85 -2.26 +1.22 -2.1 -2.7 +1.1 -3.24 -2.87

*Baseline data not provided Conclusion New incretin based therapies have the possibility to influence the treatment of T2DM. Exenatide, liraglutide and exenatide LAR appear to be relevant to the treatment of T2DM in their ability to decrease HbA1c while reducing weight and may be appropriate as monotherapy agents for some patients. Studies show that each agent exhibits a mild safety profile with modest differences in therapeutic outcomes. Currently, patient preference and dosing schedule should be considered by the practitioner when determining the preferred agent for the patient. Additional head-to-head trials may be beneficial to adequately compare exenatide, liraglutide, or exenatide LAR to further determine the specific role in therapy for each agent.

References 1. Christensen M, Knop FK. Once-weekly GLP-1 agonists: how do they differ from exenatide and liraglutide. Curr Diab Rep. 2010;10:124-132.

2. Gallwitz B. Benefit-risk assessment of exenatide in the therapy of type 2 diabetes mellitus. Drug Saf. 2010; 33(2): 87-100.

3. Brixner DI, McAdam-Marx C, Ye X, Boye KS, Nielsen LL, Wintle M, et al.

Six-month outcomes on A1C and cardiovascular risk factors in patients with type 2 diabetes treated with exenatide in an ambulatory care setting. Diabetes Obes Metab. 2009; 11: 1122-1130.

4. Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. 2010; 33(2): 428433.

5. Lexi-Comp Online. Lexi-Comp, Inc. 2010. Available at online.lexi.com/ crlsql/servlet/crlonline. Accessed May 3, 2010.

6. Byetta (exenatide) injection [product information]. San Diego (CA): Amylin Pharmaceuticals, Inc. September 2010.

7. Byetta (exenatide) and altered kidney function. Pharmacistâ&#x20AC;&#x2122;s Letter/Prescriberâ&#x20AC;&#x2122;s Letter 2009; 25(12): 201-203.

8. Moretto TJ, Milton DR, Ridge TD, MacConell LA, Okerson T, Wolka AM, et al. Clin Ther. 2008; 30(8): 1448-1460.

9. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 mono): a randomized, 52 week, phase III, double blind, parallel treatment trial. Lancet. 2009; 373: 473-81.

10. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Monotherapy with liraglutide, a once-daily human GLP-1 analog, provides sustained reductions in A1c, FPG, and weight compared with glimepiride in type 2 diabetes: LEAD-3 mono 2-year results [abstract no. 162-OR]. 69th Scientific Sessions of the American Diabetes Association; 2009 Jun 5-9; New Orleans (LA).

11. Buse JB, Rosenstock J, Setsi G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26 week, randomized, parallel-group, multinational trial (LEAD-6).

Lancet. 2009; 374: 39-47.

12. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Shuang D, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomized, open-label, non-inferiority study. Lancet 2008; 372:1240-50.

13. Best JH, Boye KS, Rubin RR, Cao D, Kim TH, Peyrott M. Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily. Diabetic Medicine 2009;26:722-28.

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Gastrointestinal

Use of Gastric Bypass Surgery for the Treatment of Type 2 Diabetes Mellitus Kaitlin A. Sanders, fifth-year pharmacy student from Kendallville, Ind.; Jenna L. Schaffner, fifth-year pharmacy student from North Canton, Ohio; Leslie M. Hart, sixth-year pharmacy student from Cooperstown, Pa.; Whitney N. Detillion, sixth-year pharmacy student from Portsmouth, Ohio; Anne Gentry, PharmD

Abstract: Over the past decade, the incidence of type 2 diabetes mellitus (T2DM) has increased significantly. Evidence has shown that a clear association exists between obesity and diabetes development. This association has inspired researchers to explore bariatric surgery as an option for diabetes management and possible disease reversal.

Improvement of T2DM using Roux-En-Y gastric bypass (RYGB) is thought to result from a combination of weight loss, decreased caloric intake, hormonal changes and rearrangement of the gastrointestinal anatomy. Positive outcomes resulting from the procedure include decreased mortality rates, normalization of HbA1c levels, decreased dependence on diabetic medications, and increased insulin sensitivity. Gastric bypass, specifically RYGB, appears to be a promising treatment for T2DM. Due to possible complications and limited research in some populations, treatment should be restricted to patients with a BMI > 35 with concurrent diabetes. Patients with diabetes who qualify should be counseled on the potential benefits of gastric bypass as a viable option for diabetes management.

Introduction: The incidence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide and is stated to be the sixth leading cause of death in the U.S.1 More than 24 million Americans have been diagnosed with diabetes, and approximately 800,000 new cases arise each year.2 Between 1995 and 2025, prevalence is expected to increase from 130 million to roughly 300 million.3 Although causation cannot be linked to one specific source, rising diabetes rates are undeniably associated with the obesity epidemic. In Western countries, 15-30 percent of the adult population is obese (BMI > 30). Studies have observed that insulin resistance and diabetes often follow a large increase in body weight. One such study, the Nurses’ Health Study, found that both men and women who gain 11-19.9 kg after the age of 18 have 5.5 times the risk of developing T2DM.3 Furthermore, other analyses have linked centrally patterned fat distribution with an increased diabetic risk. Therefore, the development of diabetes depends not only on lifestyle choices, but also on genetic components.

Patients with T2DM account for approximately 90 percent of all diabetics.4 One characteristic commonly seen in T2DM is insulin resistance.

Endogenously, insulin acts to dispose of glucose within the skeletal muscle as well as to suppress hepatic glucose production. A patient is considered to have insulin resistance when these endogenous effects of insulin are decreased. The early stages of T2DM are often marked by hyperinsulinemia accompanied by accelerated endogenous glucose production. Hepatic insulin resistance is considered the major contributor to hyperglycemia in these patients. Cytokines, hormones and nonesterified fatty acids (NEFA) all moderate insulin action and arise in the adipocytes. A rise in triglyceride stores increases adipocyte size and alters the ability of insulin to suppress lipolysis. This leads to high circu8

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lating levels of NEFA and glycerol, which cause insulin resistance in the liver and skeletal muscle. Ectopic fat storage (fat storage in non-adipose cells) also may intensify insulin resistance. The American Association of Clinical Endocrinologists suggests T2DM diagnosis be based on the presence of one of three factors:5 Symptoms of diabetes, such as polyuria, polydipsia and unexplained weight loss, and the causal plasma glucose concentrations > 200 mg/dL, fasting glucose concentration > 126 mg/dL, or a two-hour post-challenge glucose concentration ≥ 200 mg/dL during a 75 g oral glucose tolerance test.

The 2010 American Diabetes Association (ADA) Standards of Care Guidelines recommend that a physician-coordinated team, including the pharmacist, oversee the management of diabetes and provide the patient with proper medical nutrition therapy and diabetes self-management education.6 For glucose management, the ADA recommends self-monitoring of blood glucose (if on insulin), testing HbA1c two to four times yearly dependent on patient’s blood glucose control, and initiating metformin therapy and lifestyle changes at the time of diagnosis with medicinal therapy augmentation as needed. Furthermore, diabetes leads to accelerated development of micro and macrovascular disorders. Cardiovascular disease is the leading cause of morbidity and mortality among diabetic patients. The guidelines therefore indicate that blood pressure control, lipid management and aspirin therapy as needed, in addition to proper screening and treatment for coronary heart disease, nephropathy, retinopathy and neuropathy, are important components of care. Finally, for the first time, the ADA has included bariatric surgery as a treatment option for those patients with a BMI > 35 and concurrent T2DM in their 2010 guidelines.

Bariatric surgery Due to the evident association between obesity and diabetes, many researchers are exploring the option of bariatric surgery for diabetes management and possibly disease reversal. Currently, four types of gastric bypass are generally performed. The adjustable gastric band (AGB) is a band that can be placed around the top of the stomach to form a small pouch.7 Band size is controlled by modifying the amount of saline solution in the band in order to increase or decrease the size of the band’s circular balloon, thereby altering stomach outlet size. In Roux-en-Y gastric bypass (RYGB), digestive tract size is reduced through bypassing most of the stomach, duodenum and upper intestine. This not only limits food intake to that which can fit in a small pouch, but also decreases gastrointestinal absorption. Biliopancreatic diversion with a duodenal switch (BPD-DS) consists of a reduction in stomach size to reduce food intake, a redirection of food away from the small intestine to drastically decrease absorption, and a redirection of bile and digestive juices to impair digestion. Typically, BPD-DS results in the most weight loss but also has the highest risk of long-term complications because of the malabsorption that results. Lastly, vertical sleeve gastrectomy (VSG), one of the three components of BPD-DS, drastically reduces stomach size as mentioned previously. This size reduction also may decrease the amount of ghrelin produced, reducing hunger to a greater extent than the lap band operation and aiding in patient success.

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Use of Gastric Bypass Surgery for the Treatment of Type 2 Diabetes Mellitus

How it works Since the 1980s, research has been conducted to assess the efficacy of using gastric bypass surgery for the treatment of T2DM, and, as previously stated, the ADA has recently included gastric bypass as a therapeutic option for T2DM within their guidelines.2,6 Scientists hypothesized that the excessive amount of weight loss resulting from the surgery may diminish the symptoms of T2DM. It has been verified that surgery is the most effective way to produce sustained and substantial weight loss in patients.8 The weight reduction strategies that have been used include gastric restriction via the reduction of stomach volume and intestinal malabsorption due to the shortening of the small intestine and decreasing the surface area available for nutrient absorption.9 One of the main surgeries currently being investigated that has shown the most promising results is RYGB. During this surgery, the stomach is divided into two sections, where a small stomach pouch (15-30 ml in volume) is formed in the upper part of the stomach by using surgical staples or a gastric band.2 This small pouch is directly connected to the middle portion of the jejunum, thus bypassing the lower part of the stomach, the duodenum and part of the jejunum. Gastric juices, bile and pancreatic enzymes continue to flow from the lower part of the stomach and duodenum through the small intestines and meet the other channel at a Y-shaped junction.

Improvement of T2DM using RYGB is thought to be a result of a combination of weight loss, decreased caloric intake, hormonal changes and rearrangement of gastrointestinal anatomy.2 The amount of overall weight loss does not prove to be the primary mechanism of treatment for diabetes because the resolution of diabetes occurs within days after surgery, prior to the majority of the weight loss. Complete eradication of the disease, however, is seen more frequently in those patients who lose more weight. It has been observed that the decreased caloric intake resulting from RYGB may help with short-term glycemic control, but overall resolution of T2DM cannot be accounted for due to decrease in caloric intake. Hormonal changes are thought to be one of the main reasons for this possible success in T2DM. RYGB has shown to result in increased levels of GLP, Peptide YY (PYY), adiponectin and decreased levels of GIP, acylation-stimulating protein (ASP), leptin, and ghrelin.

These hormones have a major impact on the function of the GI tract and, when altered due to RYGB, may lead to many of the positive effects of the surgery (table 1).

Gastrointestinal

Benefits Diabetes often is a life-altering and life-defining disease that many individuals have difficulty managing. Gastric bypass surgery can be very beneficial for some patients that have had difficulty in achieving adequate diabetes control. Positive outcomes resulting from the surgery include decreased mortality rates, normalization of HbA1c levels, decreased dependence on diabetic medications, and increased insulin sensitivity. A study including 608 morbidly obese patients that were followed for 14 years post-gastric bypass operation reported an average excess weight loss of 49 percent.9 Of the 608 patients, 330 had either diabetes (n=165) or impaired glucose tolerance (n=165) at baseline. At the end of the study, 82 percent of those with T2DM had normal HbA1c levels. Another study including 232 morbidly obese patients, all with T2DM, was conducted to assess long-term mortality rates. It was found that the mortality rate of the control group was significantly higher (P<0.0003) than the surgical group. The number of cardiovascular deaths was the major variant between the two groups. By decreasing mortality rates and HbA1c levels, a diabetic patient may have a prolonged and better quality of life.

Once diagnosed with diabetes, it is rare that there will be a day that a patient will go without taking a pill again. Gastric bypass has shown to minimize the number of medications needed for a diabetic patient, which will help with patient compliance issues and allow for simpler medication therapy.2 In general, RYGB shows a reduction in the dependence on diabetic medication of 80-98 percent of patients for up to 14 years of follow-up. Surgery is more effective than medicinal treatment alone for improving diabetes for long-term effects. A study comparing 154 morbidly obese type 2 diabetics that had gastric bypass surgery to 78 control patients showed that 87 percent of the control group required medication intervention after nine years of follow-up. After 6.2 years of follow-up, medication intervention required for the surgery group fell from 31 percent to 9 percent. Another study, which included 378 type 2 diabetic patients that underwent weight reduction surgery, 72 of which were medicated, showed that there was a significant reduction in blood sugar level from 9.1 mmol/L (preoperative) to 6.6 mmol/L (postoperative) with a P=0.005.8 Of the 72 patients who were medicated, 36 patients had stopped all medication for diabetes, and none had an increase in dose post-operation. There was a 75 percent reduction in patients that

Table 1: Effect of RYGB on Gastrointestinal Tract (GIT) Hormones2 Hormone

Increase/Decrease in Hormone following RYGB

Endogenous Effect

GLP-1

Increase

Acts to suppress glucagon, reduce glucose production by the liver, increase insulin production, slow gastric emptying, and enhance satiety

GIP

Decrease

Stimulates insulin release and synthesis

ASP

Decrease

Increased glucose uptake and fatty acid esterification

Ghrelin

Decrease

Appetite-stimulating hormone

PYY

Increase

Decreases food intake by inhibiting gut motility

Adiponectin

Increase

Stimulates glucose utilization and fatty acid oxidation in skeletal muscle

Incretin

Decrease

Secreted after meals to enhance insulin secretion November 2010

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Use of Gastric Bypass Surgery for the Treatment of Type 2 Diabetes Mellitus

required insulin after the operation. Sixty-nine percent of all patients that underwent RYGB surgery as the weight reduction surgery were off all medications post-operation (P<0.0001). There was no significant relationship between the amount of weight loss and change in diabetic status. While a complete reversal of diabetes may be life-changing for an individual, a reduction in diabetes medication use in those who do not achieve complete reversal also can be very beneficial. Currently available studies have generally shown a decreased need for medications following gastric bypass surgery for the diabetic patient. More studies need to be performed to further confirm and more accurately assess the benefits and mechanisms surrounding this matter.

One of the most challenging issues for diabetic patients is glucose control. It is a constant struggle for doctors and pharmacists to counsel patients on ways to minimize fluctuations in glucose levels. Gastric bypass may be a beneficial option for patients who struggle to maintain normal glucose levels. After gastric bypass surgery, a normalization of glucose metabolism is often seen within weeks of surgery.2 Long-term effects are better seen within two to five years post-operation. In a trial investigating 4,047 subjects treated for obesity, 72 percent of the patients surgically treated recovered from T2DM within two years of surgery, compared to only 21 percent of the control group.

Gastric bypass has shown its best effects in its long-term treatment of T2DM. A resolution rate of diabetes is between 83-85 percent in the long term for gastric bypass surgery.8 RYGB is more effective for the treatment of T2DM in patients with a milder form and a shorter duration of the disease.2 Patients who do not experience significant improvement from the surgery tend to be older. Unlike insulin sensitivity, B cell function improvement is more closely related to duration of diabetes rather than weight loss.9 While gastric bypass surgery has proven to show many benefits for the treatment of T2DM, these benefits should be weighed against the risks of surgery before using this method in any patient. Also, the characteristics of the patient must be considered in determining if qualifications for this surgery are met, including obesity and BMI criteria.

Risks Along with any surgery comes risk of treatment, possible complications and death, in addition to potential hardships from expenses and medical bills. Figures show that there is less than 1 percent risk of mortality for patients undergoing RYGB, and a risk of complications range from less than 10 to 20 percent.8 Medical bills for RYGB, including hospital stays, anesthesia, lab costs and surgeon fees, costs approximately $26,000 without health insurance.10 Insurance coverage varies from plan to plan, but bariatric surgery is frequently not covered in full, if at all.

Complications of these operations include bleeding, infection and blood clots that can move to the heart or lungs.7 Later problems, such as malnutrition, strictures and hernias, also may occur. Studies suggest that up to 10 percent of patients receiving bariatric surgery may experience inadequate weight loss or may regain much of the weight that is initially lost. Experts recommend that these procedures be performed only on adolescents that are extremely obese (typically with BMI greater than 40), have reached their adult height (usually 13 or older for girls and 15 or older for boys), and have serious weight-related health problems, such as T2DM, sleep apnea, heart disease, or significant functional or psychoso10

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cial impairment. Surgery should only be considered after candidates have attempted weight reduction for at least six months and have failed.

Following RYGB, the risk of developing vitamin and mineral deficiency is significantly increased. RYGB can lead to decreased levels of vitamin B12, folate, iron and calcium either through malabsorption or insufficient intake.11 Supplementation of these specific vitamins is vital following RYGB surgery.

Cost Analysis As previously mentioned, comprehensive medical costs for RYGB without insurance are an estimated $26,000.10 Insurance coverage varies, and, if coverage is provided, it normally does not cover the entire cost of surgery. Comparatively, a 2010 study employed a Cost of Diabetes Model to estimate the U.S. economic burden related to diabetes.12 The study analyzed information from peer-reviewed literature, government statistics and national survey, and medical claim databases. The average annual cost per patient standardized to 2007 dollar amounts was $2,864 for undiagnosed diabetes and $9,677 for diagnosed T2DM. As a reference, the median age of diagnoses for T2DM was 57 with annual costs increasing with age. Depending on quality of insurance coverage, length of life, age of diagnosis and success of surgery in treatment of symptoms, gastric bypass offers potentially great long-term cost savings, although the actual magnitude of these savings is still to be determined. More costeffectiveness studies need to be completed to fully and more adequately compare the costs of bariatric surgery as treatment for T2DM versus the current standard of care.

Effect on Drug Absorption Data examining the effect of bariatric surgery on drug absorption is lacking. A recent review of the literature suggests that, although there is little known, the effect of bariatric surgery on drug absorption appears to be drug-specific.13 In some cases, substantial reductions in drug absorption may occur, which may be temporally associated with the need for dosage adjustment. Overall, evidence for decreased drug absorption was found in 15 of 22 studies involving jejunoileal bypass, one of three studies of gastric bypass/gastroplasty, and none in the one study examining biliopancreatic diversion. Specifically, multiple reports described decreased absorption for anti-rejection drugs (cyclosporine and tacrolimus), thyroxine, phenytoin and rifampin. Single instances of diminished absorption of ethosuximide, amoxicillin, macrodantin, tacrolimus, sulfisoxazole and hydrochlorothiazide were reported. Conflicting evidence was present for ethambutol, digoxin and oral contraceptives. Further study is needed to assess the degree of malabsorption specific to each medication and whether there are major differences among procedure types that exist.13 Conclusion Gastric bypass, specifically RYGB, appears to be a promising treatment for T2DM. RYGB not only slows progression of the disease, but also offers potential disease resolution. The average long-term diabetes resolution rate for those who undergo surgery is an impressive 83-85 percent, which considerably improves quality and duration of life, achieved through a significant reduction in diabetes-associated complications. Also, it is suspected that a cost savings will be incurred through medication reduction or cessation. Although RYGB has shown great success, studies have revealed better outcomes in younger individuals newer to diagnosis with a

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Use of Gastric Bypass Surgery for the Treatment of Type 2 Diabetes Mellitus

Gastrointestinal

milder form of the disease. RYGB as a treatment for T2DM should be restricted to patients with a BMI > 35 with concurrent diabetes, due to potential complications of surgery and limited research support beyond use in other populations. Patients should be able and willing to exhibit high levels of compliance to current medication therapy, as physician visits and daily vitamin supplementation will be required following surgery. It is vital that patients comply with continual follow-up visits to promote optimal results. Much focus should be placed on these parameters when electing candidates for surgery. This strategy has grabbed the attention of many health care professionals, and with 30 years of supporting research, gastric bypass now has been included in clinical guidelines as an appropriate treatment option for some T2DM patients.

References 1. Leading causes of Death [website on the Internet]. Atlanta (GA): Centers for Disease Control and Prevention [updated 2009 Dec 31; cited 2010 May 1]. [2 screens]. Available at www.cdc.gov/nchs/FASTATS/lcod.htm.

2. Herron D, Tong W. Role of Surgery in management of Type II Diabetes.

J Mt Sinai Hosp N Y 2009; 76:281-293.

3. Hauner H. Managing type 2 diabetes mellitus in patients with obesity.

Treat Endocrinol 2004; 3(4):223-32.

4. Stumvoll M, Goldstein BJ, Van Haeften TW. T2DM: Principles of Pathogenesis and Therapy. Lancet 2005; 365:1333-46.

5. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force.

American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007; 13(1): 1-68.

6. American Diabetes Association. Standards of Care in Diabetes2010.

Diabetes Care 2010 January; 33(1):S11-S61.

7. Bariatric Surgery for Severe Obesity [website on the Internet]. Bethesda (MD): National Institute of Health [cited 2010 May 1].[4 screens]. Available at win.niddk.nih.gov/publications/gastric.htm.

8. Gan S, Talbot M, Jorgensen J. Efficacy of Surgery in the Management of Obesity-related T2DM Mellitus. ANZ J. Surg; 2007; 77: 958-962.

9. Ferchak C, Meneghini L. Obesity, bariatric surgery and T2DM- a systematic review. Diabetes Metab Res Rev 2004; 20: 438-445.

10. Cost of Roux-en-y Gastric Bypass Surgery [website on the Internet].

Einstein Industries, Inc. [updated 2008; cited 2010 May 1]. [4 screens].

Available at www.docshop.com/education/bariatrics/types/gastricbypass/cost.

11. Physiology and Metabolism in Obesity Surgery: Roux-en-Y Gastric Bypass.In: Jones K, Higa K, Pareja J. Obesity Surgery Principles and Practice. The McGraw Hill Companies; 2008. p. 101-104.

12. Rodbard H, Green H, Fox K, Grandy S. Impact of T2DM mellitus on prescription medication burden and out-of-pocket healthcare expenses.

Diabetes Res Clin Pract; 2010; 87(3): 360-365.

13. Padwal R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical implications. obesity reviews. 2010;11:41–50.41..50

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Pharmacogenomics

Preparing for the Genomic Age: Thiopurine S-Methytransferase Polymorphism Hilary Stewart, fifth-year pharmacy student from Centerburg, Ohio; Lisa Berni, fifth-year pharmacy student from Dennison, Ohio; Tyler Bulcher, sixth-year pharmacy student from Powell, Ohio; Joel Rittenhouse, sixth-year pharmacy student from Portland, Ind.; Ryan W. Naseman, sixth-year pharmacy student from Anna, Ohio

Abstract Interpatient variability among medication doses has been a longstanding obstacle for many prescribers. Some medications result in increased morbidity and mortality in a small percentage of the population. For many years, the cause of such toxicities was unknown.

This mystery has been resolved by the discovery that the absence or abnormality of specific genes that code for receptors, drug-targeted proteins, drug transport mechanisms and drug metabolizing enzymes could alter how an affected individual will respond to a given drug. One such incidence is the genetic polymorphism in thiopurine s-methyltranferase (TPMT). In comprehending the mechanism of this polymorphism, it is important to understand the metabolic pathway of thiopurine drugs. Through study of this pathway, researchers began to look into whether other polymorphisms aside from TPMT could be a source of the dose-related toxicity with the thiopurines.

The prospect that this polymorphism may contribute to an increase in number or exacerbation of side effects beyond the commonly presented bone marrow toxicity also has been visited. Becoming more aware of this genetic issue has presented the need to evaluate the cost effectiveness of genetic testing to counteract the expected cost of treating extreme myelosuppression. Having knowledge of new pharmacogenomic technology and the tests available can benefit pharmacists in any setting. Pharmacists will be more prepared to address patient concerns such as necessity and cost effectiveness.

Introduction Recently, opinion articles were published in the New England Journal of Medicine that discussed the controversies surrounding genetic testing and, in particular, the marketing of this testing directly to consumers.1,2 As pharmacists, we must be aware of these advances as we enter into the â&#x20AC;&#x153;genomicâ&#x20AC;? age and how they may impact our patients. In this article, we present a case study of thiopurine s-methytransferase polymorphism.

genome project described over 1.4 million SNPs in the genome, but this number continues to grow with extended research.4 There are more than 30 families of drug-metabolizing enzymes in humans, all with genetic variants causing the translation of such proteins to result in functional differences. Patients who inherit a drug-metabolizing enzyme deficiency must be treated with markedly different doses of the affected medications. Therefore, identifying genetic determinants of drug response can help optimize the selection of drug therapy.

TPMT polymorphism One of the most understood examples of a genetic polymorphism is that of TPMT, which catalyzes the s-methylation of azathioprine, mercaptopurine and thioguanine.4 These medications, together called the thiopurine drugs, are widely used in the treatment of leukemia, inflammatory bowel diseases and severe rhematic diseases and for immunosuppression following solid organ transplantation.3 Azathioprine, mercaptopurine and thiogunanine are all inactive prodrugs requiring activation to thiopurine nucleotides. The active nucleotides compete with endogenous nucleotides in many biochemical pathways, such as the synthesis of DNA accounting for the immunosuppressive effects of these drugs.5 These thiopurine drugs can undergo s-methylation by TPMT or oxidation to thiouric acid by xanthine oxidase to be inactivated (figure 1).

Due to this alternative degradation pathway, the importance of the TPMT polymorphism is diminished in most tissues.6 However, hematopoietic tissues do not have measurable xanthine oxidase activity, leaving s-methylation as the major competing metabolic pathway.3 Patients who inherit TPMT deficiency accumulate excessive concentrations of the active thioguanine nucleotides in blood cells. This causes a heightened immunosuppressive reaction, leaving the patient at high risk for developing bone marrow toxicity, resulting in pancytopenia, a reduction in red blood cells, white blood cells and platelets. TPMT is not known to be involved in any pathway for endogenous substrates.4 Azathioprine

Ten to 28 percent of patients receiving azothioprine or mercaptopurine therapy experience toxicity that requires stopping treatment or, in severe cases, results in death.3 Recognizing that this well-known occurrence is related to a genetic polymorphism in thiopurine s-methyltranferase (TPMT) has provided insights into the mechanism of intolerance and offered strategies to avoid these toxicities.

6-mercaptopurine TMPT

Numerous medications exhibit wide interpatient variability in efficacy and toxicity. Although nongenetic factors influence the effects of medications, the variability in response is many times due to single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes, drug transporters and/or drug targets. Initial reports from the human

6-methymercaptopurine (inactive)

Figure 1: Azathioprine Metabolism5

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xanthine oxidase 6-thiouric acid (inactive)

Preparing for the Genomic Age: Thiopurine S-Methytransferase Polymorphism Studies have been conducted to assess whether other genetic variations, aside from a TPMT polymorphism, affect azathioprine toxicity.7 A study from the Department of Pharmacology at Pomeranian Medical University in Poland investigated the role of another enzyme, inosine triphosphate pyrophosphohydrolase (ITPA), which takes part further down the metabolic pathway of thiopurines. The goal of the study was to determine if azathioprine drug intolerance was related to ITPA allele variants. ITPA catalyzes the dephosphorylation of inosine triphosphate (ITP) to inosine monophosphate (IMP). A lack of ITPA leads to an excess of ITP, which has not been proven to be pathogenic. However, some researchers have noted that an accumulation of ITP during azathioprine therapy can produce metabolites (such as thio-ITP), which may interfere with normal metabolic activity. The cohort study was conducted with a large group of renal transplant patients. Patients were evaluated for TPMT genetic polymorphisms and monitored for adverse effects of low white blood cell (WBC) count and hepatotoxicity. It was observed that ITPA had no effect on liver toxicity, and there was no statistical evidence that ITPA altered WBC count. Though previously determined in numerous other trials, the genetic effect of TPMT variations was confirmed yet again. Authors of the study concluded that genetic testing for ITPA during thioprine immunosuppressive therapy is not beneficial at this time because there is no statistical significance that it plays a role in adverse effects.

It also has been determined that 10-30 percent of patients cannot tolerate thiopurine therapy because of additional adverse events such as hepatotoxicity, pancreatitis, influenza-like symptoms and nausea.8 A cohort study conducted in a small group of Greek pediatric patients diagnosed with inflammatory bowel disease (IBD) observed the relationship between these adverse events and TPMT deficiency. A group of just under 100 children (mean age 11.5 years) undergoing treatment of IBD with thiopurine drugs was monitored for adverse events based on their genetic makeup in regards to their ability to metabolize TPMT. This study was conducted with the assumption that patients with a genetic variant that translates to poor TPMT activity experienced higher rates of the previously mentioned adverse events. Authors of the study concluded that, while dosages needed altering based on phenotype, the noted adverse events did not correlate with genetic variation.

The TPMT genetic polymorphism serves as a good example of the importance of pharmacogenetics because it has been well characterized at the molecular, biochemical and clinical levels.4 The importance of this polymorphism is appreciated because its effect is highly penetrant when TMPT-deficient patients are treated with standard doses. This means that essentially 100 percent of TMPT-deficient patients will develop hematopoietic toxicity. Approximately 11 variant alleles have been associated with low TPMT enzymatic activity in humans. These alleles contain SNPs leading to amino acid substitutions, formation of a premature stop codon or destruction of a splice site. TPMT*3A is the most prevalent mutant in whites while TPMT*C is the predominant mutant allele in Asian, African and African-American populations.

Pharmacogenomics

Conclusion Polymerase chain reaction tests provide a means of prospectively identifying these patients prior to drug therapy, thereby minimizing toxicities.9 Although all studies have been done based on rough estimates, research points to the cost effectiveness of such testing by comparing it to the expected cost of treating extreme myelosuppression.10 It is estimated that, by predetermining a case of TPMT deficiency, nearly $3,000 could be saved in health care costs per patient. This data clearly shows that, aside from the lives that can be saved, genetic testing has an extremely positive impact from an economic standpoint. Even so, health care providers must remember that cautious monitoring of blood counts is required in all patients, since myelosuppression with thiopurine drugs can still occur in patients with normal TPMT activity.11 References 1. Evans JP, Dale DC, Fomous C. Preparing for a consumer-driven age.

N Engl J Med. 2010:363;1099-1101.

2. Annes JP, Giovanni MA, Murray MF. Risks of presymptomatic direct-toconsumer genetic testing. N Engl J Med. 2010:363;1100-1103.

3. Krynetski EY, Tai HL, Yates CR, Fessing MY, et al. Genetic polymorphism of thiopurine s-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenomics. February 1996; 6:279-290.

4. Evans, WE. Pharmacogenetics of thiopurine s-methyltransferase and thiopurine therapy. The Drug Monit. April 2004;26(2):186-191.

5. TPMT testing before azathioprine therapy. DTB. January 2009; 47(1):9-12.

6. Evans WE. Thiopurine s-methyltransferase: a genetic polymorphism that affects a small number of drugs in a big way. Pharmacogenomics. 2002; 12(5):421-423.

7. Kurzawski M, Dziewanowski K, Lener A, Drozdzik M. TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients. Eur J Clin Pharmacol. May 2009;65(5):533-540.

8. Gazouli M, Pachoula I, Panayotou I, et al. Thiopurine S-methyltransferase genotype and the use of thiopurines in paediatric inflammatory bowel disease Greek patients. J Clin Pharm Ther. February 2010;35(1):93-97.

9. Marra CA, Esdaile JM, Anis AH. Practical pharmacogenetics: the cost effectiveness of screening for thiopurine s-methyltransferae polymorphisms in patients with rheumatological conditions treated with azathioprine. J Rheumatol. June 2002;29:2507-2512.

10. Compagni A, Bartoli S, Buehrlen B, Fattore G, et al. Avoiding adverse drug reactions by pharmacogenetic testing: a systematic review of the economic evidence in the case of TPMT and AZA-induced side effects.

Intl J of Technology Assessment in Health Care. 2008;24(3):294-302.

11. Gardiner SJ, Gearry RB, Barclay ML, Begg EJ. Two Cases of thiopurine methyltransferase (TPMT) deficiency â&#x20AC;&#x201C; a lucky save and a near miss with azathioprine. Brit J Clin Pharmaco. August 2005;62(4):473-476.

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Drugs of Abuse

Prescription Drug Abuse: The Pharmacist’s Occupational Hazard Brieann J. Miller, fifth-year pharmacy student from Fairfield, Ohio; Cynthia C. Nguyen, sixth-year pharmacy student from Troy, Ohio; Joshua P. Stevens, sixth-year pharmacy student from Milan, Ohio; Nicholas J. Edmonds, fifth-year pharmacy student from North Olmsted, Ohio; Ryan W. Naseman, sixth-year pharmacy student from Anna, Ohio; Michael M. Milks, BSPh ’76, Ph.D., R.Ph., professor of pharmacology Charles J. Broussard R.Ph., M.Ed.

Abstract Prescription drug abuse within the profession of pharmacy is a rising threat that must be addressed. While familiarity of drugs, work-related stress, family history and enabling may contribute to addiction disorders, chemical impairment by the pharmacist can pose serious risks to patient care. Help is available for the struggling pharmacist in the form of treatment facilities and support networks for recovery.

Background Prescription drug abuse is more than a concern affecting the general public; it also is a growing threat within the community of health care professionals. It is estimated by the National Institute of Drug Abuse that approximately 8-12 percent of health care workers have substance abuse problems.1 In Ohio over the past nine years, there have been investigations by the Ohio State Board of Pharmacy leading to the arrest of 851 health care professionals. Specifically, there has been an increasing trend in prescription drug abuse among pharmacists. It is thought that at one point or another within a pharmacist’s career, approximately 11-15 percent will experience substance abuse. Many of the pharmacists abusing substances are often discovered by their state Board of Pharmacy. There are more than 11,000 pharmacists licensed by the state of Ohio as of 2009; over the past nine years, 160 of these pharmacists have been arrested in violation of criminal drug laws by law enforcement.

Abuse of medication is not limited to only pharmacists; it also includes future pharmacists. According to the Ohio State Board of Pharmacy, seven pharmacy interns have been arrested over the past nine years for violations of drug laws.

Risk Factors for Pharmacists Though the immediate potential for substance abuse among pharmacists is often overlooked, the constant exposure to drugs may cause the pharmacist to underestimate the addiction potential hiding inside many prescription bottles. Although pharmacists are medication experts, they may not be fully aware of the risks associated with prescription drug abuse and addiction. Risk for prescription drug abuse increases dramatically when medication abuse potential becomes just another side-effect the pharmacist feels capable of managing. These pharmacists may feel knowledgeable enough to manage their own ailments without the aid of a physician and feel capable of resisting any abuse potential associated with treatment.2 The suffering pharmacist spends the day within inches of the prescription treatments that will bring relief. Perhaps symptoms are not being managed by a prescribed dosage; increasing the dose could better control the disease. When the pharmacist knows the recommended dosage range and sees the drugs sitting within reach, he or she may incorrectly perceive a prescribing physician as an unnecessary barrier to care. What usually starts as a legitimate affliction managed by 14

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a doctor may quickly spiral into a crippling addiction.

The high-stress work environment of the pharmacy profession may also contribute to substance abuse issues.3 A 2004 poll concluded that nearly 70 percent of pharmacists experienced job stress and work overload.

Long hours and understaffing, combined with the physical stress of the job requirements, such as spending 10-12 hours on one’s feet, can lead to leg, hip and back problems.4 Pharmacists strive for perfection in their work, which may lead to the skewed perception that a prescription drug may be the only way to perform to the high standards of their profession. Occasionally, pharmacists may feel resentment when dispensing controlled substances to patients suspected of prescription medication abuse and feel entitled to the same relief offered to their patients on a daily basis.

A pharmacist does not become addicted to drugs due to stress alone; other variables include family history or addictive personalities, which a pharmacist cannot control. Substance abuse and addiction tend to run in families. According to a 1998 study, the children of drug abusers are eight times more likely to become drug dependent themselves.5 Because genetic links to addictive tendencies can be complicated, the risk a pharmacist takes when deciding to take prescription drugs illegally for the first time is completely variable and may result in addiction after a few uses. Other personal risk factors for substance abuse include current heavy alcohol use (beginning before age 25), socializing with other substance abusers, and male gender.6 A Threat to Patient Safety A pharmacist practicing while impaired can pose devastating risks to patient safety. The mind of an addict is acutely focused on when the next source of drugs will be obtained rather than executing the task at hand, i.e., patient care. Drug addiction can have a more direct effect by impairing the ability to think clearly and make accurate, professional judgments, a side effect of many addictive substances. When professional judgment is impaired, the risk for malpractice and compromised patient safety becomes significant. This regrettable outcome was realized in 2005 when a woman found her 80-year-old mother lying unconscious on the bathroom floor bleeding heavily from her orifices.7 It was later discovered that a pharmacist had incorrectly filled the patient’s antidepressant prescription with an anticoagulant. Upon further investigation of the case, it was revealed that the dispensing pharmacist was impaired by substance abuse. The fact that the pharmacist’s coworkers were aware of his addiction problem makes the case much more alarming.

Barriers to Treatment As evidenced by the previous case, it may be difficult for pharmacy staff to report a colleague or superior when they suspect substance abuse.

However, ignoring the problem or enabling the behavior only prolongs the time that the disease goes untreated. Several factors can serve as motivation for enabling to occur, as outlined in an article by Dave Marley, the former executive director of the North Carolina Pharmacist Recov-

November 2010

Prescription Drug Abuse: The Pharmacist’s Occupational Hazard ery Network Inc.8 The factor that is most likely to be at the forefront of that motivation is financial security. Many times, family, friends and co-workers will cover up an individual’s impairment in order to avoid the threat of loss of job or financial repercussions. Seeking and getting help becomes especially hard in these individuals, as it becomes difficult for them to stop working in order to get treatment. Often, it is not until the board of pharmacy or another official agency becomes involved before an individual will check into a treatment center. Therefore, when signs of abuse are apparent, they should be reported, as it is in the best interest of the substance abuser to receive treatment sooner rather than later (table 1).

Table 1. Signs of Substance Addiction Personality changes or mood swings Changes in physical appearance

(e.g., weight loss or poor hygiene) Frequent absences from work

Showing signs of forgetfulness, irritability and tardiness

Volunteering to check in narcotics or do inventory on them

Decrease in work performance

Long or frequent disappearances from the work station

Excessive ordering of certain drugs

Increase in medication errors

Overreaction to criticism

Enabling is not the only barrier to those seeking treatment; fear of facing the consequences of an individual’s drug use can also play a role.9 Such fears can include dismissal from one’s job, the loss of one’s professional license, and prosecution by government agencies as a result of using illicit substances. In some cases, arrangements can be made to manage these outcomes if a pharmacist admits that they have a problem and goes through the proper procedures to get help. There are a number of previously impaired pharmacists who, after undergoing proper treatment and recovery programs and settling legal concerns, have returned to the profession. The primary concerns should be preventing the individual with the substance abuse problem from practicing while impaired as well as offering rehabilitation services to that individual.

Rehabilitation and Treatment Prescription drug addiction should be treated as a medical condition rather than the pharmacist’s personal decision to abuse. Many states offer assistance to impaired pharmacists in the form of rehabilitation networks. For example, the state of Ohio offers the Pharmacist Rehabilitation Organization (PRO) as a recovery tool for pharmacists suffering from addiction.6 PRO was formed in 1984 in collaboration with the Ohio Pharmacists Association and the Ohio Society of HealthSystem Pharmacists. The goals of the non-profit organization include professional awareness of chemical dependency by the profession of pharmacy, coordination of successful interventions, direction of impaired pharmacists to proper treatment, and service as an advocate to the state board on behalf of the impaired pharmacist in appropriate situations. The organization sponsors monthly regional support meetings for pharmacists in recovery as well as workshops and events to increase aware-

Drugs of Abuse

ness for the cause. Regional volunteer contact information as well as treatment site options are available on the website. When a pharmacist contacts PRO in search of help, the first course of action is usually an assessment by an inpatient or outpatient treatment facility. Once an appropriate treatment regimen has been selected, the pharmacist will sign a PRO contract agreeing to treatment for a period of at least five years.

For more information on the PRO and a list of contacts in Ohio, please visit www.ohiopro.org Post Recovery Joining a support group may aid in the pharmacist’s recovery. Options for support groups include Alcoholics Anonymous (AA) or the very similar Narcotics Anonymous (NA).10,11 These groups consider addiction a progressive illness; the abuser lacks all manner of control over substance use. Those with this illness have a physical sensitivity and obsession with the consumption of alcohol. Concerns about being recognized at group meetings are diminished because members remain anonymous. Recovery programs follow a 12-step, lifelong program designed to teach the substance abuser methods to avoid alcohol or the temptation to consume it. Most importantly, it should be noted that many addicts initially deny that they have a problem; no one should have material forced upon them. The organizations also warn substance abusers that recovery is a lifelong process, and one meeting will not “cure” their disease. A recovering addict must constantly be aware of relapse risks.

Some of these risks include not fully accepting one’s addiction, untreated underlying psychiatric disorders, family issues, or failure to take a continuous, active role in recovery.12 A wealth of information regarding direction to recovery programs, support for recovering pharmacists, and more information about the addiction and recovery process can be accessed online via the Pharmacists Recovery Network.13 Further Information For pharmacists in search of further didactic instruction on the topic of drug abuse, the University of Utah offers an annual School on Alcoholism and Other Drug Dependencies, which was established in 1951 to educate both health care and non-health care personnel on the latest in alcohol and other drug dependencies.14 The aim of the school is to educate the students of the social and health concerns of chemical dependency. At this annual international conference, there are specialized courses offered for a wide variety of health care professionals, including pharmacists.15 The overall goal of the specific pharmacy course at the University of Utah is to educate pharmacists and students on how to create programs aimed at assisting dependent individuals in finding proper treatment, support ongoing recovery, and help in the process of re-entering the pharmacy profession or pharmacy education. The course is intended for people who work at every level of the pharmacy profession, from students or pharmacy technicians to state board of pharmacy officials and national pharmacy association exceutives.14 Conclusion Due to the increase in prescription and alcohol abuse amongst pharmacists, there also should be an increase in awareness from the profession as a whole. The respective state boards are available as an enforcing body with a top priority to protect the patient not the pharmacist. The state boards have a responsibility to intervene if there is an impaired pharmacist by removing them from practice, assisting in rehabilitation

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and providing the appropriate disciplinary actions. Many resources are available to assist recovering pharmacists on their journey back to sobriety; however, these programs are of no use unless the pharmacist, a coworker or a family member addresses the addiction problem. It is important to educate not only other pharmacists, but also other health care professionals and the general public about the dangers of prescription drug abuse. As pharmacists, we take an oath vowing to do what is best for our patients’ safety and well-being; therefore, we have an obligation to ensure that quality, non-impaired pharmacists are serving our patients.

References 1. Ohio State Board of Pharmacy. pharmacy.ohio.gov/ Accessed 4/29/10.

2. Dabney D, Hollinger R. Illicit prescription drug use among pharmacists evidence of a paradox of familiarity. Work and Occupations 1999; 26:77-106.

3. Mott D, Doucette W, Gaither C, Pedersen C, Schommer J. Pharmacists’ attitudes toward worklife: results from a national survey of pharmacists. JAPhA 2004:44;326-336.

4. Levy S. Beware the dark side of pharmacy life. Drug Topics 2002:13;33. Available at drugtopics.modernmedicine.com/drugtopics/ Stories+from+2002/Beware-the-dark-side-of-pharmacy-life/ ArticleStandard/Article/detail/116668.

5. Merikangas K, Stolar M, Stevens D, Goulet J, Preisig M, Fenton B, et al.

Familial transmission of substance use disorders. Arch Gen Psychiatry 1998:55;973-79.

6. Pharmacist Rehabilitation Organization, Inc. Ohio Pharmacists Recovery Network. Updated: 2009 May 4. Accessed: 2010 May 4. Available at www.ohiopro.org.

7. Fink J. Potential legal issues surrounding an impaired pharmacist.

Pharmacy Times 2005. Available at www.pharmacytimes.com/issue/ pharmacy/2005/2005-05/2005-05-9540.

8. Marley, D. Enabling: when you can love someone to death!

Available at www.usaprn.org/AArticle7.htm.

9. Terrie, Y. Lean on me: help for the impaired pharmacist. Pharmacy Times 2006. Available at www.pharmacytimes.com/issue/ pharmacy/2006/2006-11/2006-11-6061.

10. NA World Services, Inc. Information about NA. 2008. Available at www.na.org /?ID=Home-basicinfo.

11. Alcoholics Anonymous World Services, Inc. 1992. Available at www.aa.org/pdf/ products/p-23_aaasaresourceforhcp1.pdf.

12. Bell T. The truth about relapse. North Carolina PRN Newsletter 2005.

Available at usaprn.org/A%20Article%209.htm.

13. Broussard C. Pharmacists Recovery Network. Updated: 29 Nov 2009 Available at www.usaprn.org.

14. American Pharmacists Association. University of Utah School on Alcoholism and Other Drug Dependencies. Available at www.pharmacist.com/Content/NavigationMenu2/ Meetings/University ofUtahSchoolonAlcoholismandOtherDrugDependencies/default.htm.

15. University of Utah School of Medicine. University of Utah School on Alcoholism and Other Drug Dependencies. Available at medicine.utah. edu/uas/index.htm.

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Geriatrics

A Novel Approach to Treating Alzheimer’s Disease Kristen Quertinmont, fifth-year pharmacy student from Carmel, Ind.; Breanne Rizzo, pharmacy student from Columbus, Ohio; Caitlin Swann, fifth-year pharmacy student from Strongsville, Ohio; Lindsay Coram, sixth-year pharmacy student from Eastlake, Ohio; Mary Klein, sixth-year pharmacy student from Mount Cory, Ohio; Whitney Detillion, sixth-year pharmacy student from Portsmouth, Ohio

Introduction Currently, 5.3 million Americans are living with Alzheimer’s disease (AD).1 AD is the most common cause of dementia and causes up to 5080 percent of dementia cases according to the National Institute on Aging.2 The disease is named after Dr. Alois Alzheimer, who first described amyloid plaques and neurofibrillary tangles. Neurofibrillary tangles begin to form in the entorhinal cortex and, along with plaque development in other areas of the brain, lead to neuronal damage, eventually causing malfunction and death of the neuron. Damage to the brain begins 10 to 20 years before onset of symptoms. The damage eventually spreads to the hippocampus, and, as the extent of damage and neuron death increases, the size of the brain decreases.

Although the cause of AD is still unclear, scientists have identified several probable causes, including genetic, environmental and lifestyle factors.2 Familial AD is caused by mutations on certain chromosomes, which results in the formation of abnormal amyloid precursor protein (APP), the precursor for beta-amyloid. Other genetic mutations increase the amount of beta-amyloid formed, which accumulates to form plaques.

Another genetic risk factor, SORL1, was discovered in 2007 and is responsible for the transportation of APP within cells. When present at low levels, the levels of beta-amyloid increase, increasing the harm to neurons. Current research on AD is focusing on the link between cognitive decline and heart disease, high blood pressure, diabetes and obesity. One theory examines decreased blood flow to the brain associated with high blood pressure and high cholesterol. This may result in decreased glucose metabolism and an increase in BACE1, the enzyme that cleaves APP, thus causing beta-amyloid deposition.3 Scientists also are investigating lifestyle factors that may improve the outcome and progression of patients with AD. The National Institute on Aging recommends a nutritious diet, exercise, social engagement and mentally stimulating pursuits as lifestyle factors that might help reduce the risk of cognitive decline and AD.2 Current Treatment Four drugs are currently indicated for the treatment of AD: donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Razadyne®) and memantine (Namenda®). These drugs assist in controlling neurotransmitter release, which may decrease symptoms, but do not treat the underlying cause of AD.2 Donepezil, rivastigmine and galantamine are acetylcholinesterase inhibitors. Inhibiting acetylcholinesterase increases the amount of acetylcholine available to neurons in the brain.1 Acetylcholine is important for learning and memory. The disease destroys cells that synthesize and use acetylcholine. Donepezil is approved to treat all stages of the disease, whereas rivastigmine and galantamine are approved to treat mild to moderate AD. Memantine works by regulating glutamate activity and is approved for treatment of moderate to severe AD. Current treatment is aimed at maintaining cognitive function and slowing the progression of the disease. However, new research is focus-

ing on the cause of the disease rather than treating the symptoms and progression of the disease after onset.2 New Approaches In a normally functioning brain, glucose is the primary energy source, and the contribution made by fatty acids is considered small.4 Glucose undergoes aerobic oxidation to form carbon dioxide and water. In a brain with AD, a decrease in the cerebral metabolic rate of glucose (CMRglu) is observed early on in the process. This disturbance is known as glucose hypometabolism and has been found to occur in some patients decades before the symptoms of AD develop. Because hypometabolism occurs early and is progressive, it is a reasonable target in the treatment of AD, with a therapeutic goal of increasing the neuronal energy state.

One way to reach this goal would be to maintain elevated glucose levels by using insulin sensitizers and, in some cases, insulin. However, this method is associated with significant risks, such as hypoglycemia and the lack of compliance of the patient population causing investigations into alternative energy sources.

Ketone bodies cause hyperketonemia, which can be safely induced and maintained for several hours compared to hypoglycemia. Ketone bodies readily cross the blood brain barrier and are metabolized by neurons.

For decades, ketogenic diets have been used in epilepsy and Parkinson’s disease as a way to decrease blood glucose levels and increase ketone bodies. These diets normally consist of 88 percent fat, 10 percent protein and 2 percent carbohydrates. When used in the management of seizures, 53.9 percent of patients had more than a 75 percent reduction in seizures one month after starting the diet. Parkinson’s patients using this type of diet also showed improvement in motor scores in patients with increased ketone levels after 28 days. Although the diet showed improvements in these central nervous system diseases, it is impractical for chronic use because of the high fat intake, high number of calories and an unpalatable regimen.

Caprylidene One of the major ketone bodies in humans is beta-hydroxybuterate (BHB). The main benefit of BHB is its conversion to acetoacetate (ACA) in the mitochondria. This generates a reducing equivalent of NADH, which increases energy in this redox couple. Conversion of ACA to acetyl-CoA then generates succinate, a substrate for complex II, which allows for possible bypass of complex I inhibition. BHB also increases acetyl-CoA levels in the mitochondria. The end result of having increased ketone levels is improvement of mitochondrial efficiency and a decrease in the number of reactive oxygen species produced. For these reasons, the new drug caprylidene, which is an orally administered medium-chain triglyceride, is being used in the treatment of hypometabolism in AD. Caprylidene is metabolized by the liver to the active ketone bodies BHB and ACA, providing an alternative energy source for the brain. Clinical trials of capylidene in patients with cognitive impair-

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ments that have been completed to date have proven that elevation in plasma BHB levels with an oral dose can improve memory and attention performance in individuals with memory and cognitive impairment.

Caprylidene appears to be a safe method to elevate plasma levels of ketone bodies.

Caprylidene is a medical food dispensed by prescription only that contains a formulation of medium chain triglycerides (MCTs). A medical food is defined as “a food which is formulated to be consumed or administered enterally or orally under the supervision of a physician, and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”5 Caprylidene contains a formulation of caprylic triglyceride, which is an MCT for the clinical dietary management of the metabolic processes associated with mild to moderate AD.6 Patients should take 40 grams (one full packet) mixed in liquid once a day after breakfast or lunch. The most common adverse effects reported by patients in clinical studies were gastrointestinal in nature. Most reported were nausea, abdominal discomfort and diarrhea.

This medical food was tested in trials that allowed subjects to remain on their prescribed medications for AD as long as they had been on a stable dose for at least three months. Most of the patients in these trials were receiving other medications for AD, including acetylcholinesterase inhibitors and/or NMDA receptor antagonists. It was determined that caprylidene can be administered as adjunctive therapy along with other AD medications. Caprylidene contains milk and soy, so it should not be used in patients that are allergic to either of these products. It also should be used with caution in patients with known hypersensitivity to palm or coconut oil and in patients at risk for ketoacidosis, such as alcoholics and uncontrolled diabetics. Also, elevated triglyceride levels were observed in patients who presented with probable metabolic syndrome; therefore, triglyceride levels should be monitored in patients with metabolic syndrome.6 In a double-blind, placebo-controlled clinical trial, researchers tested the hypothesis that acute elevation of serum β-hydroxybutyrate (β-OHB) levels through an oral dose of MCTs would improve memory and attention in individuals with AD or mild cognitive impairments.7 β-OHB is a type of ketone body that appears to protect hippocampal neurons. The cognitive differences were examined between subjects with and without the APOE-ε4 allele. Missing this allele is a genetic risk factor of sporadic AD. Results demonstrated that there was an increase in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) within the ε4- group (P=0.04).

in AD patients and thus resulted in significant differences in ADAS-Cog scores compared to placebo.

Patients and their caregivers should be advised that mild GI symptoms may occur with caprylidene and should be taken following a meal containing fats and proteins so that the digestion of the MCTs occurs more slowly. Sipping the drink over a period of 30 minutes can improve tolerability rather than drinking it all at once. Some patients may require starting at a lower dose (~2 tbsp) and tapering up to a full dose. Also, over-the-counter medications such as simethicone, antacids and antidiarrheals can be useful for treating GI symptoms that may occur.

Caprylidene is a novel therapeutic strategy because it treats one of the underlying causes of AD instead of treating the symptoms and progression of the disease. Because caprylidene is a safe treatment option with few side effects and no interactions with other AD medications, it can be initiated at almost any point in the treatment of AD depending on the physician’s recommendations. In order for a patient to use caprylidene, they need to get a prescription from their physician and bring it into their pharmacy to be filled. Because this drug is so new, and in a relatively new class, further studies need to be conducted to prove the long-term efficacy of the medication and to solidify caprylidene’s place in the treatment of AD. References: 1. Alzheimer’s Association. 2010. Available at www.alz.org/index.asp. Accessed April 27, 2010.

2. Alzheimer’s disease education and referral center. Alzheimer’s disease fact sheet. 2010. Available at www.nia.nih.gov/Alzheimers/Publications/ adfact.htm. Accessed April 27, 2010.

3. Cole S, Vassar R. The Alzheimer’s Disease β-secretase Enzyme: BACE1. Molecular Neurodegeneration 2007;2:22.

4. Costantini LC, Barr LJ, Vogel JL, Henderson ST. Hypometabolism as a therapeutic target in Alzheimer’s disease. BMC Neurosci. 2008, 9(Suppl 2):S16-S25 5. Definitions and official FDA information about medical foods are found at: 21 U.S.C. sec. 360ee(b) (3), 21 C.F.R. sec. 101.9 (j) (8), and “Guidance for Industry: Frequently Asked Questions About Medical Foods” (May 2007), FDA website.

6. Axona [package insert]. Broomfield, CO: Accera Inc.; 2009.

7. Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD, Watson GS, et al. Effects of β-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. 2004;25:311-314.

8. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab. 2009; 6(31).

A randomized, double-blind, placebo-controlled, parallel-group study tested the hypothesis that ketosis could improve cognitive performance in AD. Clinicians administered a ketogenic compound to 152 patients with mild to moderate AD.8 The results demonstrated that, in the population that was missing the APOE- ε4 allele, there was a significant difference in ADAS-Cog scores versus placebo on two different instances (p=0.005 and p=0.0148). It was determined that the ketogenic compound that was studied rapidly elevated serum ketone bodies

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Psychiatry

The Importance of Early Diagnosis and Treatment of Postpartum Depression Sarah E. Drake, fifth-year pharmacy student from Fairfield, Ohio; Alison L. Huet, fifth-year pharmacy student from New Kensington, Pa.; Tana M. Peterman, fifth-year pharmacy student from Jacksonville, N.C.; Jamie L. Drees, sixth-year pharmacy student from Canal Winchester, Ohio; Robert D. Raiff, sixth-year pharmacy student from Westlake, Ohio

Abstract Postpartum depression (PPD) is a major depressive episode following childbirth that can have serious consequences affecting the family. Consequences range from marital problems and issues with child development to maternal suicide and infanticide. Depression in mothers can lead to cognitive and social impairment in the child as well as paternal postpartum depression in the father. Due to the severity of these problems, it is important to diagnose and treat mothers as soon as possible. There are several symptoms that are evident in mothers suffering from PPD that lead to a diagnosis. Symptoms are similar to those of major depressive episodes, but they occur 24 hours to several months postpartum. Treatment options for PPD include psychotherapy as well as tricyclic antidepressants and selective serotonin reuptake inhibitors. While these medications have been shown to be the most effective pharmacological options, more research needs to be conducted to establish their effects on the infants. The possibility of preventative therapy also needs to be addressed to minimize the long-term effects of the disorder.

Introduction Postpartum depression (PPD) is a major depressive episode in which onset usually occurs within four weeks of delivery and affects approximately 13 percent of postpartum women.1,2 This disorder can be damaging to the mother and the rest of the family. It may result in marital problems as well as emotional, behavioral and interpersonal problems in the child subject to this situation.3 While severe postnatal depression is easily detected, less severe presentations can be easily dismissed as normal or natural consequences of childbirth. Failure to recognize postpartum mood disturbances can possibly lead to tragic consequences for the mother and/or child, most notably maternal suicide and infanticide.3 Due to these serious consequences, early diagnosis and appropriate intervention(s) are imperative for the health and well-being of the family.

Symptoms and Risk Factors Symptoms of postpartum depression, also known as puerperal depression, are listed in Table 1.

Table 1. Symptoms of postpartum depression1 Depressed mood

Fatigue or loss of energy

Marked loss of interest in most activities

Feelings of worthlessness

Significant weight loss or gain

Excessive or inappropriate guilt

Insomnia or hypersomnia

Diminished ability to think or concentrate

Psychomotor agitation or retardation

Recurrent thoughts of death

Diagnosis requires that five of these symptoms be present during a twoweek period and that at least one of them is either depressed mood or marked loss of interest in virtually all activities. A woman is at a greater risk of developing PPD if she was depressed during pregnancy, experienced anxiety or a stressful life event during pregnancy, had low levels of social support (including marital support), or had a history of depression.3 Other risk factors for PPD include annual income of less than $20,000, less than a college education, low occupational prestige, single marital status and multiple offspring.5 These issues may be stressors that lead to increased anxiety and risk of depression. Maternity blues are another possible predictor of PPD.6 The blues are described by mild depressive symptoms, tearfulness, sorrow, unstable moods, anxiety and confusion.

These symptoms usually peak within three to five days after birth and can last a couple of hours to a couple of weeks. Prevalence of maternity blues is estimated between 40-60 percent of postpartum women.

Fathers also may experience postpartum depression. The number one risk factor for paternal postpartum depression is maternal depression.4 Fathers are 2.5 times more likely to become depressed if they have a depressed partner. If both parents are depressed, this may negatively impact the development of their child. For men, the most important risk factor to note is a partner with PPD. Fathers also are at an increased risk if they have a history of depression or comorbidities, including obsessivecompulsive disorder (OCD) or anxiety. Some possible biologic risk factors include low testosterone, cortisol, vasopressin, or prolactin levels or dysregulation of estrogen levels. PPD in fathers is also an important area of study because it can adversely affect the development of the child, similar to a mother suffering from the illness.

Impact of PPD In an effort to determine the effects of PPD on an infant, researchers contacted mothers nine months postpartum who had reported low to high levels of depression two days after giving birth.7 There were 100 women included in the study, 45 percent of whom were first-time mothers. To eliminate any other contributing factors, the study included only mothers in stable relationships who were healthy and educated and delivered a healthy full-term infant. The mothers were divided into three groups: those who were diagnosed with major depressive disorder at nine months postpartum (22 mothers), those diagnosed with an anxiety disorder at nine months postpartum (19 mothers), and those who were not anxious or depressed nine months postpartum (59 mothers). The study included two home visits. At the first visit, the mothers were assessed using DSM IV and self-report measures, while the second visit involved taping the mothers playing with their infants. The infants were shown increasingly scary masks to assess fear responses. Saliva samples also were taken from both the mothers and the infants to assess cortisol levels, a stress hormone. The infants were evaluated on essential behaviors necessary for social-emotional growth, including levels of sensitivity, intrusiveness, social engagement, withdrawal, fear regulation and cortisol reactivity.

The infants with depressed mothers scored the lowest in all of these

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The Importance of Early Diagnosis and Treatment of Postpartum Depression

areas. Mothers who are depressed show a decreased sensitivity toward their infants, which can inhibit social skills that must be learned through modeling. Sensitivity from the mother, shown by actions such as giving the child attention and time to rest, helps an infant adapt to a changing environment. Since the infants of depressed mothers lack this attention, they are more likely to have an increased fear response and cry more often. Infants who have not learned to regulate their fear will be more prone to anxiety disorders in later stages of life.

A child is more likely to develop improperly if both parents are depressed.4 Research shows that a child raised with unresponsive or chaotic parenting may have increased cortisol levels, which can hinder brain development, physiological growth and immune system maturity. The cognitive and emotional regulation in an infant can be decreased as a result of lack of maturation of the orbitofrontal cortex due to a poor interaction between a depressed parent and the infant. Paternal interaction with an infant is important for a child’s cognitive, emotional and social development. Some explanations for the effects of paternal depression on a child’s behavior include poor father-child interactions, increased marital conflict (indirect effects), and genetic predisposition.8 Children with depressed fathers show greater evidence for behavioral and conduct problems, including hyperactivity disorders.4 This relationship seems to be greater in boys than in girls. Paternal depression also has been associated with low psychosocial functioning, leading to an elevated suicidal ideation and attempt rates in sons and depression in daughters. Tests show that paternal depression is strongly associated with increased risk of high total problem scores on the Rutter preschool scales and with high scores on the three problem subscales (emotional, conduct and hyperactivity). These problems become evident in children ages 3 to 5.

Treatment Treatment and recovery time for postpartum depression (PPD) varies based on the severity of the depression symptoms experienced by the mother.9 There are a number of management options available for women who experience PPD, and, as with many other psychological disorders, it is better to treat the conditions immediately following diagnosis.

Postpartum depression can begin anywhere from 24 hours to several months after delivery and in some severe cases can last up to two years. Clinical evidence has shown that sex steroids, like estrogen, have effects on the areas responsible for mood and cognition in the central nervous system.10 When childbirth occurs, there is a rapid drop in estrogen in a woman’s body that is thought to trigger depressive symptoms.

Currently, estrogen replacement therapies are being investigated for possible prophylactic use in some women; however, until more information is available on hormone-based treatments, management for PPD is still based on non-puerperal depression.

The first line of therapy for a woman experiencing the signs of PPD is often psychotherapy.10 This is heavily due to the fact that mothers who breastfeed want a nonpharmacologic option to avoid exposing their newborn to antidepressant medications. Counseling from a trained clinical psychologist or psychiatrist is often beneficial for both new mothers and fathers to find ways to cope with their feelings, solve problems and set realistic goals for parenting. The partner or the significant other also should be well-informed of the nature of PPD. While it is beneficial to support the mother, the significant other may be experiencing depres20

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sion as well due to the anxiety and changing roles that parenting brings.

Knowing that they have someone to talk to can take stress off of both parents and, in turn, help depression symptoms. For some, marital or family therapy may be beneficial as well.

For more severe cases of PPD that are not manageable through psychotherapy alone, there are many antidepressant treatment options available through prescription. If a mother is finding it difficult to take care of her baby or herself, or is having thoughts of harming herself or the child, she should talk to her doctor to weigh the benefits along with the potential risks of antidepressant therapy. In most cases, the benefits will outweigh the risks in women with moderate to severe PPD. The most frequently prescribed antidepressants for both puerperal and non-puerperal depression have been tricyclic antidepressants, including imipramine, desimipramine, amitriptyline and nortriptyline.11 These medications are thought to interfere with the reuptake of norepinephrine and serotonin. These four agents are all rated by the American Academy of Pediatrics (AAP) as drugs “of concern” and are not recommended for use by lactating mothers, although they are not currently contraindicated by the Food and Drug Administration.12 However, the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, paroxetine and fluvoxamine, which have a higher specificity for blocking serotonin reuptake, may be better tolerated and have an advantage of once-daily dosing.9 The SSRI chosen is an important issue for lactating mothers. In the case of some SSRIs, such as paroxetine and sertraline, although the agents are excreted in the breast milk, infants are exposed to a relatively low dose of the drug, with serum concentrations not even detectable in the children. No adverse effects have been reported, and, although the medication is considered to be “of concern” due to the excretion of the drugs, it may be used if it is deemed that the benefits of treatment outweigh risks to the child. Other SSRIs (escitalopram, citalopram) are excreted in the breast milk in higher quantities than sertraline or paroxetine, causing the infant to be potentially exposed to a greater amount of drug. Side effects such as excessive somnolence, decreased feeding and irritability have been reported in infants exposed to these medications through breast milk. However, the manufacturers state that the decision for a breast-feeding mother to use these agents should be based on risk to the infant versus therapeutic benefit to the mother. The FDA recommends that fluoxetine not be taken when breastfeeding due to excretion in the breast milk along with measurable serum concentrations, which can be seen in the child. Colic, slow weight gain and sleep disorders have been associated with infants exposed to this medication.

As a result, the drug is not recommended by the manufacturer for use in lactating mothers.13 As with most antidepressant medications, patients typically show improvement of symptoms within two to four weeks of starting the medication.9 If no improvement has been seen during the first two weeks of therapy, the dose of the medication can be increased. Further increasing of the antidepressant should occur no sooner than seven days after the last dosage increase. If there is no clinical improvement in six to eight weeks, the mothers should be referred to a psychiatrist for a psychological evaluation. Although the duration of treatment has not been specifically established, a rough estimate of nine to 12 months has been suggested in women experiencing their first episode of PPD.

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The Importance of Early Diagnosis and Treatment of Postpartum Depression

Psychiatry

Conclusion Childbirth is a stressful situation that causes many changes in the lives of the new parents. This new adjustment can cause significant changes in the mood and behavior of the parents, which may lead to cognitive and social impairment in the child. Managing the disorder is important for the mental health of the parents and the development of their children both emotionally and behaviorally. Tricyclics and SSRIs are currently the most effective pharmacologic treatments for mothers suffering from PPD. However, more research needs to be conducted to determine the effect of these medications on the infant and if prevention therapy can be utilized before the child is born. More studies regarding the effects of childbirth on men, their potential to develop PPD and possible treatment options should also be completed.

References: 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.

2. Goodman JH. Paternal postpartum depression, its relationship to maternal postpartum depression, and implications for family health. Journal of Advanced Nursing. 2004; 45(1): 26-35.

3. Robertson E, Grace S, Wallington, T, Stewart DE. Antenatal risk factors for postpartum depression: a synthesis of recent literature. General Hospital Psychiatry. 2004; 26: 289–295.

4. Kim P, Swain JE. Sad Dads: Paternal Postpartum Depression.

Psychiatry [serial online]. 2007; 4(2): 36-47. Available at www.psychiatrymmc.com/displayArticle.cfm?articleID=article312. Accessed April 5, 2010.

5. Segre LS, O’Hara MW, Arndt S, Stuart S. The prevalence of postpartum depression. Soc Psychiatry Psychiatr Epidemiol. 2007; 42:316–321.

6. Reck C, Stehle E, Reinig K, Mundt C. Maternity blues as a predictor of DSM-IV depression and anxiety disorders in the first three months postpartum. Journal of Affective Disorders. 2009; 113: 77–87.

7. Anderson P. Postpartum depression, anxiety, may affect infant development. J Am Acad Child Adolesc Psychiatry. 2009; 48: 919-927.

8. Ramchandani P, Stein A, Evans J, O’Connor T. Peternal depression in the postnatal period and child development: a prospective population study. The Lancet. 2005; 365: 2201-2205.

9. Epperson CN. Postpartum Major Depression: Detection and Treatment. American Academy of Family Physicians. 1999. Available at www.aafp.org/afp/990415ap/2247.html. Accessed March 22, 2010.

10. Postpartum Depression. Mayo Foundation for Medical Education and Research. 2008. Available at www.mayoclinic.com/health/postpartum-depression/DS00546. Accessed March 22, 2010.

11. Tricyclic Antidepressants. [monograph on the Internet]. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2010.

Available at www.clinicalpharmacology- ip.com/Forms/Resources/overviews.aspx?oid=75. Accessed April 14,2010.

12. Tricyclic Antidepressants. [monograph on the Internet]. Lexi-Comp Online [database online]. Bethesda, MD: AHFS Drug Information; 2010.

Available at online.lexi.com/crlsql/servlet/crlonline. Accessed April 14,2010.

13. Selective Serotonin Reuptake Inhibitors. [monograph on the Internet]. Lexi-Comp Online [database online]. Bethesda, MD: AHFS Drug Information; 2010. Available at online.lexi.com/crlsql/servlet/crlonline. Accessed April 14, 2010.

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Osteoarthritis: Natural Supplements for Joint Health Katherine Salay, fifth-year pharmacy student from Brecksville, Ohio; Kimberly Gathers, fifth-year pharmacy student from Mercer, Pa.; Lindsey McClish, fifth-year pharmacy student from Bellville, Ohio; Lisa Vranekovic, sixth-year pharmacy student from Mentor, Ohio; Kristin Seaman, sixth-year pharmacy student from Shiloh, Ohio; Ryan W. Naseman, sixth-year pharmacy student from Anna, Ohio

Abstract An estimated 46 million adults in the U.S. are affected by arthritis, with osteoarthritis (OA) being the most common. Due to the limited pharmacologic therapy available to treat this condition, many patients are turning to dietary supplements to relieve their symptoms.

Some of the most popular supplements available for the treatment of OA are glucosamine, chondroitin and methylsulfonylmethane (MSM), but many less studied products are also available. Due to limited evidence of efficacy, it is difficult to make a strong recommendation for any of these products; however, pharmacists must be able to educate the patients that choose to use these supplements in the treatment of their OA. Introduction Arthritis currently affects an estimated 46 million adults in the United States alone, and rates are expected to rise dramatically to 67 million over the next 20 years. It is most common in adults 65 years and older and consists of more than 100 different rheumatic diseases and conditions that impact joints, joint tissue and other connective tissue. Osteoarthritis (OA) is the most common and is defined as the degeneration of a jointâ&#x20AC;&#x2122;s cartilage and underlying bone, leading to pain, inflammation and stiffness in the joint. Due to the high prevalence, high lifetime risk of developing OA and many other factors, this disease has become an important public health concern. It is currently the nationâ&#x20AC;&#x2122;s leading cause of disability, causing limited activity in approximately 19 million U.S. adults.

Due to the fact that it is so difficult for people to be physically active with OA, it is a high risk factor for many other chronic diseases and conditions, including obesity, diabetes and cardiovascular disease. Arthritis has been a large expense for the United States over the past several years, costing a total of $128 billion in 2003 alone. It is the reason for approximately 992,100 hospital visits and 44 million outpatient visits every year.1 In order to address this rising concern with arthritis, there are many counseling points that pharmacists may give to their patients affected by this disease. Advising patients to be physically active, maintain a healthy body weight, protect their joints, and schedule regular visits with a physician or even referring them to a self-management education program can be extremely beneficial.1 The mainstay over-the-counter treatment option for relieving symptoms of OA is acetaminophen. Prescription treatment options are few, including COX-2 inhibitors, NSAIDs and even prednisone; however, these drugs do not come without their own adverse effects and risks. Often, patients with OA look to other means of easing the pain and inflammation. Supplements are becoming increasingly popular treatment options for those affected by the disease; however, patients need to be cautious when purchasing these products.

Some of the most popular supplements available for the treatment of OA include glucosamine, chondroitin and methylsulfonylmethane (MSM).

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Glucosamine Glucosamine is arguably the most popular supplement used for joint health. There have been more than 20 studies performed to assess the efficacy of glucosamine alone and in combination with other supplements to treat osteoarthritis of the knee.2-6 The outcomes of these trials have been mixed; for every study performed that finds glucosamine effective, another study has been performed to find it ineffective. It is also interesting to note that many trials backed by pharmaceutical companies yielded clinically significant outcomes, whereas many independently funded trials found no clinically significant outcomes. Despite many mixed outcomes, there have been two large trials that suggest glucosamine could benefit some patient populations. The European GUIDE trial compared the efficacy of glucosamine sulfate alone (1,500 mg once daily) and acetaminophen (3,000 mg once daily) in treating osteoarthritis.7 The 318 enrolled patients were followed for six months, and results proved glucosamine to be more effective than acetaminophen in treating pain. The most recent American GAIT trial followed 1,500 patients for six months and then 750 of those patients for an additional 18 months.

Patients were randomized to glucosamine HCL alone, chondroitin sulfate alone, glucosamine/chondroitin combination, celecoxib, or placebo.8 The glucosamine/chondroitin combination was the only group besides celecoxib to show significant reductions in pain, but this was only noted in the group of patients who had the most severe pain index at study onset. Interestingly, there was also a 55 percent placebo effect in this group of patients. In both cases, adverse reactions were generally mild GI effects like heartburn, diarrhea and nausea. The biggest controversy with these two trials is the use of two different glucosamine salt forms â&#x20AC;&#x201C; HCL and sulfate. The GAIT trial found glucosamine HCL to be ineffective alone, but the GUIDE trial did find the sulfate form to be effective alone.

The question also remains why glucosamine appears more effective in combination than as a stand-alone therapy. The place of glucosamine in current osteoarthritis patients has yet to be established, but recent studies have suggested it may have efficacy in some patient populations.

So, what do you tell a patient who is interested in using glucosamine?

First, explain that efficacy has only been established in certain patient populations, and it may or may not be right for them. Next, you need to inform your patient that the only form that has been proven efficacious is the oral sulfate form. The sulfate form is typically more expensive (anywhere from $9 to $32 for a one-month supply) because it is more costly to manufacture.9 Glucosamine is expensive regardless, but you want to make sure your patient gets the most effective product for their money.

Do not recommend glucosamine cream because efficacy has not been established. At least 1,500 mg daily is needed to be beneficial, and this dose is often broken up into BID or TID dosing. Research has also proven that glucosamine must be used for a minimum of 30 to 90 days to notice any effect.10 Encourage the patient to try at least a 60-day trial period before making the decision to continue or discontinue therapy.

November 2010

Osteoarthritis: Natural Supplements for Joint Health Chondroitin sulfate Chondroitin, found naturally in the human body, is marketed as a cartilage matrix enhancer that helps rebuild and prevent the breakdown of cartilage, thereby maintaining healthy joint function.11 In the body, it is a major component of connective tissue and joint cartilage, and its ability to absorb water increases cartilage thickness and its capacity to tolerate the impact of compressive forces. Additionally, it inhibits synovial enzymes, such as elastase and hyaluronidase, which are thought to destroy cartilage and, thus, weaken joints. Synthesis of chondroitin decreases with age.12 Chondroitin is one of the most common over-the-counter supplements that patients buy in an effort to improve their joint health, yet clinical evidence supporting its effectiveness is limited and inconsistent. The earliest trials that demonstrated its efficacy were not of high quality.13 More recent and superior-quality studies show that chondroitin does not reduce the pain associated with OA. While chondroitin most likely does not have a place in OA therapy for symptom relief, current research has examined its place in structural management of OA. Because of its structure-modifying effect, chondroitin may slow OA progression.14 A meta-analysis examined this beneficial effect in patients with knee OA and determined that it did have a significant protective effect on joint narrowing space, but only after two years of daily treatment. Furthermore, this study also showed that chondroitin may slow the radiological progression of OA with prolonged daily treatment.15

A normal dose of chondroitin is 200-400 mg two to three times per day, or 800-1,200 mg once daily, most often in combination with glucosamine and other supplements. These combination products usually come as a 60-day supply (120 count, taken twice daily), and prices range from $19.99-$47.99, depending on the number of ingredients and the relative milligram strength of each. There are also many dosage forms available, including tablets, capsules, softgels, drinks and flavored powder packets to add to water.16

Due to insufficient quality clinical evidence supporting its effectiveness, lack of symptom relief and high cost, chondroitin should not be recommended to patients. Further studies need to be performed to determine if the structure-modifying effect does slow the progression of OA and if this can be associated with any clinically significant outcomes for patients, such as improved quality of life.

MSM MSM is an organic compound found in green plants, certain species of algae, fruits, vegetables, grains, bovines and humans. It is the oxidized metabolite of dimethylsulfoxide (DMSO) and is commercially produced by combining DMSO with hydrogen peroxide. Preliminary research suggests it might inhibit the degenerative changes in joints, thus helping with pain and swelling and possibly improving joint or physical function.17 This might be due to the compoundâ&#x20AC;&#x2122;s ability to increase blood flow, reduce muscle spasms and inhibit type C nerve fibers from transmitting pain impulses and its power to limit the release of inflammatory mediators. The sulfur present in MSM also is an important element in proteins, connective tissues, hormones and enzymes and, therefore, is significant in the formation of cartilage.18 MSM has been shown to be safe when taken orally in amounts up to 6 g per day for three months, but safety

Preventative Medicine

when used topically or in pregnancy has not yet been established.

Adverse effects include nausea, diarrhea, bloating, headache, fatigue, insomnia and difficulty concentrating; however, these effects have not been very prevalent. Additional side effects in some patients include pruritus and enhanced allergy symptoms. In the treatment of osteoarthritis, MSM should be taken as 500 mg three times daily up to 3 g twice daily.17 A 30-day supply of 1,500 mg MSM tablets can cost anywhere from $10 to $20.19

A randomized, double-blind, placebo-controlled pilot clinical trial was conducted to evaluate the efficacy of MSM in the treatment of osteoarthritis pain in the knee. Fifty patients were given either placebo (n=25) or 3 g of MSM twice daily (n=25) and were evaluated for 12 weeks. Primary outcome parameters were evaluated using the Western Ontario and McMaster University Osteoarthritis Index VAS (WOMAC), which included pain, stiffness, physical function and aggregated total symptoms. Secondary parameters included patient and physician global assessments (disease status and response to therapy) and overall health-related quality of life. Of the 40 patients who completed the study, the MSM group was found to have a significant reduction in WOMAC pain and impairment of physical function (p<0.05). MSM also was found to significantly improve the performance of activities of daily living compared to placebo (p<0.05). There was not a significant change in stiffness or aggregated total symptoms. Even though there was a statistically significant improvement in pain and physical function, the small difference in comparison to the placebo group indicates little clinical significance.

Researchers also state that, although few adverse events were noted, the long-term benefits and safety cannot be determined from this trial and more studies need to be conducted.20

On the other hand, another randomized, double-blind, parallel, controlled clinical trial that assessed the efficacy of glucosamine, MSM, and their combination in osteoarthritis did find significantly positive clinical findings. A total of 118 patients received either 500 mg glucosamine, 500 mg MSM, glucosamine and MSM, or placebo three times daily for 12 weeks. Pain, swelling, the Lequesne index (assessed pain or discomfort, maximum distance walked and activities of daily living) and use of rescue medication were all evaluated as outcome parameters. After 12 weeks of therapy, MSM alone was found to significantly decrease the pain and swelling index from 1.53 Âą 0.51 to 0.74 Âą 0.65 (p<0.001) with the combination product producing even greater effects. The glucosamine/MSM combination also demonstrated a significant reduction in the Lequesne index (p<0.001). Overall, MSM alone and in combination with glucosamine were found to demonstrate significant analgesic and anti-inflammatory actions in the treatment of osteoarthritis.21

Due to the conflicting evidence regarding efficacy and the unknown safety of MSM, more studies need to be conducted. Any patients taking this supplement in the long-term treatment of osteoarthritis should consult a physician before beginning use.

Other Products There are numerous other products and therapies thought to have a benefit in OA. The table below discusses some of the more popular ones, including their possible benefit and presumed effectiveness, based on limited clinical evidence: 13

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Osteoarthritis: Natural Supplements for Joint Health

Product

Possible Benefit

Effectiveness

SAMe

Comparable to celecoxib/ Likely effective other NSAIDS for decreasing OA symptoms with fewer side effects. May require longer treatment period.

Avocado/soybean

Improves pain, overall disability Possibly effective

Beta-carotene

Slows progression, not development of disease

Possibly effective

Camphor (topical)

Symptom relief through counterirritant effects

Effective

Niacin (Vitamin B3)

Improves joint flexibility and reduces inflammation

Possibly effective

Vitamin C

Reduces risk of cartilage loss and disease progression

Possibly effective

Vitamin E

No decrease in symptoms, slows cartilage loss, reduces risk of disease development

Probably ineffective

Insufficient evidence: DMSO, gelatin, ginger, vitamin B5, selenium Nonpharmacologic treatment: acupuncture, mineral baths, magnet therapy, yoga

OTC Regulation The lax regulations surrounding dietary supplements are an important counseling point for all patients. The Dietary Supplement Health and Education Act (DSHEA) of 1994 mandated that the dietary supplement manufacturer is responsible for product safety, not the Food and Drug Administration (FDA).22 Manufacturers do not need to register their products with the FDA before marketing, and the FDA can only withdraw a product from the market after multiple serious adverse drug reactions (ADRs) have occurred. Some companies choose to undergo investigation and certification through paid outside sources, but this is not mandatory.23 The FDA can post lists of dietary supplements that may contain harmful ingredients but can only pull these products off the market after there have been multiple documented cases of serious ADRs (usually death).24 Encourage patients to research the product manufacturer before buying their dietary supplements.

Conclusion Osteoarthritis affects 46 million Americans and is the leading cause of disability.1 As America ages, many are looking for ways to prevent problems or treat existing problems without prescription medication. Glucosamine is likely to be efficacious, but patients must be careful of which type they buy. MSM and chondroitin lack strong evidence for use at present, and MSM has yet to prove safety, so patients should talk to their doctor prior to starting therapy.

At this time, there is a definite lack of evidence proving success or failure for many natural products on the market; however, as health care professionals, it is our responsibility to educate our patients when more evidence has been brought to light about the herbal products they may be taking.

Resources 1. Arthritis: Meeting the Challenge: At a Glance 2010 [website on the Internet].

Atlanta (GA): Centers for Disease Control and Prevention; [updated 2010 Jan 28; cited 2010 Mar 21]. Chronic Disease Prevention and Health Promotion Publications; [about 10 screens]. Available at www.cdc.gov/ chronicdisease/resources/publications/aag/arthritis.htm.

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2. McAlindon T, LaValley M, Gulin J, Felson D. Glucosamine and chondroitin for treatment of osteoarthritis. JAMA 2000;283:1469-75.

3. Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology 2002;41:279-84.

4. Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati L. Glucosamine sulfate use and delay of progession of knee osteoarthritis. Arch Intern Med 2002;162: 2113-23.

5. Cibere J, Kopec J, Thorne A, Singer J, Canvin J, Robinson D, et al. Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. American College of Rheumatology 2004;51:738-45.

6. Herrero-Beumont G, Ivorra J, Trabado M, Blanco F, Benito P, Martin-Mola E, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. American College of Rheumatology 2007;56:555-67.

7. Herrero-Beaumont G, Romรกn JA, Trabado MC, Blanco FJ, Benito P, MartinMola E, et al. Effects of glucosamine sulfate on 6-month control of knee osteoarthritis symptoms vs. placebo and acetaminophen: results from the Glucosamine Unum In Die Efficacy (GUIDE) trial [abstract]. Arthritis Rheum 2005;9 Suppl:1203.

8. Sawitzke A, Shi H, Finco M, Dunlop D, Bingham C, Harris C, et. al.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. American College of Rheumatology 2008; 58(10):3183-91.

9. Glucosamine. Drugstore.com. [cited 2010 Apr 1]. Available at www.drugstore.com.

10. Dahmer S, Schiller R. Glucosamine. Am Fam Physician 2008;78(4): 471-6, 481.

11. Chondroitin; Glucosamine [monograph on the internet]. Clinical Pharmacology [cited 2010 Mar 20] Available at 0-www.clinicalpharmacology-ip.com.

12. Chondroitin sulfate.[monograph on the internet]. Lexi-Comp Online.

Lexi-Comp, Inc. [cited 2010 Apr 1] Available at online.lexi.com/crlsql/servlet/crlonline.

13. Osteoarthritis. Natural Medicines Comprehensive Database. [cited 2010 Mar 20]. Available from www.naturaldatabase.com.

14. Bruyere O, Reginster JY. Glucosamine and chondoitin sulfate as therapeutic agents for knee and hip osteoarthritis. Drugs Aging 2007;24:573-80.

15. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatol Int 2010;30:357-63.

16. Chondroitin. Drugstore.com. [cited 2010 Apr 1]. Available at www.drugstore.com.

17. MSM [monograph on the Internet]. Stockton (CA): Natural Medicines Comprehensive Database; 2010 [cited 2010 Mar 21]. Available at www.naturaldatabase.com.

18. Natural Products Database [database on the Internet]. Hudson (OH): Lexi-Comp ONLINE. 2010 [cited 2010 Mar 21]. Available at online.lexi.com/crlsql/servlet/crlonline.

19. Drugstore.com. Drug Prices & Information. Available at www.drugstore.com/ search/search_results.asp?Ntt=MSM&Ntx=mode%2bmatchallpart.

20. Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF. Efficacy of methylfulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage 2006;14:286-294.

21. Usha PR and Naidu MUR. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clin Drug Investig 2004;24(6):353-63.

22. Segal A. CHPA regulation of over-the-counter-medicines. 2009.

23. Dietary supplements. FDA. Available at www.fda.gov/food/DietarySupplements/default.htm.

24. Using dietary supplements wisely. NCCAM. 2009. Available at nccam.nih.gov/health/supplements/wiseuse.htm.

November 2010

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