Pharmacy and Wellness Review: August 2017 by ONU Communications & Marketing

Drug Abuse Volume 8, Issue 1 Winter 2017

ISSN 2168-7382

Zika Virus: Infectious Process and Public Health Response CE Included

Morgan Homan*, Julia Dickman*, Jenna Deininger**, Austin Hopkins*, Olivia Henton*, Steven N. Leonard+, PharmD 7

Zika Virus Induced Neurological Disorders and Impacts on Public Health CE Included

Alexandra Herman*, Martha Zimmerman**, Olivia Vanscoy**, Olivia Henton*, Lindsey Peters+, PharmD, BCPS 13

Triple Therapy or Triple Threat: An Analysis of Triple Antiplatelet Therapy Compared to Dual Antiplatelet Therapy Isabel E. Cwikla*, Kara C. Horvath**, Elaina Gollmar**, Austin Hilverding*, Erin Petersen+, PharmD, BCPS

Treatment of Basal Cell Carcinoma with Vismodegib

Sunitha Johns*, Katlyn Brown**, Emily Loudermilk*, Crystal Zheng**, Anh Dao Le*, Sophocles Chrissobolis+, Ph.D,

Neonatal Abstinence Syndrome from Selective Serotonin Reuptake Inhibitor Use During Pregnancy Elizabeth Kramer*, Maria Patnella*, Rachel Bulko**, Allie Harrison**, Hannah Lamb*, Manoranjan D’Souza+, M.D., Ph.D.

Maternal and Infant Health Bene its Related to Infantile Feeding Methods

Michaela Wolford*, Alexa Bouts++, Carmen Lariccia**, Cara Walden§, Anh Dao Le*, Andrew M. Roecker+, PharmD, BCPS * ** + ++ §

PharmD candidate, 2018, Ohio Northern University PharmD candidate, 2019, Ohio Northern University Faculty, Ohio Northern University, Raabe College of Pharmacy BS, exercise physiology, 2017, Ohio Northern University BSN, 2017, Ohio Northern University

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Editorial Board: Editor-in-Chief

Steven Blake

Formatting Editor

Cassandra Hacker

Managing Editors

Haval Norman Jana Randolph

Website Editor

Emily Wells

Lead Editors

Austin Hilverding Olivia Henton Hannah Lamb Anh Dao Le

Faculty Advisors:

Mary Ellen Hethcox, BSPh, PharmD, BCPS Karen L. Kier, BSPh, Ph.D., BCPS, BCACP Natalie DiPietro Mager, PharmD, MPH

Layout

Darlene Bowers

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Drug Abuse Infectious Disease

Zika Virus: Infectious Process and Public Health Response Morgan Homan, Julia Dickman, Jenna Deininger, Austin Hopkins, Olivia Henton, Steven N. Leonard, PharmD, associate professor of pharmacy practice

Key Terms Aedes; Centers for Disease Control and Prevention (U.S.); Diagnostic Tests; Fetus; Flavivirus; Florida; Microcephaly; Public Health; Sexual Partners; Vaccines; Zika Virus

This knowledge-based activity is targeted for all pharmacists and is acceptable for 1.0 hour (0.1 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions. ACPE Universal Activity Number (UAN): 0048-0000-17-041-H04-P Expires 3/21/2020 To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/. Objectives After completion of this program, the reader should be able to: 1. Discuss the background and origin of the Zika virus, including where the Zika virus has become endemic in the United States. 2. Identify risk factors for contracting the Zika virus and its common routes of transmission. 3. Recognize the signs and symptoms of the Zika virus. 4. Prepare an appropriate plan to manage patients presenting with Zika virus, including diagnostic testing, treatment and counseling points. 5. Explain the logic behind the current investigational vaccines targeted against the Zika virus. Abstract The Zika virus has become a growing concern as a global pandemic. Since being identi ied in Uganda in 1947, the virus has spread around the world, recently emerging in South America with a great impact on Brazil. As of 2016, Zika has made its appearance in the United States and is now actively being transmitted in Florida. The virus is a mosquitovectored lavivirus primarily transmitted by the Aedes mosquito which infects a human through biting. Transmission through sexual intercourse is also possible as well as transmission from a pregnant woman to her fetus. This latter form of transmission presents the primary problem with the Zika virus; transmission to the fetus can cause microcephaly as well as other brain and developmental problems. Proper precautions should be taken based on these identi ied modes of transmission. Symptoms of Zika are similar to lu-like symptoms, such as low-grade fever, muscle pain and headache. About 20 percent of patients that come in contact with the Zika virus will originally present as asymptomatic and will not display symptoms until almost two weeks after initial contact with the virus. Zika virus can remain in the blood for about a week, but can remain in the semen for months. There are a number of methods used to detect the Zika virus— urine, blood or semen samples may be used to assess if a patient is infected.

Introduction The Zika virus was originally identi ied in Uganda in 1947. It has since spread around the world as two main strains, Asian and African, distinguishable by detailed analysis of the ribonucleic acid (RNA) sequence.1 This difference in sequence relates to a variation in availability for potential glycosylation sites in the virus. The Asian strain is responsible for the outbreaks seen in Brazil and the United States, after travelling through Paci ic Island countries such as Malaysia (1969), Philippines (2012) and Easter Island (2014). In late 2014 and early 2015, reports to the Brazilian Ministry of Health of an “acute exanthematic disease” began following the 2014 Fé dé ration Internationale de Football Association (FIFA) World Cup, and, in March 2015, the Zika virus was isolated in patients in various regions of Brazil.2 By May, the Brazilian Ministry of Health recognized local transmission of the Zika virus. In September, reports of microcephaly began to surface, and on Oct. 23, 2015, the Brazilian Ministry of Health reported the occurrences to the World Health Organization. As the link between Zika virus and microcephaly became more apparent, the Brazilian Ministry of Health published guidelines for the management of microcephaly. There were an estimated 440,000 to 1,300,000 cases of Zika in Brazil in 2015 alone, and 508 cases of microcephaly were con irmed by February 2016. As of 2016, reports of Zika virus spread to the United States, signi icantly increasing awareness of the disease. On Jan. 15, 2016, the Centers for Disease Control and Prevention (CDC) released a health alert warning travelers and health care providers to be vigilant for the signs and symptoms of the Zika virus as travel-associated cases had already been reported in travelers returning to the United States.3 Since then, there has been a rise in cases in the United States, most notably in California, Florida, New York and Texas, with 4,389 travelassociated cases reported as of Dec. 7, 2016.4 As of the same date, 185 locally acquired cases have been reported in the United States: 184 in Florida and one in Texas. The irst reports of local transmission came in late July from Miami, Florida, where Zika virus was isolated in four patients, which was likely caused by local Aedes aegypti mosquito bites, as the patients had not recently traveled outside of the United States.5 Territories of the United States have also reported locally acquired cases: 32,848 cases in Puerto Rico, 57 cases in American Samoa and 807 cases in the Virgin Islands.

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Health care professionals and researchers have worked to gather as much information about the disease as possible, in order to inform the public about proper precautions. 6 In addition, possible treatments and vaccines are currently in development. New information about the Zika virus is constantly being discovered, and the imperative task of keeping the public informed has become an emerging role of health care professionals.

problems for the child. These could include microcephaly, decreased brain tissue, restricted joints, increased muscle tone or damage to the eyes. The Zika virus has been identiied in breast milk; however, to date, there have not been any infections associated with breastfeeding. The proven bene its of breast milk currently outweigh the potential risk of Zika virus. Therefore, the CDC is still recommending breastfeeding in areas where the virus is prevalent.

Etiology and Transmission The Zika virus is a mosquito-vectored lavivirus which uses several mechanisms to alter host cellular pathways to favor viral replication.7 Transmission of the Zika virus can occur through several mechanisms: receiving a bite from an infected mosquito, vertical transmission from mother to child and transmission through sexual activity.6 Less commonly, the Zika virus may be transmitted via blood transfusion or through laboratory exposure, though these are typically not a concern in the general population. There have not been any con irmed cases of transmission via blood transfusion in the United States, though there have been cases reported in Brazil. Additionally, the virus has been identi ied in blood donors in French Polynesia during several outbreaks. In one case study, spread of the virus through sweat and tears was also identi ied as a possible route of transmission.8

An individual may also transmit the Zika virus to any sexual partners.6 Sexual transmission can occur before, during or after the infected individual develops symptoms. It has also been hypothesized that an asymptomatic carrier can still transmit the Zika virus to a sexual partner. The Zika virus has been identi ied in the semen for up to six months after the dissipation of symptoms, much longer than in the blood, urine and vaginal luids. For this reason, the CDC is currently recommending the use of condoms for at least six months after a man has returned from an area where Zika virus is endemic or six months after he has received a positive diagnosis of Zika.

Transmission through the bite of a mosquito is the primary mode of transmission associated with the Zika virus.6 Mosquitos of the Aedes genus may be infected with the virus, speci ically the Aedes aegypti and Aedes albopictus species. These species of mosquito are primary reservoirs for the virus and can transmit other tropical diseases such as dengue fever and chikungunya. An infected mosquito can transmit the virus to a human through a bite. Likewise, a mosquito may also become infected after biting a human infected with the Zika virus. In turn, the newly infected mosquito may spread the virus to any other human it bites. These mosquitos are aggressive daytime biters, though biting, and therefore transmission, is also possible at night. Studies have been conducted that demonstrate vertical transmission as a possible mechanism of survival of the Zika virus in the Aedes aegypti mosquito.9 This is important when considering environments that act as potential breeding grounds for mosquitos. For instance, the Aedes mosquito often lays eggs in standing water.6 This potential form of vertical transmission within the viral reservoir may attribute to disease survival. Vertical transmission in this manner is certainly possible in tropical climates which the mosquitos currently inhabit and may also be a concern in adverse conditions such as colder climates.9 The mosquitos may lay eggs that will hatch once the environment becomes favorable. 9,10 The Aedes mosquitos typically exist in tropical climates, but their range has extended to include the southern United States, possibly allowing for local transmission in this area. 6 If a pregnant female becomes infected, she can pass the Zika virus to her fetus.6 Transmission may occur in utero or near the time of birth and may result in a wide range of health Winter 2017 Volume 8, Issue 1 T

Signs, Symptoms and Diagnosis The Zika virus can manifest itself in many ways once it infects a host. A majority of those infected are asymptomatic or display mild symptoms such as low-grade fever, joint pain, maculopapular rash, arthralgia, nonpurulent conjunctivitis, headaches and myalgia.11,12 Approximately one in ive patients initially asymptomatic will develop symptoms as late as 12 days after infection. In the asymptomatic population without detectable symptoms, the Zika virus can still be transmitted via blood primarily through blood transfusion and sexual intercourse.13 Typically, the Zika virus remains in the blood of an infected individual for about a week, but can remain in other luids, such as semen, for much longer. If an individual suspects that he or she is infected with the Zika virus by displaying any of the above symptoms, he or she should immediately see their primary health care provider.12 A number of factors should be examined in order to give an accurate diagnosis. Factors such as the patientâ&#x20AC;&#x2122;s travel history, symptoms and test results should be examined to determine if the patient is infected with Zika.14 Available diagnostic tests include a blood (serum) test and a urine test, which are used to con irm the presence of the Zika virus in an individual.12 Reverse transcription polymerase chain reaction (RT-PCR) tests are utilized to determine if a urine specimen is positive for Zika virus. Viral RNA in urine has been found to be positive as early as the irst day of the onset of symptoms and as late as 20 days after onset of symptoms. 15 Serum samples may also be obtained to screen for viral RNA using polymerase chain reaction (PCR). If utilizing serum samples for diagnostic purposes, results are more accurate if obtained within seven days of symptom onset. Serum samples obtained more than one week after symptom onset may not yield as accurate diagnostic results as urine samples. Therefore, urine samples should be used for patients who present more than one week following onset of symptoms. 12 Patients who present as asymptomatic or are unable to give a serum P

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or urine sample can undergo serology testing to con irm the presence of Zika. This test looks for the body's reaction against the virus in the form of antibodies that are present within a week of being exposed to the virus. Antibodies also remain in the patientâ&#x20AC;&#x2122;s immune system months after infection. This serology testing is time-consuming and may not be speci ic to the Zika virus. Other viruses with similar structures, such as the yellow fever virus, may cross-react and result in a positive test. . A positive result may, in fact, represent a previous exposure to another virus or past vaccination, and therefore results are dif icult to interpret.16 Although anyone is susceptible to Zika, testing should be reserved for individuals who have traveled to high-risk areas in which the Zika virus is known to be present. Special attention should be given to women who become pregnant within two months of returning from a high-risk area, and they should be tested even if they were originally asymptomatic. Likewise, all symptomatic patients with onset of Zika-like symptoms abroad or within 14 days of return should be offered both viral and serologic testing as part of a workup. There are a number of ways to detect Zika in a potentially infected or asymptomatic individual. 12 It is advised to attempt to gather a serum sample if possible, but urine testing is becoming more favorable, as Zika virus has been found up to 20 days after onset of symptoms. Further investigations are needed to evaluate whether the live virus is excreted in urine. Although larger studies are needed for con irmation, current research strongly suggests that urine is a suitable specimen to be used to detect Zika in patients beyond 14 days after symptom onset.17 Urine specimens are also likely suitable for use in epidemiologic investigations of a larger scale such as testing returning travelers. Response from CDC/U.S. Food and Drug Administration (FDA)/National Institute of Allergy and Infectious Diseases (NIAID) One of the main concerns to patients is the risk of severe fetal brain defects, such as microcephaly, associated with Zika virus infection.18 In response to this, the CDC has established the US Zika Pregnancy Registry to collect information regarding the timing and risks associated with Zika virus infection and transmission during pregnancy. Patients who are eligible to be enrolled in the registry include pregnant women and their infants who have laboratory evidence of Zika virus infection, with or without symptomatology. This information will be used to update clinical recommendations for the treatment and prevention of Zika virus during pregnancy. Several health organizations are currently developing vaccines to target the Zika virus.19 One of these organizations, the National Institute of Allergy and Infectious Diseases (NIAID), is currently investigating several potential vaccine candidates. In a phase I clinical trial, a live-attenuated Zika vaccine based on the Dengue virus vaccine was shown to be safe and induce an immunologic response. This Dengue virus-based vaccine candidate is currently undergoing a large phase III study in Brazil. Dengue virus and Zika virus are both members of the lavivirus genus, and this similarity

was the rationale behind investigating this particular vaccine. West Nile virus is also a member of the lavivirus genus,. Consequently, a deoxyribonucleic acid (DNA)-based vaccine for the Zika virus similar to the investigational vaccine for West Nile virus is also under investigation. This vaccine candidate is currently in an early stage trial. Another vaccine candidate includes a genetically engineered vesicular stomatitis virus (VSV). The VSV recombinant vaccine expresses the Zika virus E glycoprotein,20 and is therefore being evaluated for potential use in preventing Zika virus in tissue and animal models.19 Additionally, a whole-particle inactivated Zika vaccine based on Japanese encephalitis and Dengue virus vaccines is also being investigated. These vaccines are still in early developmental stages and are not expected to be available for several years.

Current Management and Changes As the vaccines that are currently in development are still several years from FDA approval, current management of Zika consists of symptomatic treatment.21 This includes luid replacement for dehydration, rest and acetaminophen for fever and pain. Due to the presence of similar symptomatology between Zika virus and dengue fever, aspirin and other nonsteroidal anti-in lammatory drugs (NSAIDs) should be avoided until dengue can be ruled out. Administration of NSAIDs to a patient with dengue fever signi icantly increases hemorrhaging. Differential diagnosis can be performed via a PCR test. Because there are no current antiviral medications or vaccines available to treat Zika virus, preventing transmission is an important counseling point.22 The most effective way to prevent the transmission of Zika virus is to avoid traveling to areas where Zika is present, when possible. If this is not possible, or the patient lives in an area where Zika is prevalent, he or she should exercise extreme caution to prevent mosquito bites. This includes wearing long-sleeved shirts and long pants that are treated with permethrin, staying in places with window and door screens, sleeping under a mosquito bed net and using United States Environmental Protection Agency (EPA)-registered insect repellents. When using insect repellents and sunscreen, it is important to apply the sunscreen before the insect repellent. Eliminating standing water is vital to prevent further reproduction of the Aedes species mosquitos responsible for the transmission of the Zika virus. Sexual transmission of Zika virus can be prevented by using condoms or abstaining from sex. At this time, the CDC is recommending that men who are exposed to Zika virus use condoms or abstain from sex for at least six months after returning from an area where Zika virus is present. 23 Women who are exposed to Zika virus should use these methods for at least eight weeks. Couples should be educated to use a reliable form of contraception to prevent the transmission of Zika virus from mother to fetus.22 Conclusion As more information is discovered about the Zika virus, it is important for the public to remain informed about the virus demographics and possible treatments and vaccines. Understanding the virusâ&#x20AC;&#x2122;s transmission, particularly through Winter 2017 Volume 8, Issue 1

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mosquito bites, sexual activity and from mother to fetus, is imperative for taking proper preventive measures. As a vaccine for the Zika virus is still several years away from availability, these precautions become even more important. Individuals who have traveled to Zika-infested areas or have a reason to suspect they may have been infected with the Zika virus should know the signs and symptoms of Zika and should understand when or if they should be tested for the virus. It is important for health care professionals to keep up to date as data emerges and recommendations change, so they can use this information to educate patients and address concerns about the Zika virus. References 1. Chang C, Ortiz K, Ansari A, Gershwin ME. The Zika outbreak of the 21st century. J Autoimmun. 2016;68:1–13. 2. Heukelbach J, Alencar CH, Kelvin AA, de Oliveira WK, de Goes Cavalcanti LP. Zika virus outbreak in Brazil. J Infect Dev Ctries. 2016;10 (2):116–20. 3. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus: Zika emergency preparedness and response; 2016 Jan 15 [cited 2016 Nov 4]; [about 4 screens]. Available from: emergency.cdc.gov/han/han00385.asp. 4. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus: case counts in the US; [updated 2016 Dec 7; cited 2016 Dec 13]; [about 4 screens]. Available from: www.cdc.gov/zika/geo/united-states.html. 5. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus: Florida investigation links four recent Zika cases to local mosquito-borne virus transmission; 2016 July 29 [cited 2016 Nov 4]; [about 3 screens]. Available from: www.cdc.gov/media/releases/2016/p0729- lorida-zika-cases.html. 6. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus transmission & risks; [updated 2016 Oct 24; cited 2016 Dec 1]; [about 2 screens]. Available from: www.cdc.gov/zika/transmission/index.html. 7. Klase ZA, Khakhina S, Schneider ADB, Callahan MV, Glasspool-Malone J, Malone R. Zika fetal neuropathogenesis: etiology of a viral syndrome. PLoS Negl Trop Dis. 2016 Aug 25;10(8):1-32. 8. Swaminathan S, Schlaberg R, Lewis J, Hanson KE, Couturier MR. Fatal Zika virus infection with secondary nonsexual transmission. New Engl J Med. 2016 Nov 10; 375(19):1907-9. 9. Thangamani S, Huang J, Hart CE, Guzman H, Tesh RB. Vertical transmission of Zika virus in Aedes aegypti mosquitos. Am J Trop Med Hyg. 2016 Aug 29;95:1169-73. 10. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika dengue mosquito life cycle; [updated 2012 Sep 27; cited 2016 Sep 6]; [about 1 screen]. Available from: www.cdc.gov/dengue/entomologyecology/m_lifecycle.html. 11. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus symptoms; [updated 2016 Jun 28; cited 2016 Sep 23]; [about 1 screen]. Available from: www.cdc.gov/zika/symptoms/symptoms.html. 12. Hurlburt A, Brooks J, Money DM, Patrick DM. Zika virus: a summary. B C Med J. 2016 Apr; 58(3):158-61. 13. Sikka V, Kumar VC, Popli RK, Galwanker SC, Kelkar D, Sawicki SG, et al. The emergence of Zika virus as a global health security threat: a review and a consensus statement of the INDUSEM Joint Working Group. J Glob Infect Dis. 2016 Jan-Mar; 8(1):1-15. 14. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus diagnosis; [updated 2016 Nov 18; cited 2016 Dec 13]; [about 1 screen]. Available from: www.cdc.gov/zika/symptoms/diagnosis.html. 15. Bingham AM, Cone M, Mock V, Heberlein-Larson L, Stanek D, Blackmore C, et al. Comparison of test results for Zika virus RNA in urine, serum, and saliva specimens from persons with travel-associated Zika virus disease—Florida 2016. MMWR Morb Mortal Wkly Rep. 2016 May 13;58(3):475-8. 16. Government of Canada [Internet]. Ottawa (ON): Public Health Agency of Canada. Laboratory testing recommendations for Zika virus; [updated 2016 Apr 20; cited 2016 Sep 25]; [about 2 screens]. Available Winter 2017 Volume 8, Issue 1 T

17. 18.

19.

20.

21.

22.

23.

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from: www.healthycanadians.gc.ca/publications/diseases-conditions-maladies -affections/laboratory-testing-zika-analyse-laboratoire/index-eng.php?id=zika _virus_16_hcdns_pubs_dis_cond. Gourinat AC, O’Connor O, Calvez E, Goarant C, Dupont-Rouzeyrol M. Detection of Zika virus in urine. Emerg Infect Dis. 2015 Jan;21(1):84–6. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus: US Zika pregnancy registry; [updated 2016 Aug 29; cited 2016 Nov 4]; [about 2 screens]. Available from: www.cdc.gov/zika/hc-providers/ registry.html. National Institute of Allergy and Infectious Disease (NIAID) [Internet]. Bethesda (MD): National Institute of Health. Zika virus vaccine; [updated 2016 Aug 18; cited 2016 Nov 4]; [about 1 screen]. Available from: www.niaid.nih.gov/diseases-conditions/zika-vaccines Global Research Collaboration for Infectious Disease Preparedness [Internet]. Annecy (France): Foundation Merieux; c2015. Zika virus (ZIKV) outbreak: overview of relevant research, projects and expertise; 2016 Feb 3 [cited 2016 Dec 2]; [page 10]. Available from: www.glopidr.org/wp-content/uploads/2016/02/glopid-r-zika-virus-overview.pdf. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus: treatment; [updated 2016 Oct 24; cited 2016 Nov 4]; [about 2 screens]. Available from: www.cdc.gov/zika/symptoms/treatment.html. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus: prevention; [updated 2016 Aug 31; cited 2016 Nov 4]; [about 1 screen]. Available from: www.cdc.gov/zika/prevention/index.html. Centers for Disease Control and Prevention [Internet]. Atlanta (GA): US Department of Health and Human Services. Zika virus: protect yourself during sex; [updated 2016 Oct 5; cited 2016 Nov 4]; [about 2 screens]. Available from: www.cdc.gov/zika/prevention/protect-yourself-dur ing-sex.html. The authors have no con lict of interest or funding support to disclose.

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Antibiotic Stewardship and Overcoming Antibiotic Resistance in Upper Respiratory Tract Infections

Assessment Questions 1.

The irst reports of locally transmitted Zika virus in the United States came from . A. Houston, Texas B. Miami, Florida C. New Orleans, Louisiana D. San Diego, California

After what major event did reports of Zika virus begin to surface in Brazil? A. 2014 FIFA World Cup B. Carnival in 2015 C. 2016 Summer Olympics

Which of the following has not been identi ied as a pathway of transmission of the Zika virus? A. Sexual intercourse B. Respiratory droplets C. Mother to fetus D. Bite from a mosquito

What are the CDCâ&#x20AC;&#x2122;s recommendations on breastfeeding in areas where the Zika virus is prevalent? A. Zika has not been identi ied in breast milk, so breastfeeding is recommended. B. Zika has not been identi ied in breast milk, but breastfeeding should be avoided as a precaution. C. Zika has been identi ied in breast milk, so breastfeeding should be avoided. D. Zika has been identi ied in breast milk, but breastfeeding is recommended as the bene its outweigh the risks.

A patient presents to your clinic suspecting they have symptoms of Zika. Upon questioning, you ind they had travelled to Brazil and returned about a month ago, but have only had symptoms on and off for the past 17 days. Which of the following specimens could you test to determine if the patient is infected with Zika? 1. Blood 2. Urine 3. Saliva 4. Semen

Which of the following is unlikely to put a patient at risk for contracting Zika? A. Traveling to Brazil or other areas known for outbreaks of Zika. B. Having a blood transfusion from a patient who had recently been in a high risk area for Zika. C. Not obtaining a proper medical workup after travelling to a high risk area. D. Travelling to areas known for outbreaks of the yellow fever virus.

Investigational vaccines for Zika virus often mimic vaccines for which of the following infectious diseases due to their similarities? A. Human papilloma virus B. In luenza C. Herpes zoster D. Dengue fever

Appropriate treatment for Zika virus includes which of the following? A. acyclovir B. acetaminophen C. ibuprofen D. Oseltamivir

10. At a minimum, how long should a couple wait before trying to conceive a child if the man has recently traveled to an area infected with Zika virus? A. Eight weeks B. One year C. Six months D. If symptomatic, until symptoms resolve, otherwise eight weeks.

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is eligible for credit until 3/21/2020.

To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/ to enter the required information. Please allow two to three weeks for electronic distribution of your continuing education certi icate, which will be sent to your valid email address in PDF format.

All of the following are potential symptoms for Zika except . A. Fever of 99.8o F B. Headache C. Constipation D. Muscle pain

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Zika Virus Induced Neurological Disorders and Impacts on Public Health Alexandra Herman, Martha Zimmerman, Olivia Vanscoy, Olivia Henton, Lindsey Peters, PharmD, assistant professor of pharmacy practice. This knowledge-based activity is targeted for all pharmacists and is acceptable for 1.0 hour (0.1 CEU) of continuing education credit. This course requires completion of the program evaluation and at least a 70 percent grade on the program assessment questions. ACPE Universal Activity Number (UAN): 0048-0000-17-042-H04-P Expires 3/21/2020 To complete the continuing education program and receive credit, please go to www.raabecollegeofpharmacy.org/PAW/. Objectives After completion of this program, the reader should be able to: 1. Describe typical symptoms and duration of Zika virus infection. 2. Explain how Guillain-Barre syndrome and microcephaly affect the nervous system. 3. Recognize the most common neonatal neurological disorders associated with a maternal Zika virus infection during pregnancy. 4. Identify available screening tests and therapies to manage conditions associated with long-term Zika virus effects. 5. List preventive measures taken to decrease the spread of Zika virus. Abstract Zika virus is a public health emergency of international concern. Zika virus (ZIKV) is a mosquito-borne pathogen that is carried by the Aedes genus. Zika is spread through direct bite and nonvector transmission. Most individuals infected with Zika will be asymptomatic, but some may present nonspeci ic viral symptoms. A rising number of neurological disorders in newborns whose mothers were infected with ZIKV during pregnancy have been reported due to recent outbreaks. Neurological disorders affect both the central and peripheral nervous systems and can result from bacterial, viral, fungal or parasitic infections of the nervous system or from the immune response to the infection. Guillain-Barre and microcephaly are two complications that can occur due to ZIKV infection. Recent studies have shown there is a stronger correlation between a maternal ZIKV infection during her irst trimester of pregnancy and neurological disorders in the neonate. Currently, there is not an available treatment option to change the physical appearance of microcephaly or reverse the complications from Zika virus. However, there are developmental screenings and therapies that can be performed to detect and improve strength and movement needed to perform daily tasks. Precautions, such as mosquito repellents and protective clothing, should be taken to avoid exposure. Winter 2017 Volume 8, Issue 1 T

Women should wait the appropriate time lengths and be tested along with their partner, regardless of symptom status, before attempting pregnancy. Available tests include real-time reverse transcription-polymerase chain reaction (rRT-PCR), which is U.S. Food and Drug Administration (FDA) approved and considered the standard test, immunoglobulin (IgM), and plaque reduction neutralization test (PRNT). A combination of these tests will produce the most accurate results. Key Terms Aedes; Fetus; Microcephaly; Pregnancy Trimester First; Zika Virus Introduction Zika virus is a mosquito-borne pathogen that is carried by the Aedes genus. In tropical regions the Aedes aegypti is the carrier. In temperate regions the carrier is Aedes albopictus. The Aedes genus also carries dengue fever, chikungunya and yellow fever viruses.1 Transmission of Zika virus (ZIKV) occurs through direct bite. Nonvector transmission primarily involves sexual routes, speci ically from symptomatic men to partners, perinatal and blood transfusion. At this time, there is no evidence to support transmission through urine, saliva, breastfeeding or respiratory droplets. Zika virus has an incubation period that has been estimated to be four to seven days. Most individuals infected with the virus are asymptomatic. Infected individuals who are symptomatic typically experience nonspeci ic viral symptoms such as arthralgia, myalgia, headache, malaise, rash and nonpurulent conjunctivitis that have a two to seven day duration. More serious complications that have been reported include birth defects and long-term neurological complications.2 Zika is a lavivirus consisting of single stranded, positive ribonucleic acid (RNA). The Flaviviridae family includes other human pathogens including dengue, West Nile, yellow fever, tick-borne encephalitis and Japanese encephalitis virus.3 The virus is a 50 nm spherical virion that comprises three structural proteins. It is believed to form one serotype with two main lineages: African and Asian. Outbreaks in the United States have been traced back to the Asian lineage. The Asian lineage has been associated with NS1 codon usage making it better adaptable to humans. The African lineage transmission is sylvatic and has not been associated with symptoms. 4 The virus isolate enters human dermal ibroblasts, epidermal keratinocytes and immature dendritic cells.3 The initial immune receptor is the Toll Like Receptor 3 (TLR-3) which detects the infection in human ibroblasts. The activation of TLR-3 pathways in central nervous system (CNS) cells may trigger apoptosis and attenuate neurogenesis, directly conP

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tributing to fetal neuropathology.5 Transplacental delivery to fetus may occur by infection of the cytotrophoblasts or transmigration of infected primary human placental macrophages.3 Neurological Introduction With the recent outbreak of ZIKV there has been a rise in neurological disorders reported in newborns whose mothers were infected with ZIKV during their pregnancy. 6 Neurological disorders affect the central and peripheral nervous systems; this includes the brain, spinal cord, muscles, nerve roots, autonomic nervous system, peripheral nerves, cranial nerves and neuromuscular junctions. The presentation of these disorders varies based on the causative agents and what part of the nervous system is affected. Neurological disorders can result from bacterial, viral, fungal or parasitic infections of the nervous system from the host immune response to the infection. The most common bacterial causes of neurological disorders are Mycobacterial tuberculosis and Neisseria meningitides. The most common fungal infections are Cryptococcus and Aspergillus. Malaria and Chagas are the result of parasitic infections. Lastly, the viruses that can cause neurological disorders are human immunode iciency virus (HIV), Enteroviruses, West Nile virus, and Zika virus. When a pregnant mother contracts a ZIKV infection there is a risk her unborn child will develop neurological complications. These neurological complications include GuillainBarre syndrome, encephalitis, meningoencephalitis, facial paralysis, myelitis and microcephaly.7,8 Currently there is little information on the effects of a mild or asymptomatic ZIKV infection during early pregnancy. The risk of a fetus developing a neurological complication is higher when a pregnant woman experiences a symptomatic ZIKV infection. 9 While a ZIKV infection can cause all of the neurological com-

plications mentioned above, it has been observed to most commonly cause Guillain-Barre and microcephaly. Guillain-Barre In some cases of Zika there are more serious clinical outcomes reported, including Guillain-Barre syndrome. GuillainBarre syndrome is an autoimmune and neurological disease, in which the bodyâ&#x20AC;&#x2122;s immune system attacks the peripheral nervous system.7 The syndrome can affect the nerves that control muscle movement as well as those that transmit feelings of pain, temperature and touch. This can result in muscle weakness and loss of sensation in the legs and arms. GuillainBarre syndrome is triggered by previous infections, typically respiratory or gastrointestinal. Other viruses that have been associated with Guillain-Barre include dengue fever and chikungunya. Guillain-Barre syndrome is not thought to be mediated by antiglycolipid antibodies but is thought to be introduced by neurotoxic factors associated with Zika. The acute phase of Guillain-Barre syndrome is treated with either plasmapheresis or intravenous immunoglobulin and supportive care. The recovery phase typically lasts from six to twelve months but may take up to three years for some patients.10 Approximately 80 percent of patients can walk independently six months after diagnosis, and 60 percent fully recover motor strength one year after diagnosis. Microcephaly Microcephaly is a birth defect where the newbornâ&#x20AC;&#x2122;s head has a signi icant degree of reduction in the circumference when compared to other newborns of the same sex and age. The smaller head circumference is a direct result of microcephaly, that is, smaller brains, which did not develop properly, and can lead to impairment in motor, sensory and cognitive functions.11,12 Figure 1 compares an infant with a normally

Figure 1. Comparison of Normally Developed Head to Varying Severities of Microcephaly in Infant. 13

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developed head to infants with varying severities of microcephaly.13 Microcephaly is a result of a decrease in the number of cell divisions in the brain during fetal development, resulting in a decrease in production of functional neurons.12 A large number of various case reports and studies illustrate a strong correlation between a ZIKV infection in the pregnant mother and the development of microcephaly in the developing baby.8,12,14 A study by Frietas et al. looked at the overall incidence of ZIKV infections in pregnant mothers and the risk of microcephaly.8 The results of their investigation showed that more than one million people have been infected with ZIKV since its endemic onset in April 2015. They also uncovered an unusual increase in the number of newborns with microcephaly six months after the onset of the endemic. In 2015 there were 1,248 new cases of microcephaly registered, which corresponded to 99.7 cases per 100,000 live births. This incidence represents a twentyfold increase in microcephaly cases when compared to recent years. This inding helps conirm that the increase in microcephaly cases is due to the current ongoing ZIKV endemic. Studies about Zika and the Risk of Various Birth Defects A preliminary report conducted by Pacheco et al. investigated the ZIKV outbreak in Colombia by using the national public health surveillance system of the Colombian Instituto Nacional de Salud (INS).14 This surveillance system serves to collect information for noti iable conditions like dengue, chikungunya, ZIKV, acute laccid paralysis and congenital defects. The results of reported diseases are published by INS weekly. Patients met inclusion criteria for the study if they had clinical symptoms with or without laboratory con irmation of ZIKV from Aug. 9, 2015, to April 2, 2016. At the time of this study, data collection was still ongoing for the majority of the patients in this group. The researchers performed a subgroup analysis which included the 1,850 patients who had already delivered their babies. All of the patients in the subgroup analysis also reported during which week in their pregnancy they noticed the onset of ZIKV symptoms. In this subgroup, 532 patients became infected during the irst trimester, 702 in the second trimester and 616 in the third trimester. For the group of women who were diagnosed with ZIKV in the third trimester, 82 percent of the children were born with a normal birth weight without any neurological disorders. The remaining 18 percent of children born to women diagnosed with ZIKV during the third trimester fell into the following categories: 2 percent were born with a low birth weight, 8 percent were born preterm, 1 percent died during the perinatal period. The remaining 7 percent were still being followed at the time the study was published. There were no reported cases of microcephaly or brain abnormalities in any of the children whose mothers contracted ZIKV during the third trimester of pregnancy. This study also utilized the INS to look for cases of reported microcephaly. From Jan. 1, 2016, until April 28, 2016, a total of 50 infants were reported to the INS for possible microcephaly. Currently the causes of 26 of the cases are still being Winter 2017 Volume 8, Issue 1 T

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investigated.14 Twenty cases had identi iable causes that were not related to ZIKV and were determined to have been caused by syphilis, toxoplasmosis, rubella, cytomegalovirus and herpes (STORCH) infections, genetic causes or neural tube defects. These 20 children also had negative results of the diagnostic ZIKV RNA reverse transcriptase polymerase chain reaction (RT-PCR) test. The inal four infants had microcephaly caused by an asymptomatic ZIKV infection in the mother evidenced by a positive RT-PCR assay, negative STORCH evaluation and normal karyotypes. Another study conducted by Tang discussed the current evidence linking ZIKV infections as a causative agent for microcephaly.12 This study reviewed previous ZIKV outbreaks with cases from Bahia and a retrospective study from French Polynesia. It was shown with population level data analyses that there is a strong association between the pregnant mother contracting the ZIKV infection during the irst trimester, or the irst 12 weeks of pregnancy, and an increased risk of microcephaly in neonates as opposed to being infected during the second or third trimester.12,15 The second trimester consists of weeks 13 to 28, and the third trimester is from the 29th to the 40th week.15 A second study by Johansson et al. con irmed this association when they evaluated the ZIKV and the risk of microcephaly in neonates.9 They found that the risk of inducing neurological disorders in the fetus was the highest with infection during the irst trimester. This study also discovered there is a negligible risk between a ZIKV infection in the second and third trimesters and microcephaly development in the neonate. The study by Tang further discovered that some infants whose mothers had been infected with ZIKV during their irst trimester of pregnancy presented with macular atrophy and a decreased cephalic diameter.12 This inding was supported by a study done by Frietas et al. which followed 29 mothers who had a con irmed diagnosis of ZIKV while pregnant and gave birth to a newborn with microcephaly. Of the 29 newborns, 10 were found to have ocular abnormalities. These abnormalities included focal pigment mottling, chorioretinal atrophy especially in the macular area and optic disc abnormalities. It is important to note that the mothers did not have any kind of ocular disturbance or conjunctivitis during their pregnancy.8

Treatment Options for Long-Term Effects of Zika Virus Microcephaly is one of the most concerning effects of Zika virus; however, there is no treatment that will change the physical appearance, enlarge the infantâ&#x20AC;&#x2122;s head or reverse the possible complications it can cause.16 Soon after the infant is born, developmental screenings should be performed at each health care visit. Developmental milestones, growth, sleep, irritability and abnormal movements should all be monitored and reported to the health care provider. A comprehensive eye exam should be performed within one month of birth, and additional vision screenings should be addressed at each follow-up visit. Auditory brainstem responses should be performed within one month of birth and then again at four to six months.17 P

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Available treatments focus on ways to manage conditions that stem from the microcephaly. Early childhood intervention programs that include speech, physical and occupational therapy may help patients strengthen abilities.16 These therapies may improve strength, movement, con idence to perform daily tasks, language skills and even self-esteem issues associated with the condition.18 Some cases of microcephaly can lead to serious learning and speech disabilities, dif iculties with neurological functions and physical complications like seizures and facial deformities. If seizures occur, they may be treated with pharmacologic interventions. Zika and Public Health According to the Centers for Disease Control and Prevention (CDC), Zika virus is a public health emergency of international concern. As of Sept. 7, 2016, there have been 671 cases of pregnant women with evidence of Zika virus in the United States alone.19 Since a vaccine to prevent infection of Zika virus is not currently available, all populations should take precautions to avoid mosquito bites during the day and night. This can include wearing long sleeves and pants, using mosquito repellents (those with DEET or permethrin) and preventing mosquitos from entering the home by using screens on windows and doors. Zika can be spread through intercourse with an infected partner; therefore, male condoms should be used to reduce the risk of acquiring the virus. There are greater central nervous system (CNS) concerns for certain populations, such as women who are either attempting to become pregnant or are presently pregnant; therefore, these women should be tested for Zika virus if a possible exposure has occurred. Women with diagnosed Zika virus and asymptomatic women with a possible exposure should wait at least eight weeks from symptom onset (symptomatic) or Zika virus exposure (asymptomatic) before attempting pregnancy. Regardless of symptom status, men with a possible Zika virus exposure should wait at least six months after exposure or symptom onset before attempting pregnancy with their partner.20, 21 The U.S. Food and Drug Administration (FDA) has approved real-time reverse transcription-polymerase chain reaction (rRT-PCR) and considers it the standard test to detect Zika virus. Other tests include assessing immunoglobulin (IgM) levels and a plaque reduction neutralization test (PRNT). It is recommended that a combination of these tests be done for the most accurate results. In pregnant women with a possible Zika exposure, it is recommended that a prenatal ultrasound be performed, regardless of laboratory test results. 21 Many of these tests require a blood or urine sample and must be performed at a CDC center, state or federal health institution or commercial laboratory. Because the presentation of Zika virus is nonspeci ic and may be mistaken for other viral infections, a quick and reliable diagnostic test is needed that could be used in less-developed areas where Zika virus is more prevalent and access to diagnostic laboratory equipment is limited. Studies are being conducted to evaluate the effectiveness of a highly sensitive reversetranscription loop-mediated, isothermal ampli ication (RTLAMP) assay for the detection of Zika as a point-of-care test

cassette for patients.22 To date, there have been no con irmed blood transfusiontransmission cases in the United States. However, because there is a strong possibility that Zika may be transmitted through blood, the FDA recommends that whole blood and blood components be screened for the virus once a licensed test becomes available.21, 23 To gather and centralize data to understand more about the risks of Zika virus during pregnancy, the CDC established the US Zika Pregnancy Registry and is collaborating with health care professionals at the state, tribal, local and territorial levels. The registry is an active surveillance system that keeps track of pregnant women with laboratory evidence of con irmed Zika virus and pregnant women with a possible infection from con irmed exposure in the United States and its territories. It also includes weekly reporting of the number of women followed in the registry. The CDC encourages patients to submit information after birth as well. All of the information collected in the registry will be used to update recommendations for diagnostic testing, monitoring, counseling and therapy.21, 24, 25 The CDC has also established Zika Active Pregnancy Surveillance System (ZAPSS) which includes Puerto Rico.26 Conclusion Zika virus epidemic has raised concerns for health care providers worldwide. The quick transmission from mosquito to human and lack of consistent symptoms make the infection dif icult to diagnose. Neurological disorders that result from the virus can range from mild to life-threatening. The largest concern arises from pregnant mothers due to interruption of fetal development, especially in the irst trimester. Although there are currently no available treatment options for the neurological defects of ZIKV on infants, screening tests and therapies to manage the conditions are available. Caution should be taken by all populations and multiple tests should be performed to receive the most accurate diagnosis after exposure. In order to understand more details about ZIKV, the CDC has established registries and surveillance systems for high risk populations such as pregnant women. These programs will help shape future guidelines and initiatives to prevent Zika infections and long-term complications. References 1. Galan-Huerta KA, Rivas-Estilla AM, Martinez-Landeros EA, ArellanosSoto D, Ramos-Jimenez J. The Zika virus disease: an overview. Medicina Universitaria. 2016 Jul 4;18(71):115-24. 2. May M and Relich RF. A comprehensive systems biology approach to studying Zika Virus. PLoS One. 2016 Sep 1;11(9):1-15. 3. Olagnier D, Muscolini M, Coyne CB, Diamond MS, Hiscott J. Mechanisms of Zika Virus infection and neuropathogenesis. DNA Cell Biol. 2016 Jun 6;35(8):367-72. 4. Freire CC, Iamarino A, Neto D, Ferreira S, Amadou A, Zanotto P. Spread of the pandemic Zika Virus lineage is associated with NS1 codon usage adaptation in humans. bioRxiv. 2015 Nov 25;1-8. 5. Malone RW, Klase Z, Khakhina S, Callahan MV, Glasspool-Malone J, Bernardi Schneider AD. Zika fetal neuropathogenesis: etiology of a viral syndrome. PLoS One. 2016 Aug 25;10(8):1-32. 6. World Health Organization [Internet]. What are neurological disorders? [updated 2016 May; cited 2016 Oct 30]; [1 screen]. Available from: www.who.int/features/qa/55/en/.

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10. 11.

12.

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14.

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18.

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22. 23.

24.

Araujo AQC, Silva MTT, Araujo APQC. Zika virus-associated neurological disorders: a review. Brain. 2016 Jun 29;139:2122-30. Freitas B, Dias R, Prazeres J, et al. Ocular indings in infants with microcephaly associated with presumed Zika Virus congenital infection in Salvador, Brazil. JAMA Ophthalmology [Internet]. 2016 Feb 9 [cited 2016 Oct 30];134(5):529-35. Available from: archopht.jamanetwork. com/article.aspx?articleid=2491896. Johansson M, Romero L, Ree huis J, et al. Zika and the risk of microcephaly. N Engl J Med [Internet]. 2016 July 7 [cited 2016 Oct 30];375 (1): [4 p.]. Available from: www.nejm.org/doi/full/10.1056/NEJMp16 05367#t=article. Mayo Clinic [Internet]. Gullain-Barre syndrome; 2016 Jan 1 [cited 2016 Nov 27]; [2 screens]. Available from: www.mayoclinic.org/diseasesconditions/guillain-barre-syndrome/basics/treatment/con-20025832. Center for Disease Control [Internet]. Atlanta (GA): US Department of Health and Human Services. CDC’s microcephaly and other birth defects. [updated 2016 Nov 3; cited 2016 Nov 4]. Available from: www.cdc.gov/zika/healtheffects/birth_defects.html. Tang B. Zika virus as a causative agent for primary microencephaly: the evidence so far. Arch Microbiol [Internet]. 2016 July [cited 2016 Oct 30];198(7): 595-601. Available from: link.springer.com/article/10.10 07%2Fs00203-016-1268-7. Center for Disease Control [Internet]. Atlanta (GA): US Department of Health and Human Services. CDC’s response to Zika measuring head circumference [updated 2016 Sept 8; cited 2016 Nov 3]; [2 screens]. Available from: www.cdc.gov/zika/pdfs/microcephaly_measuring.pdf . Pacheco O, Beltrá n M, Nelson CA, et al. Zika Virus disease in Colombia—preliminary report. N Engl J Med [Internet]. 2016 June 15[cited 2016 Oct 30]; [10 pages]. Available from: www.nejm.org/doi/ full/10.1056/NEJMoa1604037#t=article. Womenshealth.gov [Internet]. Washington, DC: Of ice on Women’s Health at the U.S. Department of Health and Human Services. States of Pregnancy; 2010 Sept 27[cited 2016 Dec 13]; [8 screens]. Available from: www.womenshealth.gov/pregnancy/you-are-pregnant/stages-of-preg nancy.html. Mayo Clinic [Internet]. Diseases and conditions microcephaly treatments and drugs; 2016 Jan 25 [cited 2016 Oct 30]; [1 screen]. Available from: www.mayoclinic.org/diseases-conditions/microcephaly/basics/ treatment/con-20034823. Center for Disease Control [Internet]. Atlanta (GA): US Department of Health and Human Services. CDC’s update: interim guidance for the evaluation and management of infants with possible congenital Zika Virus infection—United States, August 2016. [updated 2016 Aug 29; cited 2016 Nov 4]. Available from: www.cdc.gov/mmwr/volumes/65/ wr/mm6533e2.html. Boston Children’s Hospital [Internet]. Boston (MA): Boston Children’s Hospital. Treatments for microcephaly in children [cited 2016 Oct 30]; [3 screens]. Available from: www.childrenshospital.org/conditions-and -treatments/conditions/m/microcephaly/treatments. Center for Disease Control [Internet]. Atlanta (GA): US Department of Health and Human Services. CDC’s case counts in the US. [updated 2016 Nov 3; cited 2016 Nov 4]. Available from: www.cdc.gov/zika/ geo/united-states.html. Center for Disease Control [Internet]. Atlanta (GA): US Department of Health and Human Services. CDC’s Zika Virus prevention [updated 2016 Aug 4; cited 2016 Nov 4]. Available from: www.cdc.gov/zika/ prevention/index.html. Riley L, Ecker JL, Heine RP. The American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine [Internet]. Washington, D.C. Practice advisory on Zika Virus. 2016 Oct 18 [cited 2016 Nov 4]; [24 screens] Available from: www.acog.org/AboutACOG/News-Room/Practice-Advisories/Practice-Advisory-Interim-Gui dance-for-Care-of-Obstetric-Patients-During-a-Zika-Virus-Outbreak. Song J, Mauk MG, Hackett B, Cherry S, Bau HH, Liu C. Instrument-free point-of-care molecular detection of the Zika Virus. Anal Chem. 2016 July 16; 88: 7289-94. Burton T. FDA calls for Zika testing of all blood donations. The Wall Street Journal [Internet]. 2016 Aug 26 [cited 2016 Nov 4]; [4 screens]. Available from: www.wsj.com/articles/fda-calls-for-zika-testing-of-allblood-donations-1472225303. Panchaud A, Vouga M, Musso D, Baud D. An international registry for women exposed to Zika virus during pregnancy: time for answers. Lancet Infect Dis. 2016 Sept;16(9):995-6.

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25. Center for Disease Control [Internet]. Atlanta (GA): US Department of Health and Human Services. CDC’s US Zika Pregnancy Registry [updated 2016 Aug 29; cited 2016 Nov 4]. Available from: www.cdc. gov/zika/hc-providers/registry.html. 26. Center for Disease Control [Internet]. Atlanta (GA): US Department of Health and Human Services. CDC’s possible Zika Virus infection among pregnant women - United States and Territories, May 2016 [updated 2016 May 26; cited 2016 Nov 4]. Available from: www.cdc.gov/mmwr/ volumes/65/wr/mm6520e1.htm. The authors have no con lict of interest or funding support to disclose.

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Assessment Questions 1.

Which of the following patients should be screened for Zika? A. A young woman presenting with fever and tiredness who recently attended the Olympics in Rio. B. An elderly man from Indonesia who is complaining of a rash and nonpurulent conjunctivitis. C. A pregnant woman living in Florida who is asymptomatic . D. All of the above. E. A & B.

Zika virus has an incubation period of ____ days and a symptom duration of ___ days. A. 2-7, 4-7 B. 4-7, 2-7 C. 3-5, 9-13 D. 1-4, 6-10

Guillain-Barre syndrome is thought to be A. Mediated by antiglycolipid antibodies B. Introduced by Zika associated neurotoxic factors C. Associated with memory loss D. Treated with statin therapy

True or False: Microcephaly is a result of a decrease in the number of cell divisions in the brain during fetal development resulting in a decrease in production of functional neurons which leads to motor, sensory and cognitive impairments later in life. A. True B. False

Current studies show a maternal ZIKV infection during the ____ trimester(s) is more likely to result in children born with microcephaly. A. Third B. Second C. First D. A & B E. B & C F. All of the above. All of the following are neurological disorders associated with a ZIKV infection except: A. Macular atrophy B. Microcephaly C. Neuroinfections D. Guillain-Barre syndrome E. Meningoencephalitis

For children born with possible microcephaly, how soon should a comprehensive eye exam and auditory brainstem response test be performed? A. At month 2 B. Within the irst month C. Within the irst year D. At month 6

Studies are being conducted to evaluate the effectiveness of a highly sensitive reverse-transcription loopmediated, isothermal ampli ication (RT-LAMP) assay. How would this test, if available, be administered? A. Point-of-care cassette B. Laboratory blood draw C. Physician administered POC D. Self-administered saliva swab

Asymptomatic women with diagnosis or possible exposure of Zika virus should wait _________ from symptom onset before attempting pregnancy, and men regardless of symptom status with a possible exposure to Zika virus, should wait __________ before attempting pregnancy with their partner. A. 2 weeks, 1 week B. 1 year, 6 months C. 8 weeks, 6 months D. 6 months, 8 weeks

10. Which of the following test(s) is/are currently available to detect Zika virus? A. Real-time reverse transcription-polymerase chain reaction (rRT-PCR) B. Immunoglobulin (IgM) C. Plaque reduction neutralization test (PRNT) D. Two of the above E. All of the above

Ohio Northern University is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is eligible for credit until 3/21/2020.

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Cardiology Drug Abuse

Triple Therapy or Triple Threat: An Analysis of Triple Antiplatelet Therapy Compared to Dual Antiplatelet Therapy Isabel E. Cwikla, Kara C. Horvath, Elaina Gollmar, Austin Hilverding, Erin Petersen, PharmD, assistant professor of pharmacy practice Abstract Triple antiplatelet therapy (TAPT, or triple therapy), is an oral medication regimen designed to reduce the risk of major cardiovascular events. It consists of aspirin, clopidogrel or an alternative, and an oral anticoagulant (OAC). It differs from dual antiplatelet therapy (DAPT) due to inclusion of an OAC. Multiple clinical studies have indicated that triple therapy is more effective at clot prevention, when compared to aspirin monotherapy and DAPT, but is associated with a higher risk of major bleeding. Pharmacists have a key role in determining candidates for DAPT and TAPT regimens. Other opportunities for pharmacists include patient monitoring, counseling and medication review throughout treatment with antithrombotic therapy.

infarction (MI). The primary endpoints were death from cardiovascular (CV) causes, nonfatal MI and nonfatal stroke. The secondary outcomes were stent thrombosis and planned PCI for patients enrolled in the study with acute coronary syndrome. The results of this study showed that there was a reduced death rate from MI for subjects taking prasugrel compared to those taking clopidogrel. However, the prasugrel group experienced increased bleeding (1.4 percent in the prasugrel group versus 0.9 percent in the clopidogrel group, p=0.01).5 Prasugrel is a more potent inhibitor of platelet aggregation than clopidogrel due to higher exposure of the metabolite to the receptor. It is wellabsorbed and metabolized by the body and inhibits platelet aggregation within 30 minutes of administration. In comparison, clopidogrel has a median onset of inhibition of 1.5 hours.6 It is suggested to weigh the bene its of prasugrel as an antiplatelet agent against its risks for bleeding as compared to clopidogrel.

Key Terms Acute Coronary Syndrome; Anticoagulants; Antiplatelet Drugs; Aspirin; Cardiovascular Diseases; Dabigatran; Factor Xa Inhibitors; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Thrombosis, Warfarin

Another antiplatelet agent used in place of clopidogrel is ticagrelor which acts via reversible inhibition of the P2Y 12 ADP receptor.7 Ticagrelor has been shown to have greater inhibition of the receptor than clopidogrel. In a study comparing the ef icacy and safety of ticagrelor and clopidogrel in patients hospitalized for ACS, ticagrelor decreased rates of death due to vascular MI and stroke more than clopidogrel, with a hazard ratio of 0.84 (p < 0.001, 95 percent CI [0.770.92]).7 Clopidogrel and ticagrelor did not differ in risk of bleeding, while prasugrel showed more intracranial and gastrointestinal bleeding than ticagrelor.5 This indicates that ticagrelor may be more effective as an antiplatelet agent, without the adverse effect of increased bleeding, as compared to clopidogrel and prasugrel.

Introduction Dual antiplatelet therapy (DAPT) consists of aspirin and clopidogrel (or an alternative). It is used to prevent thrombosis and inhibit platelet function for patients with coronary artery disease (CAD), atherosclerotic ischemic stroke, atrial ibrillation (AF) or acute coronary syndrome (ACS) with or without percutaneous coronary intervention (PCI).1 However, the introduction of an additional antiplatelet agent to the regimen leads to an increased risk of bleeding when compared to aspirin monotherapy. In a study comparing the effectiveness of aspirin alone to a DAPT (aspirin-clopidogrel) regimen, there was a statistically signi icant decrease (95 percent con idence interval (CI): 0.59-0.82, p < 0.05) in the incidence of stroke among those on DAPT.2

An oral anticoagulant (OAC) is added to prevent stroke and other CV events. Despite the added bene its, traditional OACs introduce risks to the regimen, including an increased risk for bleeding, which can lead to worse health outcomes and decreased compliance.3 However, an OAC exhibits greater anticoagulation than aspirin and clopidogrel combined.8

Development of triple antiplatelet therapy (TAPT, or triple therapy) has led to controversy over the ideal number of antiplatelet/anticoagulant agents to provide the best ef icacy for clot prevention while maintaining safety. The components of TAPT are aspirin, clopidogrel or an alternative, and warfarin.3 Alternative antiplatelets to clopidogrel in either therapy include prasugrel and ticagrelor. Clopidogrel is a thienopyridine antiplatelet agent that acts by irreversibly blocking the P2Y12 adenosine diphosphate (ADP) receptors on the platelet surface.4 This prevents activation of certain complexes that cause platelet aggregation. Since this action is irreversible, platelet aggregation is reduced.

Novel oral anticoagulants (NOACs) may serve as alternatives to warfarin in the TAPT regimen.9 Several NOACs have been investigated in TAPT, including dabigatran, apixaban and rivaroxaban. Dabigatran is a factor IIa (thrombin) inhibitor, and apixaban and rivaroxaban are factor Xa inhibitors. Using NOACs over warfarin may be bene icial because NOACs are not vitamin K antagonists and have fewer side effects. There is also a lower risk of bleeding associated with some NOACs when compared with warfarin. In a study comparing warfarin to dabigatran, rate of major bleeding was 3.57 percent per year in the warfarin group and 2.78 percent per year in

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Triple Therapy or Triple Threat: An Analysis of Triple Antiplatelet Therapy Compared to Dual Antiplatelet Therapy

the dabigatran group (p=0.003).9 The more traditional vitamin K antagonists do have a reversal option as vitamin K can be administered in the event of a bleed.10 While there is a reversal agent for dabigatran (idarucizumab), there is currently no reversal agent for rivaroxaban or apixaban. Another risk associated with NOACs is liver injury, with reports that 1.8 to 3.9 percent of patients taking these medications experience unpredictable and severe liver injury or liver failure.11 Therapy Selection Appropriate candidates for TAPT are PCI patients with stents implanted either electively or to treat ACS.3 A patient with stent implantation requires DAPT because monotherapy with aspirin is insuf icient to prevent thrombosis. Triple antiplatelet therapy may be suitable for these patients if they have a low risk of bleeding. Other candidates for TAPT include those with conditions that require stroke prevention as well as antiplatelet therapy, such as AF patients with ACS or mechanical valve patients with severe CAD.12,13 Percutaneous coronary intervention with stent implantation (PCI-s) has become a routine procedure for many individuals with myocardial ischemia.14 In patients with AF who have undergone PCI-s, the decision to recommend TAPT is based on prevention of cardioembolic events associated with AF and stent thrombosis after PCI-s in addition to an assessment of bleeding risk. Combined aspirin-clopidogrel therapy is less effective in preventing stroke than OAC alone, but OAC alone is insuf icient to prevent stent thrombosis.8 Thus, TAPT is often recommended. In 2010, the European Society of Cardiology (ESC) published a consensus document with the recommendation that all patients with AF who undergo PCI-s should receive TAPT for at least one month and up to 12 months, depending on the type of stent used, the clinical indication (elective stent implantation versus ACS) and the patient’s risk of hemorrhage.14 After bare metal stent (BMS) implantation, triple therapy should be utilized for two to four weeks followed by OAC monotherapy.8 Drug-eluting stents (DES), on the other hand, require three to six months of triple therapy followed by OAC monotherapy. Secondgeneration and third-generation DES may be preferred as they might be associated with shorter re-endothelialization times and shorter duration of triple therapy. However, the use of BMS is the ultimate preference in this population as the recommended duration of triple antithrombotic therapy is considerably shorter.14 Individually, antiplatelet and anticoagulant agents increase a patient’s risk of bleeding, and, when used in combination, they further worsen this risk. A meta-analysis consisting of nine clinical trials that included 1,996 participants found that TAPT is associated with a twofold increase in major bleeding complications after PCI-s compared to DAPT in patients with an indication for long-term OAC.14 Major bleeding was deined as an absolute decrease in hematocrit of more than 15 percent, the need for transfusion of two or more units of blood, the need for corrective surgery, the occurrence of an intracranial or retroperitoneal hemorrhage or any combina-

tion of the aforementioned events.8 Almost all reported major bleeding events occurred in the irst six months of follow up and were often associated with supratherapeutic international normalized ratio (INR) levels. Additionally, most bleeding events occurred in the gastrointestinal (GI) system of patients with baseline anemia. Another study that examined 4,959 patients over the age of 65 with acute MI and AF who underwent coronary stenting found that incidence of bleeding requiring hospitalization within two years postdischarge as well as incidence of intracranial hemorrhage, were signi icantly higher for patients discharged on TAPT compared to DAPT.15 Speci ic mechanisms contributing to increased bleeding associated with triple therapy have not yet been studied but are likely affected by various clinical and therapeutic factors such as advanced age, female gender, peri-interventional administration of glycoprotein IIb/IIIa inhibitors, smoking and high prevalence of comorbidities including renal dysfunction and previous major bleeding.8 In the event that a major bleeding event should occur while a patient is on TAPT, treatment should be aggressive. If minor bleeding events occur (de ined as observed blood loss and 9 to 15 percent decrease in hematocrit or decrease in hemoglobin level≥40 g/L if no bleeding is identi ied), antithrombotic therapy should not be discontinued because of the patient’s increased risk of developing stent thrombosis or vascular thromboembolism. For patients in whom a NOAC is used in place of warfarin in TAPT therapy, the lowest dose effective for stroke prevention in AF should be considered.16 A meta-analysis involving 30,866 patients with recent ACS concluded that the inclusion of a NOAC in a triple therapy regimen increased the bleeding risk by 79 to 134 percent while minimally decreasing recurrent ischemic events in patients without AF. Several other studies were conducted that evaluated triple therapy with rivaroxaban, apixaban or dabigatran combined with aspirin and clopidogrel in patients with ACS. Rivaroxaban was tested using subtherapeutic doses (2.5 mg twice daily or 5 mg daily) for complete anticoagulation because higher doses were found to produce a dose-dependent increase of bleeding risk.17,18 For this reason, use of rivaroxaban may not be preferred in triple therapy.16 Unlike rivaroxaban, apixaban in triple therapy was studied in doses recommended for complete anticoagulation.19 The study was stopped prematurely because there was a signi icant 2.5-fold increase in risk of bleeding among the apixaban group compared to the placebo group with no indication of bene it in preventing MI, stroke or CV death.13 Thus, triple therapy with apixaban may not be preferred. Dabigatran in triple therapy was also found to be associated with dose-dependent increase of bleeding risk in patients with ACS.20 A substudy analysis of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study was conducted to further assess the bleeding risk of dabigatran in TAPT by comparing dabigatran 110 mg, dabigatran 150 mg, and warfarin.21 This study determined that dabigatran 110 mg twice daily is noninferior to warfarin, with fewer bleeding incidents regardless of concomitant anWinter 2017 Volume 8, Issue 1

Triple Therapy or Triple Threat: An Analysis of Triple Antiplatelet Therapy Compared to Dual Antiplatelet Therapy

tiplatelet use in patients with AF. While the relative risk of bleeding was found to be similar with dabigatran 110 mg, dabigatran 150 mg, and warfarin, the absolute risk was lowest with dabigatran 110 mg. Overall, bleeding risk must be assessed and monitored with all NOACs. Despite the risks, TAPT is a viable option to consider for many patients, especially those with a higher risk of thrombotic events and a lower risk of bleeding events. 8 Conducting a risk assessment of bleeding and ischemic complications is highly advised for all patients who are candidates for TAPT. Triple therapy should not be continued long-term after PCI-s in patients with a high bleeding risk pro ile as even mild to moderate bleeding events are associated with poorer longterm prognosis. However, lowering the dosage of aspirin to less than or equal to 100 mg/day in the triple therapy regimen may reduce the occurrence of major or minor bleeding events.22 In patients with low risk of bleeding complications, TAPT should be highly considered as the elective antithrombotic drug treatment approach.8 In spite of being associated with increased risk of bleeding, TAPT has been found to be more ef icacious in lowering mortality in patients with AF and PCI compared to DAPT in addition to reducing major adverse CV events, including death or hospital readmission for MI, ischemic stroke or hemorrhagic stroke.15 The meta-analysis discussed previously consisting of nine clinical trials demonstrated a 40 percent relative reduction in major adverse cardiac events and a 41 percent relative reduction in all-cause mortality.14 Reduction in major adverse CV events is due to the lower occurrence of thrombotic and embolic events in the TAPT group. 8 Furthermore, reduction in all-cause mortality occurs as a direct result of signi icant reduction in major adverse CV events in the triple therapy group. One retrospective study conducted in Spain by Ruiz-Nodar et al. supports this conclusion.23 The study included a cohort of 426 patients with AF who underwent PCI-s, 50 percent of whom were discharged on TAPT and 40.8 percent of whom were discharged on DAPT. Upon completion of a multivariate analysis, it was found that patients who received TAPT had a lower all-cause mortality rate (17.8 percent versus 27.8 percent, p=0.002) and lower major adverse cardiac event rate (26.5 percent versus 38.7 percent, p=0.001) compared to patients receiving DAPT. Therapy Considerations and the Role of the Pharmacist Due to the high risk of bleeding, the 2014 American College of Cardiology and the American Heart Association Task Force on Practice Guidelines recommends refraining from the long-term use of TAPT due to exponential increase in bleeding risk.24 Additionally, DAPT is recommended to be utilized after PCI. However, the 2016 ESC Guidelines recommend the use of an OAC after stenting in patients with a history of deep vein thrombosis and pulmonary embolism and in AF patients with a stroke risk. This expert-based consensus suggests that TAPT should be used in these patients but only for a short duration.16 Based on the ESC guidelines, clinical judgment in luenced by thrombotic risk should be used Winter 2017 Volume 8, Issue 1 T

Drug Abuse Cardiology

to determine whether or not therapy should be supplemented by an OAC. When the TAPT regimen is selected, regular monitoring for bleeding risk is advised upon discharge. Pharmacists play a critical role in the monitoring process, especially when the OAC of choice is warfarin. Upon discharge, patients on warfarin should be referred for anticoagulation monitoring so that the INR can be assessed regularly. INR is a key indicator of bleeding risk in those patients who are receiving warfarin.8 Because of this increased bleeding risk with TAPT, the target range is lower and narrower than a typical warfarin treatment plan. The recommended goal INR for these patients is 2.0 to 2.5 as compared to the typical therapeutic INR range of 2.0 to 3.0.16,24-25 This narrower INR range for TAPT patients is recommended but with low evidence since this target INR range has not been evaluated in many patient populations and is based solely on expert opinion.24 Pharmacists may also utilize the HAS-BLED method for assessment of other disease states and lifestyle factors to monitor risk of bleeding in select patients. The HAS-BLED method is based on seven factors: hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly and drugs/alcohol concomitantly which all contribute to the risk of bleeding for an AF patient.14 Discussion with TAPT patients is necessary so that health care providers can identify potential drug interactions, adverse effects, effective ways to educate and other drug therapies a patient is using. This necessary information is obtained best by addressing patient concerns, asking openended questions, listening to patient responses in their entirety and assessing patient adherence based on previous medical history.14 In particular, warfarin is known to have many drug interactions that can be identi ied by talking to patients. All patients should be educated regarding warfarinâ&#x20AC;&#x2122;s potential to react with speci ic medications, which could result in altered effects of warfarin. A common list of medications that interact with warfarin should be provided to patients. Additionally, the patient should receive education on how to identify bleeding risks with the biggest identiier as bruising.14 In order to prevent GI bleeds, the use of proton pump inhibitors (PPIs), H2 antagonists and antacids is common in TAPT patients and is recommended in patients with a history of GI bleeding.16,24,26 However, close monitoring is advised to ensure ef icacy because clopidogrel and PPIs are metabolized by CYP2C19 which can decrease the effects of clopidogrel due to competitive binding. While being treated with TAPT that includes clopidogrel, patients should only be on PPIs if there is a speci ic indication to treat a disease state such as chronic heartburn or if it will bene it the patient by protection from GI bleeding.26 These discussions can happen in anticoagulation clinics, in community pharmacies and prior to discharge at the hospital. Pharmacists must work with other health care providers to promote the continuum of care for each patient, especially while in the hospital. Pharmacists have a role in the medication reconciliation process before and after PCI to ensure P

Drug Abuse Cardiology

Triple Therapy or Triple Threat: An Analysis of Triple Antiplatelet Therapy Compared to Dual Antiplatelet Therapy

that TAPT candidates will receive the best and safest outcomes while on the therapy. Even though pharmacists in anticoagulation clinics will be assessing the INR of patients on warfarin after discharge, assessment of CHADS2 scores for stroke risk in AF patients, INR monitoring and HAS-BLED are critical while in the hospital.14 For those patients on NOACs, HAS-BLED remains an effective monitoring tool. All of this information should be communicated with all health care providers involved with the care of each patient. Conclusion Overall, when choosing a treatment regimen for a patient in need of anticoagulation therapy, it is important to evaluate the bene its of using TAPT as well as its risks in comparison to DAPT. While TAPT has shown to be more effective at preventing thrombosis, the increased risk of bleeding may cause harm in patients who are already at high risk to develop bleeds. However, TAPT is recommended for speci ic patient populations such as patients with ACS undergoing PCI-s or patients with a mechanical heart valve with severe CAD as these patients require more aggressive anticoagulation therapy. This recommendation is based on expert opinion. In order to obtain evidence-based recommendations, further research needs to be done comparing long-term outcomes of TAPT and DAPT in various patient populations. The safety of patients on TAPT is dependent on careful monitoring of treatment by health care professionals and thorough patient education about medication adherence, proper medication usage and the warning signs of bleeding. References 1. Reaume KT, Regal RE, Dorsch MP. Indications for dual antiplatelet with aspirin and clopidogrel: evidence-based recommendations for use. Ann Pharmacother. 2008 Apr;42(4):550-7. 2. Shuai T, Xiao X, Ma H, Zhang Z, Chen J, Ding L, et al. Clopidogrel and aspirin versus aspirin alone for stroke prevention: a meta-analysis. PloS One. 2015;10(8):1-14. 3. Tapp LD, Lip GYH, Lane DA. Optimal antithrombotic therapy in patients receiving long-term oral anticoagulation requiring percutaneous coronary intervention: “triple therapy” or “triple threat”. Chest. 2011 Feb;139(2):240-2. 4. Lexicomp [Internet]. Hudson (OH): Wolters Kluwer. Clopidogrel; [updated 2016 Nov 1; cited 2016 Nov 4]. Available from: online.lexi.com/action/home. 5. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357:2001-15. 6. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007 Jan;153(1):66e9-66e16. 7. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361:1045-57. 8. Zhao HJ, Zheng ZT, Wang ZH, Li SH, Zhang Y, Zhong M, et al. "Triple therapy" rather than "triple threat": a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment. Chest. 2011 Feb;139(2):26070. 9. Werdan K, Braun-Duallaeus R, Presek P. Anticoagulation in atrial ibrillation: NOAC’s the word. Dtsch Arztebl Int. 2013;110(31-32):523-4. 10. De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. New oral anticoagulants in atrial ibrillation and acute coronary syndromes: ESC working group on thrombosis-task force on anticoagulants in heart disease position paper. J Am Coll Cardiol. 2012 Apr 17;59(16):1413-25.

11. Liakoni E, Rä tz Bravo AE, Krä henbü hl S. Hepatotoxicity of new oral anticoagulants (NOACs). Drug Saf. 2015;38:711-20. 12. Latib A, Ielasi A, Ferri L, Chieffo A, Godino C, Carlino M, et al. Aspirin intolerance and the need for dual antiplatelet therapy after stent implantation: a proposed alternative regiment. Int J Cardiol Heart Vas. 2011 Oct 2;165:444-7. 13. Rohla M, Weiss TQ, Wojta J, Niessner A, Huber K. Double or triple antithrombotic combination in patients who need anticoagulation and antiplatelet therapy in parallel. Eur Heart J Cardiovasc Pharmacother. 2015:191-7. 14. Barry AR, Ackman ML. Triple antithrombotic therapy in patients with atrial ibrillation who have undergone percutaneous coronary intervention with stent implantation. Am J Health Syst Pharm. 2012 Sep 1;69(17):1485-93. 15. Hess CN, Peterson ED, Peng SA, de Lemos JA, Fosbol EL, Thomas L, et al. Use and outcomes of triple therapy among older patients with acute myocardial infarction and atrial ibrillation. J Am Coll Cardiol. 2015 Aug 11;66(6):616-27. 16. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC guidelines for the management of atrial ibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg. 2016 Nov;50(5):1-88. 17. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Jan 5;366(1):9-19. 18. 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 4;374(9683):29-38. 19. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011 Aug 25;365(8):699-708. 20. Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011 May 7;32:2781-9. 21. Dans AL, Connolly SJ, Wallentin L, Yang S, Nakamya J, Brueckmann M, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation. 2013;127:634-40. 22. Massel D, Little SH. Risks and bene its of adding anti-platelet therapy to warfarin among patients with prosthetic heart valves: a meta-analysis. J Am Coll Cardiol. 2001 Feb;37(2):569-78. 23. Ruiz-Nodar JM, Marı́n F, Hurtado JA, Valencia J, Pinar E, Pineda J, et al. Anticoagulant and antiplatelet therapy use in 426 patients with atrial ibrillation undergoing percutaneous intervention and stent implantation implications for bleeding risk and prognosis. J Am Coll Cardiol. 2008 Feb 26;51(8):818-25. 24. Amsterdam EA, Wenger NK, Brindis RG, Casey Jr DE, Ganiats TG, Holmes Jr DR, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes. Executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 December;64(24):2645-87. 25. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuü nemann HJ. American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2):7S-47S. 26. Gilard M, Arnaud B, Cornily JC, Gal GL, Lacut K, Calvez GL, et al. In luence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel Aspirin) study. J Am Coll Cardiol. 2008 Jan 22;51(3):25660.

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Pharmacologic and Nonpharmacologic Approaches to Palliative Care in Oncology

Dermatology Drug Abuse

Treatment of Basal Cell Carcinoma with Vismodegib Sunitha Johns, Katlyn Brown, Emily Loudermilk, Crystal Zheng, Anh Dao Le, Sophocles Chrissobolis, Ph.D., assistant professor of pharmacology Abstract The most prevalent nonmelanoma skin cancers are basal cell carcinoma (BCC) and locally advanced basal cell carcinoma (aBCC). Current, effective irst-line treatments for BCC aim to remove and destroy cancerous skin cells through excision surgery, Mohs surgery, radiation therapy and cryotherapy, while treatment of aBCC remains limited. An emerging treatment option for aBCC that promotes tumor size reduction is vismodegib, a pharmaceutical product approved in 2012 by the U.S. Food and Drug Administration (FDA). Vismodegib was approved for the treatment of aBCC, metastasized BCC (mBCC) or recurrent BCC after surgery as well as for use in adults who are not candidates for surgery or radiation. Vismodegib is an inhibitor of the hedgehog (Hh) pathway which is essential for cell differentiation and organ formation in embryonic development. When the Hh pathway is inappropriately activated in tissues, Hh pathway cellular growth mechanisms promote the formation of several carcinomas. Two studies reported similar responses of tumor reduction to vismodegib in patients with aBCC and mBCC. One reported the assessed response rate of 30 percent tumor shrinkage in patients with mBCC and a response rate of 43 percent tumor shrinkage in patients with aBCC. Another reported objective responses in 46.4 percent of aBCC and 30.8 percent in mBCC. While vismodegib is an option for treatment, caution should be used. Pharmacists play a critical role by counseling on proper skin care, potential drug interactions and the different side effects of treatment. Vismodegib should be continuously studied as there is currently not enough information on long-term treatment options for patients.

not required to report BCC or squamous skin cell carcinomas to cancer registries. When BCC is not treated effectively or in a timely manner, progression of the disease can result in local tissue invasion and signi icant morbidity and mortality.4 Basal cell carcinoma presents as nonpainful red patches or shiny bumps on the skin of the head and neck. Risk factors for BCC include sun and radiation exposure, elderly age, light-colored skin and extended exposure to certain chemicals such as coal and tar as well as arsenic found in well waters and pesticides.1-3 Current, effective irst-line treatments aim to eradicate and destroy cancerous skin cells through excision surgery, Mohs surgery, radiation therapy and cryotherapy.4 Treatment options depend on tumor size and location as well as disease progression. Large tumors located on the face, ingers and genital areas have a better cure rate when treated with Mohs surgery, a complex but effective surgical option. When BCC progresses to invade signi icant local tissue, health care costs increase because treatment requires specialized surgical teams, postoperative hospital stays and expensive pharmacologic options.2 From 2005 to 2008, nonmelanoma skin cancer accounted for 4.5 percent of Medicare expenses making it the ifth most costly cancer to treat. Although the incidence rate of locally advanced BCC (aBCC) is hard to determine due to lack of standardized staging systems and lack of uniform reporting requirements, it has been speculated that aBCC comprises roughly 1 to 10 percent of BCC. In rare cases where the cancer advances beyond its initial site, surgery is not recommended due to potential risks for surgical dis igurement and tissue damage, depending on the extent of tissue invasion. An emerging treatment option for aBCC is vismodegib, a pharmaceutical product approved in 2012 by the FDA which promotes tumor size reduction through its inhibitory action on the hedgehog (Hh) pathway.4 This article will discuss the Hh pathway, the pharmacology of vismodegib, research studies supporting its clinical use and the role of the pharmacist in monitoring vismodegib therapy.

Key Terms Carcinoma; Basal Cell; Hedgehog Proteins; Melanoma; Pharmacists; Skin Neoplasms; Vismodegib Introduction In the United States, about 3.3 million people are diagnosed with nonmelanoma skin cancers each year, causing skin cancer to be the most common type of cancer. 1 Over the past two decades, the rate of diagnosis and treatment for nonmelanoma skin cancers has increased 77 percent, with women under the age of 40 years being a fast growing, atrisk population.2 Basal cell carcinoma (BCC) is characterized by the growth of cancerous cells located in the lower epidermis. Although BCC has a lower mortality rate in comparison to its counterpart, melanoma, BCC is the most prevalent nonmelanoma skin cancer and comprises 80 percent of all skin cancers.3 About 2,000 people die from BCC and squamous cell carcinoma each year; in comparison, an estimated 10,130 people will die from melanoma in 2016. 1,3 However, BCC deaths rates are best depicted as estimates since it is Winter 2017 Volume 8, Issue 1 T

The Hedgehog Pathway The Hh pathway is essential for cell differentiation and organ formation in embryonic development.5 The Hh pathway is normally suppressed in adult tissues; however, when it is inappropriately activated, Hh pathway cellular growth mechanisms promote the formation of several carcinomas. The Hh pathway was irst discovered in 1980 when researchers learned of gene mutations that caused deformed bodies in fruit lies. Mutation to the Drosophilia hedgehog gene resulted in the formation of the mutated polypeptide ligand (Hh ligand) which activated the abnormal Hedgehog pathway. It was subsequently reported that the gene mutaP

Treatment of Basal Cell Carcinoma with Vismodegib

Drug Abuse Dermatology

tions were involved in early embryonic development which linked the pathway to several cancers.5,6

it SMO signal transduction, and thus inhibit GLI oncogene transcription (Figure 1a).8

The irst molecule developed to inhibit the Hh pathway was cyclopamine, a teratogen isolated from corn lilies.5 This naturally derived product was found to bind and inhibit Smoothened (SMO), a seven-member transmembrane protein resembling a G-protein coupled receptor. By inhibiting SMO signal transduction, cyclopamine inhibits the activation of GLI, a protein irst isolated in human glioblastoma which is also an oncogene transcriptional activator. GLI has multiple actions: it mediates cell proliferation, causes upregulation of antiapoptotic proteins, causes down-regulation of apoptotic proteins, increases production of vascular endothelial growth factor (VEGF) and angiogenesis factors and decreases E-cadherin and tight junctions holding the epithelial cells together.5,7 Thus, inhibition of SMO by cyclopamine inhibits transcriptional responses of GLI, ultimately inhibiting tumor formation. As an endogenous natural defense against tumor formation, patched-1 (PTCH-1), a 12-member transmembrane protein receptor, suppresses SMO and prevents downstream activation of the Hh pathway. Abnormal reactivation of the Hh pathway occurs when a mutated PTCH-1 is unable to suppress SMO, or when the Hh ligand binds to and inactivates PTCH-1, allowing for SMO to activate tumorigenesis.5 Vismodegib was developed as a cyclopamine analog to inhib-

Vismodegib Pharmacology Mechanisms of Action, Uses, Pharmacokinetics and Cost Vismodegib (Erivedge® Capsule, Figure 1b8) was developed by Genentech, Inc. as the irst selective Hh pathway inhibitor which had a higher af inity for SMO and improved pharmacokinetic properties compared to cyclopamine.5 The FDA approved vismodegib in January 2012 in adults for the treatment of the following: local aBCC, metastasized BCC (mBCC), recurrent BCC and recurrent aBCC following surgery. Vismodegib is also indicated to treat BCC patients who are not candidates for surgery or radiation.7 The National Comprehensive Cancer Network guidelines for basal cell skin cancer list vismodegib as an option for high-risk patients.9 Patients may be classi ied as “high-risk” if they are immunosuppressed. Basal cell carcinoma may also be deemed high-risk if the skin lesions are recurrent, have badly de ined borders or have an aggressive growth pattern. Vismodegib and other Hh pathway inhibitors are limited to use in highrisk cases most likely due to the resistance potential and the known fertility issues.

Figure 1. The Hedgehog (Hh) Pathway.8 The Hedgehog (Hh) pathway, which is normally suppressed in adults, is reactivated in BCC to promote tumorigenesis. In healthy individuals, patched-1 (PTCH1) inhibits signal transduction of Smoothened (SMO). In cancer patients, PTCH1 is mutated or is suppressed by the Hedgehog ligand (represented as a red hexagon in Figure 1a), and SMO is fully functional to cause the activation of oncogene transcription activator, GLI. Vismodegib inhibits SMO to prevent GLI activation. As a result, vismodegib inhibits cell proliferation, apoptosis and angiogenesis mediated by GLI.

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Treatment of Basal Cell Carcinoma with Vismodegib

Vismodegib is available as 150 mg capsules taken orally daily for 28 days or until remission.10 Vismodegib can be taken with or without food. Additional pharmacokinetic properties of vismodegib are presented in Table 1. The cost for a 28-day supply of vismodegib is $12,305.52. Vismodegib is available in the United States at specialty pharmacies through the Erivedge Access Solution program. Adverse Effects, Warnings and Drug Interactions Side effects (with incidence rate in parentheses) of vismodegib include: nausea (30 percent), diarrhea (29 percent), fatigue (40 percent), weight loss (45 percent), dysgeusia (55 percent), muscle spasms (72 percent), amenorrhea (30 percent) and alopecia (64 percent).11 Vismodegib should be avoided in patients who have concerns about hair loss, who operate machinery and require full muscle functionality and in women who have irregular menstrual cycles. Cyclobenzaprine administration is recommended when patients experience drug-related muscle spasms.2 To relieve nausea and poor oral intake, dronabinol and megestrol acetate have been used, respectively. There are no contraindications on the manufacturerâ&#x20AC;&#x2122;s labeling, but use in pregnant women (Pregnancy Category D) or women who are breastfeeding is strongly discouraged.10 Vismodegib can cause severe birth defects and embryo-fetal death, so pregnancy status needs to be veri ied prior to starting vismodegib therapy.12 During an in vivo study in pregnant rats, vismodegib caused craniofacial abnormalities, anorectal defects and absent or fused digits in hindlimbs. 13 Therefore, it is recommended that patients and their partners use two forms of medically reliable birth control to avoid pregnancy during vismodegib therapy.7 Vismodegib is also present in the semen, so it is important to advise male patients to avoid donating semen during therapy and for three months after the inal dose of vismodegib. Men should also be counseled to use condoms while he or his male or female partner is on treatment.6 In addition, since women have a risk of developing amenorrhea while on vismodegib (33 percent of patients), it is important to counsel on poten-

Dermatology Drug Abuse

tial infertility.12 Patients should also be advised not to donate blood or blood products during therapy and within seven months after the end of treatment.6 Since vismodegib is a substrate for p-glycoproteins, coadministration with p-glycoprotein inhibitors such as azithromycin, clarithromycin and erythromycin may increase blood concentrations of vismodegib and thus increase risk of side effects.5 Drugs that alter the pH of the upper gastrointestinal tract such as proton pump inhibitors, histamine 2-receptor antagonists and antacids may affect the solubility of vismodegib and reduce its bioavailability. In addition, patients taking vismodegib concurrently with warfarin should be monitored for elevation in international normalized ratio (INR) and signs of bleeding as the high protein binding ability of vismodegib can displace warfarin from plasma proteins.12 A speci ic example of the interaction of vismodegib with warfarin was detailed in a case study published in the American Journal of Health-System Pharmacists.14 One patient who had been well controlled on warfarin for nine months prior to vismodegib therapy had supratherapeutic INR levels of 4.6, 9.5 and 9.3 after starting vismodegib. Other causes of the INR increase such as change in diet, alcohol or cigarette use, medications and acute illness were ruled out, so the vismodegib-warfarin drug interaction was deemed to be the probable cause of the increase in INR. Anticoagulation therapy may be necessary in vismodegib patients due to the increased risk of venous thromboembolism that occurs in malignancy. However, an alternative prophylaxis medication may be required in place of warfarin if adequate INR control cannot be maintained in patients taking concurrent warfarin and vismodegib. Ef icacy and Safety Two important studies evaluated the ef icacy and safety of vismodegib. In the irst study, Sekulic et al. conducted an experiment which involved two cohorts with the goal of measuring the ef icacy and safety of vismodegib.15 There were 104 participants enrolled in the study over 13 months at 31 sites in the United States, Europe and Australia. The study began on Feb. 10, 2009, and was concluded nine months after the

Table 1. Pharmacokinetics of Vismodegib.5,10

Absorption

Highly permeable with low aqueous solubility (Biopharmaceutical Classi ication System Class II) Bioavailability 32%

Distribution

Vd = 16.4-26.6 L Plasma protein binding > 99%, primarily to albumin and alpha 1 acid glycoprotein (AAG)

Metabolism

Oxidation, glucuronidation, pyrimidine ring cleavage carried out by CYP2C9, CYP3A4, CYP3A5 enzymes; P-glycoproteins promote ef lux of drug

Excretion

Hepatic (82% of administered dose found in feces) Renal (4.4% of administered dose found in urine) Elimination t1/2: 4 days (for continuous once daily dosing) and 12 days (after single dose) No hepatic or renal dosing adjustments Winter 2017 Volume 8, Issue 1 T

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irst treatment of the last enrolled patient on Nov. 26, 2010. Vismodegib was given until there was disease progression, unacceptable toxic effects or the discontinuation of the study. The primary endpoint was the objective response rate, and the primary hypotheses were that the response rate would be greater than 20 percent for patients with locally aBCC and greater than 10 percent for those with mBCC. For the primary endpoint, response evaluation criteria in solid tumors (RECIST) guidelines were used. This set of guidelines measures tumor shrinkage along with the development of disease progression (de ined as an increase in tumor size of 20 percent or more) or regression (de ined as a decrease in tumor size of 30 percent or more). Due to the small patient population and lack of effective therapeutic options, there was no control group in the study. 15 Patients were divided into two cohorts: 33 patients had mBCC and 71 had local aBCC. Each patient was given 150 mg vismodegib once daily. Patients received physical examination and lab testing every four weeks (including pregnancy testing for women of childbearing potential). All patients with radiographically measurable disease received a radiographic assessment of tumors, performed at baseline and every eight weeks thereafter. Both cohorts experienced a signi icant reduction in tumor size: 30 percent reduction in patients with mBCC (p < 0.001) and 43 percent reduction in patients with aBCC (p < 0.001). Furthermore, 64 percent of mBCC patients and 38 percent of aBCC patients were considered to have stable disease after treatment with vismodegib. Of the 63 patients included in the trial, 21 percent had a complete response (de ined as the absence of residual metastatic growth of BCC on assessment of a biopsy specimen). At the end of data collection, 77 percent of patients who had a complete response had not experienced disease progression. Overall results showed that the majority of patients within the study experienced tumor shrinkage. Adverse effects were reported by all patients during the study, but more than half of the patients (57 percent) experienced only mild or moderate effects. Common adverse effects included muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, decrease in appetite and diarrhea. Fatal adverse events were reported in 6.7 percent of patients. A study by Chang et el. assessed ef icacy and safety of vismodegib in patients in an open-label multicenter study with two cohorts: local aBCC and mBCC.16 The study population consisted of 120 patients; 62 in the aBCC cohort and 58 in the mBCC cohort. However, only 119 patients were considered safety-evaluable, of which 95 were considered ef icacyevaluable. Patients included in the study had to be at least 18 years of age with good organ function and having measurable disease state based on RECIST version 1.0 guidelines. Exclusion criteria included major organ dysfunction, pregnant or lactating mothers, women unwilling to practice birth control, completion of antitumor therapy less than 21 days before treatment initiation, a history of other diseases or uncontrolled medical conditions, or those who had less than 12 weeks of life expectancy. Patients received 150 mg of vismodegib daily until either the disease progressed or there was intolerable toxicity. Tumors were assessed with the RE-

CIST guidelines. One treatment cycle was de ined as 28 days, and patients were physically assessed every one to two treatment cycles. Patient assessment parameters included complete blood cell count, metabolic panel and adverse event recordings. Within the patient population, 56 patients with local aBCC and 39 patients with mBCC were evaluated for ef icacy. 16 Objective tumor responses of 46.4 percent and 30.8 percent were met by local aBCC and mBCC patients, respectively. Objective tumor responses, de ined as the best overall complete response or partial response, were con irmed by investigators using two consecutive tumor assessments performed at least four weeks apart according to RECIST version 1.0. Complete response was achieved in 8.4 percent of total patients, partial response was seen in 31.6 percent of total patients and 49.5 percent of all study patients experienced stable disease. Overall, 94.6 percent patients in the local aBCC cohort and 82.1 percent patients in the mBCC cohort had complete response, partial response or stable disease. Only three patients with mBCC exhibited progressive disease, whereas no patient within the local aBCC cohort experienced progressive disease. Almost all safety-evaluable patients experienced a treatment emergent adverse event, typically within grades 1 and 2. A grade 1 adverse event is characterized by mild symptoms or no symptoms, while a grade 2 adverse event is de ined as showing moderate symptoms requiring minimal, local, noninvasive intervention.17 The majority of adverse events, including muscle spasms, dysgeusia, alopecia, diarrhea, nausea, fatigue and weight loss, were mild to moderate and occurred within the irst seven treatment cycles.16 Grade 3 adverse events were seen in 24 patients, meaning that the patients experienced severe or medically signi icant but not immediately life-threatening effects. The only vismodegib-related serious adverse event reported was muscle spasm, seen in 1 percent of the population. Grade 4 responses, de ined as life-threatening events requiring immediate care, were seen in nine patients.16,17 These included diarrhea and muscle spasms. Only two patients experienced a grade 5 adverse event, which resulted in death. All deaths were considered due to disease progression and not treatment related. Overall, both studies showed similar responses to vismodegib in patients with local aBCC and mBCC.15,16 This medication should be continuously studied, as there is not extensive information available regarding long-term vismodegib treatment. Vismodegib is FDA-approved for use in adults but has yet to be examined in children. Clinical trials examining the ef icacy and safety of vismodegib in larger patient populations are currently underway. Clinical Relevance and the Pharmacistâ&#x20AC;&#x2122;s Role As one of the most accessible health care providers, pharmacists can play an important role in vismodegib therapy. In addition to answering questions patients may have about the drug or drug therapy, pharmacists can also counsel on the importance of proper skin care.18 Simple steps such as wearing a hat, wearing sunscreen with both ultraviolet A and ulWinter 2017 Volume 8, Issue 1

Treatment of Basal Cell Carcinoma with Vismodegib

traviolet B protection and limiting exposure during midday when the sun is at its strongest can help to prevent new or worsening skin cancer. Pharmacists can also assist with monitoring the color, size, border and symmetry of moles. As previously mentioned, it is critical that patients use proper pregnancy prevention while taking vismodegib and for a period after vismodegib is discontinued (seven months for women and three months for men).19 Pharmacists should remind both male and female patients of the teratogenicity risks associated with vismodegib and aid in selection of birth control methods. Vismodegib has been shown in animal models to have a potential for irreversible infertility which may be problematic for patients of childbearing age. 20 It may be necessary to explore other drug options if a patient desires to expand his or her family. Pharmacists are wellpositioned and quali ied to aid patients in creating reproductive life plans and selecting the best birth control methods to it the patient’s lifestyle. Furthermore, pharmacists can make referrals for counseling or other services that would bene it patients. Importantly, pharmacists can also play a part in helping minimize drug interactions. This is particularly true for the interaction between vismodegib and warfarin, especially as pharmacist-run anticoagulation clinics become more prominent. Since vismodegib is a specialty drug (a drug that is unable to be dispensed at a community pharmacy due to side effects or increased complexity of administration, handling or billing),21 pharmacists may not be included in every step of the billing process. Billing may be conducted by a specialty pharmacy division which handles prior authorizations and other steps necessary to get the medication covered by insurance. If a patient needs further inancial assistance, he or she can be directed to the manufacturer’s website, www.erivedge. com.19 In the website’s inancial support section, there are four simple questions to determine if the patient is eligible for a co-pay card from Genentech. The site also contains valuable information including tips for managing side effects, frequently asked questions and support for patients and health care professionals. Conclusion Overall, vismodegib therapy should be considered as an option for high-risk aBCC and mBCC patients who can be monitored monthly. Most patients have experienced stabilization or resolution of disease with this drug while experiencing only mild or moderate side effects. Still, monitoring of tumor size is important since there is resistance potential, which could lead to treatment failure. While vismodegib has shown bene its in patients being treated for local aBCC and mBCC, use of this drug in patients with a desire to start or expand a family should be done with extreme caution due to the importance of the Hh pathway in fetal development.

5. 6.

7. 8. 9. 10. 11.

12.

13. 14. 15. 16.

17.

18. 19. 20. 21.

References 1. American Cancer Society [Internet]. Atlanta (GA): American Cancer Society; c2016. Key statistics for basal and squamous cell skin cancers; [updated 2016 May 10; cited 2016 Oct 2]; [about 2 screens]. Available from: www.cancer.org/cancer/skincancer-basalandsquamouscell/detail edguide/skin-cancer-basal-and-squamous-cell-key-statistics. Winter 2017 Volume 8, Issue 1 T

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Mohan SV, Chang ALS. Advanced basal cell carcinoma: epidemiology and therapeutic innovations. Curr Derm Rep. 2014 Feb 9;3:40-5. Cancer.Net [Internet]. Alexandria (VA): American Society of Clinical Oncology; c2005-2016. Skin cancer (non-melanoma) – overview; [updated 2015 Jun; cited 2016 Oct 2]; [about 4 screens]. Available from: www.cancer.net/cancer-types/skin-cancer-non-melanoma/over view. American Cancer Society [Internet]. Atlanta (GA): American Cancer Society; c2016. Treating basal cell carcinoma; [updated 2016 May 10; cited 2016 Oct 2]; [about 3 screens]. Available from: www.cancer.org/ cancer/skincancer-basalandsquamouscell/detailedguide/skin-cancerbasal-and-squamous-cell-treating-basal-cell-carcinoma. Abidi A. Hedgehog signaling pathway: a novel target for cancer therapy: vismodegib, a promising therapeutic option in treatment of basal cell carcinoma. Indian J Pharmacol. 2014 Jan-Feb;46(1):3-12. U.S. Food and Drug Administration [Internet]. Silver Springs (MD): U.S. Department of Health and Human Services. Erivedge (vismodegib) capsules; [updated 2015 Jun 12; cited 2016 Oct 2]; Available from: www.fda.gov/downloads/Drugs/DrugSafety/UCM289871.pdf. Silapunt S, Chen L, Migden MR. Hedgehog pathway inhibition in advanced basal cell carcinoma: latest evidence and clinical usefulness. Ther Adv Med Oncol. 2016;8(5):375-82. Dlugosz A, Agrawal S, Kirkpatrick P. Vismodegib. Nat Rev Drug Discov. 2012 Jun;11:437-8. Bichakjian CK, Olencki T, Aasi SZ, Alam M, Andersen AS, Berg D, et al. NCCN clinical practice guidelines in oncology: basal cell skin cancer. National Comprehensive Cancer Network. 2016 May 18. Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer; c2016. [cited 2016 Oct 2]. Available from: www.online.lexi.com U.S. Food and Drug Administration [Internet]. Erivedge/vismodegib clinical review. Silver Springs (MD): U.S. Department of Health and Human Services. NDA No. 203388; 2012 Jan [cited 2016 Oct 28]. Available from: www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203388Orig1s000 MedRpdf.pdf. U.S. Department of Veterans Affairs [Internet]. Washington (DC): US Department of Veterans Affairs. Clinical guidance - drug monographs, Vismodegib (Erivedge); [cited 2016 Oct 2]; [16 p.] Available from: www.pbm.va.gov/clinicalguidance/drugmonographs.asp. Morinello E, Pignatello M, Villabruna L, Goelzer P, Bü rgin H. Embryofetal development study of vismodegib, a hedgehog pathway inhibitor, in rats. Birth Defects Res B Dev Reprod Toxicol. 2014 Apr;101(2):135-43. Lim S, Houranieh J, Crawford R. Elevated international normalized ratio in patient concurrently using warfarin and vismodegib. Am J Health Syst Pharm. 2014 Feb 1;71(3):200-3. Sekulic A, Migden M, Oro A, Dirix L, Lewis K, Hainesworth J, et al. Ef icacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012 Jun; 366(23):2171-9. Chang A, Solomon J, Hainsworth J, Goldberg L, Mckenna E, Chen D, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2013 Nov;70(1):60-9. National Cancer Institute [Internet]. Bethesda (MD): National Institutes of Health. Common terminology criteria for adverse events (CTCAE) version 4.3; 2010 Jun 14 [cited 2016 Nov 4]; [196 p.]. Available from: evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_ 5x7.pdf. Drury J. Preventative care for skin cancer. Pharm Times. 2013 May;79 (5):68. Genentech USA [Internet]. San Francisco (CA): Genetech USA; c2016. Erivedge (vismodegib); [cited 2016 Nov 19]. Available from: www.erivedge.com. Grunewald S, Jank A. New systemic agents in dermatology with respect to fertility, pregnancy, and lactation. J Dtsch Dermatol Ges. 2015 Apr;13 (4):277-89. Zweigenhaft B. Advance notice of methodological changes for calendar year (2017) for Medicare advantage capitation rates, part C and part D payment policies and 2017 call letter [Internet]. Message to: Sean Cavanaugh; Jennifer Wuggazer Lazio. 2016 Mar 4 [cited 2016 Dec 13]; [9 p.]. The authors have no con lict of interest or funding support to disclose.

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Neonatal Abstinence Syndrome from Selective Serotonin Reuptake Inhibitor Use During Pregnancy Elizabeth Kramer, Maria Patnella, Rachel Bulko, Allie Harrison, Hannah Lamb, Manoranjan Dâ&#x20AC;&#x2122;Souza M.D., Ph.D., assistant professor of pharmacology Abstract Neonatal abstinence syndrome (NAS) is a concern for infants born to mothers receiving treatment with a selective serotonin reuptake inhibitor (SSRI) throughout the pregnancy. The risk of NAS associated with SSRI use during pregnancy varies with the speci ic SSRI that is used by the patient during pregnancy. Common symptoms of NAS include premature delivery, gastrointestinal disturbances, irritability, low birth weight, short length and lack of response to various stimuli. Neonates that present with these symptoms can be scored using either the Finnegan or Lipsitz scoring tools. Neonates experiencing NAS can be calmed or treated using nonpharmacologic methods such as swaddling, rocking, exposure to calming scents, soft light and soothing music. Drugs such as morphine or phenobarbital may be used as needed. Monitoring children born with NAS is important as it is possible that these children may express long-term behavioral, social and intellectual developmental problems. While there are many health care professionals involved in the care of NAS, pharmacists can play a large role in both preventing and treating NAS. Importantly, pharmacists can work with pregnant mothers to help prevent NAS by recommending SSRIs that have less risk of causing high serotonin levels in neonates. Pharmacists can also help by offering nonpharmacologic treatment options, when appropriate, or by developing protocols for the treatment of NAS. Key Terms Depression; Neonatal Abstinence Syndrome; Therapeutics; Pregnancy; Antidepressive Agents; Breastfeeding; Mothers; Serotonin Uptake Inhibitors; Citalopram; Fluoxetine; Sertraline; Paroxetine; Nortriptyline Introduction Depression is a major concern for the overall population, including pregnant women, with about 7 to 19 percent of women experiencing depression at some point during their pregnancies.1 Depression is associated with low levels of serotonin, and selective serotonin reuptake inhibitors (SSRIs), which increase levels of serotonin in the brain, form the mainstay of treatment in all patients suffering from depression, including pregnant women.2 Most SSRIs have a pregnancy Category C classi ication which means that no controlled studies have been conducted in pregnant women, but adverse effects have been found in studies with animals, or no studies are given with either animals or women. 3 It is concluded that Category C medications can be given to the patient if the evaluated bene its of the medication outweigh the risks. Among the SSRIs, paroxetine is an exception as it has a Category D classi ication which means that studies

have shown harm to a human fetus, but the drug can be used if the bene its are considerably greater than the risk. Some reports suggest that continuation of SSRI use during pregnancy affects the growth of the infant before and after birth. Furthermore, if a woman continues to use SSRIs in pregnancy there has been a link to neonatal abstinence syndrome (NAS) and other birth abnormalities.2 However, discontinuation of therapy is likely to worsen symptoms of depression in the mother during pregnancy.4 Therefore, carefully managing depression during pregnancy is warranted to avoid adverse outcomes for both the developing fetus and the mother.

Prevalence It is estimated about 30 percent of newborns experience NAS after maternal-SSRI use.5 Infants were more likely to experience NAS with SSRI use during the third trimester.6 Particularly, paroxetine and luoxetine have caused the most reported cases of NAS.7 Sertraline and citalopram have also resulted in NAS.1 Symptoms The signs and symptoms most commonly associated with NAS include premature delivery, low birth weight and short length of neonates at the time of birth. Symptoms of NAS may also include gastrointestinal (GI) disturbances, restlessness, irritability, tremors and respiratory distress.8 Seizures, which are generally associated with opiate withdrawal, have also been reported in severe cases of NAS. Infants whose mothers took SSRIs during the third trimester of pregnancy may exhibit reactional delays when exposed to positive and negative stimuli. Oberlander et al. reported a decreased rate of facial reactions to pain in infants exposed to SSRIs in utero.9 The study further reported delayed responses including kicks, toe-curling and swatting away irritants as a result of SSRI exposure in utero. However, it must be known that motor skills in infants are not entirely coordinated at this stage of development. In a study conducted by Sie et al., neonates reportedly expressed symptoms of NAS within 48 hours of birth.10 Infants exposed to SSRIs in utero did not cry as loudly compared to infants who were never exposed to SSRIs in utero (control group). These unresponsive infants, who either cried sparingly or not at all, showed higher deviation from the control group symptomatically. The authors concluded that these symptomatic differences were most likely due to developmental alterations caused by in utero SSRI exposure. Stephannson et al. conducted a retrospective cohort study in Nordic countries looking at the use of SSRIs in pregnancy and Winter 2017 Volume 8, Issue 1

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the birth outcome.1 Not only did it look at neonatal mortality and stillbirths, but it also included data for postneonatal death which was de ined as 28 to 364 days after birth. The study reported that citalopram, luoxetine and sertraline were the most commonly used SSRIs, respectively. Importantly, the study did not ind a difference in infant mortality rates, stillbirths or postneonatal death between mothers who had taken SSRIs during pregnancy compared to those who did not. Management of Symptoms The symptoms of SSRI-induced NAS usually resolve on their own.11 However in some cases, active management is required. In such cases, treatment of NAS must begin within two hours of birth, as untreated NAS symptoms can cause irreversible physical and emotional damage to newborns. 12 The Finnegan Scoring Tool (Table 1) is a complex test utilized by health care professionals to determine the severity of withdrawal symptoms in neonates and to ensure that the best possible care is provided to these infants. Every four hours, the newborn suffering from NAS must be reassessed in order to determine the next appropriate steps in care, with three consecutive scores above eight indicating a need for pharmacologic therapy. Morphine (0.05 mg/kg) is utilized as a mainstay of treatment for withdrawal symptoms if the infant has three initial Finnegan scores that create a sum higher than 24. If the newborn suffers from polysubstance dependency, which indicates potential illicit drug use or polypharmacy in the mother, phenobarbital is utilized as a irst-line therapy following morphine administration. Phenobarbital is not coadministered with morphine, but, instead, replaces morphine therapy if the Finnegan scores do not stabilize within two rounds of treatment.

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Alternating between bottle-feeding and use of a paci ier prevents emesis and occupies the infant, lessening bouts of harsh crying and calming the child during its of withdrawal. Long-Term Effects on Neonates In addition to developing NAS, in utero exposure to SSRIs can have long-term consequences. Oberlander et al. compared neonatal exposure in the second or third trimester with either a single agent SSRI or paroxetine and clonazepam with a nonexposed control group.5 In addition, they also grouped infants based on exposure and symptoms suggesting poor neonatal adaptation such as jitteriness, respiratory dif iculty, hypoglycemia, lethargy and weak or absent cry. Regardless of exposure or neonatal symptoms, they did not ind a difference in the mental development index (MDI) or psychomotor development index (PDI) from the Bayley Scales of Infant Development (BSID) at 2 months and 8 months of age. Additionally, Nulman et al. prospectively compared child development between three groups of mother-child pairs, one that took luoxetine throughout gestation, one that took tricyclic antidepressants, and one that did not have clinical depression and therefore not taking antidepressants.14 Children were evaluated between the ages of 15 and 71 months. There were no differences found in cognitive and language outcomes, or in temperament between the groups.

The Lipsitz Scoring Tool (Table 1), an alternative test to the Finnegan Scoring Tool, simpli ies the symptom assessment process and facilitates routine transfers of infants to different levels of care as needed.13 This method requires a nurse to check the infant and assign a score every three hours within the irst four days after birth. Parameters to be scored include timing of re lexes, irritability, bowel movements, respiratory distress and presence of vomitus. If a Lipsitz score of at least four is obtained, the infant must receive care and more intensive treatment. Table 1 compares the symptoms assessed in the Finnegan Scoring Tool and the Lipsitz Scoring Tool.

A second study by Nulman et al. compared intelligence in four groups of children.15 Group 1 was born to women that took venlafaxine, group 2 took SSRIs, group 3 was made up of women who had depression but took no medications and group 4 consisted of children born to healthy women that were not depressed. They completed a variety of age appropriate assessments between the ages of 3 and 6 years. In the groups exposed to antidepressants, 11.3 percent showed signs of NAS at birth. These children did not show any differences in cognitive function compared to children who did not show signs of NAS, however some did have differences in behavioral assessments. Children in groups 1 and 2 did not show any clinical signi icant differences compared to group 3 in any of the intelligence quotient (IQ) tests for cognition. There were differences in IQ and in the behavioral assessments for antidepressant exposed children versus children who were not exposed. However, the authors concluded that the cognition difference may have been accounted for by differences in the motherâ&#x20AC;&#x2122;s IQ.

Several nonpharmacologic treatment methods can also help in the management of NAS symptoms in neonates. These treatments can be used independently or can help aid pharmacologic treatment. The nonpharmacologic treatment includes swaddling, rocking, exposure to calming scents, soft light and soothing music. These interventions possibly help by stimulating release of endogenous serotonin levels in infants suffering from NAS.12 Additionally, administering maternal breast milk to the child whenever possible, preferably milk that does not contain traces of SSRIs or other addictive substances, aids in the recovery of serotonin pathways and stimulates natural growth and development of the infant.

Since having maternal depression may have adverse neonatal outcomes, Casper et al. compared women who were diagnosed with major depressive disorder (MDD) that remained medication free versus women diagnosed with MDD that used SSRIs during pregnancy.16 Children had follow-up after six to 40 months. Using BSID II, no signi icant differences were found in the MDI between the two groups. They did, however, ind a slight difference on the PDI and the Behavioral Rating Scale (BRS). The group that was exposed to SSRIs in utero had lower scores than those that were not exposed to SSRIs. Casper et al. concluded that although there were differences in the PDI and BRS between the exposed

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Table 1. Finnegan versus Lipsitz Scoring Tools12,13 Metabolic/Vasomotor/Respiratory Disturbances Finnegan

Score

Lipsitz

Score

High Pitched Cry Continuous High-Pitched Crying

2 3

Irritability or excessive crying

None (0) Minimal (1) Moderate (2) Marked or continuous (3)

Sleeps <1 hr after feeding Sleeps <2 hrs after feeding Sleeps <3 hrs after feeding

3 2 1

Hyperactive Moro re lex

Normal (0) Increased (1) Markedly increased (2)

Mild Tremors Moderate/severe tremors

1 2

Tremors

None (0) Minimal (1) Moderate (2) Marked increase or continuous (3)

Increased Muscle Tone

Muscle Tone

Normal (0) Increased (1) Rigidity (2)

Excoriation

Skin Abrasions

None (0) Redness of knees and elbows (1) Breaking of skin (2)

Myoclonic jerks

Generalized convulsions

Lipsitz

Score

Central Nervous System Disturbances

Finnegan

Score

Sweating

Fever <37.2-38 degrees Celsius Fever >38.4 degrees Celsius

1 2

Fever

No (0) Yes (1)

Frequent Yawning

Repetitive Yawning

No (0) Yes (1)

Mottling

Nasal stuf iness

Sneezing >3-4 times

Repetitive Sneezing

No (0) Yes (1)

Nasal Flaring

Respiratory Rate > 60/min Respiratory Rate >60/min with retractions

1 2

Respiratory Rate

<55 (0) 55-75 (1) 76-95 (2)

Finnegan

Score

Lipsitz

Score

Excessive Suckling

Poor Feeding

Regurgitation Projectile Vomiting

2 3

Vomiting

No (0) Yes (1)

Loose Stools Watery Stools

2 3

Stools

Normal (0) Explosive, normal frequency (1) Explosive, >8/day (2)

Gastrointestinal Disturbances

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and nonexposed group, these differences may not be clinically signi icant. A more recent study conducted by Klinger et al. also evaluated long-term outcomes following SSRI-induced NAS.17 Two groups of children were assessed, one that had NAS symptoms as evidenced by a Finnegan score of greater than four, and another group that did not have withdrawal symptoms (Finnegan score 0-3). Developmental pediatricians evaluated children at around 3 years of age using the Denver Developmental Screening Test II (DDST-II), which evaluates four areas including gross motor, ine motor-adaptive, language and personal-social functioning. They did not ind a difference in the overall scores on the DDST-II. However, in the group that had NAS, children were more likely to have an abnormal result on the social functioning component. There were no signi icant differences found in the intelligence tests. In summary, the combination of studies described above provides some evidence that SSRIs do not have long-term effects on neurocognitive development but may have long-term behavioral effects. Role of the Pharmacist: Recognizing at-Risk Pregnant Women and Combating the Problem It is important for the pharmacist to recognize NAS associated with SSRI use during pregnancy. The pharmacist may also play an important role in the inpatient setting by developing protocols for NAS induced by other drugs such as opiates, benzodiazepines and other medications. Importantly, pharmacists can contribute signi icantly in managing depression during pregnancy. Pregnant women struggling with depression can be divided into two categories; those who may need to be started on antidepressants while pregnant and those who are already being treated who will continue their therapy while pregnant.18 In either category, a woman should consult a health care professional to decide whether to start, change or continue her therapy regimen while pregnant. This should include a discussion of both pharmacologic and nonpharmacologic treatments as leaving depression untreated could have serious health consequences for both the mother and baby. Counseling pregnant women with depression about consequences of antidepressant use during pregnancy and the effects on the developing infant is an important role for pharmacists in both outpatient and inpatient settings. Doctors, OBGYNs, psychiatrists, pharmacists and all other personal health care providers are important in the decisionmaking process.18 Further, pharmacists can look at the diagnosis, con irm the severity of the depression and identify comorbidities that may complicate treatment. Discussing a treatment plan with the patient can be complex, as the decision to stop or change medications can come with a risk of relapse, and generally should not be changed if a patient is well-controlled on a medication. Pharmacists can discuss some nonpharmacologic treatment options that may be useful in patients with mild-moderate depression to use as substitutes to antidepressant medicaWinter 2017 Volume 8, Issue 1 T

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tions if it is determined that tapering off SSRIs is safe by the pharmacist and other health care professionals. Two of these alternative treatments are acupuncture and psychotherapy. In studies comparing acupuncture and psychotherapy to SSRIs during pregnancy, treatment for both was found to be comparable to SSRIs and well-tolerated, with mild to no side effects reported.19,20 It was found that acupuncture yielded response rates comparable to the rates observed in standard treatments for depression and was associated with little to few side effects. However, in the acupuncture study, 90 percent power was not met and included only nine people in the analysis that did not receive the treatment at all. 19 In the psychotherapy study, although power was not calculated and there was a small sample size, recovery criteria was met in 60 percent of women treated and there was a signi icant correlation between maternal mood and mother-infant interaction.20 By recognizing these safer alternatives to pharmacologic therapy, the pharmacist can recommend these options to patients and, in consultation with the physician or psychiatrist, undertake a bigger role in managing patientsâ&#x20AC;&#x2122; depression. If nonpharmacologic treatment is not a viable option, as in severe cases of depression, SSRIs can be used under the direction and supervision of health care providers. However, SSRI choice and timing are important considerations when evaluating therapy options. A study by Chambers et al. looked at birth outcomes in pregnant women taking luoxetine.21 Speci ically, adjusted relative risks were calculated in those who were exposed to luoxetine in the third trimester compared to those who had been exposed to it earlier in the pregnancy. The study reported that women had a much greater risk for neonatal problems from later exposure to antidepressants. The relative risk was 4.8 for prematurity, 2.6 for admission to special care nurseries and 8.7 for NAS. In summary, the study concluded that women taking luoxetine in the third trimester were at increased risk for SSRI-induced NAS. As for the other SSRIs, a placental passage study was done at UCLA Pregnancy and Postpartum Mood Disorders Program comparing SSRI levels in the mother to the levels in the umbilical cord.22 The women were receiving one of four SSRIs; citalopram, paroxetine, sertraline or luoxetine. Each woman had been taking the medications for at least ive half-lives before delivery. A blood sample was taken from the umbilical vein before delivery of the placenta. This study found that the umbilical cord serum concentrations were lower than the maternal concentrations. The ratio of cord to maternal concentrations of antidepressants ranged from 0.29 to 0.89. Citalopram produced the highest ratio, followed by luoxetine, paroxetine and then sertraline. Sertraline had a signi icantly lower ratio than the rest, which suggests that sertraline might be the best agent in treating depression in pregnancy. Many mothers on antidepressant therapy may want to start breastfeeding, so it is important to also take this into consideration. In a pooled analysis of 67 appropriate studies on P

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Neonatal Abstinence Syndrome from Selective Serotonin Reuptake Inhibitor Use During Pregnancy

antidepressant levels in lactating mothers, breast milk and infants; nortriptyline, paroxetine and sertraline produced undetectable levels in the infants, making them safest to use while breastfeeding.23 Fluoxetine produced the highest proportion (22 percent) of infant levels that were elevated above 10 percent of the average maternal level with citalopram only slightly lower (17 percent). Further research is needed on this topic. However, it was noted that based on current evidence, breastfeeding women may reasonably choose to continue to use antidepressants. Although it appears that sertraline may be the safest option in both populations of women, choosing an antidepressant for pregnant and breastfeeding mothers is something that should always be discussed with a doctor and other health care professionals. Conclusion With increasing evidence becoming available that SSRI use during pregnancy may cause NAS, it is becoming more important that health care professionals are aware of the potential short-term and long-term effects of SSRI use during pregnancy and how they will affect a newborn. Health care professionals must also be prepared to weigh the risks versus bene its of treating a mother with SSRIs. In addition, pharmacists play a unique role in recognizing the potential for NAS and educating other health care professionals to make them aware of the risk. Then, if needed, the team is prepared to handle the symptoms. The health care team, particularly pharmacists, can provide both pharmacologic and nonpharmacologic therapies to expecting mothers needing antidepressant treatment as well as treat infants that are experiencing NAS. References 1. Stephansson O, Kieler H, Haglund B, Artama M, Engeland A, Furu K, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA. 2013 Jan 2;309(1):48-54. 2. Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchel AA. Firsttrimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007 June 28;356(26):2675-83. 3. Tuccori M, Testi A, Antonioli L, Fornai M, Montagnani S, Ghisu N, et al. Safety concerns associated with the use of serotonin reuptake inhibitors and other serotonergic/noradrenergic antidepressants during pregnancy: a review. Clin Ther. 2009;31:1426-53. 4. Evans J, Heron J, Francomb H, Oke S, Golding J. Cohort study of depressed mood during pregnancy and after childbirth. BMJ. 2001 Aug 4;323:257-60. 5. Oberlander TF, Misri S, Fitzgerald CE, Kostaras X, Rurak D, Riggs W. Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure. J Clin Psychiatry. 2004;65(2):230-7. 6. Koren G, Matsui D, Einarson A, Knoppert D, Steiner M. Is maternal use of selective serotonin reuptake inhibitors in the third trimester of pregnancy harmful to neonates? CMAJ. 2005 May 24;172(11):1457-9. 7. Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet. 2005 Feb 5;365:482-7. 8. Ordean A, Chisamore BC. Clinical presentation and management of neonatal abstinence syndrome: an update. Res Rep Neonatol. 2014; 4:73-86. 9. Oberlander TF, Grunau RE, Fitzgerald C, Ellwood A, Misri S, Rurak D, et al. Prolonged prenatal psychotropic medication exposure alters neonatal acute pain response. Pediatr Res. 2002;51(4):443-53. 10. Sie SD, Wennink JMB, van Driel JJ, te Winkel AGW, Boer K, Casteelen G, et al. Maternal use of SSRIs, SNRIs and NaSSAs: practical recommendations during pregnancy and lactation. Arch Dis Child Fetal Neonatal Ed. 2012;97:F472–F476.

11. Holmes AP. NICU Primer for Pharmacists. Chapter 5: Neonatal Abstinence Syndrome. 1st edition. Bethesda, MD: ASHP;2016. 12. Tierney S. Identifying neonatal abstinence syndrome (NAS) and treatment guidelines. University of Iowa Children’s Hospital. Rev. 2013. 13. Ohio Perinatal Quality Collaborative. Neonatal drug withdrawal: Lipsitz scoring tool. OPQC.net. Rev. 2014 September 30. 14. Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, et al. Child development following exposure to tricyclic antidepressants or luoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry. 2002;159(11):1889-95. 15. Nulman I, Koren G, Rovet J, Barrera M, Pulver A, Streiner D, et al. Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression. Am J Psychiatry. 2012 Nov;169:1165-74. 16. Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, et al. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr. 2003;142:402-8. 17. Klinger G, Frankenthal D, Merlob P, Diamond G, Sirota L, LevinsonCastiel R, et al. Long-term outcome following selective serotonin reuptake inhibitor induced neonatal abstinence syndrome. J Perinatol. 2011;(31):615-20. 18. Hackley B. Antidepressant medication use in pregnancy. J Midwifery Women’s Health. 2010;55(2):90-100. 19. Manber R, Schnyer RN, Lyell D, Chambers AS, Caughey AB, Druzin M, et al. Acupuncture for depression during pregnancy: a randomized controlled trial. Obstet Gynecol. 2010;115(3):511-20. 20. Spinelli MG, Endicott J. Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry. 2003 Mar;160(3):555-62. 21. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking luoxetine. N Engl J Med. 1996;335 (14):1010-15. 22. Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications. Am J Psychiatry. 2003;160 (5):993-6. 23. Weissman AM, Levy BT, Hartz AJ, Bentler S, Donohue M, Ellingrod VL, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry. 2004;161(6):106678. The authors have no con lict of interest or funding support to disclose.

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Maternal and Infant Health Bene its Related to Infantile Feeding Methods Michaela Wolford, Alexa Bouts, Carmen Lariccia, Cara Walden, Anh Dao Le, Andrew M. Roecker, PharmD, RPh, BCPS, professor of pharmacy practice Abstract Human breast milk is known to provide the most complete nutrition to growing infants. There may be more gained from breastfeeding than simply nutritional ful illmentâ&#x20AC;&#x201D; recent research has uncovered bene its related to the development and health of infants. Breastfeeding has been shown to stimulate immune system development by exposing the infant to bacteria and antibodies from the mother. Breastfeeding may also bene it nursing mothers by improving insulin sensitivity and glucose tolerance as well as decreasing postpartum weight gain. In place of breastfeeding, formulas are able to provide an infant with necessary nutrition. Many infant formulas have been enriched with probiotics and prebiotics to provide formula-fed infants with similar immune system bene its. Research on these formulas is inconclusive at this time, though hydrolyzed formulas have the potential to prevent autoimmune diseases and food allergies. Research has found many differences between breastfed and formula-fed infants. For instance, children who had been exclusively breastfed for more than three months showed signi icantly higher cardiovascular itness levels than those who were formula-fed. Additionally, at 6 months of age, breastfed infants were found to have a lower protein intake and leaner body mass compared to formula-fed infants. The microbiome of breastfed infants also differs from formula-fed infants, with breastfed infants having higher concentrations of bene icial Bi idobacterium species (spp.) and formula-fed infants hosting a wide range of potentially pathogenic bacteria including Clostridium spp., Streptococcus spp., Staphylococcus spp. and Enterobacteriaceae family. Pharmacists can play a vital role by providing breastfeedingrelated services to patients including education, breast pump or infant formula selection, and counseling regarding medication use during lactation.

Recent research suggests that differences may exist between the development of breastfed and formula-fed infants, speci ically in areas of cardiovascular health, growth, gastrointestinal lora composition and immune system function. Studies have been conducted to examine these effects, and this article will explore some of the facts gleaned from research. Effects on the mother and infant with regard to weight gain, cardiovascular health, infant microbiome and immune development and function will be discussed as well as the role of the community pharmacist in providing breastfeeding-related services to patients. Health Bene its In general, public health programs across America have marketed that breastfeeding can bene it a child and mother in a variety of ways, including cardiovascular itness. Studies suggest that the more cardiovascular exercise children complete, the less likely they are to become overweight and the more likely they are to maintain an active lifestyle as they grow. Labayen et al. looked at exclusive breastfeeding duration and cardiorespiratory itness in 1,996 children and adolescents.1 Cardiovascular itness of each participant was measured on a cycle ergometer and adjusted for country, sex, age, pubertal status and body mass index (BMI). Children who were exclusively breastfed for longer than three months as infants displayed signi icantly higher itness levels than children who were formula-fed (p<0.001). With increasing duration of breastfeeding, there was a corresponding increase in the cardiovascular itness level. To examine the relation of breastfeeding to maternal cardiovascular health, the HUNT-study was conducted in Norway, the nation with the highest rate of breastfeeding in the world.2 The study followed 21,368 women aged 20 to 85 years, focusing on their duration of lactation and cardiovascular risk factors. Worsening cardiovascular health can lead to a greater risk of developing diseases such as type 2 diabetes. It was found that breastfeeding is most bene icial when women are 50 years of age or younger from a cardiovascular health perspective. The HUNT-study also concluded that breastfeeding can improve insulin sensitivity and glucose tolerance, which is bene icial for the prevention of type 2 diabetes.

Key Terms Autoimmune; Breastfeeding; Gastrointestinal Microbiome; Growth; Immune System; Infant; Infant Formula; Maternal Health; Prebiotic; Probiotic Introduction Breastfeeding has been the primary means for feeding infants since the beginning of human existence. Yet, early man did not realize that breast milk was not just a food source but also a key factor in child development on the microscopic level. The advent of modern technology has allowed scientists and researchers to look more closely at the role breastfeeding may play in early development and the possible lasting effects it may produce on children as they age. Technology has also provided parents with other options for feeding children, as a plethora of infant formulas are marketed to meet the nutritional needs of a growing child. Winter 2017 Volume 8, Issue 1 T

A study by McClure et al. found that the lactation method is a predictor of future risk of developing diabetes, hypertension and cardiovascular disease.3 This study focused on maternal visceral adiposity in post-breastfeeding mothers. A total of 351 women aged 45 to 58 years were included. The researchers determined that maternal BMI is in luenced by the motherâ&#x20AC;&#x2122;s choice to formula-feed or breastfeed her infant. Mothers who breastfed consistently gained less weight and P

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visceral adiposity over an eight-year period postpartum as compared to mothers who formula-fed. “Women who had never breastfed had 28 percent greater visceral adiposity (95 percent con idence interval (CI): 11-49, p=0.001), 4.7 percent greater waist-hip ratio (95 percent CI: 1.9-7.4, p<0.001) and 6.49 cm greater waist circumference (95 percent CI: 3.71- 9.26, p<0.001) than mothers who breastfed all of their children for three months or greater”.3 The study adjusted for age, parity and years since last birth as well as socioeconomic, lifestyle and family history variables. The more visceral adiposity a woman has, the higher the risk of developing diabetes, hyperlipidemia or coronary artery disease. This information was true only for women who were not obese during pregnancy. Women who were obese during pregnancy showed no difference in these health risks whether they formula-fed or breastfed their infants. Researchers have conducted numerous studies on breastfed and formula-fed infant growth. The study by Prentice et al. is the largest report describing human milk macronutrient contents and was the irst extensive report to discover the relationship between macronutrients and infancy growth. 4 The main factor contributing to the difference of infant growth in breastfed versus formula-fed infants is the amount of protein intake. Human milk was found to have lower percentage of protein compared to formula (7.3 percent in human milk, 8.3 percent in formula milk, p<0.05). The percent of protein content was found to be positively related to BMI, which can have an effect for years after infancy. At about 6 months of age, breastfed infants are leaner than formula-fed infants, most likely because of the increased caloric load in the formula compared to breast milk. The human milk contains 58.7 kcal per 100 mL compared to formula which contains 62.6 kcal per 100 mL. In summary, research indicates that breastfeeding may positively impact cardiovascular health and contribute to maintenance of a healthy weight in both infants and mothers. Microbiome The gastrointestinal (GI) lora composition is important in the digestion of complex starches along with other food products.5 Gastrointestinal bacteria are also a source of vitamins K and B12 which are both essential for functions such as clotting and healthy nerve function. Additionally, infants need gut bacteria to develop immune activity. The gut is irst colonized by bacteria provided by the mother through a vaginal birth, contact with skin and the mother’s GI tract. A child who is delivered vaginally, compared to cesarean delivery, is exposed to bacteria from the mother’s vagina, feces and skin. These bacteria can be ingested through the mouth to enter the infant’s GI. After birth, the gut microbiome is further developed through the ingestion of either formula or breast milk.6 In breastfed infants, the microbiome is dominated by the presence of Bi idobacteriaceae, a gram positive family of bacteria that is typically composed of anaerobes and is located in the GI tract, among other lactic acid bacteria. 6 Bi idobacteriaceae have the capability to prevent pathogenic GI infections

and also have anticarcinogen characteristics.7 Bi idobacteriaceae are also increased in infants who were delivered naturally at full term.6 Formula-fed infants have an entirely different and diverse group of bacteria which dominate the microbiome. These bacteria include Bi idobacteriaceae family as well as Bacteroides spp., Clostridum spp., Staphylococci spp., Streptococci spp. and Enterobacteriaceae. These additional bacteria are more likely to cause pathogenic infections, such as Clostridium dif icile, than the Bi idobacteriaceae which predominate in breastfed infants. Additionally, human milk contains natural antimicrobial agents which help to combat infections from GI lora. 8 Formula, however, does not have antimicrobial properties like those of breast milk. Also, the infant formula of today is unable to be made sterile per current processing methods. Thus, the microbial agents present in the formula have increased growth potential if the formula is not stored properly. Schwartz et al. performed a study to evaluate the microbiome of infants.7 In this study, the feces of six breastfed infants and six formula-fed infants were evaluated. Messenger ribonucleic acid (RNA) and gut epithelial cells were extracted from the collected feces. It was found that the formula-fed infants had a lower overall number of bacterial genes expressed in comparison to breastfed infants. Breastfed infants also had genes speci ic to promoting gut motility, such as tachykinin receptor 1, as well as genes that are involved in reactive oxygen species homeostasis, thus preventing damage to the body by free radicals. However, genes that promote mucosal in lammation, such as vascular adhesion protein 1 and interleukin 1 alpha, were downregulated in breastfed infants compared to formula-fed infants. Therefore, a higher potential GI in lammation in formula-fed infants is expected. Additionally, the higher number of genes expressed in breastfed infants is viewed as advantageous because the bacteria promote a more developed and diverse microbiome. The current trend of using probiotics to increase gut health has consequently led to the inclusion of probiotics in infant formula. Several studies have been performed to evaluate the effects of probiotics in formulas. Costeloe and colleagues performed a multicenter, randomized, controlled trial to compare the effect of Bi idobacterium (a probiotic) to placebo. 9 All infants included in the study were preterm (gestational age of 23 to 30 weeks and 6 days), with 650 infants in the probiotic group and 660 infants in the placebo group. The primary outcome included three main events: an episode of necrotizing enterocolitis, sepsis or death before discharge. Sepsis was de ined as a positive blood culture of an organism outside the realm of normal skin lora and was drawn more than three days after birth and before 46 weeks postmenstrual age or discharge if sooner. The postmenstrual age is de ined by the gestational age plus the conceptional age (time since birth) of the infant. None of the primary outcomes were found to be signi icantly different between the probiotic and placebo groups. The following are the speci ic results for the primary outcomes of the probiotic and placeWinter 2017 Volume 8, Issue 1

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bo group, respectively: necrotizing enterocolitis 9 percent, 10 percent (95 percent CI of 0.68 to 1.27), sepsis 11 percent, 12 percent (CI 0.73 to 1.29), and death 8 percent, 9 percent (CI 0.67 to 1.30). Therefore, this study found that probiotics had no bene it in preventing necrotizing enterocolitis, sepsis or death in preterm infants. One of the limitations of this study is the choice of primary outcome since the prevention of serious conditions is not the primary goal of most mothers who would be interested in using a probiotic-enhanced formula. Indrio and colleagues also performed a study to examine prebiotics and probiotics in preterm newborns.10 The 49 infants studied were split into four groups, 17 infants in the breastfed group, 10 in the prebiotic group, 10 in the probiotic group and 12 in the placebo group. The prebiotics used were short chain galacto-oligosaccharides and long chain fructo-oligosaccharides, which are nondigestible food products that stimulate the growth of gut bacteria. The probiotic used was Lactobacillus reuteri, which differs from the prebiotic because it is a microorganism which replenishes the gut lora. The primary outcome was the percentage of electrogastrography (EGG), a way to measure the electrical signals which travel through the stomach muscles, measuring contraction and gastric emptying rate. The prebiotic, probiotic and breastfed groups all showed statistically signi icant results for the primary outcome, demonstrating that feeding of preterm infants with prebiotic or probiotic-supplemented formulas improves gastric emptying and the maturation of EGG activity, and does so in a way that closely mimics the effects of breast milk. Cekola and colleagues evaluated much more practical primary outcomes, such as mean weight gained (in grams/day). 11 This study was a randomized, controlled trial which was double-blinded and multicentered. It included infants 14 days old (+/- three days) who were administered either a probiotic enriched formula or a placebo formula until day 112 (+/- three days). The probiotic Lactobacillus reuteri was administered to 60 infants, and the placebo was administered to 62 infants. The weight of the infant was measured at the irst visit (14 days) and at the fourth visit (day 112). Secondary outcomes of head circumference and length were also evaluated. There was no statistically signi icant difference in the mean weight gain between the probiotic and placebo groups (p>0.5). Mean weight gains were 29.4 g/d and 30.7 g/d for probiotic and placebo groups, respectively. Additionally, the length and head circumference were also not statistically signi icant. Another study of similar design, performed by Maldonado and colleagues, included a three-year follow up of an earlier study.12 The original study included infants in a probiotic group who were administered Lactobacillus fermentum and infants in a placebo group. The study lasted ive months, and the primary outcome was the safety and ef icacy of the probiotic. Once safety and ef icacy were established, a three-year follow up was done to evaluate the primary outcome of growth in children (including weight, length and head circumference). Secondary outcomes included incidence of inWinter 2017 Volume 8, Issue 1 T

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fectious and noninfectious diseases or disorders that were related to intestinal function. For these outcomes, a portion of the infants from the original study were evaluated (45 in the probiotic group and 46 in the control group). The weights of both groups were in the 75th percentile of the World Health Organization (WHO) child growth standards. Since neither the primary nor secondary outcomes were signi icant, it cannot be concluded that early administration of probiotics helps increase infant weight or decrease rate of infection. The probiotic was only administered for ive months, a short period in comparison to an infant in a practical setting which would be breastfed for much longer, thus rendering a weakness to the study. However, it is understandable to have a short duration within the original study due to the primary outcome being safety and ef icacy.

Breastfed infants naturally receive more advantageous gut lora from their mothers, helping them form a healthy gut microbiome. Because all mothers are not able to breastfeed, these studies have been conducted to evaluate the addition of prebiotics and probiotics to help supplement the formulas available. Although the evidence is contradicting at times, and therefore cannot de initively be deemed bene icial, the use of these supplements is safe in infants. Autoimmune Disease Development Thus far, the bene its of breastfeeding infants have been displayed through exploring cardiovascular health outcomes, postpartum maternal well-being, infant growth, GI development of the infant and prevention of life-altering infections in infants. An infant’s gut microbiota contributes to immune system development and may impact the development of autoimmune diseases.13 Breast milk contains regulatory cytokine transforming growth factor-b (TGF-b), secretory immunoglobulin A (IgA) antibodies and the innate immune receptor soluble CD14, all of which help to build an infant’s immune defenses.14 However, it is unclear if these bioactive factors alone are enough to combat the development of autoimmune diseases. Formula-fed infants and breastfed infants develop different gut microbiomes. The combination of an infant’s environmentally decided microbiome with the infant’s genetic predisposition to develop certain diseases in luences the development of type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA) and atopic eczema/ dermatitis syndrome (AEDS). Type 1 Diabetes Mellitus (T1DM) Type 1 diabetes mellitus develops when pancreatic islet βcells do not produce enough insulin due to autoimmune destruction.15 While biological factors, such as the presence of the human leukocyte antigen (HLA) complex gene, do contribute to risk of T1DM, environmental factors such as infant nutrition are also instrumental in determining if the disease will develop. Breastfed infants have a decreased gut permeability to enterovirus infections in comparison to formula-fed infants. Since enterovirus infections can trigger the development of β-cell autoimmunity, breastfeeding may help prevent T1DM. To investigate the relationship between infantile feeding patterns and the development of T1DM in infants with P

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the HLA gene, Lund-Blix et al. took blood samples and surveyed 726 children carrying the HLA gene at ages 3, 6, 9 and 12 months and then annually. Survey questionnaires gathered data about the types of milk consumed, vitamin supplements administered and whether solid food had been introduced to the infant. Statistical analysis of this data revealed that the duration of breastfeeding did not signi icantly differ between those who developed T1DM and those who did not (p=0.44). However, further investigation did reveal that “breastfeeding for 12 months or longer predicted a lower risk of progressing [from islet autoimmunity] to T1DM” with a hazard ratio of 0.35 (95 percent CI [0.13-0.94]).15 Similarly, Rabiei investigated the duration of exclusive breastfeeding in 100 Iranian children diagnosed with T1DM and 200 nondiabetic Iranian children.16 Children who were breastfed for fewer than four months were found to have higher instances of T1DM (p<0.008). Although Rabiei did not control for genetic contributions to the development of disease, these results suggest that exclusive breastfeeding for at least four months may have a preventive effect on the development of T1DM. Furthermore, a case-control, retrospective study performed in the Czech Republic by Malcova et al. obtained questionnaires from 868 parents of children with T1DM and 1,466 parents of children who had not been diagnosed with T1DM.17 Survey questions gathered information about infant feeding patterns including duration of breastfeeding, timing of introduction to formula and supplementation with vitamin D. Statistical analysis displayed a correlation between a lack of breastfeeding and a risk of developing T1DM (OR=1.93). Moreover, extending breastfeeding to 12 months or longer appeared to have a negative correlation with the development of T1DM (OR=0.42). A similar case-control study was performed in Brazil by Alves et al., but the control subjects were the siblings of children diagnosed with T1DM.18 Overall, 123 children with T1DM, along with their respective siblings, were assessed based on rates and duration of breastfeeding as an infant. Although children with T1DM and their nondiabetic siblings had similar rates of breastfeeding, children who developed the disease were breastfed for shorter durations (3.3 versus 4.6 months, p<0.001). This possible connection between breastfeeding and the development of T1DM has caught the attention of a global audience. Due to this widespread interest, the Trial to Reduce Insulin-Dependent Diabetes Mellitus in the Genetically at Risk (TRIGR) study was initiated in 77 centers across 15 countries.19 The TRIGR project is a randomized, doubleblind, controlled intervention trial designed to explore the question of whether weaning to an extensively hydrolyzed formula in infancy will decrease the risk of T1DM in later childhood. Researchers recruited 5,606 newborns with family members affected by T1DM and 2,159 carrying the HLA genotype for this study. The TRIGR study will not be completed until 2017, but it seeks to provide uniform data regarding the bene its and consequences of supplementing infants at a higher genetic risk with hydrolyzed formula to prevent T1DM.

Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic, in lammatory, autoimmune disease that causes pain and deformity of the joints. For postpartum women with RA, breastfeeding for at least 13 months has been associated with decreasing signs and symptoms of the disease.20 In addition, recent studies have explored the positive protective bene its of breastfeeding for the infant who may genetically be at risk of developing RA secondary to the mother’s diagnosis. Parents of 688 of the 1,386 children involved with Diabetes Autoimmunity Study in the Young (DAISY) consented to have the child’s blood tested for rheumatoid factor (RF) to evaluate the risk of RA development.21 Children who were HLA genotype negative (not genetically at risk for T1DM) but RF positive were less likely to have been breastfed for longer than three months (OR=0.18). This statistic suggests that breastfeeding could have a protective effect against the development of RA. However, none of the children in this study developed RA, nor were they physically examined. In contrast, Simard et al. retrospectively examined how long adults with RA were breastfed as infants.22 This study was a subgroup analysis of women with con irmed RA who had taken part in the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII). While breastfeeding for longer than nine months seemed to be protective against RF-negative RA in the NHS cohort (RR=0.6), no other breastfeeding duration appeared to be signi icantly associated with RF-negative or RF-positive RA. Furthermore, having been breastfed was not associated with RA in either cohort, resulting in a combined RR of 1.0. These results suggest that infants who lack a genetic risk for RA may experience protective bene its of breastfeeding. Ultimately, research indings discussing the bene its of breastfeeding and their effect on RA are inconsistent. This may be due to multiple confounding factors, such as tobacco smoke exposure, birth weight, maternal diet or simply an inability to accurately recall breastfeeding lengths. 20 Moreover, RA may not develop until much later in life which makes correlating the effects of breastfeeding as an infant with the prevention of this disease a dif icult task. Atopic Eczema/Dermatitis Syndrome (AEDS) When discussing the role of breastfeeding in the prevention or development of atopic disease, literature indings have been inconsistent. However, AEDS is often associated with an increased occurrence of food hypersensitivities. Hypothetically, the levels of IgA and IgE within breast milk mediate the development of AEDS as well as several food allergies. 23 Thus, AEDS development can be controlled through infantile feeding habits and there is a possibility that allergy development could be prevented. Schoetzau et al. randomly assigned 1,172 study subjects into one of four cohorts to investigate the relationship between style of feeding and the development of AEDS. The cohorts included the following: exclusively breastfed, cow’s milk formula-fed, partially bottle-fed and exclusively bottle-fed. At 1 year of age, the infants who were exclusively breastfed were 47 percent less likely to develop Winter 2017 Volume 8, Issue 1

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AEDS than the cow’s milk formula group (p=0.015). Likewise, Chiu et al. evaluated 186 children for four years to examine the correlation between breastfeeding and the development of atopic diseases.24 While Chiu et al. found that breastfeeding for greater than six months was correlated with a lower occurrence of AEDS (p=0.015), partial breastfeeding for less than six months was associated with an increased risk of eczema at 1 year of age (p=0.046) and 2 years of age (p=0.006). A limitation of these two studies by Schoetzau et al. and Chiu et al. is that they only investigated the effect of breastfeeding on AEDS development in the irst one to two years of life. However, Bergmann et al. performed a cohort study including 1,314 infants who were followed from birth to 7 years of age.25 This study discovered that the prevalence of AEDS increased with each year of life (OR=1.05) and with each year of breastfeeding (OR=1.03). Unlike Schoetzau et al. and Chiu et al., Bergmann et al. focused on parental history and its relationship to the development of AEDS in high risk infants (OR=2.06). Similarly to Bergmann et al., Ito and Fujiwara studied 38,757 infants from birth to age 42 months using questionnaires which surveyed pattern and duration of infant feeding and the development of AEDS.26 Results from these questionnaires indicated a signi icant correlation between longer exclusive breastfeeding and the development of AEDS (p < 0.001). This further supports the indings of Bergmann et al., suggesting that a prolonged period of breastfeeding increases an infant’s risk of developing AEDS. Schoetzau et al. and Chiu et al.’s indings contradict Bergmann et al. and Ito et al.’s indings in that, with longer duration of breastfeeding in infancy, the risk of developing AEDS is increased with increased age. Further confounding this debate, JeldingDannemand et al. evaluated 335 children with asthmatic mothers for risk factors of AEDS (increased IgE levels and skin pricks) and correlated these factors with the duration of breastfeeding.27 Results from this study found no signi icant association between exclusive breastfeeding and the development of eczema in the genetically at-risk children within the irst six years of life. Ultimately, the correlation between AEDS and breastfeeding is highly controversial with several confounding factors such as parental smoking, genetic risk, timing of introduction of solid foods and having domestic pets in the household. From these con licting results, it is dif icult to make an absolute conclusion regarding the effects of breastfeeding on the development of AEDS. With inconclusive information regarding breastfeeding’s direct impact on the development of AEDS, several researchers moved to evaluate the effectiveness of probiotics in reducing the occurrences of AEDS. Dotterud et al. enrolled 415 pregnant women in a randomized, doubleblind trial in which the participants consumed either probiotic-infused milk or a placebo from 36 weeks of gestation until three months postpartum.28 The probiotics included in the supplemented milk were Lactobacillus rhamnosus GG, Lactobacillus acidophilus La-5 and Bi idobacterium animalis. The children of these women were evaluated at age 2 years for the presence of AEDS. Dotterud et al. ultimately found a Winter 2017 Volume 8, Issue 1 T

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correlation between probiotic use in the mothers and a decreased incidence of AEDS (p=0.013). Supplementing the mother with probiotics thus supplemented her breast milk and her nursing child. Similarly, Viljanen et al. divided 230 infants into three differing feeding groups and evaluated their genetic predisposition for developing AEDS.29 Group 1 consumed Lactobacillus rhamnosus within their formula while group 2 was supplemented with Lactobacillus rhamnosus, Bi idobacterium breve and Propionibacterium freudenreichii. Group 3 received placebo supplementation. Genetic predisposition was assessed through skin prick results and IgE levels. Infants were only included in the study if these indings indicated a risk for AEDS. Infants with elevated levels of IgE who were in group 1 displayed a decreased occurrence of AEDS symptoms in comparison to infants in the placebo group (p=0.036). This statistical signi icance suggests that supplementing infants who are at risk for AEDS with Lactobacillus rhamnosus may reduce outbreaks of skin irritation. Similarly, Kukkonen et al. studied 1,223 pregnant women who either received a prebiotic and probiotic treatment or a placebo for two to four weeks prior to birth.13 Following birth, infants received the same combination treatment or placebo for six months. At a two year follow-up evaluation, infants with mothers who had received the treatment had a reduced incidence of AEDS (p=0.025). The combination of these consistent results further reinforces the suggestion that altering the gut microbiota of infants at high-risk for developing AEDS by adding probiotics to the infants’ diets can prevent the development of this disease. Role of the Pharmacist Community pharmacists are easily accessible to the public and are, therefore, in a unique position to provide education and services related to breastfeeding.30 Providing patients with facts that have been discovered through scienti ic research will help patients make fully informed decisions about whether to breastfeed. However, studies show that while pharmacists are willing to educate patients about breastfeeding, pharmacists lack education on the subject themselves. It has been suggested that including breastfeeding in pharmacy school curriculums and providing information about breastfeeding to practicing pharmacists through continuing education can reduce this information gap. Perhaps most pertinent to the pharmacist is the ability to counsel patients on medication use during lactation.31 It is important to note that U.S. Food and Drug Administration (FDA) pregnancy risk categories assigned to medications are not applicable to breastfeeding. It is always best to avoid medications or alternative medicines during lactation; however, if a medication is needed for the mother, the risks to the infant are minimal as the amount of drug in the breast milk is generally less than 10 percent of the maternal dose. For this reason most drugs are considered safe for use during breastfeeding, but each case should be evaluated for safety based on characteristics of the drug, infant age and weight, and whether the infant was premature or a low birth weight. P

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When choosing a medication for a nursing patient to treat a common ailment such as a cold or pain, drugs with short half-lives or high protein binding are preferred. It should be noted that the age and weight of the infant can play a role in possible harm from a drug. Older and heavier infants will be able to metabolize a drug excreted in breast milk with reduced risk of side effects or harm. Use of local topical agents, such as eye drops, should be encouraged whenever possible. Medications that should not be used while breastfeeding include antineoplastic agents, ergotamine, methotrexate and radiopharmaceuticals. Trained pharmacists can also help parents select an appropriate formula or breastfeeding pump.32 There are many options for infant formula available, and, with the proper knowledge, a pharmacist is a great resource to assist parents in choosing a formula. Pharmacists can also help mothers choose an appropriate breast pump to meet their individual needs and can provide instructions for using the pump. Under the Affordable Care Act, most private health insurance plans are required to pay for breast pumps under the umbrella of women’s preventive health services, although this may not apply to grandfathered plans. Breast pumps may also be covered under some state Medicaid programs which will vary from state to state. Pharmacists may direct patients to contact their Medicaid provider to determine if breast pumps are covered by their state Medicaid program. If a patient is unable to get a breast pump through Medicaid, a pharmacist may suggest that the patient seek assistance through the Special Supplemental Nutrition Program for Women, Infants and Children (WIC). Conclusion Research has shown several differences between the health and development of breastfed infants compared to formula-fed infants. One difference is the composition of gut microbiota—breastfed infants have higher concentrations of bene icial bacteria, including Bi idobacterium spp., while formula-fed infants have more potentially pathogenic bacteria including Clostridium spp., Staphylococcus spp. and Enterobacteriaceae. Breastfeeding may have a positive impact on the development of a child’s immune system while formula feeding has been linked to increased incidence of allergies. However, hydrolyzed formulas and formulas fortiied with prebiotics may have protective effects against food allergies. Additionally, breastfeeding has been shown to actively stimulate an infant’s immune system and can enhance the child’s response to vaccinations. Breastfeeding has also been shown to bene it the health of the nursing mother as well as the infant. Breastfeeding has been linked to higher itness levels in infants as well as increased insulin sensitivity and reduced postpartum weight gain in mothers. Pharmacists can assist in educating patients about breastfeeding and preparing patients to make a fully informed choice about whether to breastfeed. Pharmacists are also able to help parents select an appropriate infant formula or breast pump as well as counsel patients on the safety of medication use during lactation.

References 1. Labayen I, Ruiz JR, Ortega FB, Loit HM, Harro J, Villa I, et al. Exclusive breastfeeding duration and cardiorespiratory itness in children and adolescents. Am J Clin Nutr. 2012; 95:498-505. 2. Natland SR, Nilsen TIL, Midthjell K, Andersen LF, Forsmo S. Lactation and cardiovascular risk factors in mothers in a population-based study: the HUNT-study. Int Breastfeed J. 2012;7:8. 3. McClure CK, Schwarz EB, Conroy MB, Tepper PG, Janssen I, SuttonTyrrell KC. Breastfeeding and subsequent maternal visceral adiposity. Obesity (Silver Spring). 2011;19(11):2205-13. 4. Prentice P, Ong KK, Schoemaker MH, van Tol EAF, Vervoort J, Hughes LA, et al. Breast milk nutrient content and infancy growth. Acta Paediatr. 2016;105:641-7. 5. Pop M. We are what we eat: how the diet of infants affects their gut microbiome. Genome Biol. 2012;13:52. 6. Wall R, Ross R, Ryan C, Hussey S, Murphy B, Fitzgerald G, Stanton C. Role of gut microbiota in early infant development. Clin Med Pediatr. 2009;3. 7. Schwartz S, Friedberg I, Ivanov I, Davidson L, Goldsby J, Dahl D, et al. A metagenomic study of diet-dependent interaction between gut microbiota and host in infants reveals differences in immune response. Genome Biol. 2012;13:r32. 8. Arsalan A, Anwar Z, Ahmad I, Saba A, Naqvi S. Microbes in pediatric infant formula. Annals Food Science and Technology. 2013 May;14(1). 9. Costeloe K, Hardy P, Juszczak E, Wilks M, Millar M. Bi idobacterium breve BBG-001 in very preterm infants: a randomized controlled phase 3 trial. Lancet. 2016 Feb;387:649-60. 10. Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. Effects of probiotic and prebiotic on gastrointestinal motility in newborns. J Physiol Pharmacol. 2009 Dec;60Suppl 6:27-31. 11. Cekola P, Czerkies L, Storm H, Wang M, Roberts J, Saavedra J. Growth and tolerance of term infants fed formula with probiotic Lactobacillus reuteri. Clin Pediatr (Phila). 2015 Sep;54(12):1175-84. 12. Maldonado-Lobon J, Campos MG, Maldonado J, Lopez-Huertas E, Flores -Rojas K, Valero A, et al. Long-term safety of early consumption of Lactobacillus fermentum CECT5716: a 3-year follow-up of a randomized controlled trial. Pharmacol Res. 2015 May;95-96:12-9. 13. Kukkonen K, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, et al. Probiotics and prebiotic galacto-oligosaccarides in the prevention of allergic diseases: a randomized, double-blind, placebocontrolled trial. J Allergy Clin Immunol. 2007 Jan;119(1):192-8. 14. Ismail IH, Licciardi PV, Oppedisano F, Boyle RJ, Tang ML. Relationship between breast milk sCD14, TGF-β1 and total IgA in the irst month and development of eczema during infancy. Pediatr Allergy Immunol. 2013 Mar 6;24:352-60. 15. Lund-Blix NA, Stene LC, Rasmussen T, Torjesen PA, Andersen LF, Rønningen KS. Infant feeding in relation to islet autoimmunity and type 1 diabetes in genetically susceptible children: The MIDIA study. Diabetes Care. 2015;38:257-63. 16. Rabiei S. The association of nutrition style through the irst 2 years of life with type 1 diabetes mellitus and some of the other effective factors in 2-15 years old children [abstract]. Iran J Endocrinol Metab. 2011 May;13(1):113-21. 17. Malcova H, Sumnik Z, Drevinek P, Venhacova J, Lebl J, Cinek O. Absence of breast-feeding is associated with the risk of type 1 diabetes: a casecontrol study in a population with rapidly increasing incidence. Eur J Pediatr. 2006;165:114-9. 18. Alves JG, Figueiroa JN, Meneses J, Alves GV. Breastfeeding protects against type 1 diabetes mellitus: a case-sibling study. Breastfeed Med. 2012;7(1):25-8. 19. Knip M, Virtanen SM, Becker D, Dupre J, Krischer JP, Akerblom HK. Early feeding and risk of type 1 diabetes: experience from the trial to reduce insulin-dependent diabetes mellitus in the genetically at risk (TRIGR). Am J Clin Nutr. 2011;94:1841-20. 20. News-Medical.Net [Internet]. London (UK): AZO Network; c2000-2016. Breast feeding for thirteen months or more reduces mother’s risk of developing rheumatoid arthritis; 2007 Jun 19 [cited 2016 Dec 13]; [about 2 screens]. Available from: www.news-medical.net/ news/2007/06/19/26581.aspx. 21. Young KA, Parrish LA, Zerbe GO, Rewers M, Deane KD, Holers VM, et al. Perinatal and early childhood risk factors associated with rheumatoid factor positivity in a health paediatric population. Ann Rheum Dis. 2007 Feb;66(2):179-83. 22. Simard JF, Costenbader KH, Hernan MA, Liang MH, Mittleman MA, Winter 2017 Volume 8, Issue 1

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23.

24.

25. 26. 27.

28. 29.

30. 31. 32.

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Karlson EW. Early life factors and adult-onset rheumatoid arthritis. J Rheumatol. 2010 Jan;37(1):32-7. Schoetzau A, Filipiak-Pittroff B, Koletzko S, Franke K, von Berg A, Grubl A, et al. Effect of exclusive breast-feeding and early solid food avoidance on the incidence of atopic dermatitis in high-risk infants at 1 year of age. Pediatr Allergy Immunol. 2002;13:234-42. Chiu CY, Liao SL, Su KW, Tsai MH, Hua MC, Lai SH, et al. Exclusive or partial breastfeeding for 6 months is associated with reduced milk sensitization and risk of eczema in early childhood: the PATCH birth cohort study. Medicine. 2016 Apr;95(15):1-6. Bergmann RL, Diepgen TL, Kuss O, Bergmann KE, Kujat J, Dubenhausen JW, et al. Breastfeeding duration is a risk factor for atopic eczema. Clin Exp All. 2002;32:205-9. Ito J, Fujiwara T. Breastfeeding and risk of atopic dermatitis up to age 42 months: a birth cohort study in japan. Ann Epidemiol. 2014;24:26772. Jelding-Dannemand E, Malby Schoos AM, Bisgaard H. Breast-feeding does not protect against allergic sensitization in early childhood and allergy-associated disease at age 7 years. J Allergy Clin Immunol. 2015 Nov;135(5):1302-8. Dotterud CK, StorrĂ¸ O, Johnsen R, Ă&#x2DC;ien T. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial. Br J Dermatol. 2010;163:616-23. Viljanen M, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Eur Ann Allergy Clin Immunol. 2005 Apr;60(4):494-500. Edwards RA. Pharmacists as an underutilized resource for improving community-level support of breastfeeding. J Hum Lact. 2014;30(1):149. Amir LH, Pirotta MV, Raval M. Breastfeeding: evidence based guidelines for the use of medicines. Aust Fam Physician. 2011;40(9):684-90. U.S. Department of Health and Human Services [Internet]. Washington (DC): U.S. Department of Health and Human Services. Breast pumps and insurance coverage: what you need to know; [updated 2014 Sept 30; cited 2016 Oct 4]; [about 2 screens]. Available from: www.hhs.gov/ healthcare/facts-and-features/fact-sheets/breast-pumps-andinsurance-coverage-what-you-need-to-know/. The authors have no con lict of interest or funding support to disclose.

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T P W R Contributing Student Writers and Staff

The Ohio Northern Pharmacy and Wellness (PAW) Review is a student-run organization whose vision is to provide a professional, educational and relevant journal for both practicing and student pharmacists while further developing our own leadership, research skills and professional writing ability. The Review is published semiannually.

Winter 2017 Volume 8, Issue 1