Drug information news

Drug Information News
Volume 1, Issue 2
Second Quarter - 2009
Texas Southern University’s Drug Information Center is By: Adlia M. Ebeid PharmD, Drug Information Resident proud to welcome Dr. Portia Davis as the new Drug In the last issue of the Drug Information Newsletter, an Information Resident for the 2009-2010 year. Dr. Davis article regarding the effect of proton pump inhibitors is a member of the Rho Chi Pharmacy Honor Society (PPIs) on clopidogrel caught the attention of many of our and president of the Gamma Delta Chapter at Texas readers suggesting that PPIs decrease the effect of this Southern University. She is affiliated with antiplatelet therapy. Since then, other research and multiple professional organizations such as publications have surfaced to confirm the effect and mechanism of this interaction. In March of 2009, a clinical trial aimed at comparing the risk of adverse outcomes in patients taking clopidogrel with a PPI to those without a positions in the Alpha Sigma Chapter of Lambda Kappa PPI following acute coronary syndrome (ACS) was Sigma International Professional Pharmacy Fraternity. published. The results suggested that there was an With earning her doctor of pharmacy degree from Texas increased risk of death or re-hospitalization in patients Southern University and her continuing service to the taking clopidogrel and a PPI in comparison to those not community, Dr. Davis looks forward to dedicating herself taking a PPI, 29.8% vs. 20.8%, respectively with a 95% to the profession of pharmacy through the drug confidence interval and an adjusted odds ratio of 1.25 information center and being accessible to provide drug (1.11-1.41). The study also revealed a statistically information services to local health care professionals. significant increased re-hospitalization for ACS in We are excited to have Dr. Davis on our team as we patients taking the PPI compared to those not taking the continue to advance in providing current, unbiased, PPI (p<0.001), therefore concluding that concomitant evidence based drug information to the Houston therapy with PPIs and clopidogrel result in greater community and look forward to another productive year. adverse outcomes.1 The question still remains of the mechanism responsible for this reaction. As suggested in the April issue of Pharmacology weekly, PPIs, more specifically, omperazole is known to be a competitive inhibitor of specific liver enzymes necessary for clopidogrel’s oxidation to its active metabolite and thereby impedes the antiplatelet effects of clopidogrel. INSIDE THIS ISSUE:
This reasonable discovery may truly explain the mechanism for the interaction between omeprazole and clopidogrel but is not inclusive of all PPIs. Further studies need to be conducted to determine the effects of multiple PPIs on clopidogrel and on patients not undergoing Racially Influenced Response to Hepatitis C antiplatelet therapy to rule out the possibility of PPI induced cardiovascular problems. With the accessibility of over the counter omeprazole and health care provider’s attempt to prevent gastric bleeding, information such as this needs serious consideration and patients need to be evaluated on an individual basis. Cardiovascular Mortality in Elderly Patients Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. Bain AM, Busti AJ, Lehew DS, et al. What is the mechanism by which the proton pump inhibitor, omeprazole reduces the antiplatelet effects of clopidogrel thereby decreasing its cardioprotective effects? PW Drug Interact News.2009;1(14):1-5. Drug   Information News  Volume 1, Issue 2 By: Leroysha Reese, Doctor of Pharmacy By: Jacqueline Banboye, Doctor of Pharmacy With the Food and Drug Administration’s (FDA) approval On January 2, 2009, film actor John Travolta tragically of acetaminophen in 1951, over a half of a century ago, lost his teenage son to complications of a disease known pharmaceutical companies are continuing to come up as Kawasaki syndrome. Kawasaki syndrome is a disease with innovations in drug products that distinguish them of the immune system which affects various organs of from their competitors. Cadence™ Pharmaceuticals has the body but particularly the heart. The disease can be recently acquired the rights of Acetavance™, an fatal if not well managed and mostly occurs in children intravenous formulation of acetaminophen for treatment less than five years of age and in males twice as much of acute pain and fever, from Bristol-Myers Squibb. as in females. Dr. Tomisaku Kawasaki was the first Marketed as Perfalgan® throughout Europe and other person to describe this disease also known as parts of the world since 2002, acetaminophen injections mucocutaneous lymph node syndrome (MLNS) in Japan are the leading injectable analgesic based on dollars and in the late 1960’s. Since then the disease has been on units sold in Europe with an estimated total of nearly 80 the rise in the United States with nearly 3,000 new cases million sold in 2007. In comparison to other injectable reported each year. The etiology for this disease remains analgesics, Acetavance™ is said to be equally undetermined and is neither hereditary nor efficacious with a safety profile comparable to the oral communicable, however there is some suggestion that acetaminophen formulation. The results of two phase III the disease could be caused by a virus. The major clinical trials were recently announced to help support the symptoms of Kawasaki syndrome include, persistent high fever, rash on chest and genital area, red lips, and In two clinical trials one used to assess pain relief and strawberry colored tongue. In addition patients may also the other fever reduction, 330 patients and 60 subjects, suffer from joint pain, pneumonia, diarrhea and cracked respectively were randomized to receive acetaminophen lips. Since Kawasaki syndrome occurs mostly in children, or placebo. The results showed a positive response to the disease is usually first diagnosed by a pediatrician. pain relief and overall increased satisfaction in patients There is no confirmatory laboratory test for this disease taking the acetaminophen injections following abdominal but it is diagnosed by ruling out other diseases that may gynecological surgery but a statistically insignificant pain have similar symptoms. The patient must however also reduction compared to placebo a clinically significant have a high grade fever lasting five days or more and not reduction in fever compared to that of placebo in the responding to antibiotics. Aspirin is the drug of choice second trial. The FDA has agreed to not require due to its antipyretic and anti-inflammatory effects. additional clinical trials prior to the submission of the new Immune globulins are also used to prevent complications drug application (NDA) under the notion that that may arise in the coronary arteries. Corrective acetaminophen is a well known drug. Researchers surgery may sometimes be necessary in advance cases. argue that the formulation itself needs further evaluation About one to two percent of patients suffering from and more clinical trials are necessary but as of May 14, Kawasaki Syndrome die from complications of blood 2009, the NDA has been submitted to the FDA. clots or heart attacks. Kawasaki syndrome is not a very common disease but can be fatal. It is thus important that Ogbru O. Acetaminophen; MedicineNet. http://www.medicine parents follow the recommended treatment and take net.com/acetaminophen/article.htm. Accessed on February 27, appropriate precautions with their children. Cadence Pharmaceuticals. Cadence Pharmaceuticals Announces FDA Concurrence With Clinical Development Plan for US news.com. http://usnews.healthline.com/galecontent AcetavanceTM. http://files.shareholder.com/down loads /CADX /kawasaki-syndrome/3.Accessed on January 11, 2009. /567723575x0x216939/c7e111a7-dc0f-442e-8e6c- Wikipedia Online. http://en.wikipedia.org /wiki/ Kawasaki_disease. 4afb6ee74a33/CADX_News_2008_7_30_General_ Releases.pdf. Encyclopedia of children’s health: Infancy through Adolescence, 3. Reuters. Cadence Pharmaceuticals Announces Topline Results of http://www.health ofchildren.com/I-K/Kaw asaki-Syndrome.html. Two Phase III Clinical Trials. http://www.reuters. com /article/pressRelease /idUS118019+11-Jan-2008+PRN20080111. Drug   Information News  Volume 1, Issue 2 Lexicomp Online. http://online.lexi.com/crlsql/ servlet/crlonline. Accessed March 11, 2009. Rodriguez-Torres M, Lennox J, Sheikh M, Rossaro L, et al. Peginterferon Alfa-2s and Ribavirin in latino and Non-Latino Whites with Hepatitis C. NEJM. Jan 2009;360:257-267. http://content.nejm.org/cgi/content/short/360/3/257. Accessed By: Lillian Mendoza, Doctor of Pharmacy Candidate Latinos are the fastest growing race in the United States Strader D, Wright T, Thomas D, Seef L. Diagnosis, Management, and it is estimated that they will represent 15% of the and Treatment of Hepatitis C. Hepatology 2004 Apr;39(4):1147-71. U.S. population by 2010. Studies have shown that 2.1% of all Latinos are infected by the hepatitis C virus (HCV) compared to only 1.5% of non-Latino whites. The mortality rate among Latinos with HCV is twice the rate of non-Latino whites. In an effort to assess the effect of race on certain HCV medications and target the underrepresented Latino population, a comparative prospective study was performed to determine the effect of peginterferon alfa-2a and ribavirin in HCV genotype 1 By: Portia N. Davis, Doctor of Pharmacy infected individuals. The study consisted of 269 Latino Menopause is defined as the cessation of menstruation and 399 non-Latino whites from 52 centers in the United for twelve months, and usually occurs naturally in women State and Puerto Rico. The patients included in the around the age of 50.1 Menopause may also begin Latino population were between the ages of 18 and 65, directly following an oophrectomy, or radiation therapy. had no prior history of treatment for HCV infections, had Symptoms of menopause include irregular periods, mood Spanish speaking parents and grandparents from Latino swings, vaginal dryness, urinary incontinence, insomnia, descent. The treatment group was given peginterferon depression, dry skin, loss of libido, alopecia, alfa-2a 180 mcg/weekly and ribavirin depending on their osteoporosis, and vasomotor symptoms of hot flashes weight.1,2 Researchers assessed their virologic and and night sweats. Vasomotor symptoms (VMS) may biochemical responses at weeks 4, 12, 24, 48, 60, and begin prior to the onset of menopause and continue for 72 along with the assessment of compliance at each years. These symptoms vary in intensity, and are one of the primary reasons that women seek medical care. The adjustment, and clinical adverse events were monitored National Menopause Society released a position throughout the study and adjustments were made as statement in 2004 which supports that hormonal therapy needed. Histological assessments were done at the time remains the most effective treatment for VMS.2 Currently, of screening or within 18 months before the study began only hormonal preparations carry FDA approval for this and during the final week. Relapses were assessed indication, however all patients are not candidates for between weeka 48 and 72. The results of the study hormonal regimens. Women with contraindications to showed that Latino patients infected with chronic HCV hormonal therapy include those with undiagnosed genotype 1 have a lower rate of response to standard therapy with peginterferon alfa-2a and ribavirin than non- breast cancer or any estrogen/progesterone dependent Latino whites. Also, found was that the sustained tumor, venous or arterial thromboembolic disorders virologic response rate was significantly lower in the (including DVT, PE, MI, or stroke), or hepatic diseases. Latino group than in the non-Latino group (P<0.001). In a Non-hormonal agents currently being utilized in the post hoc analysis it was shown that the rates of treatment of menopausal VMS include selective sustained virologic response were similar regardless of serotonin reuptake inhibitors (SSRIs), selective the country of origin of Latinos. Adverse effects occurred norepinephrine reuptake inhibitors (SNRIs), alpha-2 in 98% of the patients with the most common being agonists, and gabapentin. Desvenlafaxine (Pristiq®), depression, suicidal ideation, and fatigue which lead to FDA approved February 29, 2008, is the newest 9% of the Latinos and 14% of the non-Latinos dropping commercially available SNRI. Although indicated for the out of the study. This study demonstrated that there treatment of major depressive disorder, studies have should be more race focused clinical trials due to varied shown that this agent, as well as other SNRIs has proven treatment responses in certain disease states among useful in the treatment of menopause related VMS symptoms. To determine the efficacy and safety of desvenlafaxine in this condition, Wyeth Research Laboratories conducted a double-blind, placebo- Drug   Information News  Volume 1, Issue 2 controlled, randomized study that followed 567 postmenopausal women experiencing 50 or more hot flashes (HFs) per week. Subjects were recruited and participated in the study for 26 weeks in 32 US sites which included private and institutional practices and By: Joseph Ukonu, Doctor of Pharmacy Candidate research centers. Women were included in the study if Venous thromboembolism (VTE) is a potentially fatal they were diagnosed as postmenopausal, healthy, had a disorder and a significant national health problem in our BMI ≤ 40 kg/m2, and experienced at least 7 or more society. Although it can strike young, otherwise healthy moderate to severe hot flashes (HF) per day for 7 adults, it most frequently occurs in patients who sustain consecutive days. Women were excluded if they had a multiple traumas, undergo major surgery, are immobile history of cancer, certain psychiatric disorders, seizures, for a lengthy period of time, or have a hypercoagulable cardiovascular disease, glaucoma, or if they had disorder. The true incidence of VTE in the general received any hormone-containing drug within 6 months of population is unknown since in over 50% of the patients the study. The subjects were randomly assigned to the disease remains silent. An estimated 2 million people receive placebo, 100mg, or 150mg of desvenlafaxine in the United States develop VTE each year; of which once daily for 26 weeks. The primary endpoint of the 600,000 are hospitalized and 60,000 die.1 study was drug efficacy which was measured by several Blood coagulation is initiated when “Tissue Factor”, (a variables including number and severity of HFs, and protein-phospholipid complex normal y present on nighttime awakenings. The secondary endpoints were vascular cells and activated monocytes), are exposed to safety and tolerability, which were measured by the factor VII in the presence of calcium. The activated tissue number of adverse events experienced during and after factor-VII complex activates factors IX and X. Factor IXa treatment. The study results indicated that most women enhances the production of Xa, especially in the in the desvenlafaxine treatment groups achieved presence of the co-enzyme VIIIa. Factor Xa converts between a 50% to 75% decrease in the number of HFs, prothrombin to thrombin (factor IIa). Thrombin cleaves and the majority of women in these groups also reported fibrinogen yielding monomers of fibrin which then improvement in the severity of HFs as well. The treatment groups reported significantly more adverse Rivaroxaban (Xarelto®) is an oxaxolidinone derivative effects than the placebo group, however only 7 subjects that exerts its action by binding to the active site of factor from the treatment group reported serious adverse Xa which acts at the convergence point of the extrinsic events. The author of the study concluded that and intrinsic coagulation pathways and catalyzes the desvenlafaxine at 100mg and 150mg doses is a conversion of prothrombin to thrombin thereby inhibiting generally safe, well-tolerated treatment for moderate to factor Xa. The L-shape structure of rivaroxaban allows it severe vasomotor symptoms associated with to be highly selective for factor Xa. This high selectivity menopause.3 As the number of women entering allows the drug to inhibit free factor Xa, prothrombinase menopause continues to grow, the demand for hormone- activity and clot-associated factor Xa, giving it the ability free menopausal treatment will continue to increase as to prevents clots from forming and possibly break down well. Desvenlafaxine may serve as a treatment option for of pre-existing clots.4 Rivaroxaban is well absorbed women who suffer from moderate to severe vasomotor orally, with an appropriate bioavailability of 80%. The symptoms that may not be able, or may not be willing to pharmacokinetic and pharmacodynamic characteristics of rivaroxaban are moderately altered by food, resulting in delayed absorption and increased peak concentration, American Menopause Association website. Available at: http://www.americanmenopause.org/. Accessed on March 9, 2009. but are unaffected by changes in gastric PH. 2. Santoro NF, et al. Treatment of Menopause-associated Vasomotor Rivaroxaban is highly protein bound and it is unknown if Symptoms: Position Statement of the North American Menopause its metabolism mimics that of other Xa inhibitors through Society. Menopause. 2004; 11(1):11-33. the liver. It is eliminated through both renal (66%) and 3. Pristiq [package insert] Philadelphia, PA: Wyeth Pharmaceuticals, biliary (28%) pathways, with 36% of the drug 4. Archer DR, et al. Desvenlafaxine for the treatment of vasomotor unchanged.4 The effect of rivaroxaban was tested in a symptoms associated with menopause: a double-blind, double-blind study where 4541 patients were randomized randomized, placebo-controlled trial of efficacy and safety. Am J to receive either 10mg of oral rivaroxaban once daily Obstet Gynecol. 2009; 200:238.e1-238e.10. beginning after surgery, or 40mg of enoxaprin subcutaneously once daily beginning the evening before surgery plus a placebo tablet or injection, respectively. A Drug   Information News  Volume 1, Issue 2 total of 3153 of the patients were included in the superiority analysis and 4433 were included in the safety analysis. The primary efficacy outcome occurred in 18 of the 1595 patients (1.1%) in the rivaroxaban group and 58 of the 1558 patients (3.7%) in the enoxaparin group By: Chidima Azuike,Doctor of Pharmacy (absolute risk reduction, 2.6%; 95% confidence interval, Antithrombin, a natural anticoagulant that regulates 1.5 to 3.7; p<0.001). Major thromboembolism occurred in thrombin, holds an important role in the formation of 4 of 1686 patients (0.2%) in the rivaroxaban group and in blood clots. Antithrombin deficiency is a rare hereditary 33 of 1678 patients (2.0%) in the enoxaparin group. deficiency that is usually diagnosed after a patient has Major bleeding occurred in 6 of the 2209 patients (0.3%) suffered from recurrent thromboembolic events. Patients in the rivaroxaban group and in 2 of the 2224 patients with hereditary antithrombin deficiency are prone to (0.1%) in the exonaparin group (p=0.18).The developing blood clots. It is said that about 1 in 5,000 investigators concluded that a once-daily 10mg oral dose people are at risk of developing blood clots in their veins of rivaroxaban was significantly more effective for because they do not produce enough protein. This extended thrombophylaxis than a once-daily 40mg condition can not only be very painful, but also extremely subcutaneous dose of enoxaparin in patients undergoing dangerous if the clot were to break loose. It can also hip surgery.2 A separate study measuring rivaroxaban’s pose a threat to pregnant women because blood clots in ability to treat preexisting clots and act as a long-term the placenta can lead to miscarriage or stillbirth. The anticoagulant looked at the treatment of proximal DVT’s. hereditary deficient population, as previously stated, is Subjects were given oral rivaroxaban in doses of 10, 20, about 1 in 5,000 and until now has been dependent upon and 30 mg twice daily, 40mg once daily or enoxaparin plasma-derived antithrombin products for use during 1mg/kg subcutaneously twice daily followed by a vitamin high-risk procedures. As what could be considered the K antagonist for 12 weeks. The investigators concluded first of its kind, ATryn® has moved even closer to after their findings, that the range of doses of rivaroxaban becoming government approved. ATryn® is the only was as safe and effective at treating proximal DVT was recombinant antithrombin product that is geared towards enoxaparin.4 Rivaroxaban is currently in Phase III clinical treating people with hereditary antithrombin deficiency trials and does not have any approved indications at this that are at risk of developing serious or even potentially time. FDA approval for the drug was sought in the third life-threatening venous thromboembolic events. This quarter of 2008 by Bayer Healthcare and decision can be recombinant form of antithrombin will be an alternative to treatment with plasma-derived product for deficient There is indeed a need for a new anticoagulant that is patients. ATryn® was developed by the biotechnology just as effective as warfarin, but without such a rigorous company GTC Biotherapy who develops human monitoring schedule. Once daily dosing of rivaroxaban therapeutic proteins in the milk of transgenic animals. has been shown to produce 24 hours of inhibition of With this they are able to express human therapeutic factor Xa and thrombin generation, allowing for a proteins in their milk. These recombinant proteins can convenient once-daily dosing regimen with minimal then be purified from the milk for therapeutic use. In monitoring.4 Trials to date have not shown an increased GTC’s case they produce transgenic goats. They use risk of major or minor bleeding compared with goats because their mammary gland efficiently expresses high levels of different types of proteins during milk production. For patient with the hereditary disorder, 1. Borris, CL. New compounds in the management of venous the conventional treatment standard will still apply. The thromboembolism after orthopedic surgery: focus on rivaroxaban. use of ATryn® is reserved only for patients who are Vasc Health Risk Manage. 2008; 4(4):855-862. 2. Eriksson. B, Borris.L, Friedman. R et al. Rivaroxaban versus undergoing surgery or having a baby. It is basically used Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. The only in times when there is a high risk of dangerous clots forming. The drug is administered by infusion and 3. Assessing Coagulation: The Coagulation System. patients receiving the medication will do so for a limited www.anaesthetist.com/icu/organs/blood/coag.htm. (Assessed on 2/27/09) time before and after their procedures. Pregnant patients 4. Rivaroxaban (Bay59-7939), Xarelto®. A possible replacement for and those undergoing surgery with a serious blood warfarin (Coumadin, Jantoven). Warfarin Institute of America. disorder have responded well to treatment with a man- www.warfarinfo.com/rivaroxaban.htm. (Assessed on 2/27/2009) made anti-clotting protein. If approved by the FDA, a major step will have been made in the shift from Drug   Information News  Volume 1, Issue 2 medications made from chemicals to those made from (43%). Individuals with plasma Hcy levels in the top third compared with the bottom third had a two-fold higher risk of all-cause mortality (P<0.001) and CVD mortality (P 1. ATryn® - RECOMBINANT HUMAN ANTITHROMBIN. GTC <0.001) after adjustment for age, sex and other Biotherapeutics Web Site.2008. Available at: http://www.gtc- covariates, but with no association of plasma folate or bio.com/products/atryn.html. Accessed on January 9, 2009. vitamin B-12 levels.4 The Leiden 85-plus Study, an FDA Advisory Committee Recommends GTC Biotherapeutics' ATryn* (antithrombin [Recombinant]) If approved, ATryn will be observational prospective cohort study, conducted by first recombinant human antithrombin available in the U.S. GTC Ruijter et al investigated the performance of classic risk Biotherapeutics Web Site.2008. Available at: http://www.gtc- factors using the Framingham scale, and of some new bio.com/pressreleases/pr010909.html. Accessed on January 9, biomarkers, in predicting cardiovascular mortality in very 3. The Associated Press. New Drug Uses Milk from Gene Spliced old people with no history of CVD. The study sample Goats. CBS News Web Site. 2008. Available at: consisted of participants aged 85 years and older (215 http://www.cbsnews.com/stories/2009/01/07/health/main4704807.
women and 87 men) with no history of CVD. During a follow-up period of 5 years, 108 of the 302 participants died of which 32% (35/108) were from cardiovascular causes. The authors concluded that there was no difference in cardiovascular mortality between the risk categories and, only homocysteine resulted in a statistically significant differences between the risk categories (P=0.002) such that the high risk category had a 3.4-fold increased risk of cardiovascular mortality By: Sneha Valimattathil, Doctor of Pharmacy Candidate compared with the low risk category. The study Cardiovascular disease (CVD) is the leading cause of concluded that in the elderly with no history of CVD, morbidity and mortality in elderly in the United States. concentrations of homocysteine alone can accurately Among the new biomarkers in predicting and preventing identify those at high risk of cardiovascular mortality these events, homocysteine (Hcy) - a sulfur containing whereas classic risk factors included in the Framingham amino acid produced by the conversion of methionine in risk score do not.1 In conclusion, homocysteine levels the presence of folic acid and vitamin B12 and an can be used in predicting cardiovascular mortality in the important substrate in protein synthesis and metabolism, elderly. In future, the practice of medicine may target is associated with increased risk of cardiovascular therapy in reducing homocysteine level to lower the risk disease in the elderly.1 The discovery of this new of having any cardiovascular event and, thereby biomarker in predicting cardiovascular events may decrease the economic costs associated with it. improve quality of life in elderly. There are several hypothesis proposed to explain how elevated Hcy levels 1. Ruijter W, Westendorp RG, Assendelft WJ et al. Use of lead to cardiovascular events. One hypothesis is that it Framingham risk score and new biomarkers to predict can destroy the endothelial cells of blood vessels leading cardiovascular mortality in older people: population based to plaque formation and also impair nitric oxide activity. It observational cohort study. BMJ 2009;338;a3083. is also hypothesized that Hcy can promote vascular 2. Fanapour PC, Yug B, Kochar MS. Hyperhomocysteinemia: an additional cardiovascular risk factor. WMJ. 1999;98(8):51-4. smooth muscle cell hypertrophy.2 Both these processes 3. Carlsson CM. Homocyteine Lowering with Folic Acid Vitamin B leads to occlusion of blood vessels resulting in ischemia. Supplements: Effects on Cardiovascular Disease in Older Adults. Studies have reported that an increase in Hcy levels promotes atherosclerosis, endothelial dysfunction, 4. Dangour AD, Breeze E, Clarke R, Shetty PS et al. Plasma oxidative stress, coagulation and platelet dysfunction Homocysteine, but Not Folate or Vitamin B-12, Predicts Mortality in Older People in the United Kingdom. J. Nutr. 2008;138:1121–28 only in the absence of folic acid or cyanocobalamin.3 Therefore whether the elevated Hcy level is an indicator of cardiovascular event remains unclear. A population- based prospective cohort study conducted by Dangour et al examined the association of plasma levels of folate, vitamin B-12 and homocysteine, and all-cause and CVD mortality in patients 75 years old and older in the United Kingdom. The study included 853 men and women and during the median follow up period of 7.6 years, 429 individuals died of with the leading cause being CVD 185

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