Marys Medicine

Indiana pharamcists alliance (ipa) continuing pharmacy education (cpe)

INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
Evaluation of Oral and Topical Therapies for Mild to Moderate Ulcerative Colitis
inflammation and ulceration of the intestinal Jasmine Ho, PharmD mucosa and submucosa. The disease affects Columbus Regional Hospital approximately 700,000 Americans.1 Disease Clinical Pharmacist severity is highly variable in patients, and is considered a lifelong disease requiring long- ACPE UAN: 0120-0000-14-011-H01-P term treatment. Time frames between flare-ups 1.5 Contact Hours (1.5 CEU's) can vary from months to years. Men and This is a knowledge based activity women are equally affected by UC, with most See end article for CE details diagnoses made during the 30s age range. However, the disease can occur at any age, and Target Audience: Pharmacists up to 20% of patients have a first degree Faculty Disclosure: The faculty have no conflicts relative with the disease as well.1 of interest to disclose Learning Objectives: Patients presenting with chronic diarrhea lasting for weeks may be assessed for At the completion of this activity, the diagnosis. Proctosigmoidoscopy or colonoscopy participant will be able to: procedures are complete to reveal mucosal changes characteristic of UC. Positive findings 1. Classify disease severity using the ulcerative include loss of typical vascular pattern, colitis disease activity index. granularity, friability, and ulceration. Mucosal 2. List topical and oral therapies for mild to biopsy results suggestive of UC can include moderate ulcerative colitis. separation, distortion, atrophy of crypts, 3. Identify advantages and disadvantages of inflamed cells, and increased lymphocytes and Uceris®, Remicade®, and Humira®. plasma cells. A complete history should also be completed prior to diagnosis for possible causes 4. Identify medications for maintenance of diarrhea such as recent travel or antibiotic remission in mild to moderate ulcerative colitis. use. Some other helpful tests include stool studies testing for Escherichia coli, Salmonella, Shigella, Campylobacter, Giardia and Yersinia.2 Inflammatory bowel disease (IBD) Symptoms depend on the severity of consists of two conditions known as ulcerative inflammation and the extent of colon affected. colitis (UC) and Crohn's disease (CD). UC Common symptoms of mild to moderate UC primarily affects the colon and rectum; while include rectal bleeding, diarrhea, abdominal alternatively, CD may affect any location of the cramping, stool urgency, and tenesmus.1,2 As a gastrointestinal tract. IBD should not be result, other possible symptoms include a loss confused with Irritable Bowel Syndrome (IBS) of appetite, weight loss, fatigue, fever, which involves abnormal muscle contractions of tachycardia, and anemia. A few other the colon. While the exact cause of UC is laboratory tests that should be done include a unknown, genetic, environmental, microbial complete blood count (CBC,) basic metabolic factors, and autoimmune triggers have been panel (BMP), erythrocyte sedimentation rate studied. UC is characterized by continuous (ESR), and C-reactive protein. The perinuclear INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
CONTINUING PHARMACY EDUCATION (CPE) Article
antineutrophil cytoplasmic antibody (pANCA) Table 1: Ulcerative Colitis Disease Activity Index4 has been detected in 60-70% of UC patients, but also in 40% of CD patients. Due to its low sensitivity, pANCA is not typically used 1-2 stools/day > normal diagnostically; however, it may be useful in 3-4 stools/day > normal patients lacking other clinical or pathologic > .4 stools/day > normal findings of UC.2 Streaks of blood In general, patients with mild UC Signs of systemic toxicity experience four or less stools per day, with or Heart rate > 90 bpm without blood, and do not present with signs of Temperature > 37.5°C systemic toxicity. Patients with moderate UC Hemoglobin < 10.5 gm/dL experience more frequent bowel movements ESR > 30 mm/hr and minimal systemic effects. Severe UC is defined by more than six bloody stools a day and signs of systemic toxicity.3 Fulminant disease classification includes more than ten Mucosal appearance stools a day with continuous bleeding, signs of systemic toxicity, and abdominal tenderness and distension.3 One severity scoring tool Moderate friability classifies remission, mild, moderate, or severe Exudation, spontaneous bleeding disease based on composite scores. The rubric Physician's rating of disease activity is often referred to as the Ulcerative Colitis Disease Activity Index (UCDAI) (Table 1). The four variables assessed are stool frequency, extent of rectal bleeding, colonic mucosal appearance, and the physician's assessment of Total index score ranges: disease. Each variable is graded from 0-3, and the sum is used for classification.4 However, it is still imperative to review patient specific symptomatology concerns such as abdominal pain, nocturnal bowel patterns, urgency, and fear of incontinence. Location is another important item to address during classification, particularly for treatment options. Table 2 describes UC locations by the extent of inflammation known as proctitis, proctosigmoiditis, left-sided colitis, and pancolitis. Also to note are locations distal or proximal to the descending colon, which may decide treatment routes. Distal colitis is best treated with topical agents, whereas proximal colitis may require oral or combination INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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Table 2: Locations of Ulcerative Colitis2 Proctitis - confined to the last six to seven inches of the rectum Proctosigmoiditis - extends to the sigmoid colon Proximal colitis Left-sided colitis – extends to the descending colon, and may reach the splenic flexure Pancolitis – extends through the entire colon and cecum Treatment Options dosing, and less systemic absorption.2 If Medication management should be patients are unable to tolerate topical therapy, based upon disease distribution, response to oral therapy is an alternative, however, previous treatments, side-effect profile, and response may be delayed.5 patient preferences. Goals of therapy include For more extensive disease, oral inducing and maintaining remission, improving aminosalicylate therapy should be utilized first.2 quality of life, providing mucosal healing, Patients failing to achieve remission should avoiding colectomy, minimizing cancer risk, and then trial oral and topical aminosalicylate reducing the need for long-term therapy, followed by oral steroids, and lastly corticosteroids.2 Medication doses and uses are oral thiopurines.2 If patients are unable to differentiated by whether induction or obtain remission within 4-6 weeks of maintenance of remission is goal. Available drug aminosalicylates and steroid therapy, classes for mild to moderate UC include oral thiopurines have also been shown to benefit and topical aminosalicylates, oral or topical steroids, and oral thiopurines. In distal colitis, maximum benefit has Aminosalicylates been seen with combining oral and topical Available aminosalicylates for UC are aminosalicylate agents versus either treatment listed in Table 3. Sulfasalazine was the first alone.2 Topical mesalamine is also more aminosalicylate used for IBD treatment and is effective than topical steroids or oral comprised of 5-aminosalicylate (5-ASA) and aminosalicylates.2 Since proctitis and sulfapyridine components. Adverse effects of proctosigmoiditis are limited to the rectum, sulfasalazine are attributed to the sulfapyridine topical treatment with suppositories or enemas moiety while therapeutic benefits are are preferred dosage forms, although attributed to 5-ASA. Sulfasalazine has suppositories may be more tolerable for some traditionally been the first-line agent for patients.2 Proctitis is best treated with extensive mild to moderate UC, with an suppositories, which can reach up to ten estimated 80% of patients likely to achieve centimeters within the rectum. remission within 4 weeks on daily doses of 4- Proctosigmoiditis is best treated with an enema, 6g.10,11 The best advantage of using which can reach the proximal sigmoid colon and sulfasalazine over newer agents could splenic flexure in patients able to retain them. potentially be a lower cost.2 Guidelines Foam, available as hydrocortisone, has potential recommend titrating to a dose of 4-6 g daily, to reach between 15-20 centimeters.2 however, higher doses increase adverse Advantages of topical versus oral medications effects.2 Contraindications for use include for UC include a faster response, less frequent allergies to sulfonamides and salicylates, INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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intestinal or urinary obstruction, and discontinuing use.11 Severe adverse effects porphyria.12 Common side effects include reported include hematologic abnormalities, nausea, vomiting, dyspepsia, anorexia, systemic lupus erythematosus, and headache, possible urine discoloration, hepatotoxicity.12 For patients that experience abdominal pain, skin rash, and fever.12 Men gastrointestinal intolerance, a lower starting may experience oligozoospermia which is dose of 1-2 g daily may be helpful.12 reversible approximately two months after Table 3: Available aminosalicylates for UC treatment2,12,16,22,23,25 Brand name Strength supplied Maintenance dose 3-4g/day orally in 2g/day orally in evenly divided doses; not exceeding 8-hour exceeding 8-hour 3-4g/day orally in 2g/day orally in evenly divided doses; not exceeding 8-hour exceeding 8-hour 1.6g/day orally in divided doses times daily for 6 1.6g orally 3 times daily for 6 weeks 1.6g orally daily in divided doses times daily (1 hour before or 2 hours after a meal) for 6 2.4 - 4.8 g orally 2.4g orally once daily with food food for up to 8 1g orally 4 times 1g orally 4 times daily daily for up to 8 1.5g orally once daily in the 500 mg – 1g suppository rectally rectally (retain for hours) at bedtime INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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1 enema rectally 2-4g enema rectally at bedtime* at bedtime (retain for 8 hours) for 3- times daily for 8 - 3.3g orally twice daily for up to 8 1g/day orally in 2 divided doses *Unlabeled FDA indication Abbreviations: EC=enteric coated, DR=delayed release, ER= extended release The newer 5-ASA formulations, colon.13 Bioequivalence between Delzicol® and mesalamine, balsalazide, and olsalazine, were Asacol HD® or Asacol® and Asacol HD® have not developed to provide therapeutic effects of 5- been established and are not interchangeable.16 ASA and to increase patient tolerability. They Mesalamine was first approved with a daily have demonstrated superiority to placebo and dose of 2.4g, but the ASCEND I and II trials were equivalence to sulfasalazine in acute therapy.2 completed to gather safety and efficacy results The available therapies can be overwhelming at of a higher 4.8g dose (Tables 4 and 5). To first glance, but can be differentiated once summarize the studies, patients with mild UC formulations are reviewed. Eighty percent of may be treated with 2.4g/day, since 4.8 g/day patients unable to tolerate sulfasalazine are did not provide additional benefit.14,15 For able to be treated with a newer agent.2 patients with moderate UC, the higher dose is The pH increases with ascension into more likely to help achieve overall the intestinal tract, requiring pH specific improvement, and therefore, can benefit from formulations. Mesalamine only provides starting at the 4.8 g/day dose.14,15 For both therapeutic use when in direct contact with the treatment arms, quality of life and inflamed colon; therefore, pH specific delivery Inflammatory Bowel Disease Questionnaire systems were required for creating mesalamine (IBDQ) scores improved from baseline to week as an oral medication. Coatings used to prevent 6 of therapy.14 The ASCEND II trial, however, did absorption throughout the gastrointestinal tract not find a significant statistical difference include Eudragit-S, Eudragit-L, ethylcellulose, between dose groups for improvement in stool and Multi-Matrix System (MMX).13 frequency, rectal bleeding, physician's global Asacol®, Asacol HD®, and Delzicol® are assessment (PGA), or sigmoidoscopy scores.15 coated with Eudragit-S resin polymer that disintegrates at a pH greater than 7. The Eudragit-S coating allows mesalamine to be delivered to the terminal ileum and proximal INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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Table 4: Results from the ASCEND I trial14 Primary outcome results Mesalamine DR 2.4g Mesalamine DR 4.8g Overall improvement (%) Days for clinical assessments to resolve (rectal bleeding, stool frequency) Secondary outcome results with moderate disease Mesalamine DR 2.4g Mesalamine DR 4.8g Treatment success (%) Median days to symptom relief for stool frequency and rectal bleeding Table 5: Results from the ASCEND II Trial15 Mesalamine 4.8g/day Primary outcome results Overall improvement (%) Secondary outcome results Mesalamine DR 2.4g Mesalamine DR 4.8g Median days for clinical assessments to (rectal bleeding, stool frequency) Pentasa® is a controlled-release dosage form containing mesalamine microgranules encapsulated in a moisture-sensitive ethylcellulose coating, which is not pH dependent. This allows slow release of the medication through a semi-permeable coating.13 In one of the first studies comparing Asacol® to Pentasa®, Asacol® provided a greater reduction in UCDAI scores, percentage of patients achieving remission, and experiencing an overall improvement.17 The study, however, did not use the target dose of 4g/day. The newest mesalamine formulation is a Multi-Matrix System (MMX) allowing for once daily dosing, also decreasing pill burden for patients. Lialda® combines the Eudragit-S resin polymer and MMX to deliver mesalamine to the ileum and cecum.13 In mild to moderate UC, patients taking mesalamine MMX at a dose of 2.4g or 4.8g/day were able to achieve clinical and endoscopic remission at comparable rates compared to placebo (Table 6).18,19 INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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Table 6: Results from Lichtenstein GR, Kamm MA, et al19 2.4g/day given BID 4.8g/day given once daily Primary outcome results Clinical & endoscopic Secondary outcome results Clinical improvement Clinical remission (%) Treatment failure (%) ***P<0.001 **P<0.01 *P<0.05 Apriso® contains mesalamine granules application side effects consist of within an Eudragit-L coating triggered to gastrointestinal symptoms, arthralgia, asthenia, dissolve at a pH of 6 or greater.13 In one study, dizziness, and/or headache. In elderly patients, 78.9% of patients taking Apriso® remained in blood dyscrasias may occur.16 Patients should remission at 6 months compared to 58.3% on carefully handle Canasa® as staining with placebo (p < 0.001).20 Apriso® is only approved contacted surfaces and clothes can occur.25 For for remission maintenance, is taken once daily, enema and suppository treatment, patients and administration should be separated by at should be counseled to empty their bowels least two hours from antacids.16 before use, if possible. In other studies, balsalazide and Nephrotoxicity with 5-ASAs is rare, but olsalazine did not provide statistically significant patients with renal impairment should use results, however they were shown to be more aminosalicylates with caution.2 Appropriate tolerable than sulfasalazine and are options for laboratory monitoring include a baseline serum patients with sulfa allergies.21,22 Olsalazine, creatinine before treatment begins, every 3-6 however, produced an adverse dose-related months during the first year of therapy, and diarrhea effect.23 Colazal® is approved for use in annually thereafter.26 patients between ages 5-17.24 Giazo®, during clinical trials, did not provide therapeutic Glucocorticosteroids benefit in females and is recommended for use Glucocorticoids were first used in the only in males.16,24 1950s for IBD, however due to their adverse Topical 5-ASA preparations include and long-term use effects, they have been suppositories and enemas. Mesalamine reserved for patients failing to achieve suppositories are effective in maintaining remission with oral and topical aminosalicylate remission in proctitis, whereas mesalamine therapy.2,27,28 First-line treatment with steroids enemas are effective in patients with should be avoided as one retrospective review proctosigmoiditis.2 Rowasa® and sfRowasa® found early corticosteroid use increased the differ in sulfite content, allowing for patients risk of relapse and steroid-dependence.29 with sulfite allergies to use sfRowasa®. Topical Glucocortocoid adverse effects include INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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Cushingoid appearance, emotional and decrease within 3-5 days of therapy, but psychiatric disturbances, increased risk for proctological improvement may not occur until infection, metabolic disturbances, ocular 2-3 months of therapy.32,33 After completing 21 changes, and decreased bone mineral density.2 days of therapy, the dose of hydrocortisone Patients should have an annual eye exam if they enemas should be decreased to every other are continued on steroids, should be considered night for 2-3 weeks, and then finally for dual energy X-ray scanning, and should be discontinued.32,33 If patients fail to achieve monitored for endocrine disorders.2 improvement within 2-3 weeks of enema Glucocorticosteroids are effective in initiation, therapy should be discontinued. inducing remission and doses are listed in Table Important counseling points include shaking the 7. In one meta-analysis, steroids reduced bottle well before administration, and retaining remission failure in 54% of patients compared the enema for at least an hour, and all night if to 79% on placebo, with a number needed to treat (NNT) of 3.27 A prednisone dose range Another option for topical therapy is between 20-60mg daily have been used in foam, available as Cortifoam®, which may be randomized trials.2 Patients can expect to see more tolerable for patients unable to retain improvement within 10 to 14 days of treatment enemas. Hydrocortisone acetate 10% rectal initiation.2,30 Once clinical improvement has foam is supplied with an applicator, and when been reached, the dose should be tapered filled properly, delivers 90mg of hydrocortisone down 5-10mg weekly until the dose reaches acetate.34 Patients can expect to have a 20mg daily, followed by another dose decrease minimum of 14 applications with one aerosol of 2.5mg weekly.2 can.34 Administration technique include shaking Hydrocortisone enemas are available as the canister well before each use and Colocort® and Cortenema®.31 Generally, they positioning the canister upright when are used until the patient reaches clinical and dispensing.30,34 proctological remission. Symptoms may Table 7: Glucocorticosteroids for UC 2,3134,37,38 Brand (generic) drug name Suggested dosing Methylprednisolone* 40-60mg orally every morning or in two 1 applicatorful rectally 1-2 times daily for 2-3 (hydrocortisone acetate) weeks, then every other day thereafter Colocort®, Cortenema® 100mg/60mL enema 1 enema rectally every night for 21 days or (Hydrocortisone) until remission, then every other night for 2-3 9mg orally daily in the morning for up to 8 Uceris® (budesonide) 9mg orally daily in the morning for up to 8 *Unlabeled FDA indication DR= delayed-release MMX= Multi-Matrix System INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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Budesonide, like mesalamine, requires direct contact with inflamed colon to provide therapeutic use in UC. Delayed release budesonide, currently available as Entocort EC®, does not have an approved indication for UC, but has been compared to conventional UC treatments. Through the development of an MMX extended-release dosage form, the role of budesonide has expanded into the oral treatment options for inducing remission in mild to moderate UC. The oral formulation helps deliver the glucocorticosteroid throughout the length of the colon. The CORE I Study compared budesonide MMX to standard oral mesalamine therapy. During the 8 week trial, more patients receiving MMX budesonide compared to all other treatment arms were able to achieve clinical and endoscopic remission (Table 8).35 Due to its extensive first pass metabolism, budesonide was hypothesized to have fewer systemic effects, and the study reported similar AEs among all treatment groups.35 Table 8: Results from the CORE I35 Primary endpoint results Combined clinical and endoscopic remission (%) Secondary endpoint results Clinical improvement (%) Endoscopic improvement (%) Histological healing (%) Symptom resolution (%) *Statistically significant (p < 0.025) ¥Statistically significant (p < 0.05) The CORE II study further evaluated budesonide MMX to Entocort EC®. A larger percentage of participants receiving budesonide MMX achieved remission, clinical improvement, endoscopic improvement, histological healing, and symptom resolution (Table 9).36 Overall, increased glucocorticosteroid-related AEs were similar among treatment arms. Mean cortisol level reductions occurred in budesonide MMX and DR treatment groups, but remained within normal ranges.36 INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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Table 9: Results from the CORE II36 Primary endpoint results Clinical & endoscopic remission Secondary endpoint results Clinical improvement (%) Endoscopic improvement (%) Histological healing (%) Symptom resolution (%) α=0.025 +=0.05 *p < 0.05 critical role in the metabolism of AZA and MP. Multi-Matrix System budesonide 9mg Genetic TPMT enzymatic activity varies, possibly was introduced into the US market in January resulting in increased adverse effects or 2013 as Uceris®. Uceris® should be taken once reduced response to treatment. The active daily in the morning for up to eight weeks and metabolite 6-thioguanine (6-TGN) has been has only been studied for remission induction.38 associated with myelotoxicity while 6-methyl- Uceris® should not be chewed, crushed, or mercaptopurine (6-MMP) has been associated broken due to the MMX formulation. Because with hepatotoxicity. Patients with decreased budesonide's release is pH dependent, patients TPMT activity tend to accumulate more 6-TGN should avoid taking acid reducing agents such resulting in increased bone marrow as proton pump inhibitors, H2 blockers, and/or suppression. Patients with intermediate TPMT antacids38. Common AEs patients should be activity are recommended to start at 50% of the counseled on include diarrhea, nausea, recommended starting dose. Patients with arthralgia, and headache.38 Postmarketing minimal TPMT activity should not be treated reporting has reported anaphylactic reactions, with thiopurines due to the risk of developing benign intracranial hypertension, and mood severe, life-threatening myelotoxicity.39 Thiopurines find their place in therapy for remission induction in patients refractory to oral steroids or who continue to have active Thiopurines are a class of disease, but do not require intravenous immunomodulators available as azathioprine therapy.2 In remission maintenance, thiopurines (AZA) and mercaptopurine (MP). The are used to transition patients from steroid- recommended dosing for induction and dependence. In a meta-analysis assessing the maintenance of remission are listed in Table 10. efficacy of AZA and MP, they were found to be Thiopurine methyltransferase (TPMT) plays a INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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more beneficial in maintaining remission monitoring is required. CBCs and liver function compared to placebo.40 tests (LFTs) should be completed at least every Patients should be made aware that up other week for the first 6-8 weeks of therapy, to 3-6 months may be needed before followed by once every three months therapeutic effects are seen.2 Common adverse thereafter.41 Pancreatitis has also been effects of MP include drug fever, reported within 3 to 4 weeks of therapy and is hyperpigmentation, and hyperuricemia. Nausea dose-independent.42 Signs and symptoms of and vomiting are the most reported adverse malignancy (splenomegaly, hepatomegaly, effects with AZA.43 Due to the high risk of abdominal pain, persistent fever, night sweats, myelosuppression, hepatotoxicity, and infection and weight loss) should also be monitored.43,44 from both agents, routine laboratory Table 10: Thiopurines for UC treatment2,43,44 Brand (generic) drug name Maintenance dose Imuran® (azathioprine)* 1.5-2.5 mg/kg/day orally 1.5-2.5mg/kg/day orally Azasan® (azathioprine)* 1.5-2.5 mg/kg/day orally 1.5-2.5mg/kg/day orally 50mg once daily or 1- 1-1.5mg/kg/day orally (mercaptopurine)* 1.5mg/kg/day orally *Unlabeled FDA indication Pharmacist's role outweigh the benefits.2,48 Therefore, nicotine Pharmacists can take an active role in has a limited role in UC treatment, particularly counseling patients for possible exacerbating in select cases refractory to available treatment triggers such as diet, smoking habits, or using nonsteroidal anti-inflammatory drugs.45 Diets Live vaccines are contraindicated for high in red or processed meat, margarine, and patients on glucocorticoid steroids or alcohol have been linked to relapses.46 Evidence thiopurines. If live vaccinations are warranted, supporting the use of omega-3 fatty acids is they should be administered 4-12 weeks prior weak.47 Dairy and lactose free diets were not to initiation of treatment. All patients should shown to worsen symptoms or provide a receive influenza and pneumococcal vaccines.26 greater benefit to patients.47 It's also imperative pharmacist counsel As pharmacists, smoking cessation patients on medication adherence. A reported should be promoted and encouraged. There is 43-72% of patients are nonadherent due to question, however, if cigarette smoking is adverse effects or failing to use maintenance beneficial for patients with UC. Some studies therapy.49 Barriers to adherence surveyed have demonstrated protection against include lifestyle, risk of side effects, and developing UC and improving symptoms. financial factors. An increased risk of relapse, Compared to placebo, transdermal nicotine was hospitalizations, and surgery may result from more effective for inducing remission as well. lack of complicance.13 Providing disease However, the advantages of smoking or awareness and emphasizing the importance of nicotine use are not superior to conventional adherence may improve patients' willingness to UC treatment options, and the consequences continue their treatment regimens. Along with INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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side effect profiles and drug-drug interactions, utilizing aminosalicylates, then other patient specific factors that should be glucocorticosteroids, and lastly evaluated prior to and during therapy include immunomodulators. Top-down therapy has health status, financial resources, willingness to been evaluated for more aggressive treatment complete laboratory monitoring, and options in hope of altering disease progression; perception of pill burden. however its efficacy has not been seen in UC. In summary, treating mild to moderate UC should be by the "step-up" approach, The Pharmacists Education Foundation (PEF) is accredited by the Accreditation Council for
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1. What is Ulcerative Colitis? Available at: http://www.ccfa.org/what-are-crohns-and-colitis/what- is-ulcerative-colitis/. Accessed 5/14/13. 2. Kornbluth A, Sachar DB, et al. Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105:501–523. 3. Satsangi J, Silverberg MS, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006 June;55(6):749-53. 4. Tursi A, et al. Treatment of Relapsing Mild-to-Moderate Ulcerative Colitis With the Probiotic VSL#3 as Adjunctive to a Standard Pharmaceutical Treatment: A Double-Blind, Randomized, Placebo-Controlled Study. Am J Gastroenterol. 2010;105:2218-2227. 5. Safdi M, DeMicco M, et al. A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol. 1997;92(10):1867. 6. Chapman NJ, Brown ML, et al. Distribution of mesalamine enemas in patients with active distal ulcerative colitis. Mayo Clin Proc. 1992;67(3):245. 7. Marteau P, Probert CS, et al. Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study. Gut. 2005;54(7):960. INDIANA PHARAMCISTS ALLIANCE (IPA) 2014
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Barriers to rheumatoid arthritis treatment access in europe

A Survey of Barriers to Treatment Access in Rheumatoid Arthritis Country Annex Report: Argentina August 2010 Barriers to RA treatment access across Latin America: Argentina Barriers to RA treatment access across Latin America: Argentina 1 Interviews Six respondents were interviewed in the Argentinean part of the study. Four of the respondents were doctors whilst two were patient representatives. All doctors were hospital based, three from public Hospital and one from a private Hospital. The two patient representatives were from an NGO which provides counsel to RA patients.

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Bleaching products fade areas of unwanted pigmentation by disrupting the production and distribution of melanin in the skin by targeting overactive melanocytes (pigment-producing cells). There are a variety of ways to accomplish this and studies have shown that the best results occur when using a combination of two or more of these ingredients. Tyrosinase Inhibitors: Tyrosinase is a copper enzyme which stimulates melanin production in the melanocyte. Most whitening agents fall under this category, interfering with the enzymes function and reducing pigment production in the melanocyte. Hydroquinone Hydroquinone is a hydroxyphenolic compound that has been widely used for skin lightening for 50 years. It is the only FDA approved product for bleaching and a prescription is required to obtain products with a concentration above 2%. It is the most widely studied and scientifically backed bleaching agent on the market, but its use can come at a cost. It can be very irritating to sensitive skin and cause pigmentation to darken and get worse. In very dark skin types, long term use of highly concentrated products (4% or more) can lead to a development of Exogenous Ochronosis, "an irreversible disfiguring cosmetic problem." It is also very difficult to stabilize and can oxidize quickly if exposed to light and air. If a product containing Hydroquinone has darkened from an off-white or a creamy, pale yellow to a gold or brown color, it will no longer be effective and should be discarded. When using Hydroquinone, it is imperative to stay out of the sun for the treatment to work. Always wear a full spectrum sunblock and a hat. Exposure to sun deteriorates the Hydroquinone, rendering it ineffective. Kojic Acid Kojic Acid, a byproduct of the fermentation of rice, was first discovered in Japan in 1907. Kojic acid is the most common bleaching agent next to Hydroquinone. Kojic Acid is a natural and more gentle on the skin alternative to using Hydroquinone. It penetrates the upper skin layers and inhibits the production of epidermal melanin. Kojic Acid does pose a risk of causing allergic or sensitizing reactions in a small number of people. Azelaic Acid A natural skin brightener found in wheat, rye, and barley. Azelaic acid is most effective in concentrations of 20% - an amount that makes is near comparable in activity to 4% Hydroquinone. In a study consisting of 329 melasma sufferers, half were treated with a 20% Azelaic Acid solution, and half were treated with a 4% Hydroquinone solution. 56% of patients treated with AZA had good to favorable results while 73% treated with HQ had a similar result. When combined with Tretinoin or Alpha Hydroxy Acids, the results were noticeably improved. Azelaic Acid, is also antibacterial and anti-inflammatory, so it is also effective in the treatment of rosacea and acne. Arbutin (also known as Alpha Arbutin, Bearberry Extract or Uva Ursi Extract) A botanical, naturally-occuring cousin to Hydroquinone, Arbutin was first discovered in the Uva Ursi plant. Compared to HQ, Arbutin has been shown to be significantly less cytotoxic to the melanocyte — making it a much safer, yet very effective alternative to Hydroquinone. In a clinical trial involving Japanese women with melasma, a 3% concentration of Arbutin produced good to excellent results in 71.4% of patients within a three month period. Licorice Extract One of the safest and most gentle bleaching agents around, Licorice Extract is a potent anti-inflammatory and antioxidant. The ingredients responsible for the skin whitening aspect of the plan are known as Glabradin and Liquiritin. Liquiritin (in a 20% concentration) has been shown to provide good to excellent results in 70-90% of patients with hyperpigmentation and melasma — with minimal side effects and only minor irritation. Mulberry Extract Mulberry Extract is derived from the root bark of the mulberry tree, Morus Alba L. Studies have confirmed it to effectively reduce tyrosinase activity at much lower concentrations than either Hydroquinone or Kojic Acid. N-Acetyl Glucosamine N-Acetyl Glucosamine is a more stable form of Glucosamine, an agent most widely known as an arthritis treatment. Studies have recently shown it to successfully reduce the amount of melanin in melanocytes by blocking tyrosinase conversion and its results improve significantly when combined with Niacinamide. Inhibition of Melanosome Transfer: These skin lightening agents lighten unwanted pigmentation by interfering with the transfer or melanosomes from the melanocyte to the keratinocytes. Niacinamide or Nicotinamide is a biologically active form of Niacin (Vitamin B3) that has been shown to interrupt melanocyte transfer by 35-68%.