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By I. Killian. Davis and Elkins College. 2019.

To pierce the walls of other languages buy 100 mg avanafil visa causes of erectile dysfunction in younger males, you need more extensive qualities 200 mg avanafil amex vasodilator drugs erectile dysfunction. We begin to understand that the true reasons for ‘not having talent for foreign languages’ may not be related to memory or grammar or laziness avanafil 100mg with visa erectile dysfunction treatment bangalore, but might well be psychological in nature avanafil 200mg fast delivery erectile dysfunction treatment news. I assume that you are willing to pay the price, so that your speaking skills will gradually improve and accelerate. You will notice that over the years (yes, we are now talking about years and not about weeks or months), speech production will become increasingly unconscious. Even your foreign accent will eventually soften, although probably never disappear. If you choose the right words and fold them in perfect grammar, nobody will ever dare blame you. As in other areas, content is more important than packaging. As long as you speak fluently, an accent is not debilitating, on the contrary. In today’s world, especially in times of peace, some accents are truly charming. To go through the process of language acquisition, you will 1. Knowing the operating mode of a machine can be helpful before turning it on. And another question surely springs to mind: Is there some sort of talent involved in language learning? Before summarizing the learning strategies for the monumental task of absorbing thousands of words, let’s dig into your memory. Workload after Chapter 1–5 Due to heavy exposure to human speech during your CD and/or TV training (see Chapter 2), once you start speaking, progress will be fast. For your initial training sessions, we generously allocate 50 extra hours. Your total workload is now 850 to 1,850 hours Print: Amazon. That is in stark contrast to what you will experience with subsequent languages where initially nothing ever happens in milliseconds. Imagine that, during your first trip to Paris, a friendly local takes you on a two-hour stroll from Notre Dame to the Louvre, then northwards up to the Sacré- Cœur, and, finally, down to Pigalle. If I put you back at Notre Dame a few months later, you would probably find your way to Pigalle alone, recalling places, streets, crossroads, shops, and buildings. It is hard to believe that this wealth of information is approximately equivalent to learning 20 miserable words. Why does it take adults so long to learn languages while young children seem to do so whilst playing, laughing and having a great time? Do we all, shortly after infancy, suffer a subtle form of partial Alzheimer’s disease? Or are adult brains tuned to find their way in urban jungles rather than in word jungles? Imagine that I put my finger on it and ask you what it is. You would answer ‘glass’, instantly, without hesitating. The word pours out of your mouth as water pours out of a spring. It does so because ‘glass’ is woven into your brain in many different ways: you have a mental image of a glass; you Print: Amazon. Any single of your 50,000+ native words is intertwined in multiple locations of your brain, floating in a sea of meanings, facts, and emotions. As soon as you wake up in the morning, all brain words go into stand-by mode, waiting to jump into consciousness as soon as their equivalents – written or spoken words – enter the brain via your eyes or ears. Grown over decades, this vast network of word webs is the most precious asset of your life. First, it contains 11 around 100 (10 ) billion neurones, which are the main information-processing cells. Second, these neurones are connected to neurones either in the vicinity or far away. In young adults, the long distance fibre tracts total around 176,000 km in length – that is roughly half way to the moon. These are highly specialised interfaces where information is passed from axons – slim extensions that carry the electric signals generated by the neurones – to dendrites, which are highly branched tree-like structures that receive the signals originated in other neurones (Figure 6. A single neurone, its dendrites and its multiple synapses (orange dots). The resulting picture is majestic: one billion synaptic connections in a single cubic millimetre of specialised brain Print: Amazon. One thousand TeraSynapses – that is the number of stars in ten thousand Milky Ways. Yet the most surprising detail is still to come: synapses are not carved in stone. They come and go as their support, so-called dendritic spines, appear and disappear. These spines are tiny protrusions from a neurone’s dendrite. If you teach a mouse to reach out with its forelimb to a single seed, dendritic spines form as rapidly as within one hour. Most of these new spines will regress again, but some are preserved and stabilised during subsequent training. The resulting change in circuitry is most likely the anatomical substrate for long-term memory storage. The resulting plasticity of the brain can even be observed macroscopically, for example in London, taxi drivers from pre- GPS times who developed a hypertrophy of the brain region that is involved in spatial orientation, or in violin players who have an enlargement of the left hand representation in the sensorimotor cortex. Most newly formed spines vanish within days, and only a fraction persists for months. Using 20 percent of all the oxygen you breathe, your brain is constantly sorting out newly received information, enforcing what is important and discarding what is irrelevant. The extent of the deconstruction going on in your brain was th nicely shown by 19 century experiments that measured the time of learning – and subsequent forgetting – of chains of 2,300 nonsense consonant-vowel-consonant syllables such as KOJ, BOK, and YAT. Happily, you will learn meaningful word pairs rather than nonsense syllables, for example, agua–water, vino–wine, queso–chesse, and should therefore obtain better results after 24 hours. However, at Day 31, you might not perform much better than the memory pioneers more than 100 Web: TheWordBrain. Brain physiology isn’t prone to instant word learning. In order to protect young spines from erosion, schedule multiple training sessions. You will note that, before getting fixed into lifelong memory, words pass subsequent degrees of knowing. At the weakest stage, you don’t even remember that you have seen a word; however, you would recognise it when presented in a list of words.

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Subjects with significant comorbidities were excluded generic 100mg avanafil free shipping erectile dysfunction keywords, including congestive heart failure of any New York Heart Association class avanafil 50mg amex erectile dysfunction kamagra. Maximal drug dosages were rosiglitazone 4 mg twice a day buy 100mg avanafil with amex erectile dysfunction effects, metformin 1000 mg twice a day buy generic avanafil 200 mg line erectile dysfunction medications drugs, and glyburide 7. Randomized subjects numbered 4360, of which 95% were included in the intention-to-treat analysis. Median duration of treatment with rosiglitazone was 4 years. Mean age was 57 years (standard deviation 10) and 57. The cumulative incidence of monotherapy failure at 5 years was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide (P<0. A1c decreased in all treatment groups in the first 6 months of treatment, with the greatest effect with glyburide and A1c curves were similar between metformin and rosiglitzone for the first 1 year. A1c rose steadily in all treatment groups, with the rate of increase lowest with rosiglitazone (P<0. At 4-year follow-up, the percentage of subjects with A1c <7. The proportion of subjects who either reached the primary outcome or completed the study was 63% for rosiglitazone, 62% for metformin, and 56% for glyburide. Subjects who withdrew had similar baseline characteristics to completers. The choice of primary outcome of FPG greater than 180 mg/dl was unusual, as current recommendations are to achieve far lower FPG levels. The results of 2 smaller rosiglitazone monotherapy trials with active controls were similar to the results from ADOPT when appropriate follow-up intervals are compared. Hanefeld and coauthors found no significant difference between glibenclamide and rosiglitazone at 52-week 147 follow-up. A poor-quality study demonstrated no significant difference between rosiglitazone 149 and glibenclamide at 12 weeks. This follow-up interval is too short to be meaningful when examining thiazolidinediones. Among the combination therapy trials of rosiglitazone and metformin, 2 trials did not 143, 144 show significant differences between rosiglitazone and metformin. On the other hand, 145 Garber and colleagues did demonstrate more benefit for the fixed combination of Thiazolidinediones Page 41 of 193 Final Report Update 1 Drug Effectiveness Review Project glibenclamide 5 mg/metformin 1000 mg (once or twice daily) than for rosiglitazone 4-8 mg daily combined with metformin 1500-2000 mg daily (between-group difference in A1c 0. Combination therapy studies comparing rosiglitazone to metformin with both groups 148, 151 receiving other oral agents did not show significant differences between treatment groups. Rosiglitazone was superior to repeglanide (each as monotherapy; no statistics provided). Subjects taking metformin at study entry were randomized to add-on sulfonylurea. Thiazolidinediones Page 42 of 193 Final Report Update 1 Drug Effectiveness Review Project Table 9. Pioglitaz one active-controltrials:Study and populationch aracteristics a a Dosage M eanage (SD) B aseline m ean Sam ple siz e Sam ple siz e G ender W eigh t(SD) C om bination intervention placebo O th erpopulation B M I (SD) Q uality Study th erapy group group F ollow-up ch aracteristics A 1c(SD) F under Glipiz ide:start5m g daily;m eanm ax im al dosage41m g daily 67(8. Com binedwith 100% with overtdiabetic variousoral nephropathy hypoglycem ic agents orinsulin Glipiz ide:10m g daily (m ediandose) 92(SE 7)kg F air 134 56(2)yr 2 Basu 2006 Pio:45m g daily 8 11 12wk 32(SE 2)kg/m Takeda 33% fem ale 6. Pioglitaz one active-controlstudies:C h ange inA 1c A 1cbetween- group A 1cat A 1catfollow- difference F ollow- A 1cbaseline follow-up A 1cbaseline up, (pioglitaz one B etween- up pioglitaz one pioglitaz one com parison com parison – com pared groupP Study (weeks) Treatm ents group(SD) group(SD) group(SD) group(SD) drug (95% C I) value Glipiz idestart 5m g daily,m ean m ax im aldosage 7. Thiazolidinediones Page 47 of 193 Final Report Update 1 Drug Effectiveness Review Project Table 11. R osiglitaz one active-controlltrials:Study and populationch aracteristics a a Sam ple Sam ple M eanage (SD) B aseline m ean Dosage siz e siz e G ender W eigh t(SD) interventi placebo F ollow- O th erpopulation B M I (SD) Q uality Study C om binationth erapy ongroup group up ch aracteristics A 1c(SD) F under R osi:start4m g daily Glyburide:start5m g ITT population: 90. Thiazolidinediones Page 49 of 193 Final Report Update 1 Drug Effectiveness Review Project Table 12. R osiglitaz one active-controlstudies:C h ange inA 1c A 1cbetween- group A 1cat A 1catfollow- difference F ollow-up A 1cbaseline follow-up A 1cbaseline up, (rosiglitaz one B etween- interval rosiglitaz one rosiglitaz one com parison com parison – com parator) groupP Study (weeks) Treatm ents group(SD) group(SD) group(SD) group(SD) (95% C I) value R osi:start4 m g daily Glyburide: start5m g daily Change Change Bakris 8. Thiazolidinediones Page 52 of 193 Final Report Update 1 Drug Effectiveness Review Project Key Question 2. For patients with type 2 diabetes do thiazolidinediones differ from each other, from placebo, and from other oral hypoglycemic agents in their effects on macrovascular and microvascular complications, and mortality from diabetes? Summary of the Evidence • Data were not sufficient to determine the comparative effectiveness of pioglitazone and rosiglitazone on microvascular or macrovascular complications of diabetes. Detailed Assessment None of the head-to-head studies identified in the original or updated review examined macro- or microvascular outcomes. Three placebo-controlled or no-treatment comparison studies identified in the original review examined cardiovascular outcomes; all examined patients with known 60, 103, 152 60 macrovascular disease and type 2 diabetes, including the PROACTIVE trial. These 3 trials did not provide sufficient data to determine comparative effectiveness of pioglitazone and rosiglitazone on microvascular or macrovascular complications of diabetes. Both studies provided some evidence of positive effects of these drugs on macrovascular outcomes among patients with preexisting coronary artery disease. Ninety-six percent of patients were taking other glucose-lowering agents, including insulin. The primary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Congestive heart failure was not included in this composite endpoint, although congestive heart failure was examined as an adverse event. When examined individually (as secondary endpoints), none of the components of the primary endpoint changed significantly (P>0. The hazard ratio of the main secondary endpoint (a composite of all-cause mortality, myocardial infarction [excluding silent myocardial infarction], and stroke) was 0. Included patients were aged 50 to 73 years, had a diagnosis of coronary artery disease (>50% stenosis as proven on angiography), had established type 2 diabetes, and had undergone a percutaneous coronary intervention (Evidence Table 9). Forty-one percent took other anti-diabetic medications. At 6-month follow-up the incidence of coronary events was decreased in the rosiglitazone group (between-group P<0. A single-center poor-quality study examined the preventive effects of rosiglitazone on 152 restenosis after coronary stent implantation among 95 persons with type 2 diabetes. In this Thiazolidinediones Page 53 of 193 Final Report Update 1 Drug Effectiveness Review Project open-label, randomized controlled trial, the treatment group was placed on rosiglitazone 8 mg before undergoing catheterization and 4 mg daily thereafter, combined with conventional antidiabetic therapy using a variety of agents (details of concurrent therapy were not provided). The comparison group received conventional therapy only. The rate of restenosis was 18% in the rosiglitazone group and 38% in the control group (between-group P=0. There was also a significant difference in stenosis diameter between groups at 6 months (P=0. The available data provided no information on the comparative effectiveness of pioglitazone and rosiglitazone on macro- and microvascular outcomes when used as monotherapy or when added to or substituted for other oral hypoglycemic agents. Dormandy and 60 colleagues addressed the question of combined therapy as pioglitazone was added to other anti- 103 diabetic therapy in 96% of patients. In the study by Wang and coauthors monotherapy and combined therapy patients were aggregated, so conclusions cannot be drawn about each of these 2 approaches. In the updated review several additional trials provided evidence on macrovascular outcomes and on mortality, with 5 trials providing additional evidence on pioglitazone. Two of 137, 154 these studies were published after the end-date for our searches. The primary endpoint was the change in carotid artery intima-media thickness after 72 weeks. Secondary endpoints included the composite of cardiovascular mortality, non-fatal MI, or nonfatal stroke, and the composite of these outcomes plus coronary revascularization, carotid endarterectomy/carotid stenting, hospitalization for unstable angina, or hospitalization for heart failure. There were few events reported, and no cardiovascular deaths.

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All placebo patients became symptomatic buy avanafil 200mg visa erectile dysfunction herbal, experienced ulcer recurrence generic 100mg avanafil visa erectile dysfunction rap, or withdrew from the study by month six buy 100mg avanafil with visa erectile dysfunction vacuum pump. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Kovacs 1999 six patients (two TAP placebo avanafil 50mg discount erectile dysfunction vitamin e, three Pharmaceuticals, lansoprazole 15 mg and one lansoprazole 30 mg) withdrew from the study prematurely at least in part due to an adverse event Proton pump inhibitors Page 220 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Norman Hansen Esomeprazole 20 mg od ranitidine 150 mg twice-daily Mean age 51 Male and female patients 2005 continuously or on-demand continuously for 6 months. Race/ethnicity NR symptoms suggestive of 281 Norwegian GERD (heartburn as the General predominant symptom with or Practitioner (GP) without acid regurgitation) for clinics 3 days or more in the past 7 days Proton pump inhibitors Page 221 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Norman Hansen 11. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Norman Hansen 125 (6. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Baldi Lansoprazole 30mg in AM Lansoprazole 30mg in AM Mean age: 54. Proton pump inhibitors Page 224 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Baldi Severity of cough: visual analog scale 45/36/36/1/0/35 4 months Both groups improved, with no 2006 (VAS) graded from 0 to 10 and to a four- difference between the two level scoring system, regarding the treatment groups. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Baldi None NR 2006 Proton pump inhibitors Page 226 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Bigard Lansoprazole 15mg on- Placebo Mean age: 53. Proton pump inhibitors Page 227 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Bigard Primary efficacy point: % of patients 203/181/181/54/0/181 6 months Lansoprazole vs Placebo 2005 included in this phase who completed the study in each treatment group after 6 Completion of study (ITT months of on-demand treatment. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Bigard 3 discontinued due to Takeda France 2005 Aes (2 considered related to study drug) 58 AEs were reported by 41 patients Proton pump inhibitors Page 229 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Björnsson Gp 1: Omeprazole 20mg oid Gp 2: Omeprazole 20mg/day Median age: 65 years (range: Patients with > 8 weeks of 2006 for 1 week, omeprazole 51-70 years) regular daily use of PPIs 10mg/day for 1 week, 45. Must have mild reflux symptoms that would not affect daily activities of the patients and persisted > 3 months prior to the visit. Proton pump inhibitors Page 230 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Björnsson 24-h pH recording 593/286/97/1/0/96 12 months Comparing Gp 1 to Gp 2, no 2006 Questionnaires concerning GI symptoms significant differences except for and quality of life (Gastrointestinal prevalence of hiatal hernia was symptom rating scale-GSRS; higher in Gp 2 than in Gp 1 (67% Psychological general well-being-PGWB) vs 47%, respectively; p=0. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Björnsson NR Federation of County 2006 Councils in Sweden Faculty of Medicine, Göteborg University Cibor None NR 2006 Proton pump inhibitors Page 232 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Giannini Gp 1: Esomeprazole Gp 2: Treatment assignment Mean age: 43. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Giannini Basal endoscopy to determine esophagitis 649/616/612/82/72/429 6 months Gp 1 vs Gp 2 2008 grade % of patients reporting hearburn as Quality of Life in Reflux and Dyspepsia the predominant symptom (QOLRAD) questionnaire Week 4: 6. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Giannini 7 withdrew, but reason AstraZeneca 2008 not specified Proton pump inhibitors Page 235 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Mine Lansoprazole 15mg/day for Lansoprazole 30mg/day for 8 Mean age: 61. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Mine Los Angeles classification of reflux NR/NR/43/NR/NR/43 16 weeks No step vs Step down1 vs Step 2005 esophagitis was used for evaluation. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Mine NR NR 2005 Proton pump inhibitors Page 238 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Morgan Rabeprazole 20mg/day Rabeprazole 20mg/day for 4 Mean age: 48 years Male and females aged 25-65 2007 (COT) weeks than 20mg on-demand 48% male years, with > 3 months history (ODT) 96% Caucasian of GERD, with hearburn as the predominant symptom, on continuous PPI therapy > 1 month with adequeate heartburn control and < 3 days of hearburn with < 1 episode rated as moderate and hearburn rated satisfactorily or completely controlled during the last week of the acute phase. Proton pump inhibitors Page 239 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Morgan Daily diary of symptom severity NR/331/268/26/8/234 6 months COT vs ODT 2007 Quality of life questionnaire Heartburn free days: 90% vs 65% (p<0. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Morgan 7 patients reported 9 Janssen-Ortho Inc 2007 events No significant difference between groups COT vs ODT Sinusitis: <3% vs 6. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Scholten Pantoprazole 20mg/day on- Pantoprazole 40mg/day on- Mean age: 52. Proton pump inhibitors Page 242 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Scholten Patient diary 634/548/548/NR/NR/543 24 weeks P20 vs P40 vs Pla 2005 Perceived average symptom load: 2. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Scholten 36% reported AEs ALTANA Pharma AG, 2005 Only 5% were deemed Konstanz, Germany related to drug Proton pump inhibitors Page 244 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Sjöstedt Esomeprazole 20mg/day Esomeprazole 20mg/day on- Mean age: 55 years (range: Patients > 18 years, with 2005 demand 20-87 years) erosive reflux oesophagitis of 61% male LA grades A-D, history of Ethnicity: NR hearburn episodes over > 6 months and > 4 days with hearburn episodes during the week prior to visit 1. Proton pump inhibitors Page 245 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Sjöstedt Endoscopic remission NR/539/477/107/NR/370 6 months Daily vs On-demand 2005 In remission at 6 months: 81% vs 58% Symptomatic relapses: 12 (5%) vs 13 (5. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Sjöstedt Daily vs On-demand NR, but 2005 Nasopharyngitis: 1. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Annibale Omeprazole 20mg/day Ranitidine 150mg/day Mean age: 49 years Patients aged 18-75 years 1998 64% males with eroseive or ulcerative Ethnicity: NR esophagitis, grade 2 or 3. Proton pump inhibitors Page 248 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Annibale Macrosopic appearance of the esophageal 231/223/217/18/13/217 6 months O20 vs R150 1998 mucosa was scored from 0 to 4 according to the following scale: Overall symptom remision at 6 0=normal esophageal mucosa; months 1=erythema or diffusely red mucosa, Abstent: 54. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Annibale 4 patients reported AEs Schering-Plough 1998 (loss of libido, headache, itching, and leg erythema) Proton pump inhibitors Page 250 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Houcke Lansoprazole 30mg every Lansoprazole 15mg/day Mean age: 55. Proton pump inhibitors Page 251 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Houcke Endoscopi relapse of oesophagitis was NR/NR/52/10/5/52 6 months L30 vs L15 2000 primary outcome, defined by an oesophagitis greater than or equal to Endsoscopic relapse at 6 months: grade II or symptomatic relapse defined as 36% vs 25. An aggravation of hearburn and functional handicap was noted in L30 (p<0. Proton pump inhibitors Page 252 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Houcke 8 patients had 9 AEs NR 2000 (only 1 was noted to be related to study drug) Proton pump inhibitors Page 253 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Vakil Esomeprazole 40mg/day Esomeprazole 20mg/day or Mean age: 44. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Vakil E40 vs E20 vs E10 vs NR, but one author is 2001 Pla employee of AstraZeneca Patients with >1 AE: 31. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Talley Esomeprazole 40mg on- Esomeprazole 20mg on- Mean age: 48. Proton pump inhibitors Page 257 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13. Standard dose compared with low dose proton pump inhibitor Author Esophagitis Grade (Grading Criteria), or Number Screened, Eligible, Enrolled, Year other measures of symptom severity Withdrawn, Lost to Followup, Analyzed Study duration Results Talley Assessments included: NR/NR/721/177/26/721 6 months E40 vs E20 vs Plac 2002a -heartburn frequency -heartburn severity Unwilling to continue -severity of other GORD symptoms General: 11. Standard dose compared with low dose proton pump inhibitor Author Withdrawals Due to Year Adverse Events Funding source Talley E40 vs E20 vs Pla NR 2002a Withdrawals due to AEs: 2. Standard dose compared with low dose proton pump inhibitor Intervention treatment Comparison treatment Author strategy (drug, dose, strategy (drug, dose, Baseline demographics Year duration) duration) (age, sex, race/ethnicity) Eligibility criteria Talley Pantoprazole 20mg/day Ranitidine 150mg twice a day Mean age: 52. Proton pump inhibitors Page 260 of 304 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 13.

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These data Many pathways and targets must be explored to identify a few that provide a rationale for the development of Mer kinase inhibitors as are appropriate for drug discovery and even then many targets will selective therapeutics for ALL and other Mer-related diseases order 50mg avanafil fast delivery impotence jokes. Each the role of kinases as drivers of proliferation and survival (research member of the TAM family contains an extracellular domain order avanafil 50 mg drugs for erectile dysfunction in nigeria, a done mostly in academia) to their establishment as druggable targets transmembrane domain buy 100mg avanafil mastercard erectile dysfunction diabetes permanent, and a conserved intracellular kinase do- (research done mostly in industry) with clinically useful levels of main purchase avanafil 100 mg overnight delivery erectile dysfunction medicine with no side effects. This foundation has rendered any new kinase domain of the TAM family is quite dissimilar (the average potential kinase target in cancer readily accessible for drug discov- sequence identity of the Mer kinase domain to other RTK families is ery with proven technologies. This makes Mer an excellent candidate to be targeted novel members of tractable target classes is entirely appropriate to selectively by small molecules. In addition, there are many kinases with connections to cancer that have not been pharmacologically Based on the crystal structure of a weak inhibitor with Mer,20 we explored. The substituents at the R1,R, and R2 3 positions were initially chosen on the basis of their chemical features and the In the postgenomic era, tumor genome sequencing efforts such as existing x-ray cocrystal data. At the R1 and R3 kinase targets for therapy (eg, B-RAF-vemurafinib and Alk- positions, a variety of groups were tested to explore structure- crizotinib). However, such efforts have also shown epigenetic activity relationships (SARs) driving potency, cellular permeability, phenomena to be critical for tumor initiation and maintenance. Iterative cycles of compound Outside of the histone deacetylase area, chromatin modifiers design and evaluation led to Mer inhibitors such as UNC56921 and represent a relatively underexplored area for drug discovery and few UNC1062 (Figure 1B, x-ray cocrystal structure of UNC569 and potent and selective small-molecule ligands for these targets exist. Further rounds of synthesis and profiling eventually led to efforts toward Mer kinase. Mer is ectopically expressed in at least 50% compound optimization is familiar ground to experienced medicinal of pediatric T-cell ALL samples, as well as in pre-B-ALL samples, chemists, but can prove daunting to academic groups less accus- particularly those with a (1;19)(q23;p13) translocation encoding an tomed to following multiple SAR trends across diverse assays. In previous studies, transgenic expression of Mer in developed that can accurately reflect the activity of a quality mouse lymphocytes resulted in the development of T-cell leukemias compound; at the beginning of the process, neither assay nor and lymphomas. In addition, a Mer-expressing human T-ALL cell compound is necessarily optimal. The general impression that line was able to produce a lethal malignancy in immunocompro- optimized compounds drop right out of screening exercises is a very mised mice; the development of leukemia was significantly delayed significant limitation to many academic drug discovery efforts that or completely eliminated by Mer shRNA knock-down in these cells. For example, process of hit to lead to candidate progression. R1,R, and R2 3 represent substituents that can be synthetically varied to optimize the biological properties of this template. In the CICBDD, this accessible state within each cell. Thanks to significant funding through the National Cancer The chemical modification of chromatin is carried out by families of Institute’s chemical biology consortium (http://dctd. We are focused on compara- excitement in the area of inhibitor discovery for protein lysine tive mouse efficacy studies with several compounds structurally methyl transferases, which is the focus of the Jin laboratory within related to UNC1062 (Figure 1, compound 2) possessing im- the CICBDD. The ability to explore both compound inherent in the chemical transformations they perform and the SAR and assay optimization while working directly with the precedent for medicinal chemistry success, these chromatin- discoverers of the target who also treat ALL patients exemplifies modifying enzymes also frequently create a binding site for the what can go right with academic drug discovery: a combination recruitment of other proteins. MBT domains, and the WD40 repeat proteins consisting of WDR5 and EED. A unifying feature of these domains is histone 3, lysine 4 trimethyl (H3K4me3)-binding PHD finger such the existence of an aromatic cage that comprises the Kme-binding as the carboxy-terminal PHD finger of PHF23 or JARID1A to a pocket, facilitating recognition of the methyl-ammonium group via common fusion partner nucleoporin-98 (NUP98), as also identified cation– , hydrogen bond, and van der Waals interactions (Figure in sequencing of human leukemias, generated potent oncoproteins 2A). Cation– interac- abolished leukemic transformation, supporting the hypothesis that tion energies are significant, with solution phase values on the same small-molecule inhibitors of methyl-lysine binding domains might order of magnitude as hydrogen bonds. Because the recognition of methyl marks is a cornerstone of The unique recognition mode of Kme reader proteins and the lack of chromatin regulation, Kme readers are also of interest as potential known high-affinity ligands prompted us to undertake a target class therapeutic targets. In this approach, all synthetic Kme mimics, Cancer Research Fund and Federal Funds from the National Cancer designed by using the abundant structural biology information for institute, National Institute of Health, under Contract No. Kme readers interacting with histone peptides,36 are biochemically HHSN261200800001E. The methyl-lysine antagonist work re- screened against a panel of proteins from the MBT domain family search described was supported by the National Institute of General and other representative Kme readers. By maximizing the breadth of Medical Sciences, the National Institutes of Health (grants our Kme reader assay panel, the chances of finding potency and RC1GM090732 and R01GM100919), and the Carolina Partnership selectivity enhancing features in synthetic ligands is increased via and the University Cancer Research Fund of the University of North testing each ligand hypothesis against a large number of function- Carolina at Chapel Hill. The Structural Genomics Consortium is ally homologous, but structurally distinct binding sites. This is in also acknowledged for their contributions to the methyl-lysine contrast to a typical disease-oriented approach (such as our Mer antagonist project. Our panel is also Disclosures biased to include Kme reader proteins that have been linked to 39 Conflict-of-interest disclosure: The author is on the board of specific disease states, increasing the chances that a potent directors or an advisory committee for, has received research chemical probe could lead to target validation data that would funding and honoraria from, has consulted for, and has equity encourage a drug discovery effort. Thus far, this method of ownership in Biotech and Pharma. Off-label drug use: None structure-based ligand discovery has led to UNC1215 (Figure 2B, disclosed. Frye, UNC Eshelman School of Pharmacy, 2095 L3MBTL3 in cellular differentiation and disease. Our approach of Genetics Medicine Bldg, 120 Mason Farm Rd, Box 7363, Chapel freely sharing chromatin-directed chemical probes with collabora- Hill, NC 27599-7363; Phone: 919-843-5486; Fax: 919-843-8465; tors and the scientific community at large with no requirement for an e-mail: svfrye@email. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz (http://www. Stevens AJ, Jensen JJ, Wyller K, Kilgore PC, Chatterjee S, Conclusions Rohrbaugh ML. The role of public-sector research in the If progress in the treatment of cancer is to continue, the innovation, discovery of drugs and vaccines. The importance of new companies for drug discov- new medicines. Fortunately, there are increasing efforts to embed ery: origins of a decade of new drugs. US academic drug be patient with collaborators—we all juggle multiple priorities (see discovery. Drug discovery in an academic setting: playing to your knowledge and compounds freely. Targeting cancer with small discovery also requires deep expertise in both biology and chemis- molecule kinase inhibitors. The (un)targeted cancer disciplines can succeed while working together will have an kinome. I do not believe that academic institutions will 10. Epigenetic reprogramming in contribute by designing more efficient scientific or business pro- cancer. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Although this effort will undoubtedly lead directly to new medi- 12. Clin Pharma- cines, it will more broadly define the tractable frontier for industrial col Ther. Graham DK, Dawson TL, Mullaney DL, Snodgrass HR, Earp appropriate and achievable. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Phagocytosis and The author acknowledges the University of North Carolina and clearance of apoptotic cells is mediated by MER. University of Colorado Mer project team members whose indi- 2001;411(6834):207-211. TAM discussed was supported by the University of North Carolina receptor tyrosine kinases: biologic functions, signaling, and 304 American Society of Hematology potential therapeutic targeting in human cancer. BET bromodomain in T-cell acute lymphoblastic leukemia. Suppression of tyrosine kinase is a therapeutic target in melanoma.

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