Enteric-coated Research Articles

Su176 Ulcerogenic Effects of Plain and Enteric-Coated Aspirin on the Gastrointestinal Mucosa in Cats

BACKGROUND/AIM: Recently, low-dose aspirin (ASA) has been widely used as the firstchoice drug for the prophylaxis and treatment of thrombosis. Enteric-coated (EC) ASA has been used to limit gastric lesions as a side effect, but even low doses of EC ASA often cause mucosal damage in the small intestine in humans. However, there are few studies on the ulcerogenic effect of ASA on the small intestine in experimental animals. We examined the ulcerogenic effects of plain and EC ASA on the gastrointestinal (GI) mucosa in cats: i.e., 1) the effect of feeding (fasted vs fed) on ASA-induced GI lesions; 2) the effects of cimetidine and misoprostol on ASA-induced GI lesions; and 3) the ulcerogenic effect of EC ASA on the GI mucosa. METHODS: Adult cats were used (4 to 6 animals per group). In the fed group, either plain ASA (20 mg/kg) or 1 EC ASA tablet (containing 100 mg ASA) was administered p.o. once daily after the morning meal for 3 days, whereas in the fasted group, ASA was given in the morning after an overnight fast. The animals were sacrificed 24 h after the final ASA dose and mucosal lesions in the GI tract were examined. Both cimetidine and misoprostol were administered p.o. 30 min before the morning meal. RESULTS: (1) In the fasted condition, ASA caused lesions in the corpus, antrum, duodenum and small intestine; the mean lesion area (MLA) was 0.25±0.1 cm2, 0.04±0.01 cm2, 0.24±0.1 cm2 and 0.11±0.05 cm2, respectively. When ASA was given after feeding, the duodenal lesions were markedly increased; the MLA was 0.75±0.31 cm2 (P<0.05 vs. fasted). (2) Both cimetidine (20 mg/kg, p.o.) and misoprostol (3 μg/kg, p.o.) markedly inhibited lesion formation in the stomach, but they did not affect duodenal lesions. Furthermore, cimetidine significantly (P<0.01) increased the area of lesions in the small intestine; the MLAs were 0.93±0.14 cm2 (cimetidine) and 0.13±0.05 cm2 (vehicle group). (3) EC ASA tablet (18.5-29.4 mg/kg) given orally once a day for 3 or 7 days did not cause any visible lesions in the stomach, but lesions were evident both in the duodenum and small intestine. The area of lesions increased with the duration of treatment; the MLAs following 7-day treatment were 0.98±0.13 cm2 (duodenum) and 1.58±0.82 cm2 (small intestine). CONCLUSIONS: 1) Adverse effects of ASA on the GI mucosa seemed to be decreased when ASA was given in the fasted condition. 2) ASA-induced duodenal lesions are resistant to cimetidine and misoprostol, suggesting that ASA caused the lesions by directly injuring the mucosa. 3) Histamine H2-receptor antagonists may aggravate small intestinal lesions caused by ASA. 4) Adverse effects of ASA on the stomach were markedly improved with EC ASA, but this treatment still caused lesions in the duodenum and small intestine, indicating that additional research is necessary to determine how to further reduce the toxicity of EC ASA.

10 PA32540, a Tablet Containing Enteric-Coated (EC) Aspirin 325 mg and Unbuffered Immediate-Release Omeprazole 40 mg, Provides Percent Time Gastric pH >4 Significantly Less Than EC Omeprazole 40 mg, but With Faster Onset and Less Exposure to Omeprazole

Background:It has been proved thatH. pylori eradication prevents the incidence of metachronous gastric cancer after endoscopic resection (ER) of primary early gastric cancer during short-term follow-up. However, it has not been clarified whether preventive effect of H. pylori eradication for gastric cancer continues in the long term. To determine the long-term effect of H. pylori eradication on the development of gastric cancer, a follow-up study of a JGSG trial (Lancet 2008; 372: 392-7) was conducted. Methods: In this multi-center, openlabel, randomized controlled trial, 544 patients who received ER of early gastric cancer were randomly assigned to the H pylori eradication group (n=272) or to the control group (n= 272). Endoscopy was performed every year after randomization to evaluate metachronous cancer. Diagnosis of a new gastric cancer at another site of the stomach was defined as primary endpoint. Metachronous cancers were confirmed through histological examination. The frequency of metachronous cancer in the eradication group was compared to that in the control group. Results: There were no significant differences between eradication and control groups in baseline characteristics. The follow-up period was 10 years at maximum. After three years of follow-up, metachronous gastric cancer was detected in 32 participants. In the end, metachronous gastric carcinoma had developed in 22 patients in the eradication group and 43 in the control group. In the modified intention-to-treat population, including patients with at least one post-randomization assessment of tumor status and adjusting for loss to follow-up (255 patients in the eradication group, 250 in the control group), the hazard ratio for metachronous gastric carcinoma was 0.497 (95% CI 0.2970.831; p=0.008). The eradication group and the control group showed no difference in characteristics of metachronous cancer. Conclusions: This study showed that H. pylori eradication prevented the development of metachronous gastric cancers after ER during long-term follow-up.

Single-Dose Pharmacokinetics of Different Oral Sodium Nitrite Formulations in Diabetes Patients

Diabetic foot ulcers, although associated with macrovascular disease and neuropathy, have a microvascular disease causing ischemia not amenable to surgical intervention. Nitrite selectively releases nitric oxide in ischemic tissues, and diabetes subjects have low nitrite levels that do not increase with exercise. This study explores the safety and pharmacokinetics of a single dose of sodium nitrite in subjects with diabetic foot ulcers. Using a blinded, randomized crossover study design, 12 subjects with diabetes mellitus and active or healed foot ulcers received a single dose of sodium nitrite on two occasions 7-28 days apart, once with an immediate release (IR) formulation and once with an enteric-coated (EC) formulation for delayed release. Serum nitrite, nitrate, methemoglobin, sulfhemoglobin, blood pressure, pulse rate, complete blood count, chemistry panel, electrocardiogram, and adverse events were followed for up to 6 h after each dose. The IR and EC nitrite levels were analyzed by one-way analysis of variance and by pharmacokinetic modeling. The IR formulation elevated nitrite levels between 0.25 and 0.75 h (P<0.05). The EC formulation did not elevate nitrite levels significantly, but both formulations gave plasma nitrite levels previously suggested to be therapeutic (approximately 2-5 μM). The IR formulation gave an asymptomatic blood pressure drop of 10/6 mm Hg (P<0.003), and two subjects experienced mild flushing. There was no elevation of methemoglobin or other safety concerns. Pharmacokinetic modeling of plama nitrite levels gave r(2) values of 0.81 and 0.97 for the fits for IR and EC formulations, respectively. Oral sodium nitrite administration is well tolerated in diabetes patients.

171 3-Year Results of the CeMyLungs Study, a 3-Year Randomised, Open Label, Multi-Centre Investigator Driven Study Comparing De Novo Enteric Coated Mycophenolate Sodium with Delayed Onset Everolimus, Both Arms in Combination with Cyclosporin (Using C2 Monitoring) and Corticosteroids for the Prevention of Bronchiolitis Obliterans Syndrome in Heart-Lung, Bilateral Lung and Single Lung Transplant Recipients

171 3-Year Results of the CeMyLungs Study, a 3-Year Randomised, Open Label, Multi-Centre Investigator Driven Study Comparing De Novo Enteric Coated Mycophenolate Sodium with Delayed Onset Everolimus, Both Arms in Combination with Cyclosporin (Using C2 Monitoring) and Corticosteroids for the Prevention of Bronchiolitis Obliterans Syndrome in Heart-Lung, Bilateral Lung and Single Lung Transplant Recipients

Development of a novel tablet-in-capsule formulation of mesalamine for inflammatory bowel disease

Objective: The objective of the present work was to develop a tablet-in-capsule type of multiunit system, which releases the drug in a controlled manner at pre-programmed time intervals.Methods: The system consists of an enteric-coated hydroxypropyl methylcellulose capsule filled with four units of mesalamine minitablets, each of which was further coated with different ratios of Eudragit® E100 and Eudragit® RS100.Results: In vitro evaluation of tablets coated with Eudragit® E100 and Eudragit® RS100 at different pH conditions revealed that at lower pH levels (2.0, 3.6 and 5.5 pH), the drug release is mainly governed by the dissolution of Eudragit® E100 from the Eudragit® E100 and Eudragit® RS100 coat. In vitro evaluation of capsules enteric coated with Eudragit® L100 and Eudragit® S100 revealed that a maximum lag time of 3 h and 4 h was obtained, respectively. In vivo roentgenographic evaluation in rabbits revealed that the developed system remained intact until it reaches the targeted region of the gastrointestinal tract, i.e. ileum and colon, where the tablets were released after the dissolution of the enteric coat Eudragit® L100 and Eudragit® S100, respectively.Conclusion: The developed system exhibited a promising targeting behavior and hence may be used for the treatment of inflammatory bowel disease.

A review on recent advances of enteric coating

–Enteric coated tablets are solid unit dosage forms which are designed to bypass the stomach and release the drug in small intestine and are meant for oral administration. The word “enteric” indicates small intestine; therefore enteric coatings prevent release of medication before it reaches the small intestine. Most enteric coatings work by presenting a coated surface that is stable at the highly acidic pH found in the stomach, but breaks down rapidly at a less acidic (relatively more basic) pH. Materials used for enteric coatings include CAP, CAT, PVAP and HPMCP, fatty acids, waxes, shellac, plastics and plant fibers. The present review describes enteric coating, their ideal properties, benefits and limitation, various polymers used, their chemical structure, criteria for drug selection and mechanism, methods of manufacturing and evaluation of enteric coated tablets. Recently, these have attracted the interest of many formulators due to their advantages over the conventional drug delivery systems as they prolong the dosing intervals and also increase patient compliance. The study provides an overview of the recent advances that have taken place in this arena. Keywords––Enteric coated tablet, Evaluation, Ideal Properties, Mechanism and Methods of enteric coated tablets.

Pharmacodynamic Evaluation of Clopidogrel Plus PA32540: The Spaced PA32540 With Clopidogrel Interaction Gauging (SPACING) Study

PA32540 combines 325 mg enteric-coated (EC) aspirin (ASA) with 40 mg immediate-release omeprazole; its influence on the antiplatelet effect of clopidogrel (C) is unknown. In this randomized, open-label study, subjects (n = 30) were treated with (i) 300 mg C + 325 mg ECASA followed by 75 mg C + 325 mg ECASA on days 2-7, (ii) 300 mg C + PA32540 followed by 75 mg C + PA32540 on days 2-7, or (iii) PA32540 in the morning + 300 mg C 10 h later on day 1 and PA32540 in the morning + 75 mg C 10 h later on days 2-7. We analyzed the noninferiority of PA32540 relative to ECASA, as defined by the upper bound of the 95% confidence interval ≤10% for the difference in least-square means of platelet inhibition between the treatments. As compared to ECASA+C, synchronous treatment of PA32540+C was not noninferior, whereas the spacing strategy of PA32540+C was noninferior. Spacing the administration of PA32540 and clopidogrel lessens the interaction observed with synchronous administration; PA32540 administration with clopidogrel may be associated with a different antiplatelet profile.

PHP49 The Pharmacist'S Perception of the Splitting Extended Release and Enteric-Coated Formulation Drugs

Extended release and enteric coated formulations make up 7.8% of all drugs, and the most frequently used drug is an agent affecting circulatory, digestive system. The objective of this study is to analyze of extended release and enteric coated drugs on pharmaceutical reimbursement item list in Korea and evaluate the dispensing of extended release and enteric coated drugs, which is enforced by the National Health Insurance. The analysis used a questionnaires survey for 169 pharmacists in the hospital pharmacy and community pharmacy(Response rate: 73.8%). The questions include; prescribing change after enforcement by National Health Insurance, prescription correction, change of pharmacy works, expansion of the range of enforcement, provision of information and prescribing error prevention. The statistics methods use Chi-square, AVOVA, t-test, McNemar test by STATA/SE10.(p<0.05). Of extended release and enteric coated formulations, 33.9% were not available in other dosage forms. After enforcement by National Health Insurance, the rate of splitting and crushing of extended release and enteric coated drugs decreased, but pharmacies in tertiary care hospitals had increased workload because of prescription corrections. Prescription was not changed, because patients take medicines for a long time. Most of pharmacists agreed on the expansion of drug range, but 65.7% of pharmacists wanted the enforcement only for hospitals. When pharmacists corrected their prescribing error, the biggest problem was a lack of other dosage forms. To prevent extended release and enteric coated from splitting and crushing, pharmacists want in the following ways; prescribing code prohibits into order computer system, warnings and alerts on prescribing, developing many other dosage forms. What is needed are medication-use system improvements and the creation of lists with suggestions for alternative products on the formulary. Also, pharmaceutical companies should make an effort to develop other dosage forms.

Administration status of enteric-coated aspirin among diabetic patients in Xujiahui subdistrict of Shanghai

The administration status of enteric coated aspirin in 348 diabetic patients aged over 40 from Xujiahui Subdistrict of Shanghai was surveyed. One hundred and two out 348 patients ( 29. 3% ) used aspirin regularly, among them only 36 cases used the correct dosage (75 - 162 mg/d), accounting for 10. 3% (36/348) of all patients surveyed. The results indicate that aspirin was not used properly in diabetic patients to prevent the heart and cerebrovascular diseases,and it is necessary for medical providers to promote health education for diabetic patients. Key words: Diabetes mellitus, type 2; Asprin

The permeability of enteric coatings and the dissolution rates of coated tablets.

The effect of an increasing concentration of plasticizer and pigment on the permeability to both water vapour and simulated gastric juice of cellulose acetate phthalate and polyvinyl acetate phthalate has been evaluated. There were significant differences between the permeability coefficients of each polymer, particularly with regard to water vapour. The presence of additives within the film coatings had a greater effect on the properties of cellulose acetate phthalate than those of polyvinyl acetate phthalate. Suitable formulations of each polymer were used to enteric coat 325 mg aspirin tablets, which were subsequently subjected to both the Disintegration Test for Enteric Coated Tablets B.P. and a dissolution procedure to monitor the release of drug in simulated gastric juice and simulated intestinal fluid. Both polymers demonstrated their suitability for producing enteric coatings. However, polyvinyl acetate phthalate yielded a faster release of aspirin in simulated intestinal fluid than did cellulose acetate phthalate.

Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a common cause of liver disease in children. Hepatic fat accumulation and oxidative stress contribute to its pathogenesis. Cysteamine bitartrate readily traverses cellular membranes and is a potent antioxidant. To evaluate the safety and efficacy of enteric-coated (EC) cysteamine in children with NAFLD. Children, aged ≥10 y, meeting screening criteria with biopsy-proven NAFLD and serum ALT ≥60 IU/L, received twice-daily EC-cysteamine for 24 weeks. Monthly ALT, AST, body mass index (BMI) and gastrointestinal symptom scores were measured. Subjects with >50% reduction or normalisation of ALT achieved the primary endpoint. Of the 13 children enrolled (mean age 14.0 years), 11 completed EC-cysteamine therapy (mean dose 15.2 mg/kg/day) and were included in the final analysis. For these 11 subjects, the mean ALT levels at baseline and 24 weeks were 120.2 and 55 IU/L respectively (P = 0.002), and the AST levels were 60 and 36 IU/L respectively (P = 0.007). The primary endpoint was reached in 7 and normalisation (≤40 IU/L) of ALT in 5. After 24 week therapy, mean adiponectin levels increased (P = 0.009) and CK-18 fragment levels decreased (P = 0.013), insulin levels remained unchanged (P = 0.99). Mean leptin levels were decreased in responders (P = 0.044). Mean BMI was 34.5 at baseline and 34.2 kg/m(2) after treatment (P = 0.35). Mean symptom scores at baseline (1.1) and at 24 weeks (0.7) were similar. No major adverse events were reported. Enteric-coated cysteamine reduces ALT and AST levels in children with NAFLD without reduction in body mass index. Further studies will evaluate optimal cysteamine therapeutic dose and effect on liver histology in NAFLD (Clinicaltrials.gov protocol ID: 07-1699).

Evolution of a physiological pH 6.8 bicarbonate buffer system: Application to the dissolution testing of enteric coated products

The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro– in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH 7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP-55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT® L100-55, EUDRAGIT® L30D-55 and EUDRAGIT® L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1 M HCl for 2 h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer ( mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer.

Use of a Mutilumen Catheter to Assess the Bioavailability of an Enteric- Coated High-Buffered Pancrelipase Formulation in Patients with Exocrine Pancreatic Insufficiency

Treatment of exocrine pancreatic insufficiency (EPI) secondary to conditions including cystic fibrosis or chronic pancreatitis requires exogenous supplementation with a specially formulated pancreatic enzyme product (PEP). The FDA has mandated that the intestinal bioavailability of these preparations be evaluated in vivo in patients. This pilot clinical study examined the feasibility of using a multi-lumen catheter with an occluding balloon to measure changes in intraduodenal enzyme concentrations following oral administration of a PEP. In this two arm cross-over study, patients with mild-severe EPI were administered enteric coated (EC) highbuffered pancrelipase or placebo capsules with a liquid Lundh meal. Gastric and duodenal samples were aspirated at 15-minute intervals over 3 hours in each treatment arm. The concentrations of three pancreatic enzymes (lipase, amylase, and protease) were measured in the collected fluids. The maximum concentration (Cmax), and area under the duodenal enzyme concentration vs. time profile (AUC) were determined. Comparison of enzyme concentrations between placebo and treatment phases demonstrated appreciable increases in all three enzymes in the subject with cystic fibrosis (CF+), but only a modest increase in the subject with mild-to-moderate EPI (CF-). During the EC-high-buffered pancrelipase+meal phase, the fold increase in the Cmax of lipase, amylase, and protease concentrations compared to the placebo+meal phase in subject CF- were 0.96, 1.65, and 1.64, respectively. In subject CF+, who had severe pancreatic enzyme insufficiency, the fold increase in the AUC of lipase, amylase and protease concentrations compared to the placebo+ meal phase was 66.1, 15.9, and 651, respectively. Time to peak concentration occurred earlier during the active treatment phase. In both subjects and both treatments a peak duodenal pH of 8 was measured. The catheter employed in this study can be used to determine bioavailability of PEPs in severe EPI in a single day pretreatment vs. post treatment setting (NCT00744250).

Study on curative effect of clopidogrel bisulfate combined with low molecular weight heparin in the treatment of acute progressive cerebral infarction

Objective To explore the curative effects of clopidogrel bisulfate combined with low molecular weight heparin in the treatment of acute progressive cerebral infarction. Methods 117 patients with progressive cerebral infarction were randomly divided into two groups, There were 62 patients in the treatment group and 55 patients in the control group. In the treatment group, clopidogrel bisulfate 300mg was apphed initial dose, followed by 75mg qd×13d and the low molecular weight Heparin 4000IU, twice a day,subcutaneous injection,for 7d; the control group were treated with oral enteric-coated aspirin 100mg, once a day. All of them were controlled with blood glucose, blood pressure, blood fat, dehydration and improved brain cells metabolism etc. Results The curative effects were compared between two groups, the treatment group was much better than that in the control group(P＜ 0.01) Conclusion Clopidogrel bisulfate combined with low molecular weight heparin in the treatment of acute progressive cerebral infarction is effective and safe. Key words: Clopidogrel bisulfate; Low molecular weight heparin; Progressive brain infarction

Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease

Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with increased risk of cardiovascular (CV) events. Direct inhibition of this proinflammatory enzyme with darapladib may benefit CV patients when given as an adjunct to standard of care, including lipid-lowering and antiplatelet therapies. STABILITY is a randomized, placebo-controlled, double-blind, international, multicenter, event-driven trial. The study has randomized 15,828 patients with chronic coronary heart disease (CHD) receiving standard of care to darapladib enteric-coated (EC) tablets, 160 mg or placebo. The primary end point is the composite of major adverse cardiovascular events (MACE): CV death, nonfatal myocardial infarction, and nonfatal stroke. The key secondary end points will include major coronary events, total coronary events, individual components of MACE, and all-cause mortality. Prespecified substudies include 24-hour ambulatory blood pressure monitoring, albuminuria progression, changes in cognitive function, and pharmacokinetic and biomarker analyses. Health economic outcomes and characterization of baseline lifestyle risk factors also will be assessed. The study will continue until 1,500 primary end points have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be 2.75 years. STABILITY will assess whether direct inhibition of Lp-PLA(2) with darapladib added to the standard of care confers clinical benefit to patients with CHD.

The efficacy of high-dose clopidogrel for elderly patients with acute non-ST segment elevation myocardial infarction

Objective To explore the efficacy of high-dose clopidogrel for elderly patients with acute non-ST segment elevation myocardial infarction. Methods 118 elderly patients who had heen hospitalized during the period of January 2006 to January 2010 were randomly assigned to receive combination therapy with enteric-coated aspirin, low-molecular-weight heparin, and antianginal drugs (59 patient, control group) or combination therapy plus high-dose clopidogrel (59 patients, study group).The efficacy, alteration of ST-segment on ECG, and changes in blood PT, APTT, and PLT were compared between the two groups. Results The total effectiveness rate differed significantly between the study group and the control group (98.31% vs. 81.36%, P<0.05).There were significant differences in serum markers between the two goups (P< 0.05). Conclusions High-dose clopidogel is safe, effective,and reliable in the treatment of elderly patients with acute non-ST segment elevation myocardial infarction. Key words: Elderly; Non-ST-segment elevation myocardial infarction; Clopidogel

Correlation of Two Patient-Reported Outcomes to Assess Dyspepsia: Patients Listening to Their Gut Feeling: 2010 Presidential Poster

Purpose: Results from two identical 6-month, multicenter, randomized, double-blind, parallel-group, controlled, Phase 3 studies, involving H. pylori-negative patients aged ≥50 yrs or 18-49 yrs with a history of ulcer, have shown a reduced incidence of endoscopic gastric ulcers and improved upper gastrointestinal (UGI) tolerability (including patient-reported outcomes [PROs]) with a fixed-dose combination of enteric-coated (EC) naproxen 500 mg and immediate-release esomeprazole 20 mg vs. EC naproxen 500 mg (Goldstein, et al. Aliment Pharmacol Ther 2010; in press). PRO assessments of dyspepsia included the Severity Of Dyspepsia Assessment (SODA; a validated 17-question tool measuring domains of pain intensity, non-pain symptoms, and satisfaction with a 7-day recall period) and the Overall Treatment Evaluation of Dyspepsia (OTE-DP; a short tool that assesses change in upper abdominal pain and/or discomfort as better, worse, or same since start of treatment). The aim of this analysis was to determine if a correlation exists between the SODA and OTE-DP findings. Methods: In this combined post-hoc analysis, a Spearman's correlation coefficient (CC) was used to evaluate the relationship between the three SODA domains (assessed at baseline and Months 1, 3, and 6) and OTE-DP outcomes (assessed at Month 6). Correlations were derived using mean change in SODA score from baseline to Month 6 (or last visit) and OTE-DP scores at Month 6 using a 15-point scale (same=0; better=1 to 7; worse=-1 to -7); no treatment effect was considered.Results: A total of 861 patients were randomized (Study 301, n=438; Study 302, n=423); of these, 735 (Study 301, n=378; Study 302, n=357) with both SODA and OTE-DP scores were included in this analysis. Both SODA and OTE-DP scores trended in the same direction; a moderate yet significant treatment-independent correlation was observed between each of the three SODA domain scores and OTE-DP scores (table). Conclusion: In conclusion, OTE-DP outcomes appear to correlate consistently with SODA scores for the evaluation of NSAID-associated dyspepsia in each of these studies. The combined data provide a stronger estimate of the correlation magnitude. Based on these findings, OTE-DP may provide a valid and simpler tool than SODA for the practicing physician to measure dyspepsia, and may offer an alternative to SODA in trials evaluating the UGI tolerability of NSAIDs. Disclosure: Dr Goldstein - consultant, speakers bureau, advisory committee member, independent contractor, research/educational grants: AstraZeneca; consultant, independent contractor, research grant: POZEN. Dr Datto - Employee: AstraZeneca Ms Hwang: Employee: AstraZeneca These studies were sponsored by POZEN Inc. Medical writing support was provided by James Sampayo of Complete Medical Communications, funded by AstraZeneca.

Pharmacokinetics of mycophenolic acid in severe lupus nephritis

Mycophenolic acid (MPA) is an effective treatment for active lupus nephritis despite its variable efficacy in different ethnic groups. Here we tested whether pharmacokinetic monitoring may help to optimize dosing of MPA in an Asian population. Patients with biopsy-proven class III or IV lupus nephritis (ISN/RPS category) were treated with mycophenolate mofetil or enteric-coated mycophenolate sodium. One month after initiating treatment we measured plasma MPA levels in eight samples taken over a 12-h period after drug administration. The mean area under the time-dependent curve for MPA of responding patients was significantly higher than those not responding. Successful treatment was seen in patients with areas >45 mg h/l. The dosage of the drug was not related to MPA pharmacokinetics. In the mycophenolate mofetil group, however, MPA-area under the curve was positively, and significantly, correlated with trough or 1 h after dose concentrations and associated with a therapeutic response. Thus, our study shows that MPA pharmacokinetics were positively correlated with therapeutic responses of mycophenolate, suggesting that controlling the concentrations may improve its therapeutic efficacy in lupus nephritis. As the absorption and pharmacokinetic peak of enteric-coated tablets is slower, it is important to take different formulations into account when determining optimal MPA concentrations.

Clinical observation on the treatment of diabetic neurogenic bladder with Guantong decoction

Objective To discuss the therapeutic effect of treating diabetic neurogenic bladder with integrative medicine. Methods 60 patients with diabetic neurogenic bladder were randomly recruited into a treatment group and a control group. The treatment group (30 cases) treated with methylcobalamin, pancreatic kallikrein enteric-coated tablets and Guantong decoction, while the control group (30 cases) was treated with western medicine exclusively. The residual urine volume and symptoms were observed before and after the treatment. Results The treatment group showed significantly better results in improving the symptoms and reducing the residual urine volume than the control group(P＜0.05).Conclusion It is curative to treat diabetic neurogenic bladder with integrative medicine. Key words: Guantong decoction; Integrative medical treatment; Diabetes; Neurogenic bladder

Clinical trial: the incidence of NSAID‐associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric‐coated naproxen alone

Gastroprotective co-therapy may reduce the risk of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers, but adherence is suboptimal. To compare the incidence of gastric ulcers with PN 400 [enteric-coated (EC) naproxen 500 mg and immediate-release esomeprazole 20 mg], or EC naproxen. Two randomized, double-blind, multicentre studies (PN400-301, PN400-302). Patients [stratified by low-dose aspirin (< or =325 mg) use] aged > or =50 years or 18-49 years with a history of ulcer, received PN 400 BID (301, n = 218; 302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210) for 6 months. The primary endpoint was the cumulative incidence of endoscopic gastric ulcers. The cumulative incidence of gastric ulcers was significantly lower with PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs. 24.3%, P < 0.001). PN 400 was associated with a lower combined incidence of gastric ulcers vs. EC naproxen in low-dose aspirin users (n = 201) (3.0% vs. 28.4%, P < 0.001) and non-users (n = 653) (6.4% vs. 22.2%, P < 0.001). The incidence of, and discontinuations due to, upper gastrointestinal (UGI) AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01, both studies). PN 400 significantly reduces the incidence of gastric ulcers, regardless of low-dose aspirin use, in at-risk patients, and is associated with improved UGI tolerability relative to EC naproxen (ClinicalTrials.gov, NCT00527782).