Inhibitors in haemophilia A: a perspective on clotting factor products as a potential contributing factor.

INTRODUCTION: The occurrence of a neutralizing antibody in previously untreated patients (PUPs) with haemophilia A appears to be the result of an intricate interplay of both genetic and environmental factors. Recently, the type of factor VIII (FVIII) product used in the PUPs population has been implicated as a risk factor for inhibitor development. AIM: The aim of this review was to explore in a systematic manner potential hypotheses for the product-related findings in these studies (i.e. differences in the expression system of the cell lines used to produce recombinant FVIII [rFVIII], differences in the administered antigen load or changes in clinical practice over time). RESULTS: Review of the available clinical studies illustrates the high degree of variability for the risk of inhibitor development for the same products across different studies. Differences in cell lines or antigen load were not found to provide a reasonable explanation. CONCLUSION: The possibility of changes in clinical practice over time and patient selection bias (i.e. the preferential use of one product over another in patients at higher risk for inhibitors) offers a potential explanation and should be carefully considered when evaluating the studies.

Managing chronic pain in adults with haemophilia: current status and call to action.

Haemophilic arthroses are associated with acute pain during bleeding episodes and with chronic pain caused by arthritic complications of repeated bleeding into joints. Unlike other conditions (e.g. osteoarthritis, rheumatoid arthritis, sickle cell disease), there are limited data on pain management in haemophilia. Management of arthritic individuals and those with sickle cell disease relies heavily on administration of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics. In haemophilia, acetaminophen often has limited efficacy at therapeutic doses, offering a narrow dosing range in those with liver disease due to chronic hepatitis C. NSAIDs can effectively manage pain in patients with haemophilia, but these agents are potentially associated with a significant risk of precipitating or exacerbating bleeding complications in an already coagulopathic population. Opioids have proven effective in osteoarthritis and sickle cell disease, but outcomes data in those with haemophilia are virtually non-existent. Patients with haemophilia are at least as vulnerable as other chronic pain populations to opioid-related adverse events and to developing abusive behaviours and addiction. Despite pain management strategies for patients with haemophilia being far from optimal, the predominant precept of haemophilia management still applies. As such, it is critically important to aggressively reverse or prevent acute symptomatic bleeding in a timely and effective manner to at least minimize pain and progressive joint damage. This review should serve as a call to action to prioritize pain management in haemophilia care and spur interest in the development, improvement and standardization of tools to assess and manage acute and chronic pain in haemophilia.

Cardiovascular comorbidities are increased in U.S. patients with haemophilia A: a retrospective database analysis.

There is conflicting evidence in the literature on whether individuals with haemophilia in the USA have greater, reduced, or similar risks for cardiovascular disease as the general population. This study evaluated the prevalence of cardiovascular comorbidities among USA males with haemophilia A, relative to an unaffected general male population with similar characteristics. Males with haemophilia A and continuous insurance coverage were identified by ICD-9-CM code 286.0 (1 January 2007-31 December 2009) using the MarketScan Commercial and Medicare Research Databases. Individuals with haemophilia A were exact matched 1:3 with males without a diagnosis of haemophilia A. The prevalence of cardiovascular comorbidities identified by ICD-9-CM code was determined for matched cohorts. Of the study population, 2506 were grouped in the haemophilia A cohort and 7518 in the general cohort. Proportions of individuals with haemorrhagic stroke (2.0% vs. 0.5%, P < 0.001), ischemic stroke (4.7% vs. 2.7%, P < 0.001), coronary artery disease (10.7% vs. 5.8%, P < 0.001), myocardial infarction (0.8% vs. 0.3%, P = 0.003), hypertension (22.6% vs. 15.5%, P < 0.001), hyperlipidaemia (15.9% vs. 11.9%, P < 0.001), arterial thrombosis (12.1% vs. 5.9%, P < 0.001), and venous thrombosis (4.4% vs. 1.1%, P < 0.001) were significantly greater for the haemophilia A cohort. Results were consistent across most age groups, and comorbidities appeared at an earlier age in those with haemophilia A than in the general population. Among the USA haemophilia A population cardiovascular comorbidities are more prevalent and they appear earlier in life in comparison to the general male population, suggesting the need for earlier, enhanced screening for age-related comorbidities in the haemophilia community.

PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers.

PEGylation is the technology involving the covalent attachment of polyethylene glycol (PEG) to a protein-, peptide- or small-molecule drug to improve their pharmacokinetic, pharmacodynamic and immunological profiles, and thus, enhance the therapeutic effect. Today, PEGylation of proteins is a well-established technology and is being used in the treatment of a variety of clinical disorders. Several PEGylated coagulation proteins for haemophilia A and B are under development with the goal of prolonging the circulation half-life of factor VIII (FVIII) or factor IX. The prolongation of half-life, resulting in less frequent injections can provide significant benefits in improving the quality of life of subjects with haemophilia and improvement in adherence to treatment. A review of published literature on PEGylated therapeutic products currently approved for human use and a discussion of a PEGylated recombinant FVIII molecule (BAY 94-9027, Bayer HealthCare, Berkeley, CA, USA) currently being investigated in the pivotal clinical trial prior to registration is provided. Available safety information of PEGylated proteins containing high molecular weight PEG does not indicate any safety concerns to date, following long-term (chronic) use in animal models or patients. Chronic use of currently available PEGylated products has been shown to be safe, paving the way for chronic use of PEGylated coagulation products in persons with haemophilia.

The challenge of pain evaluation in haemophilia: can pain evaluation and quantification be improved by using pain instruments from other clinical situations?

Pain is a critical aspect in the lives of individuals with congenital haemophilia A or B. Initially, pain serves as a warning sign for an active bleeding event; however, after multiple bleeding episodes, pain may become chronic, debilitating, and distracting. It is essential that pain instruments be developed and validated for use in persons with haemophilia, especially in paediatric cohorts, so that new therapies to treat acute bleeds can be assessed in a standardized manner. This review evaluates the existing pain instruments utilized in the English language haemophilia literature and compares their features and practicality with instruments published for other clinical pain scenarios associated with non-coagulopathic disease states, such as cancer and surgical convalescence, in paediatric, adolescent, and adult populations. In clinical trials involving haemophilia cohorts, few pain instruments have been validated. Only one instrument has addressed pain specifically in individuals less than 16 years of age. In contrast, multiple instruments have been applied extensively to other pain situations, especially in the paediatric oncology area, where the age range extends to less than 3 years. We conclude that trials quantifying pain in haemophilia would benefit from the addition and validation of instruments in use in other pain situations. Suggestions for modifying the pain instruments currently used in haemophilia are presented, specifically to address paediatric haemophilia cohorts.

Steroid-sparing properties of sargramostim in patients with corticosteroid-dependent Crohn's disease: a randomised, double-blind, placebo-controlled, phase 2 study.

OBJECTIVE: Although treatment with corticosteroids induces remission in Crohn's disease, prolonged exposure to corticosteroids is undesirable. This randomised clinical trial evaluated the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (sargramostim), an activator of innate immunity, in corticosteroid-dependent patients with Crohn's disease. DESIGN: Patients were randomised in a 2:1 ratio, to sargramostim 6 microg/kg subcutaneously once daily or placebo for up to 22 weeks. The study consisted of (1) an adjunctive phase (weeks 1-4) in which patients received study drug plus corticosteroid therapy; (2) a forced corticosteroid tapering phase (weeks 4-14); and (3) an observation phase (4 weeks) in which patients received study drug plus prednisone < or =7.5 mg. The primary endpoint was corticosteroid-free remission (Crohn's Disease Activity Index (CDAI) < or =150) 4 weeks after corticosteroid elimination. Secondary endpoints were corticosteroid-free response (CDAI decreased by > or =100) and induction of remission in patients who reduced the dose of corticosteroid to 2.5-7.5 mg. RESULTS: Eighty-seven patients were randomised to sargramostim and 42 to placebo. Significantly more sargramostim-treated patients than placebo patients achieved corticosteroid-free remission (18.6% vs 4.9%; p = 0.03). Similar differences were seen for corticosteroid-free response and in patients who tapered corticosteroids to 2.5-7.5 mg/day. Sargramostim treatment was also associated with significant improvements in health-related quality of life. Patients who received sargramostim were more likely to experience musculoskeletal pain, injection site reactions and dyspnoea. CONCLUSIONS: Sargramostim was more effective than placebo for inducing corticosteroid-free remission in patients with Crohn's disease with corticosteroid dependence. Sargramostim may provide significant benefit in this population if these findings are confirmed.

Mass balance study of [14C] rabeprazole following oral administration in healthy subjects.

The study was designed to determine the excretion balance of radiolabeled rabeprazole in urine and feces and to examine the metabolite profile in plasma, urine and feces after a single oral dose of [14C] rabeprazole, preceded by once daily dose of rabeprazole for 7 days. Six healthy subjects were enrolled in this study. The study was a single-center, open-label, multiple-dose, mass-balance study. Each subject received a single 20 mg dose of rabeprazole tablet for 7 days followed by the administration of 20 mg of [14C] rabeprazole as an oral solution after an overnight fast on Day 8. After oral dosing of [14C] rabeprazole, the mean Cmax of total radioactivity was 1,080 +/- 215 ng equivalent/ml with 0.33 +/- 0.13 hours of the mean tmax. The apparent elimination half-life of total [14C] radioactivity was 12.6 +/- 3.4 hours. The total [14C] recovery in urine and feces was 99.8 +/-0.7% by 168 hours after oral administration of [14C] rabeprazole, and mean cumulative [14C] radioactivity excreted in urine was 90.0 +/- 1.7% by 168 hours and 79.8 +/- 2.5% of the radioactivity was excreted in urine within 24 hours. Excretion via feces added to the total by 9.8%. The major radioactive component in the early plasma samples was rabeprazole, however the thioether and thioether carboxylic acid metabolites were the main radioactive components in the later plasma sample. These results support the previous finding that the substantial contribution of the non-enzymatic thioether pathway minimizes the effect of CYP2C19 polymorphism on the inter-individual variation ofplasma clearance of rabeprazole compared with other PPIs. Low levels of the sulfone metabolite were detected only in early plasma samples. No rabeprazole was detected in any urine and feces samples. The main radioactive components in urine were thioether carboxylic acid and mercapturic acid conjugate metabolites, and in the feces, the thioether carboxylic acid metabolite. The administration of [14C] rabeprazole was safe as evidenced by the lack of serious adverse events and the fact that all observed events were mild in intensity. [14C] rabeprazole was rapidly absorbed after oral administration and mostly excreted in urine.

A randomized, double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years.

BACKGROUND: Gastro-oesophageal reflux disease has a chronic course, and often requires long-term treatment. Proton pump inhibitors are the treatment of choice for both acute and maintenance treatment, but little is known from randomized controlled trials of their effects beyond 1 year. AIM: To compare the efficacy and safety of two doses of rabeprazole with 20 mg omeprazole in the maintenance treatment of erosive gastro-oesophageal reflux disease over 5 years. METHODS: Two hundred and forty-three patients who had previously responded to acute treatment for erosive gastro-oesophageal reflux disease were prospectively randomized to receive 5 years of treatment with rabeprazole (10 or 20 mg daily) or omeprazole (20 mg daily). The primary outcome measure was endoscopically confirmed relapse of erosive gastro-oesophageal reflux disease. RESULTS: One hundred and twenty-three patients (51%) completed all 5 years of the study, with similar completion rates in the three groups. Relapses occurred in nine of 78 (11.5%), eight of 82 (9.8%) and 11 of 83 (13.3%) patients in the rabeprazole 20 mg, rabeprazole 10 mg and omeprazole 20 mg groups, respectively. Gastric biopsy showed no evidence of any harmful effects. All treatments were well tolerated. CONCLUSIONS: Rabeprazole 10 mg, rabeprazole 20 mg and omeprazole 20 mg all had similar efficacy in the maintenance treatment of gastro-oesophageal reflux disease. All three were safe and well tolerated during 5 years of treatment.

Decreasing oesophageal acid exposure in patients with GERD: a comparison of rabeprazole and omeprazole.

BACKGROUND: Rabeprazole has been shown to be more potent and faster than other proton pump inhibitors in in vitro studies and highly effective in decreasing oesophageal acid exposure in patients with gastro-oesophageal reflux disease (GERD). AIM: This study was a multicentre, double-blind, placebo-controlled, randomized, parallel-group comparison of three active treatment regimens utilizing two different proton pump inhibitors, or placebo, administered over 7 days in patients with GERD. METHODS: Eighty-two patients with symptomatic GERD were given placebo, rabeprazole 10 mg b.d., rabeprazole 20 mg o.m., or omeprazole 20 mg o.m. for 7 days. Twenty-four hour oesophageal pH monitoring was performed at baseline and repeated at the conclusion of the treatment period. RESULTS: At the end of study, the percentage time (mean +/- s.d.) with pH < 4 over a 24-h period was significantly decreased by the three active regimens but without significant difference between them (9.27 +/- 4.77; 2.53 +/- 4.27; 2.02 +/- 1.71 and 2.91 +/- 4.06 for placebo, rabeprazole 10 mg b.d., rabeprazole 20 mg o.m. and omeprazole 20 mg o.m., respectively). Acid exposure was normalized in 90% of patients treated with rabeprazole 10 mg b.d., 95% treated with rabeprazole 20 mg o.m., 78% treated with omeprazole 20 mg o.m., and only 9.5% of patients treated with placebo. Both rabeprazole and omeprazole were well-tolerated. CONCLUSIONS: Although rabeprazole 20 mg o.m. showed greater activity numerically, this study demonstrates that rabeprazole 10 mg b.d. and 20 mg o.m. are equivalent to omeprazole 20 mg o.m. in decreasing oesophageal acid exposure.

Rabeprazole versus ranitidine for the treatment of erosive gastroesophageal reflux disease: a double-blind, randomized clinical trial. Raberprazole Study Group.

OBJECTIVE: The objective of this study was to compare the efficacy and safety of the proton pump inhibitor rabeprazole to that of the histamine-2 (H2)-receptor antagonist ranitidine in the treatment of erosive gastroesophageal reflux disease. The primary indicator of efficacy was the absence of esophageal erosions or ulcerations as determined by posttreatment endoscopy. Secondary indicators of efficacy included improvement in frequency and severity of daytime and nighttime heartburn. METHODS: A total of 338 patients were enrolled and randomly assigned to therapy with rabeprazole 20 mg once daily in the morning or to ranitidine 150 mg four times daily. At baseline and at 4 wk, patients underwent endoscopy for evaluation of esophageal lesions. Patients whose lesions healed by wk 4 had therapy discontinued; others remained on therapy and had repeat endoscopy at 8 wk. Also recorded at study visits were patients' ratings of heartburn symptoms and overall sense of well being, patients' reports of time lost from daily activities, antacid use, and adverse events. Serum gastrin levels were measured and argyrophil enterochromaffin-like cell histology evaluated at baseline and when the patient ended therapy. RESULTS: At wk 4, healing was observed in 59% (98/167) of patients assigned to rabeprazole therapy, compared with 36% (60/169) of those receiving ranitidine (p < 0.001). By 8 wk, healing was seen in 87% (146/167) and 66% (112/169) of patients in the rabeprazole and ranitidine groups, respectively (p < 0.001). There were also significant differences between the two groups favoring rabeprazole with respect to resolution or improvement of heartburn symptoms and improvement in sense of well-being. No drug-related serious adverse events were seen with either therapy; fewer patients assigned to rabeprazole had treatment-emergent signs and symptoms. Serum gastrin levels increased over baseline in the rabeprazole group, but the mean value remained within normal limits. CONCLUSIONS: Rabeprazole was superior to ranitidine in esophageal healing and symptom relief in patients with erosive gastroesophageal reflux disease, and was equally well tolerated.

Rabeprazole produces rapid, potent, and long-acting inhibition of gastric acid secretion in subjects with Helicobacter pylori infection.

AIM: To compare acid inhibiting activity and duration of action of different doses of rabeprazole, a substituted benzimidazole characterized as a highly potent and irreversible H+, K+-ATPase inhibitor, administered for 7 days to subjects infected with Helicobacter pylori. METHODS: A total of 38 subjects (mean age 39.3 years) were enrolled in a single-centre, double-blind, randomized, crossover study. All subjects were confirmed positive for H. pylori by 14C urea breath test and ELISA serologies. Subjects were divided into two groups of 19 to receive two doses of rabeprazole, either 5 and 20 mg or 10 and 40 mg, and placebo, given in random order daily in the morning for 7 days. Peptone-stimulated acid, pH, and gastrin measurements were made for 24 h after the 1st dose and for 48 h after the 7th dose. RESULTS: Peptone-stimulated acid secretion rates were decreased from 12.5 to 6.7, 4.0, 1.5, and 0.26 h after initial 5, 10, 20, and 40 mg doses, respectively; to 7.3, 4.3, 2.1, and 1.2 mmol/h 23 h after the initial dose; and to 2.4, 2.6, 0.6, and 0.8 mmol/h 23 h after the 7th dose. After 48 h, stimulated acid secretion had recovered less than 40% for all treatment groups compared to placebo. Median intragastric pH also increased from 2.0 with placebo to 4.9, 6.2, 6.6 and 6.9 during the 24-h period after the 7th dose of 5, 10, 20, and 40 mg. The 20 mg dose of rabeprazole produced equivalent acid inhibition to the 40 mg dose with less increase in plasma gastrin. CONCLUSION: Rabeprazole in doses from 5 to 40 mg was a highly effective inhibitor of gastric acid secretion in subjects infected with H. pylori. The inhibition was rapid, dose-related, and long-acting, with less than 50% recovery of acid by 48 h after the 7th dose. The optimal acid inhibitory dose in these subjects appeared to be 20 mg daily, however 5 mg and 10 mg doses produced potent inhibition of gastric acid secretion.

Rabeprazole versus omeprazole in preventing relapse of erosive or ulcerative gastroesophageal reflux disease: a double-blind, multicenter, European trial. The European Rabeprazole Study Group.

Gastroesophageal reflux disease (GERD) is a chronic condition, with 50-80% of patients experiencing recurrence within one year of completing initial treatment. In patients with erosive GERD, proton-pump inhibitors (PPI) provide faster healing and symptom relief than do H2-receptor antagonists and have become the treatment of choice. Rabeprazole is a new PPI with demonstrated efficacy in both the acute and maintenance treatment of erosive GERD. The primary objective was to compare efficacy and tolerability of rabeprazole and omeprazole in preventing relapse of healed erosive GERD. Secondary objectives included comparison of efficacy in preventing GERD relapse symptoms and in maintaining quality of life. In this multicenter, double-blind, parallel-group study, 243 patients with healed erosive GERD were randomised to receive rabeprazole 10 mg once daily in the morning (QAM) (N = 82); rabeprazole 20 mg QAM (N = 78); or omeprazole 20 mg QAM (N = 83). Endoscopies were performed at weeks 13, 26, 39 (if clinically indicated), and 52, or when symptoms suggested recurrence. Corpus biopsies were performed at each endoscopy, and antral biopsies were performed at study entry and exit. Rabeprazole 10 mg and 20 mg QAM were equivalent to omeprazole 20 mg QAM for all efficacy parameters. At week 52, relapse rates in the intent-to-treat populations were 5%, 4%, and 5% for rabeprazole 10 mg and 20 mg and omeprazole 20 mg, respectively. All treatments were well tolerated. In conclusion, both rabeprazole 10 mg and 20 mg QAM are equivalent to omeprazole 20 mg QAM in preventing recurrence of erosive GERD.

Rabeprazole is superior to ranitidine in the management of active duodenal ulcer disease: results of a double-blind, randomized North American study.

OBJECTIVE: The primary purpose of this study was to compare the efficacy and tolerability of rabeprazole versus ranitidine in the treatment of patients with active duodenal ulcer disease. METHODS: This multicenter, double-blind, randomized, parallel-group study enrolled 376 patients. Patients were randomly assigned to receive rabeprazole 20 mg administered once daily in the morning (q.a.m.) with matching ranitidine placebo twice daily (b.i.d.) (n = 188), or ranitidine 150 mg b.i.d. with matching rabeprazole placebo q.a.m. (n = 188). Three visits were scheduled: wk 0 (baseline; days -3 to -1), wk 2 (day 15+/-3 days), and wk 4 (day 29+/-3 days). The primary efficacy response variable was defined as complete regeneration of the mucosa at the site of all ulcers identified during the study. Secondary efficacy variables included patients' ratings of frequency and severity of ulcer pain, frequency of antacid use, and improvement of overall physical well-being. Tolerability was evaluated with analyses of adverse events, laboratory evaluations, fasting serum gastrin levels, vital signs, body weight, and electrocardiograms. RESULTS: Up to 4 wk of treatment with rabeprazole 20 mg q.a.m. produced significantly greater healing rates, compared to treatment with ranitidine 150 mg b.i.d. (83% vs 73%; p = 0.017). Significant differences between treatment groups were also observed for secondary efficacy indices. At wk 2, rabeprazole was more likely than ranitidine to produce complete resolution of duodenal ulcer pain (39% vs 25%; p = 0.006), improvement in duodenal ulcer nighttime pain severity (76% vs 65%; p = 0.044), and improvement in overall well-being (55% vs 41%; p = 0.009). At wk 4, the proportion of patients with normalization of overall well-being was significantly higher in the rabeprazole group than in the ranitidine group (45% vs 29%; p = 0.003). Rabeprazole was safe and well tolerated in this study. CONCLUSIONS: In patients with active duodenal ulcer disease, rabeprazole 20 mg q.a.m. is superior to ranitidine 150 mg b.i.d. in healing, resolving ulcer pain frequency, improving nighttime pain severity, and improving overall well-being. Rabeprazole is an effective and well-tolerated alternative treatment for patients with active duodenal ulcer disease.

Rabeprazole, 20 mg once daily or 10 mg twice daily, is equivalent to omeprazole, 20 mg once daily, in the healing of erosive gastrooesophageal reflux disease.

BACKGROUND: Proton pump inhibitors are the most potent pharmacologic inhibitors of gastric acid secretion currently available, and have proven effective in the treatment of gastro-oesophageal reflux disease (GERD). The object of this study was to compare the efficacy and tolerability of a new proton pump inhibitor, rabeprazole at two different dosages, with that of omeprazole in the healing of erosive GERD. METHODS: Rabeprazole 20 mg once daily (QD) and 10 mg twice daily (BID) were compared with omeprazole 20 mg QD in a double-blind, multicentre, parallel group study involving 310 patients with erosive GERD. The primary efficacy endpoint was oesophageal mucosal healing determined by endoscopy. Secondary endpoints included reduction in symptoms and improvements in quality-of-life scores. RESULTS: The healing rates between both rabeprazole groups and the omeprazole group were equivalent in both the per-protocol and intent-to-treat populations. In the per-protocol population, rabeprazole 20 mg was noted to have a numerical trend toward more rapid daytime heartburn relief. However, by 4 and 8 weeks of treatment, no significant differences were found between groups for secondary endpoints, adverse events, or laboratory abnormalities including elevation of serum gastrin levels. CONCLUSIONS: Rabeprazole 20 mg in two different dosing schedules is as effective as omeprazole 20 mg QD with regard to efficacy and tolerability in patients with erosive GERD.

Review article: rabeprazole's profile in patients with gastrointestinal diseases.

The selection of agents to treat patients with acid-related gastrointestinal diseases requires knowledge of their efficacy, tolerability, and ease of dosing among individuals with differing disease severities and other baseline characteristics. The efficacy and favourable benefit-risk profile of rabeprazole, a new proton pump inhibitor, has been demonstrated in controlled clinical trials of patients with gastro-oesophageal reflux disease (GERD), duodenal ulcers, and gastric ulcers. In comparative trials, rabeprazole is at least as effective as omeprazole for the treatment of GERD, duodenal ulcers, and gastric ulcers, and it is superior to histamine2-receptor antagonists for the treatment of GERD and duodenal ulcers. Its once-daily dosing regimen and low potential for interaction with drugs metabolized by the cytochrome P450 system make it a particularly attractive option for the treatment of acid-related diseases among older individuals. Rabeprazole is likely to be a valuable new addition to its class in treating patients with acid-related gastrointestinal diseases given its efficacy in acid suppression, high healing rates, rapid symptom relief, and convenient dosing.