A critical role of gastric mucosal ascorbic acid in the progression of acute gastric mucosal lesions induced by compound 48／80 in rats

AIM: To study the role of gastric mucosal ascorbic acid (AA) in the progression of acute gastric mucosal lesions induced by compound 48/80 (C48/80), a mast cell degranulator, in rats. METHODS: C48/80 (0.75 mg/kg) was intraperitoneally injected to fasted Wistar rats. Oral administration of AA (10, 50 or 100 mg/kg) was performed 0.5 h after C48/80 treatment. Determinations for gastric mucosal lesion severity and blood flow, and assays for gastric mucosal total AA, reduced AA, oxidized AA, vitamin E, thiobarbituric acid reactive substances (TBARS), adherent mucus, nitrite/ nitrate (NOx), non-protein SH (NPSH), and myeloperoxidase (MPO), and serum total AA, reduced AA, oxidized AA, and NOx were conducted 0.5 and 3 h after C48/80 treatment. RESULTS: Gastric mucosal lesions occurred 0.5 h after C48/80 treatment and progressed at 3 h. Gastric mucosal blood flow decreased 0.5 h after C48/80 treatment but the decrease was recovered at 3 h. Gastric mucosal total AA, reduced AA, vitamin E, and adherent mucus concentrations decreased 3 h after C48/80 treatment. Gastric mucosal oxidized AA concentration remained unchanged after C48/80 treatment. Gastric mucosal NPSH concentration decreased 0.5 h after C48/80 treatment, but the decrease was recovered at 3 h. Gastric mucosal TBARS concentration and MPO activity increased 0.5 h after C48/80 treatment and further increased at 3 h. Serum total AA and reduced AA concentrations increased 0.5 h after C48/80 treatment and further increased at 3 h, while serum oxidized AA concentration increased at 0.5 h. Serum and gastric mucosal NOx concentrations increased 3 h after C48/80 treatment. AA administration to C48/80-treated rats at 0.5 h after the treatment prevented the gastric mucosal lesion progression and the changes in gastric mucosal total AA, reduced AA, vitamin E, adherent mucus, NOx, and TBARS concentrations and MPO activity and serum NOx concentration found at 3 h after the treatment dose-dependently. The AA administration to C48/80-treated rats caused further increases in serum total AA and reduced AA concentrations at 3 h after the treatment dose-dependently. CONCLUSION: Gastric mucosal AA plays a critical role in the progression of C48/80-induced acute gastric mucosal lesions in rats.     

Combination therapy of hydroxycarbamide with anagrelide in patients with essential thrombocythemia in the evaluation of Xagrid? efficacy and long-term safety study

Available information is limited regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid^® Efficacy and Long-term Safety study. Of 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167, 54.9%) and anagrelide (n=123, 40.5%). Median weekly doses of hydroxycarbamide and anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581×10⁹/L and 411×10⁹/L before and after starting hydroxycarbamide + anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts less than 400×10⁹/L increased from 33 (21.6%) to 74 (48.4%; P<0.0001), and with platelet counts less than 600×10⁹/L, from 82 (53.6%) to 132 (86.3%; P<0.0001). Hydroxycarbamide + anagrelide was discontinued in 158 patients: 76 (48.1%) stopped hydroxycarbamide, 59 (37.3%) stopped anagrelide, 19 (12.0%) stopped both and 4 (2.5%) had another therapy added. The most frequent reasons for discontinuation were intolerance/side-effects, lack of efficacy, and therapeutic strategy. Combination therapy, usually hydroxycarbamide + anagrelide, is used in approximately 10% of all high-risk patients with essential thrombocythemia and may be a useful approach in treating patients for whom monotherapy is unsatisfactory. (Clinicaltrials.gov identifier:{"type":"clinical-trial","attrs":{"text":"NCT00567502","term_id":"NCT00567502"}}NCT00567502)     

Growth hormone (GH) deficiency in patients with β-thalassemia major and the efficacy of recombinant GH treatment

Patients with -thalassemia major still suffer growth retardation. After excluding patients with cortisol deficiency, hypothyroidism, hypogonadism, delayed puberty, malnutrition, severe congestive heart failure, and severely impaired liver function, 29 patients were enrolled in this study. Fifteen (52%) patients exhibited growth retardation and underwent two growth hormone (GH) provocation tests. Eight (53%) of the 15 patients had GH deficiency and were subsequently treated with subcutaneous recombinant human GH (Genotropin, Pharmacia Corporation, Sweden). Growth velocity increased from the pretreatment rate of 3.1±0.4 cm/year to 7.1±1.6 cm/yr (p<0.001) after 1 year and to 6.8±1.3 cm/year (p<0.001) after 2 years. Patients with growth retardation had lower insulin like growth factor-1 (p=0.001) and insulin like growth factor binding protein-3 (p=0.003) levels than those without growth retardation. In patients with -thalassemia major, growth retardation is a common complication and GH deficiency plays an important role. Thalassemic patients with GH deficiency can safely increase their growth velocity with recombinant human GH for2 years; however, the effect on final height still needs to be determined.     

Predictors of the efficacy of interferon therapy for patients with chronic hepatitis C before and during therapy: how does this modify the treatment course?

Antiviral therapy for hepatitis C virus (HCV) infection should be based on the natural history of HCV infection; there is a sequential, but slow, progression from chronic hepatitis to cirrhosis, leading to death from either liver failure or hepatocellular carcinoma (HCC). The risk of HCC development increases in association with the advance of fibrosis, and antiviral therapy can reduce this risk. More than 30 indices have been proposed as ‘predictors’ of favourable response to IFN therapy: host factors (age, gender, duration of HCV‐infection, alcohol intake, hepatic iron stores, platelet count, histological staging of the liver disease), viral factors (HCV RNA levels in serum, HCV subtype, diversity of the hypervariable region, mutation of non‐structure 5A gene), and IFN factors (dose, duration of treatment, type, treatment regimens i.e. every day vs three times a week, escalating dose regimen). Before starting IFN therapy, HCV subtype and pretreatment HCV RNA load, as well as the fibrotic stage of the liver, should be determined. The response to IFN therapy should be monitored by the HCV RNA status in serum during therapy, and the treatment regimen modified, or discontinued as required. A sustained virological response should be checked at more than 3 months after the completion of therapy. Even though the risk of HCC is markedly reduced in sustained responders, it is possible to develop HCC several years after completion of IFN therapy.     

Effect of the misoprostol–rebamipide combination on iron deficiency anemia in patients under long-term cyclooxygenase-2 selective inhibitor treatment for small bowel ulcers

The use of cyclooxygenase-2 (COX-2) selective inhibitors has been recommended to reduce the risk of upper and lower gastrointestinal adverse events. However, it is not clear whether the long-term use of COX-2 inhibitors reduces the risk of gastrointestinal injury. We report the case of a 60-year-old woman with rheumatoid arthritis who had ongoing anemia and intermittent tarry stools after the long-term use of meloxicam, a COX-2 selective inhibitor. Although gastrointestinal injuries were suspected, the findings of gastroduodenoscopy and ileocolonoscopy were normal. However, capsule endoscopy revealed multiple circumferential ulcers with bleeding in the small bowel. With the patient requiring continued meloxicam use, misoprostol, a prostaglandin (PG) analog and rebamipide, an endothelial PG inducer and cytoprotective agents were prescribed for the ulcers. After treatment, her anemia improved promptly, but it relapsed after she stopped regular use of these drugs. However, the anemia improved again after resumption of treatment. In conclusion, the long-term use of a COX-2 selective inhibitor may induce small intestinal injuries and multiple circumferential ulcers. Combination therapy with misoprostol and rebamipide may be useful for treating COX-2 selective inhibitor-induced anemia and small intestinal injuries.     

A comparison of 48-week treatment efficacy between clevudine and entecavir in treatment-naïve patients with chronic hepatitis B

Purpose  

Clevudine and entecavir are currently available in Korea as antiviral drugs against chronic hepatitis B (CHB). We aimed to compare the efficacy of clevudine and entecavir therapy.     

The efficacy of tramadol/acetaminophen combination tablets (Ultracet?) as add-on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID)

The purpose of this study is to compare the efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (tramadol/APAP) with that of nonsteroidal anti-inflammatory drugs (NSAIDs) as maintenance therapy following tramadol/APAP and NSAID combination therapy in knee osteoarthritis (OA) pain which was inadequately controlled by NSAIDs. Subjects with knee OA for over 1 year and moderate pain (numerical rating scale [NRS] ≥5) despite at least 4 weeks’ NSAID therapy (meloxicam 7.5 mg or 15 mg qd or aceclofenac 100 mg bid) received tramadol/APAP add-on (combination with NSAID) for 4 weeks. Thereafter, subjects with significant pain improvement (NRS <4) were randomized to receive either tramadol/APAP or NSAID for 8 weeks. On days 29 and 57, Western Ontario and McMaster Universities (WOMAC) OA index score was measured. Secondary measures included pain intensity (NRS), pain relief score, and subjects’ and investigators’ overall medication assessments. Of 143 subjects enrolled, 112 completed the 4-week tramadol/APAP and NSAID combination phase and 97 (67.8%) experienced significant pain improvement. Of the 97 subjects randomized, 36 in tramadol/APAP group and 47 in NSAID group completed the 8-week comparator study. On days 29 and 57, WOMAC scores and pain intensities did not increase in both groups compared to measurements immediately after the combination therapy. At these two time points, there were no significant differences in WOMAC scores, pain intensities, and other secondary measures between the two groups. Overall adverse event rates were similar in both groups. Tramadol/APAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs. In those subjects who showed favorable response to tramadol/APAP and NSAID combination therapy, both tramadol/APAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadol/APAP and NSAIDs.     

Natalizumab: pharmacology,clinical efficacy and safety in the treatment of patients with Crohn’s disease

Natalizumab is a humanized monoclonal antibody against α4 integrin. In preclinical and clinical studies, natalizumab, which interferes with leukocyte trafficking in the intestinal tract, demonstrated effectiveness in inducing clinical response and maintaining remission in patients with moderate-to-severely active Crohn’s disease. However, during clinical trials, three natalizumab-treated patients (one Crohn’s disease patient and two multiple sclerosis patients) developed progressive multifocal leukoencephalopathy (PML). As a consequence of this unexpected serious adverse event, a retrospective safety evaluation was conducted; in that safety evaluation, no new cases of PML were identified. Natalizumab returned to the market in June 2006 for the treatment of relapsing multiple sclerosis. As of May 2007, an estimated 12,000 patients worldwide had received natalizumab, with no new confirmed cases of PML or opportunistic infections reported. Natalizumab is currently being investigated for use in treating patients with Crohn’s disease. If it is approved for treatment of Crohn’s patients, the clinical benefit of natalizumab should be weighed carefully against the potential risk of serious adverse events.     

Density of Helioobacterpylo／Ymay affect the efficacy of eradication therapy and ulcer healing in patients with active duodenal ulcers

AIM: To evaluate the association of pre-treatment Helicobacter pylori (H. pylori) density with bacterial eradication and ulcer healing rates in patients with active duodenal ulcer. METHODS: One hundred and four consecutive duodenal ulcer outpatients with H. pylori infection ascertained by gastric histopathology and (13)C-urea breath test (UBT) were enrolled in this study. H. pylori density was graded histologically according to the Sydney system (normal, mild, moderate, and marked). In each patient, lansoprazole (30 mg b.i.d.), clarithromycin (500 mg b.i.d.) and amoxicillin (1 g b.i.d.) were used for 1 week, then 30 mg lansoprazole once daily was continued for an additional 3 weeks. Follow-up endoscopy was performed at 4 weeks after completion of the therapy, and UBT was done at 4 and 8 weeks after completion of the therapy. RESULTS: The H. pylori eradication rates were 88.9 %/100.0 %, 94.3 %/100.0 %, and 69.7 %/85.2 %; and the ulcer healing rates were 88.9 %/100.0 %, 94.3 %/100.0 %, and 63.6 %/77.8 % (intention-to-treat/per protocol analysis) in the mild, moderate, and marked H. pylori density groups, respectively. The association of pretreatment H. pylori density with the eradication rate and ulcer healing rate was both statistically significant (P=0.013/0.006 and 0.002/<0.001, respectively; using results of intention-to-treat/per protocol analysis). CONCLUSION: Intragastric bacterial load may affect both the outcome of eradication treatment and ulcer healing in patients with active duodenal ulcer disease.     

A randomized, single-blind comparison of the efficacy and tolerability of hyaluronate acid and meloxicam in adult patients with Kashin–Beck disease of the knee

The aim of this study was to prospectively evaluate the efficacy and tolerability of hyaluronic acid (HA) and meloxicam for the treatment of knee pain due to Kashin-Beck disease (KBD). A total of 162 patients with KBD-based knee pain were randomly assigned to treatment with a 3-week course of HA (n = 80) and a 12-week course of meloxicam (n = 82). Clinical assessments for each patient were made at 0 (baseline), 1, 2, 4, 8, and 12 weeks. The primary efficacy measure was visual analog scale (VAS) pain score. Second efficacy measures comprised the Western Ontario and McMaster Universities (WOMAC) A (pain), B (stiffness), and C (function) scores as well as patients' and physicians' global assessments. Tolerability was evaluated based on adverse events (AEs) and physician reporting. The VAS rapidly decreased in both groups over 12 weeks. The VAS improvement observed in HA group was lower at week 1 (p = 0.001) but better at weeks 8 and 12 (p < 0.001) than the meloxicam group, which were supported by the secondary variables of WOMAC A (p = 0.001) and WOMAC C (p < 0.001) scores and the global assessments of the patients and their physicians (p = 0.020 and 0.003, respectively). No serious AEs were reported, and the overall incidence of AEs among patients treated with meloxicam was higher than in patients treated with HA (p = 0.012). This study suggests that intra-articular injection of HA and administration of oral meloxicam should be efficacious and well tolerated in the treatment of knee pain due to KBD; the onset of action of meloxicam was faster than that of HA, whereas HA therapy resulted in a more prolonged increasing improvement of symptoms than meloxicam. In addition, HA treatment was likely superior to meloxicam with respect to tolerability. Other randomized double-blind studies are needed to confirm the findings of our open-label study.     

Esomeprazole-based therapy in Helicobacter pylori eradication: any effect by increasing the dose of esomeprazole or prolonging the treatment?

AIM: To study the efficacy of esomeprazole-based triple therapy in Helicobacter pylori eradication and to evaluate, by a randomized trial, the effect of increasing the dose of esomeprazole or prolonging the treatment. METHODS: Four-hundred and fifty duodenal ulcer patients were randomized to receive: (1) esomeprazole (20 mg b.i.d.), clarithromycin (500 mg b.i.d.), and amoxicillin (1 g b.i.d.), for 7 days (E20-7d); (2) esomeprazole (40 mg b.i.d.) with the same antibiotics, also for 7 days (E40-7d); and (3) esomeprazole (40 mg b.i.d.) with the same antibiotics, for 10 days (E40-10d). Cure rates were evaluated by (13)C-urea breath test. RESULTS: One-hundred and fifty patients received each treatment. Groups were comparable in terms of demographic variables. Eight percent of the patients did not return for follow-up. Compliance (98%) and side effects (only mild to moderate) in the two groups were comparable. Per-protocol cure rates were 83.5% (E20-7d), 84.8% (E40-7d), and 88.2% (E40-10d). Intention-to-treat cure rates were, respectively, 74%, 78%, and 80% (nonstatistically significant differences). CONCLUSIONS: Esomeprazole-based triple therapies offer comparable efficacy to omeprazole-based therapies used in previous studies. Increasing the dose of esomeprazole or prolonging the treatment does not improve the results. Therefore, if esomeprazole-based triple therapy is used in duodenal ulcer patients, a regimen with only 20 mg twice daily of esomeprazole and for only 7 days may be sufficient.     

Does body mass index (BMI) influence morbidity and long-term survival in gastric cancer patients after gastrectomy?

BACKGROUND/AIMS: The long-term survival of patients with gastric cancer is governed by various factors, such as the clinical stage of the cancer, the patient's nutritional state, and the treatment and may be governed by the volume of intraperitoneal adipose tissue. The aim of this study is to clarify the relationship between the degree of the patients' body mass index and their long-term survival. METHODOLOGY: Gastric cancer patients who had undergone a gastrectomy with D2-lymphadenectomy and with resection A and B according to the criteria of the Japanese Research Society for Gastric Cancer Rules were subgrouped into those patients with a body mass index < 0.185 (the lower body mass index group) and those patients with a body mass index > 0.210 (the higher body mass index group). The patient's morbidity and long-term survival rate was retrospectively compared between the 2 groups. RESULTS: A significantly longer mean survival rate was observed for the lower body mass index group in stage 2 (1667 vs. 1322 days, P = 0.0240). Also, a significantly longer mean survival rate was observed for the higher BMI group in stage 3a (1431 vs. 943, P = 0.0071). CONCLUSIONS: The body mass index is one of the prognostic factors of stage 2 and stage 3a gastric cancer. However, it does not appear to be useful for determining the prognosis of stage 1a, 1b, 3b, and 4a gastric cancers.     

Two phenotypes of arthropathy in long-term controlled acromegaly? A comparison between patients with and without joint space narrowing (JSN)

BackgroundArthropathy is an invalidating complication of acromegaly, also in long-term controlled patients, and is radiographically characterized by osteophytes and preserved joint spaces. However, joint space narrowing (JSN) is observed in the minority of patients. It is unknown whether JSN is the end-stage of acromegalic arthropathy or whether this feature develops independently of acromegaly.ObjectiveTo gain insight into the pathophysiology of acromegalic arthropathy, and, more specifically, in the process of JSN, risk factors for radiographic JSN were studied in a cross-sectional study.MethodsWe studied hips and knees of 89 well-controlled acromegaly patients (mean age 58.3 yr, 51% female). Joints were divided into two groups based on the presence of JSN, defined as an Osteoarthritis Research Society (OARSI) score ≥ 1. Potential risk factors for JSN were assessed, and its relationship to joint complaints. Individual knees and hips were analyzed in a Generalized Estimating Equations model, adjusted for age, sex, BMI and intra-patient effect.ResultsIn controlled acromegaly, JSN was found in, respectively, 10.3% and 15.4% of the hips and knees. Increasing age and female sex were associated with more JSN; acromegaly-specific risk factors for JSN were joint-site specific. In the hip, JSN was related to more active disease: higher pre-treatment GH/IGF-1, longer and more severe GH exposure and immediate postoperative cure was less frequently achieved. In the knee, especially previous knee surgery, not acromegaly-specific characteristics, was associated with JSN. The presence of JSN was associated with more joint complaints.ConclusionsJSN is an infrequent finding in patients with acromegalic arthropathy, but it is associated with more symptoms. This study indicates that, at least in the hip, early and ongoing GH/IGF-1 activity play a role in JSN development.