Vivian W. Y. Lee

Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial

BACKGROUND Guidelines on pain management recommend that patients at risk of ulcers receive either a cyclo-oxygenase (COX 2) inhibitor or a non-steroidal anti-inflammatory drug (NSAID) with a proton-pump inhibitor (PPI). These two treatments have similar effectiveness, but they are insufficient for protection of patients at very high risk for ulcer bleeding. We aimed to test the hypothesis that in patients with previous ulcer bleeding induced by non-selective NSAIDs, combined treatment with the COX 2 inhibitor celecoxib and the PPI esomeprazole would be better than celecoxib alone for prevention of recurrent ulcer bleeding. METHODS 441 consecutively presenting patients who were taking non-selective NSAIDs for arthritis were recruited to our single-centre, prospective, randomised, double-blind trial after admission to hospital with upper-gastrointestinal bleeding. Patients were enrolled after their ulcers had healed and a histological test for Helicobacter pylori was negative. All patients were given 200 mg celecoxib twice daily. 137 patients were randomly assigned to receive 20 mg esomeprazole twice daily (combined-treatment group), and 136 to receive a placebo (control group) for 12 months. The primary endpoint was recurrent ulcer bleeding during treatment or within 1 month of the end of treatment. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00365313. FINDINGS Combination treatment was more effective than celecoxib alone for prevention of ulcer bleeding in patients at high risk. The 13-month cumulative incidence of the primary endpoint was 0% in the combined-treatment group and 12 (8.9%) in the controls (95% CI difference, 4.1 to 13.7; p=0.0004). The median follow-up was 13 months (range 0.4-13.0). Discontinuation of treatment and the incidence of adverse events were similar in the two treatment groups. INTERPRETATION Patients at very high risk for recurrent ulcer bleeding who need anti-inflammatory analgesics should receive combination treatment with a COX 2 inhibitor and a PPI. Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding.

ABCG2 Polymorphism Is Associated With the Low‐Density Lipoprotein Cholesterol Response to Rosuvastatin

The ATP‐binding cassette G2 (ABCG2) c.421C>A (rs2231142) polymorphism influences the pharmacokinetics of rosuvastatin. We examined whether this polymorphism influences the low‐density lipoprotein cholesterol (LDL‐C)‐lowering efficacy of the drug. In 305 Chinese patients with hypercholesterolemia who were treated with rosuvastatin at a dosage of 10 mg daily, the c.421A variant was found to be significantly associated with greater reduction in LDL‐C level, in a gene‐dose‐dependent manner. As compared with subjects with the c.421CC genotype, those with the c.421AA genotype showed a 6.9% greater reduction in LDL‐C level, which would be equivalent to the effect obtained by doubling the dose of rosuvastatin.

Screening for Atrial Fibrillation A Report of the AF-SCREEN International Collaboration

Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.

Ziprasidone: An atypical antipsychotic drug for the treatment of schizophrenia

BACKGROUND Over the past decade, use of the atypical antipsychotic drugs clozapine, risperidone, olanzapine, and quetiapine has significantly changed the treatment of schizophrenia in the United States. The ability to make optimal drug choices will depend on determining whether there are clinically important differences between these drugs. OBJECTIVE This review describes ziprasidone, the most recently introduced antipsychotic drug. Its mechanism of action, pharmacokinetics, and adverse-effect profile are discussed, and the results of clinical efficacy trials are summarized. METHODS This review of ziprasidone is based on data from premarketing clinical efficacy and safety trials, a briefing document from the US Food and Drug Administration Psychopharmacological Drugs Advisory Committee, published studies, and abstracts presented at national and international meetings. International Pharmaceutical Abstracts and MEDLINE were searched for relevant citations, with no limitation on year. RESULTS Ziprasidone has been reported to be an effective antipsychotic drug for both positive and negative symptoms of schizophrenia, and long-term use has been effective in preventing relapse. Its 5-hydroxytryptamine (HT)1D-antagonist and 5-HT(1A)-agonist activity are consistent with a potential for antidepressant and anxiolytic activity beyond its antipsychotic effects. Ziprasidone has been associated with a low incidence of sedative effects, a low likelihood of extrapyramidal symptoms and postural hypotension, and no anticholinergic effect, although it may cause transient hyperprolactinemia. Unlike most atypical antipsychotic drugs, ziprasidone is not associated with weight gain, hyperlipidemia, or elevated plasma glucose levels. It is, however, more likely than other atypical antipsychotic drugs to increase the QTc interval (QT interval corrected for heart rate). For acute psychotic symptoms in patients with schizophrenia, schizoaffective disorder, or acute mania, ziprasidone is administered twice daily at a usual daily dose of 80 to 160 mg, whereas 40 mg/d may be an effective maintenance dose. CONCLUSIONS Differences in efficacy and tolerability between existing atypical antipsychotic drugs allow individualization of drug therapy for patients with schizophrenia or schizoaffective disorder. Ziprasidone differs from other atypical antipsychotic drugs in several clinically important ways, although further experience is necessary to clarify the significance of these differences.

Adiponectin Is Required for PPARγ-Mediated Improvement of Endothelial Function in Diabetic Mice

Rosiglitazone is a PPARγ agonist commonly used to treat diabetes. In addition to improving insulin sensitivity, rosiglitazone restores normal vascular function by a mechanism that remains poorly understood. Here we show that adiponectin is required to mediate the PPARγ effect on vascular endothelium of diabetic mice. In db/db and diet-induced obese mice, PPARγ activation by rosiglitazone restores endothelium-dependent relaxation of aortae, whereas diabetic mice lacking adiponectin or treated with an anti-adiponectin antibody do not respond. Rosiglitazone stimulates adiponectin release from fat explants, and subcutaneous fat transplantation from rosiglitazone-treated mice recapitulates vasodilatation in untreated db/db recipients. Mechanistically, adiponectin activates AMPK/eNOS and cAMP/PKA signaling pathways in aortae, which increase NO bioavailability and reduce oxidative stress. Taken together, these results demonstrate that adipocyte-derived adiponectin is required for PPARγ-mediated improvement of endothelial function in diabetes. Thus, the adipose tissue represents a promising target for treating diabetic vasculopathy.

The impact of flare on disease costs of patients with systemic lupus erythematosus

OBJECTIVE To evaluate both direct and indirect costs of systemic lupus erythematosus (SLE) patients with and without flares from a societal perspective, and to investigate the impact of the severity and clinical manifestations of flares on direct/indirect costs. METHODS A retrospective cost-of-illness study was performed on 306 SLE patients. Participants completed questionnaires on sociodemographics, employment status, and out-of-pocket expenses. Health resources consumption was recorded by chart review and patient self-reported questionnaire. The total number of flares and involved organs during the preceding 12 months were recorded. Multiple linear regression was performed to determine the cost predictors. RESULTS Patients with flares were younger, had shorter disease duration, and had higher disease activity at the time of the assessment. The overall incidence of lupus flares was 0.24 episodes per patient-year. Patients with flares used more health care resources and incurred significantly higher annual direct and indirect costs. The mean total costs per patient-year were 2-fold higher for patients with flares (

Systemic lupus erythematosus with neuropsychiatric manifestation incurs high disease costs: a cost-of-illness study in Hong Kong

22,580 versus

Levofloxacin-Resistant Helicobacter pylori in Hong Kong

10,870 [2006 US dollars]; P < 0.0005). Multiple regression analysis showed that the number of flares was an independent explanatory variable associated with increased direct costs. Patients with multiorgan flares or renal/neuropsychiatric flares incurred higher direct costs compared with those with single-organ flares or with other organ flares. CONCLUSION Patients with flares incur higher direct and indirect costs compared with those without flares. Major organ flares incur higher disease costs than other organ flares. Treatments that effectively control disease activity and prevent flares, especially major organ flares, may reduce the high costs associated with flare in SLE.

Pharmacogenetic analysis of lipid responses to rosuvastatin in Chinese patients.

OBJECTIVE To determine the direct and indirect costs of SLE in Hong Kong, and to ascertain the relationship between neuropsychiatric SLE (NPSLE) and disease costs. METHODS A retrospective, cross-sectional, non-randomized cost-of-illness study was performed in a tertiary rheumatology specialty centre in Hong Kong. Participants completed questionnaires on sociodemographics, employment status and out-of-pocket expenses. Healthcare resources consumption was recorded by chart review. The occurrence of NPSLE since onset of SLE was determined using the 1999 ACR nomenclature and standard definitions. Mann-Whitney U-test was used to compare disease costs between patients with and without NPSLE. Multiple linear regression was used to determine the predictors of the costs. RESULTS Three hundred and six Chinese patients were recruited, with a mean age of 41 years and mean disease duration of 9.6 years. A total of 108 NPSLE events were recorded by 83 patients. The most common manifestations were seizure and cardiovascular disease. The mean annual total costs were USD 13,307 per patient. The direct costs dominated the total costs, and the costs of inpatient care contributed 52% of the direct costs. Patients with NPSLE incurred significantly higher direct and indirect costs compared with those without NPSLE. The number of NPSLE events was an independent explanatory variable associated with both direct and indirect costs. CONCLUSION The economic impact of SLE in Hong Kong is considerable and patients with NPSLE incur higher disease costs compared with those without NPSLE. Improvement in prevention of end-organ damage, especially neuropsychiatric manifestation, may reduce costs of SLE patients.

Rosuvastatin improves endothelial function in db/db mice: Role of angiotensin II type 1 receptors and oxidative stress

Background: Fluoroquinolone-resistant Helicobacter pylori emerged in 1995 and the resistance was due to point mutation in the gyrA gene. In this study we investigate the resistance mechanism and the antimicrobial susceptibilities of clarithromycin, metronidazole, amoxicillin, tetracycline and telithromycin against levofloxacin-resistant H. pylori in Hong Kong. Methods: One hundred and ninety-one nonduplicate H. pylori isolates were collected during 2004 and 2005, and 25 isolates with levofloxacin zone sizes less than 30 mm were selected for minimal inhibitory concentration determination by agar dilution, gyrA gene amplication and sequencing the amplified gyrA gene. Results: The prevalence of levofloxacin-resistant H. pylori was 11.5% (22/191). Among these levofloxacin-resistant strains, 7 (31.8%) and 10 (45.5%) were resistant to clarithromycin and metronidazole, respectively, 17 (77.3%) had point mutations in gyrA gene at amino acids 87, 91 and 130 and the most frequent mutation point was at position 91. Conclusions: Amoxicillin, tetracycline and telithromycin were active against levofloxacin-resistantH. pylori and levofloxacin resistance was mainly due to point mutation in the gyrA gene, especially at amino acid position 91.