Detection of karakin poisoning using a targeted mass spectrometric workflow.

Treatment and management of plant toxicosis is made more difficult when an alien plant species is ingested, as identification of the toxin may pose a challenge. High-resolution mass spectrometers are required for the toxicological analysis of samples in these cases owing to their ability to scan large mass ranges and accurately identify mass features. We present this case to highlight the value of this technology in clinical toxicology. A middle-aged woman reported visual impairment, dizziness and numbness of her mouth and tongue following the ingestion of a berry. Over time her condition deteriorated, warranting toxicological analysis. The tree the berry came from was identified as Cornynocarpus laevigatus, which is known to produce the karakin neurotoxin. The patient's samples and the husk and pulp of the berries were analysed using a high-resolution mass spectrometer. This resulted in the identification of the toxin in the berry kernel and husk and patient's hair, suggesting that karakin could have contributed to the patient's condition.

Manganese-enhanced magnetic resonance imaging depicts brain activity in models of acute and chronic pain: A new window to study experimental spontaneous pain?

Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10µg/50µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1mg/50µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats.

The association of flushing bother, impact, treatment satisfaction and discontinuation of niacin therapy.

BACKGROUND: Niacin has lipid-modifying efficacy and cardiovascular benefit, but is underutilised because of niacin-induced flushing (NIF). This real-world, prospective, observational study characterised the severity and impact of NIF symptoms among participants who were newly prescribed extended-release (ER) niacin. METHODS: Participants were surveyed daily during week 1 of therapy, at weeks 5, 9, 13, and at months 7, 10 and 13. Surveys included the Flushing Symptom Questionnaire (FSQ), which includes the Global Flushing Severity Score (GFSS) question, the Flushing Impact Questionnaire (FIQ) and the Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: Overall, 306 participants were enrolled. During week 1, 30.0% of participants reported a maximum GFSS ≥ 4 (moderate or greater). Mean FIQ domain scores increased with increasing flushing severity, primarily driven by the Irritation/Frustration domain. By week 13, only 2.5% of participants had attained a 2 g ER niacin dose. By month 13, 43.5% (n = 133) had discontinued ER niacin. At discontinuation, only 3.1% of participants had attained the 2 g dose. Over half of the participants who discontinued experienced flushing symptoms: 82% reported moderate to extreme flushing (GFSS ≥ 4), and 68% reported severe to extreme flushing (GFSS ≥ 7). Participants who discontinued and had flushing side effects reported high degrees of impact in the FIQ Irritation/Frustration domain, and high dissatisfaction as a result of side effects, as measured by the TSQM. CONCLUSION: In a real-world setting, NIF side effects were bothersome and had an impact on the continuation of therapy.

A discrete-choice experiment of United Kingdom patients' willingness to risk adverse events for improved function and pain control in osteoarthritis.

OBJECTIVE: To assess patient preferences for treatment-related benefits and risks associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of osteoarthritis (OA). DESIGN: Using a chronic-illness panel in the United Kingdom, patients 45 years or older with a self-reported diagnosis of OA were eligible to participate in the study. Patient preferences were assessed using a discrete-choice experiment that compared hypothetical treatment profiles of benefits and risks consistent with NSAID use. Benefit outcomes (ambulatory pain, resting pain, stiffness, and difficulty doing daily activities) were presented on a 0-to-100 mm scale. Risk outcomes (bleeding ulcer, stroke, and myocardial infarction [MI]) were expressed as probabilities over a fixed time period. Each patient answered 10 choice tasks comparing different treatment profiles. Preference weights were estimated using a random-parameters logit model. RESULTS: Final sample included 294 patients. Patients ranked reductions in ambulatory pain and difficulty doing daily activities (both: 6.32; 95% confidence interval [CI]: 5.0-7.6) as the most important benefit outcomes, followed by reductions in resting pain (2.80; 95% CI: 1.8-3.8) and stiffness (2.65; 95% CI: 0.9-4.4). Incremental changes (3%) in the risk of MI or stroke were assessed as the most important risk outcomes (10.00; 95% CI: 8.2-11.8; and 8.90; 95% CI: 7.3-10.5, respectively). CONCLUSION: Patients ranked ambulatory pain as a more important benefit than resting pain; likely due to its impact on ability to do daily activities. For a 25-mm reduction, patients were willing to accept four times the risk of MI in ambulatory pain vs resting pain.

Titration of synaptotagmin I expression differentially regulates release of norepinephrine and neuropeptide Y.

Synaptotagmin (syt) I is a Ca(2+) sensor that has been thought to trigger all vesicle secretion with similar mechanisms. However, given the calcium and stimulation requirements of small clear, and large dense core vesicles, we hypothesized that syt I expression differentially regulates vesicle release. Therefore, in this study, we generated multiple stable cell lines of PC12 cells that each had a different and stable level of syt I expression. We determined the functional effects of titrated syt I expression on transmitter release from the two vesicle types, and showed that the transmitters, norepinephrine (NE) and neuropeptide Y (NPY), each have a threshold level of syt I expression required for their release that is different for the two transmitter types. We used carbon fiber amperometry to measure release of NE from single vesicles, and found that release ranged from 50% to 100% in the syt I-targeted cells compared to release from control cells. We used an immunoassay to measure NPY release and found that NPY release was abolished in cells that had abolished syt I expression, but cell lines that expressed 50-60% of control levels of syt I exhibited NPY release levels comparable to release of NPY from control cells. Furthermore, the vesicle fusion pore exhibited a reduced open duration when syt I was abolished, but a longer open duration time for 50% syt I expression than control cells. Therefore, vesicles have a threshold for syt I that is required to control opening of the fusion pore, expansion, and full fusion to release large dense core proteins, but not for full fusion of the small molecules like NE.

Animal models of schizophrenia.

Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble 'positive-like' symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed.

Measuring flushing symptoms with extended-release niacin using the flushing symptom questionnaire: results from a randomised placebo-controlled clinical trial.

INTRODUCTION: Niacin is underutilised because of flushing. Lack of a quantitative tool to assess niacin-induced flushing has precluded the objective evaluation of flushing associated with extended-release (ER) niacin formulations. We developed the Flushing Symptom Questionnaire((c)) (FSQ), a quantitative tool to assess patient-reported flushing, and assessed its ability to characterise ER niacin-induced flushing. METHODS: This study focused on the responses to one question in the FSQ, the Global Flushing Severity Score (GFSS), reported on a 0-10 scale (none = 0, mild = 1-3, moderate = 4-6, severe = 7-9 and extreme = 10) to assess flushing during ER niacin initiation (week 1) and maintenance (weeks 2-8). RESULTS: Flushing severity with ER niacin was greatest during week 1 and remained greater than placebo for the study duration. During weeks 2-8, 40% of patients on ER niacin vs. 8% of those on placebo had > 1 day/week with 'moderate or greater' GFSS. CONCLUSIONS: In conclusion, the GFSS component of the FSQ was a sensitive and responsive quantitative measure of ER niacin-induced flushing that will aid in the objective comparison of novel strategies intended to improve tolerability and adherence to niacin, an agent proven to reduce cardiovascular risk.

Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function.

Traumatic brain injury (TBI) causes selective hippocampal cell death which is believed to be associated with the cognitive impairment observed in both clinical and experimental settings. The endogenous neurotrophin-4/5 (NT-4/5), a TrkB ligand, has been shown to be neuroprotective for vulnerable CA3 pyramidal neurons after experimental brain injury. In this study, infusion of recombinant NT-4/5 increased survival of CA2/3 pyramidal neurons to 71% after lateral fluid percussion brain injury in rats, compared with 55% in vehicle-treated controls. The functional outcome of this NT-4/5-mediated neuroprotection was examined using three hippocampal-dependent behavioral tests. Injury-induced impairment was evident in all three tests, but interestingly, there was no treatment-related improvement in any of these measures. Similarly, injury-induced decreased excitability in the Schaffer collaterals was not affected by NT-4/5 treatment. We propose that a deeper understanding of the factors that link neuronal survival to recovery of function will be important for future studies of potentially therapeutic agents.

In vivo and ex vivo MRI detection of localized and disseminated neural stem cell grafts in the mouse brain.

The application of stem cells as delivery vehicles opens up the opportunity for targeting therapeutic proteins to the damaged or degenerating central nervous system. Neural stem cell (NSC) lines have been shown to engraft, differentiate and correct certain central nervous system diseases. The present study was performed to test the ability of magnetic resonance imaging (MRI) in detecting transplanted NSCs under conditions of limited migration in the normal adult mouse brain versus widespread migration when the cells are transplanted neonatally. The C17.2 NSC line was labeled in vitro with superparamagnetic iron oxide (SPIO) particles and the labeled cells were implanted intracranially. Serial in vivo gradient echo MR imaging was performed using a 4.7 T horizontal bore magnet. High resolution ex vivo images of the isolated brains were performed at 9.4 T, and the presence of iron was correlated with Prussian blue staining in histological sections. Adult animals injected with SPIO-labeled stem cells exhibited hypointense regions near the injection site that were observed up to 32 days after injection. In neonatally transplanted animals, MR signal intensity from transplanted NSCs was not apparent in in vivo imaging but ex vivo MR images revealed small hypointense regions throughout the brain including the olfactory bulbs, cortex and the cerebellum, reflecting the wide distribution of the engrafted cells. These regions were correlated with Prussian blue staining, which confirmed the presence of SPIO particles inside the engrafted cells. We have shown that MRI is capable of differentiating localized and widespread engraftment of C17.2 stem cells in the central nervous system.

Initiation of antihypertensive therapy among new users of cyclooxygenase-2-selective and nonselective NSAIDs.

BACKGROUND: The comparative effects of cyclooxygenase-2- (COX-2) selective inhibitors and nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure are debated. Clinicians have been concerned about the need for antihypertensive treatment following therapy with these agents. OBJECTIVE: To compare initiation of antihypertensive treatment among new users of the COX-2-selective inhibitor rofecoxib and of nonselective NSAIDs in clinical practice. METHODS: Retrospective cohort study using the MediPlus (UK) database that covers 1.8 million patients throughout the UK. Patients included were at least 50 years of age, had at least 1 prescription for either diclofenac, ibuprofen, naproxen or rofecoxib (drugs of interest, DOIs), and had no prescription for any NSAID, COX-2 inhibitor, or antihypertensive treatment during the 6 months prior to their first/index prescription date. A subset of patients, classified as chronic and persistent new users, had at least 3 prescriptions of the index prescription DOI and did not switch to another DOI during the 6-month follow-up period. Logistic regression analysis, adjusted for potential predictors, was used to assess initiation of new antihypertensive treatment. RESULTS: 18,737 suitable patients were identified (diclofenac 7,861, ibuprofen 8,423, naproxen 1,556 and rofecoxib 897). Those using rofecoxib were older and more likely to be female than those using NSAIDs. During the 6 months following the index prescription, 7.0% of all new users and 11.5% of chronic and persistent new users initiated antihypertensive treatment. After adjusting for potential predictors there were no statistically significant differences in the risk of initiating antihypertensive treatment between new or chronic and persistent new users of rofecoxib, diclofenac, ibuprofen and naproxen (p > 0.05). CONCLUSION: The results of this study did not indicate any significant differences in the initiation of antihypertensive therapy among patients who were prescribed rofecoxib and NSAIDs, even after multiple prescriptions.

Use of gastroprotective agents and discontinuations due to dyspepsia with the selective cyclooxygenase-2 inhibitor etoricoxib compared with non-selective NSAIDs.

BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) are non-selective cyclooxygenase-1 (COX-1) and COX-2 inhibitors and are associated with upper gastrointestinal (GI) dyspeptic symptoms often resulting in GI co-medication usage or treatment discontinuation. OBJECTIVE: To compare the rates of new use of gastroprotective agents and discontinuations due to dyspepsia with the COX-2 selective inhibitor etoricoxib compared with non-selective NSAIDs. RESEARCH DESIGN AND METHODS: This pre-specified combined analysis used data from nine randomized, double-blind, controlled, clinical trials with etoricoxib in patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis. The cumulative incidences of (1) new use (new prescription or increased dose) of gastroprotective agents (GPA) and (2) discontinuation due to dyspeptic symptoms were compared among patients treated with etoricoxib (60 mg, 90 mg, or 120 mg daily) vs. non-selective NSAIDs (diclofenac 50 mg. t.i.d. or naproxen 500 mg. b.i.d.). RESULTS: The overall rates/100 patient-years for new use of GPAs were 9.1 and 13.0 for etoricoxib and NSAIDs, respectively (RR = 0.75; 95% confidence interval [CI] 0.64, 0.89; p < 0.001). A benefit with etoricoxib was seen in the first 6 months when most new GPA usage occurred; after 6 months new use of GPAs was similar between etoricoxib and NSAIDs. The rates/100 patient-years of treatment discontinuation due to dyspeptic symptoms with etoricoxib and NSAIDs were 1.5 and 2.7, respectively (RR = 0.60; 95% CI 0.41, 0.87; p = 0.007). Analyses of placebo-controlled treatment periods showed significantly more new GPA use and more discontinuations due to dyspeptic symptoms with NSAIDs vs. placebo, but not with etoricoxib vs. placebo. CONCLUSION: In this combined analysis of clinical trials of patients with OA, RA, chronic low back pain, or AS, new use of gastroprotective agents was significantly lower with etoricoxib than with the comparator non-selective NSAIDs during the initial 6 months of treatment and similar thereafter. There were significantly fewer discontinuations for dyspeptic symptoms with etoricoxib than with NSAIDs over the entire follow-up period.

Heart failure in patients admitted to hospital: mortality is still high.

BACKGROUND: Two separate cohorts of consecutive patients admitted to hospital with a primary diagnosis of heart failure were studied, the first in 1986 in Rochdale, and the second in 1995 in Brighton. METHODS: We observed the clinical profile, treatment and mortality during hospital admission and reviewed their status at 6 months. There were 132 patients in the Rochdale cohort and 223 in the Brighton cohort. RESULTS: The Rochdale cohort was characterised by a lower mean age and longer hospital stay. Significant differences were also observed in co-morbidity and the use of ACE inhibitors, but hospital mortality was almost identical (25% in Rochdale and 24% in Brighton). A low systolic blood pressure, hyponatraemia, hyperkalaemia and a raised blood urea at presentation were independent adverse prognostic factors. In contrast, prior treatment with ACE inhibitors in patients with congestive cardiac failure led to a more favourable hospital outcome. Age, gender and co-morbidity did not affect mortality apart from patients with acute myocardial infarction. Follow-up of these cohorts showed that mortality of the two groups remained high at 180 days after admission (40% in Rochdale and 39% in Brighton). There were marked differences in the use of ACE inhibitors in survivors, but target doses of ACE inhibitors (enalapril 20 mg/day or equivalent) were only achieved in 31%, despite direct communication between the hospital and primary care physicians. CONCLUSIONS: Although clinical and treatment profiles differed between the two periods studied, the hospital and 6-month mortality of patients with heart failure remained high. More emphasis needs to be given to optimising ACE inhibitor use in primary care.

Materials for restoration of primary teeth: 2. Glass ionomer derivatives and compomers.

A wide variety of materials have been used for the restoration of primary teeth. Resin-modified glass ionomers and the more recently introduced viscous glass ionomers have been developed from conventional glass ionomer materials in an attempt to overcome the suboptimal properties of conventional glass ionomers. These materials would appear to have the necessary physical characteristics for restorations in load-bearing situations in primary teeth, as have the resin-based compomer materials, which now have well documented success rates in a number of studies. The first of these two articles described 'traditional' restorative materials, including amalgam and conventional glass ionomer, for the restoration of primary teeth. This paper describes materials derived from traditional glass ionomers in an attempt to overcome the suboptimal properties of conventional glass ionomers and resin-based materials such as compomer.

Cost of prescribed NSAID-related gastrointestinal adverse events in elderly patients.

AIMS: It is well established that nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal (GI) side-effects. However, the cost of health care resources spent on preventing and managing these side-effects is not clear. The objective of this study was to estimate the direct cost of NSAID-related GI events in an elderly population. METHODS: From the Régie de l'assurance-maladie du Québec (RAMQ) database, we obtained medical, pharmaceutical and demographic records of a 10% random sample (n = 49 033) of seniors who, between January 1, 1993 and December 31, 1997, had a dispensed prescription of a NSAID. Patients who did not have any GI events during the year prior to their first dispensed prescription were included in the cohort. All patients were followed-up for 2 years. The daily direct Canadian dollar costs of GI events that were incurred by these patients while they were on NSAID therapy were compared with those of GI events that were incurred by these same patients while they were not on NSAID therapy. The difference in these daily costs was attributed to NSAIDs. RESULTS: A total of 12 082 new NSAID users were included in the study. Two hundred and seventeen (1.8%) were hospitalized for GI-related problems; of these, 130 (60%) had their GI hospitalization as their first GI event; 3257 (27.0%) used gastroprotective agents (GPAs), and 857 (26.3%) took GPAs without any apparent prior GI symptoms; 801 (6.6%) had GI diagnostic tests; and 661 (5.5%) died. The average direct costs of GI side-effects per patient-day on NSAIDs were 3.5 times higher than those of a patient-day not on NSAIDs. The direct cost of GI side-effects per patient-day on NSAIDs was $1.34, of which more than 70% ($0.94) was attributed to GI events resulting from NSAID treatment. CONCLUSIONS: Approximately one Canadian dollar was added to patient costs for every day he/she was on NSAID therapy. Safer therapies and appropriate patient risk management may potentially reduce NSAID-related health care resource use.

Economic evaluation of rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs for the treatment of osteoarthritis.

BACKGROUND: Results of phase III clinical trials of rofecoxib, a selective inhibitor of cyclooxygenase 2, have shown that osteoarthritis patients treated with rofecoxib had significantly fewer clinically significant gastrointestinal (GI) adverse events than those who received nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: This paper explores the potential economic implications of the use of rofecoxib versus nonselective NSAIDs for the treatment of osteoarthritis via a decision analytic model based on rofecoxib clinical data and the published literature. METHODS: Base-case 1-year analyses were done with data on GI adverse events, specifically perforations, ulcers, and bleeds (PUBs), obtained from a prespecified pooled analysis of the rofecoxib clinical trials. Analyses were also performed using pooled results of two 12-week endoscopic surveillance trials, with adjustments for silent ulcers of 40% and 85%. RESULTS: Under base-case conditions, the expected cost savings in GI problems and comedications averted with rofecoxib versus NSAIDs was 0.81 dollars per day, representing an 85% offset of the difference in drug price. For rofecoxib versus NSAIDs, the expected cost per PUB avoided with rofecoxib was 4738 dollars, and expected cost per year of life saved was 18,614 dollars. In analyses based on endoscopic data, therapy with rofecoxib was less expensive than therapy with NSAIDs, regardless of silent ulcer adjustment. Results were most sensitive to prophylactic GI comedication rates, and were robust over a range of model assumptions and costs. CONCLUSIONS: In this analysis based on differences in clinically significant GI events for osteoarthritis patients, cost differences between rofecoxib and NSAIDs were markedly offset by expected cost savings in GI problems and comedications averted with rofecoxib. Costs per year of life saved with rofecoxib versus NSAIDs were well within accepted benchmarks for cost-effectiveness. When endoscopic data alone were considered, rofecoxib was cost saving across all assumptions about silent ulcer rates.

Effect of rofecoxib therapy on measures of health-related quality of life in patients with osteoarthritis.

BACKGROUND: Bodily pain and physical disability can negatively impact health-related quality of life (HRQL) in patients with osteoarthritis (OA). OBJECTIVE: To assess the effects of treatment with a new agent, rofecoxib, on HRQL in patients with OA. STUDY DESIGN: Randomized, double-blind, 6-week clinical trial comparing treatment with rofecoxib, 5 to 50 mg, with placebo in 672 patients with OA of the hip or knee. MAIN OUTCOME MEASURE: Patient HRQL was assessed at baseline and at the end of treatment using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: At 6 weeks, mean change from baseline in all SF-36 mental and physical health domain scores demonstrated significant improvement with rofecoxib use (P < .05 for all doses for all SF-36 domains), with evidence of a dose-response relation. Improvements in mental and physical HRQL domains with rofecoxib treatment were significantly greater than those with placebo treatment (P < .05 for each dose of rofecoxib vs placebo for all domains except general health) and highly correlated with improvements observed using disease-specific OA outcome measures such as the Western Ontario and McMaster Universities Osteoarthritis Index-visual Analog 3.0 OA index pain and physical function subscales. The effect of rofecoxib vs placebo treatment on mental health largely disappeared after adjustment for improvement in OA disease-specific measures. CONCLUSIONS: Rofecoxib treatment increased physical and mental HRQL domain scores on the SF-36. Improvements in mental health with rofecoxib use primarily resulted from effective treatment of OA (i.e., reduction in pain and improvement in physical function).

Gastrointestinal-related healthcare resource usage associated with a fixed combination of diclofenac and misoprostol versus other NSAIDs.

OBJECTIVE: To compare gastrointestinal (GI) healthcare resource use (HCRU) and associated costs in patients taking a fixed combination of diclofenac and misoprostol versus other nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We analysed a sample (49,033 patients) of the Government of Quebec Health Insurance Agency database. Patients were included in the study if they did not have GI events during the year preceding the date of their first NSAID prescription dispensing (the index date). Patients were followed up for 2 years. A 3-stage model was used to determine the factors that influenced the direct medical costs of GI HCRU: (i) a logistic regression model (model 1) to estimate the risk of GI HCRU; (ii) a linear regression model (model 2) to estimate the direct costs of GI HCRU for those who had such events; (iii) multiplying the estimated risks from model 1 by the estimated costs from model 2 gave the estimated direct costs of GI HCRU for all patients. STUDY PERSPECTIVE: Provincial government of Quebec, Canada. RESULTS: 1,533 patients were prescribed diclofenac/misoprostol at the index date and 10,540 another NSAID. Comorbidity markers were not significantly different between the 2 groups. Of the diclofenac/misoprostol patients, 23 (1.5%) were hospitalised for GI problems compared with 194 (1.8%) of the NSAID group; 403 (26.3%) of diclofenac/misoprostol patients used gastroprotective agents compared with 2,849 (27.0%) of the NSAID patients; 118 (7.7%) of diclofenac/misoprostol patients had GI diagnostic tests compared with 682 (6.5%) of the NSAID patients. The average direct medical cost of GI HCRU was 310.52 Canadian dollars ($Can)/patient (1997 values) in the diclofenac/misoprostol group compared with $Can231.19/patient (1997 values) in the NSAID group. When adjusted for baseline factors, the ratio of the total direct medical cost of GI HCRU in the diclofenac/misoprostol group to that of the NSAID group was 1.15 (95% confidence interval: 0.89, 1.48). CONCLUSIONS: Our data showed no significant differences in GI HCRU among patients taking diclofenac/misoprostol compared with those taking NSAIDs.

Gastrointestinal medications and procedures in osteoarthritis patients treated with rofecoxib compared with nonselective NSAIDs.

CONTEXT: Patients treated with nonselective cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) often experience dyspepsia and upper gastrointestinal (GI) adverse effects, and frequently require GI comedications and diagnostic procedures. OBJECTIVE: This study combined existing data to test the hypothesis that GI comedications and GI diagnostic procedures occur less frequently in osteoarthritis (OA) patients treated with rofecoxib compared with nonselective NSAIDs. DESIGN: Combined analysis of 8 randomized controlled clinical trials. SETTING: Rheumatology and general practice clinics. PATIENTS: Men and women aged 40 years and older with OA. INTERVENTIONS: Random assignment to placebo (n = 514), rofecoxib (n = 3357; 12.5, 25, or 50 mg daily combined; average 24.7 mg), or NSAIDs (n = 1564; ibuprofen 800 mg thrice daily, diclofenac 50 mg thrice daily, or nabumetone 1500 mg daily, combined). MAIN OUTCOME MEASURES: The cumulative incidence of patients using GI comedications (antacids, antispasmodics, antiflatulents, antiregurgitants, H2 antagonists, proton pump inhibitors, sucralfate, prostaglandins, other antiulcer therapy) and needing GI procedures (upper GI barium studies, upper or lower GI endoscopies) over 12 months. RESULTS: Compared with those treated with NSAIDs, patients treated with rofecoxib had a significantly lower incidence of GI comedication use (17.5% vs 27.0%, P <.001) and GI procedures (3.3% vs 5.3%, P =.02) over 12 months. Similar results were seen in analyses of protocols with placebo; in these studies, rates of GI comedications and procedures were highest with NSAIDs, while those with rofecoxib and placebo were similar to each other. CONCLUSIONS: OA patients treated with rofecoxib for up to 12 months required significantly less GI comedication and significantly fewer GI procedures than those treated with NSAIDs.

Materials for restoration of primary teeth: I. Conventional materials and early glass ionomers.

This paper demonstrates how the treatment of primary dentition may present the clinician with increased difficulties compared with the preparation and placement of restorations in adult dentition. Established dental materials (dental amalgam and conventional glass ionomer cements) and less well established alternative materials (copper cements) are reviewed. The use of amalgam to restore primary dentition is the subject of concern amongst the dental profession in terms of lack of adhesion and potential toxicity concerns, while the low tensile strength of traditional glass ionomer cements make them less suitable for the restoration of primary dentition.

Use of nonsteroidal anti-inflammatory drugs and gastroprotective agents before the advent of cyclooxygenase-2-selective inhibitors: analysis of a large United States claims database.

BACKGROUND: Previous studies have shown that 20% to 40% of patients requiring nonsteroidal anti-inflammatory drugs (NSAIDs) are concomitantly prescribed gastroprotective agents (GPAs) such as proton pump inhibitors (PPIs) and H2-receptor antagonists. OBJECTIVE: The purpose of this study was to examine NSAID prescription patterns and the concurrent use of GPAs in a large national sample of patients who were prescribed NSAIDs for the first time. METHODS: Patterns of NSAID use, particularly chronic NSAID use, and of concomitant use of GPAs were examined using a large US-based prescription database. Patients with at least 1 NSAID prescription dispensed between May 1 and August 31, 1998, were identified. Persons with any NSAID prescription within 4 months prior to the first (index) prescription were excluded. The remaining patients were defined as new NSAID users and then classified as chronic users (> or = 30 days of supply of NSAIDs during the 120 days of follow-up after the first NSAID prescription) or acute users (<30 days of NSAID supply during the 120 days of follow-up). Concomitant GPA use was defined as receipt of any GPA prescription between the fill date of NSAID prescription and 125% of days of supply. NSAIDs included diclofenac/misoprostol (in a fixed combination), diclofenac, naproxen, nabumetone, ibuprofen, and "other" (comprising several less frequently prescribed agents). Patients were classified as users of a particular NSAID based on the first NSAID prescription they received. GPAs included PPIs, H2-receptor antagonists, and misoprostol. RESULTS: A total of 3,028,808 new NSAID users were identified. Chronic NSAID users (47.8% of the sample) were older than acute users. The percentage of new chronic users aged > or = 65 years for each of the NSAIDs was 41.2% for diclofenac/ misoprostol, 33.0% for nabumetone, 30.8% for diclofenac, 20.4% for naproxen, and 20.3% for ibuprofen. The percentage of women was higher among patients treated with diclofenac/misoprostol than among patients treated with all other NSAIDs (P < 0.001). During the 120 days of follow-up, the percentages of NSAID users with concomitant GPA use were 22.7% for diclofenac/misoprostol, 16.3% for diclofenac, 11.5% for naproxen, 18.0% for nabumetone, 12.3% for ibuprofen, and 14.8% for other NSAIDs. Based on days of supply, the rates of concomitant GPA use were 31.1%, 23.6%, 17.6%, 27.3%, 18.8%, and 22.5% for diclofenac/misoprostol, diclofenac, naproxen, nabumetone, ibuprofen, and other NSAID users, respectively. Among those who were taking GPAs before the NSAID index prescription date, -89% continued GPA therapy. CONCLUSIONS: Approximately 22% of the days of NSAID supply were covered by GPAs. Prior GPA use was the strongest predictor of subsequent concomitant GPA/ NSAID use. Differences in GPA use were observed among patients using different NSAIDs.