Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial

BACKGROUND: Guidelines recommend inhaled corticosteroids (ICS) as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD) with a post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and frequent exacerbations, although they have only a small preventive effect on the accelerated decline in lung function. Combined treatment with ICS and long acting beta2 agonists (LABA) may provide benefit to the stability of COPD, but it is unknown if withdrawal of ICS will result in disease deterioration. METHODS: The effects of 1 year withdrawal of the ICS fluticasone propionate (FP) after a 3 month run-in treatment period with FP combined with the LABA salmeterol (S) (500 microg FP + 50 microg S twice daily; SFC) were investigated in patients with COPD in a randomised, double blind study. 497 patients were enrolled from 39 centres throughout the Netherlands; 373 were randomised and 293 completed the study. RESULTS: The drop out rate after randomisation was similar in the two groups. Withdrawal of FP resulted in a sustained decrease in FEV1: mean (SE) change from baseline -4.4 (0.9)% (S) v -0.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p<0.001). Corresponding figures for the FEV1/FVC ratio were -3.7 (0.8)% (S) v 0.0 (0.8)% (SFC) (p = 0.002). The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups, respectively (adjusted rate ratio 1.2; 95% CI 0.9 to 1.5; p = 0.15). The mean annual incidence rate of mild exacerbations was 1.3 (S) v 0.6 (SFC), p = 0.020. An immediate and sustained increase in dyspnoea score (scale 0-4; mean difference between groups 0.17 (0.04), p<0.001) and in the percentage of disturbed nights (6 (2) percentage points, p<0.001) occurred after withdrawal of fluticasone. CONCLUSIONS: Withdrawal of FP in COPD patients using SFC resulted in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights. This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration, even under treatment with a LABA.     

Drug costs developments after patent expiry of enalapril, fluoxetine and ranitidine

Background

In order to increase price competition, government regulations focus on controlling drug costs. Drug costs after patent expiry are an area of particular interest because the substitution of branded medication with generics represents an opportunity for lowering drug costs. However, drug costs may not decrease after patent expiry, because of a lack of price competition and different national pricing systems.

Aim

The aim of this study was to investigate the trends in the use of generics after patent expiry for enalapril, fluoxetine and ranitidine and the subsequent changes, if any, in the costs of these medications.

Methods

A drug-utilisation study was performed using data from a large sample of Dutch pharmacies. Both volumes (measured as defined daily doses [DDD] per 1000 population) as well as drug costs (calculated per DDD) prior to and after patent expiry were calculated. Costs per DDD were compared using trend-line analysis. In addition, the relative market shares of the different trade channels (branded, parallel imported and generic) were compared before and after patent expiry.

Results

The costs per DDD decreased for all three drugs and, as expected, these costs decrease more rapidly after patent expiry. Significant differences in the trend lines were found for enalapril and fluoxetine.

Conclusions

Despite relatively high reimbursement prices for generics in the Netherlands, this example from the Dutch pharmaceutical market demonstrates the benefit of generic substitution for containing pharmaceutical costs, which contrasts with concerns raised by the Dutch government.     

Visual hallucinations and delirium during treatment with amantadine (Symmetrel).

In 13 elderly patients, 12 of whom had Parkinson's disease, visual hallucinations and delirium developed as a side effect of amantadine hydrochloride (Symmetrel) therapy. The symptoms promptly disappearred when amantadine was discontinued. Thereafter, each parkinsonian patient was treated satisfactorily with levo-dopa. Treatment with a combination of amantadine and an anticholinergic agent increases the likelihood of delirium because of the hazard of retention of urine. Although amantadine is effective in the treatment of Parkinson's disease in the elderly, the incidence of delirium as a complication seems higher in this age group.     

Relapsing polychondritis studied by computed tomography

Computed tomographic findings in a patient with relapsing polychondritis are described. Collapse of the cartilage of the nose and calcification in cartilages of the ears were clearly demonstrated. CT scanning was also helpful in evaluating the tracheobronchial tree for airway compromise, which could prove fatal in this condition.     

Patients with isolated laryngopharyngeal reflux are not obese

OBJECTIVES: The gastroenterology literature suggests that gastroesophageal reflux disease (GERD) is often associated with obesity. The National Institutes of Health uses body mass index (BMI) to identify patients who are overweight (BMI 25-30) or obese (BMI > 30). The aim of this study was to determine whether there is a relationship between laryngopharyngeal reflux (LPR) and elevated BMI. STUDY DESIGN: The study involved a retrospective review of 500 pH-probe studies performed consecutively within the department. METHODS: Studies performed on antireflux medication or after fundoplication were excluded. From the included study reports, age, sex, height, weight, use of tobacco or alcohol, and pharyngeal and esophageal probe findings were recorded. After controlling for other factors, the relationship between LPR and BMI was determined and statistical analysis performed. RESULTS: Two hundred and eighty-five of the 500 pH studies met inclusion criteria. The overall mean BMI was 27.9 +/- 6.42. The mean BMI for patients with normal studies was 25.6 +/- 5.07, for those with isolated LPR 25.9 +/- 6.44, for those with isolated GERD 28.3 +/- 6.81, and for those with globally abnormal studies (LPR and GERD) 28.8 +/- 6.55. Abnormal pharyngeal reflux did not correlate with increasing BMI; however, abnormal esophageal reflux events correlated with increasing BMI (P = .002). The mean number of pharyngeal reflux events was not elevated in obese patients, whereas the mean number of esophageal reflux events was significantly elevated in obese (P = .02) when compared with nonobese patients. CONCLUSION: This study demonstrates that pharyngeal reflux is not associated with increasing BMI or obesity in LPR patients. In contrast, abnormal esophageal reflux (GERD) is associated with increasing BMI and obesity. Because of the LPR patient selection bias of this study, these findings may not be applicable to the GERD populations routinely seen by gastroenterologists.     

Validity and reliability of the glottal function index

OBJECTIVE: To evaluate a symptom-focused vocal impairment instrument for the evaluation of patients with voice disorders. DESIGN: Prospective, nonrandomized study of patients with voice disorders undergoing treatment with validation of a new symptom index, the Glottal Function Index (GFI). SETTING: Voice disorders clinic at an academic tertiary care hospital. PATIENTS: Consecutive patients undergoing therapy for glottal insufficiency, adductor spasmodic dysphonia, nodules, and granuloma (40 patients in each group) and 40 control patients. INTERVENTIONS: The Pearson correlation coefficient was used to evaluate GFI reproducibility and to compare it with the Voice Handicap Index (VHI). The paired-samples t test was used to compare pretherapy and posttherapy GFI values. MAIN OUTCOME MEASURES: Correlation of GFI with VHI; comparison of the GFI in normals, and in pretherapy and posttherapy GFI and VHI scores. RESULTS: The mean +/- SD normative GFI score was 0.87 +/- 1.32. The correlation coefficient for GFI between independent pretherapy measurements was 0.56 (P<.001). The correlation coefficient between total GFI and total VHI scores was 0.61 (P<.001). The mean posttherapy GFI scores improved among all groups as follows: glottal insufficiency: presenting GFI score, 12.7 +/- 4.1; posttherapy GFI score, 6.8 +/- 5.4; nodules: presenting GFI score, 12.9 +/- 4.2; posttherapy GFI score, 8.9 +/- 4.6; adductor spasmodic dysphonia: presenting GFI score, 13.2 +/- 4.1; posttherapy GFI score, 8.9 +/- 4.9; and granuloma: presenting GFI score, 7.8 +/- 4.6; posttherapy GFI score, 3.8 +/- 2.1. Relative to controls, the GFI score at presentation was significantly elevated and demonstrated significant reduction following treatment across each of these entities (P<.05). CONCLUSIONS: The GFI is a reliable, reproducible, 4-item, self-administered symptom index with excellent criterion-based and construct validity. Its advantages over existing indexes include brevity and ease of administration. The GFI is a useful adjunct in the evaluation and treatment of patients with glottal dysfunction.     

Implicit and explicit memory for spatial information in Alzheimer's disease

There is abundant evidence that memory impairment in dementia in patients with Alzheimer's disease (AD) is related to explicit, conscious forms of memory, whereas implicit, unconscious forms of memory function remain relatively intact or are less severely affected. Only a few studies have been performed on spatial memory function in AD, showing that AD patients' explicit spatial memory is impaired, possibly related to hippocampal dysfunction. However, studies on implicit spatial memory in AD are lacking. The current study set out to investigate implicit and explicit spatial memory in AD patients (n=18) using an ecologically valid computer task, in which participants had to remember the locations of various objects in common rooms. The contribution of implicit and explicit memory functions was estimated by means of the process dissociation procedure. The results show that explicit spatial memory is impaired in AD patients compared with a control group (n=21). However, no group difference was found on implicit spatial function. This indicates that spared implicit memory in AD extends to the spatial domain, while the explicit spatial memory function deteriorates. Clinically, this finding might be relevant, in that an intact implicit memory function might be helpful in overcoming problems in explicit processing.     

Elicitation of allergic asthma by immunoglobulin free light chains

The observation that only 50% of patients with adult asthma manifest atopy indicates that other inflammatory mechanisms are likely involved in producing the characteristic features of this disorder; namely reversible airway obstruction, hyperresponsiveness, and pulmonary inflammation. Our recent discovery that antigen-specific Ig free light chains (LCs) mediate hypersensitivity-like responses suggests that these molecules may be of import in the pathophysiology of asthma. Using a murine experimental model of nonatopic asthma, we now have shown that an LC antagonist, the 9-mer peptide F991, can abrogate the development of airway obstruction, hyperresponsiveness, and pulmonary inflammation. Further, passive immunization with antigen-specific LCs and subsequent airway challenge can elicit a mast cell-dependent reaction leading to acute bronchoconstriction. These findings, and the demonstration that the concentration of free kappa LCs in the sera of patients with adult asthma were significantly increased (as compared with age-matched nonasthmatic individuals), provide previously undescribed insight into the pathogenesis of asthma. In addition, the ability to inhibit pharmacologically LC-induced mast cell activation provides a therapeutic means to prevent or ameliorate the adverse bronchopulmonary manifestations of this incapacitating disorder.