Mismatch negativity in subjects at high risk for alcoholism

BACKGROUND: Evidence from P300 studies in both alcohol-dependent and high-risk (HR) individuals suggests that the reduced P300 amplitudes that often characterize these individuals may reflect a deficit in inhibition (hyperexcitability) in the central nervous system. In this context, the mismatch negativity (MMN) was investigated in the male and female HR offspring of alcohol-dependent fathers and a mixed-sex, low-risk (LR) control group. METHODS: As subjects read popular materials, they received a random sequence of 500 binaurally presented tones of 600 Hz and 1600 Hz. The designation of the rare stimulus (n = 60 trials) and frequent stimulus (n = 440 trials) was alternated across subjects. Recordings of MMN were made from 61 electrodes; risk group comparisons were restricted to the five frontal midline electrodes: Fpz, Afz, Fz, Fcz, and Cz. The MMN was obtained by calculating the integral of the area under the curve for both the frequent and rare waveforms over an interval from 100 to 190 msec and then subtracting the former from the latter. RESULTS: The primary observation was that MMN responses in the HR group were significantly larger than those in the LR group. In addition, both LR and HR individuals manifested differential responses to the rare and frequent stimuli, and MMN responses in both groups were largest at Fcz and smallest at Fpz. DISCUSSION: The results indicate that individuals at high risk for alcoholism differ electrophysiologically from LR controls. These differences were manifested as larger magnitudes of the MMN. The findings suggest the possibility that as measured by the MMN, individuals at high risk for alcoholism may be characterized by a deficit in inhibition (excessive neural excitation). The presence of these preexisting central nervous system states may lead to ethanol use for self-medication, which then may facilitate the development of both tolerance to and dependence on ethanol.     

Screening of subjects at high risk for diabetic microangiopathies

Chronic hyperglycemia is the single most important pathogenic factor in the diabetic triad: retinopathy, glomerulopathy and neuropathy. But at equal serum glucose balance, diabetics are not equally at risk of microangiopathy. Hence the importance of timely screening of patients who should be convinced to accept the constraints and risk of perfect serum glucose balance or to whom specific therapy independent from serum glucose balance could be proposed. But at present, there is no genetic or immunologic marker allowing for the individual identification of at risk patients. Attention is thus directed towards factors which may be directly involved in the pathogenesis of diabetic microangiopathy: --Special sensitivity of vascular collagen to protein glycosylation which could be reflected in the involvement of tendon and aponeurotic collagen, --platelet abnormalities of which the exacerbating role appears to be confirmed by the significant efficacy of aspirin in the treatment of nonproliferative retinopathy in insulin-independent diabetics, --rheological abnormalities which might essentially be secondary to chronic hyperglycemia, --hormonal abnormalities, in particular hypersecretion of growth hormone and/or somatomedin C, whose role has long been suspected and could be established by therapeutic trials with new somatostatin analogues. But the most recent advances concern the study of hemodynamic factors. Irreversible organic diabetic microangiopathy is thought to be preceded by a phase of reversible functional microangiopathy, characterized by increased capillary blood flow, vascular dilatation, hyperpermeability and altered regulation of flow. Thus, diabetic glomerulopathy with decreased glomerular filtration is preceded by a phase of renal "hyperfunctioning" and irreversible proteinuria is the outcome of a progressive increase in microalbuminuria, reversible at least while the levels are not too high.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vilanterol trifenatate,a novel inhaled long-acting beta2 adrenoceptor agonist,is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD

Vilanterol (VI; GW642444M) is a novel inhaled long-acting β2-agonist with inherent 24 h activity in vitro in development as a combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. These studies were conducted to determine the safety, tolerability, pharmacodynamics and pharmacokinetics of VI in healthy subjects and subjects with mild to moderate persistent asthma and moderate to severe COPD.Single doses of VI (25–100 μg) were given once daily to subjects with asthma and COPD and repeat doses once daily for 14 days to healthy subjects. Adverse events (AEs), vital signs, ECGs, pharmacodynamic endpoints, FEV₁ and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing.VI (25–100 μg) was well tolerated. The incidence and severity of AEs were comparable to placebo. Following VI administration there were no clinically significant abnormalities in vital signs, 12-lead ECG, Holter ECG, blood glucose or potassium. There were no statistically significant effects on QTc of single and repeat VI doses up to 50 μg; some differences were seen following the 100 μg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV₁ from as early as 5 min after dosing which were maintained up to 24 h post-dose in subjects with asthma and COPD. In all subjects VI was rapidly absorbed (healthy subjects median Tmax at 5 min; asthma and COPD subjects median Tmax at 10 min) with systemic exposure increasing in an approximately dose proportional manner across the VI dose range. Marginal accumulation was seen on repeat dosing.Single doses of inhaled VI in subjects with asthma and COPD and repeat doses in healthy subjects were well tolerated with no clinically significant unwanted systemic effects. VI produced a rapid and prolonged bronchodilation over 24 h suggesting the potential for once daily administration.     

Advances in asthma and COPD management: delivering CFC-free inhaled therapy using Modulite technology

Inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) are currently used in the management of asthma and chronic obstructive pulmonary disease (COPD). Localized targeted delivery of these drugs into the lungs is achieved by means of two types of inhalation devices; pressurized metered-dose inhalers (pMDIs) and dry powder-inhalers (DPIs). For environmental reasons, the chlorofluorocarbon (CFC) propellants used in pMDIs are now being replaced by ozone friendly hydrofluoroalkanes (HFAs). These new generation HFA-based pMDIs, developed to provide effective lung deposition of the active moiety, have a favorable safety and tolerability profile. However, HFA-based re-formulation of LABAs and ICS for pMDIs presents particular technical difficulties, especially in terms of ensuring dose content uniformity. This review focuses on the technology and clinical efficacy of the HFA solution pMDIs using Modulite platform technology (Chiesi Farmaceutici S.p.A). Modulite technology allows the development of HFA solution formulations that can mimic the established CFC-based drug formulations on a microgram to microgram basis and provides formulations with novel particle size distributions that improve on existing delivery systems; by manipulation of aerosol clouds and particle size, the delivery of HFA-formulated drugs can be optimized to either achieve fine particle fractions and deposition patterns similar to established CFC-based drug formulations, thus facilitating the transition to new environment-friendly pMDIs in the clinical setting, or achieve finer drug particles able to penetrate deeper into the bronchi for targeted drug delivery as medical need may dictate. Long-term, multiple-dose clinical studies of Modulite formulations of beclomethasone dipropionate (BDP), budesonide and formoterol have been demonstrated to be therapeutically equivalent to their respective previously established CFC or DPI formulations. As a result, a number of Modulite pMDIs have either recently gained regulatory approval in several European countries, or have completed clinical trials and are in the regulatory submission phase. Availability, in pMDI form, of drugs like formoterol, ICSs, and ICS/LABA combinations, all central to the effective management of asthma and COPD, is therefore expected to impact positively in assuring the continued availability of vital treatment options to patients and physicians.     

Safety of nifedipine in subjects with bronchial asthma and COPD

This prospective study was undertaken to evaluate the safety of nifedipine, a calcium channel blocking agent, on 60 subjects with asthma, chronic obstructive pulmonary disease (COPD), angina, and normal subjects. All subjects received nifedipine, 20 mg, sublingually. Spirometry was done pre-drug administration and every 20 minutes after for two hours. Parameters measured were forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and forced expiratory flow at 25 percent to 75 percent of total volume (FEF25-75%). Subjects with asthma and COPD were also given nifedipine 20 mg three times daily, orally for two weeks, and tested biweekly during this period. All bronchodilators, beta-blockers, and long acting nitrates were withheld for five half-lives of the drug prior to test day. There was no adverse effect on the pulmonary function. We found a statistically significant improvement (p less than 0.05) in FEV1 after nifedipine. There was no tachyphylaxis at the end of two weeks. Nifedipine is safe in patients with asthma and/or chronic bronchitis.     

Efficacy of inhaled steroids (beclomethasone dipropionate) for treatment of mild to moderately severe asthma in the emergency department: a randomized clinical trial

STUDY OBJECTIVE: To examine the efficacy of an inhaled steroid, when added to a standard regimen of beta-agonist therapy, in the treatment of patients with mild to moderately severe asthma in the emergency department. METHODS: A convenience sample of adult patients with asthma (FEV1 % predicted 40% to 69%) presenting to the ED was randomly assigned in a double-blind fashion into 2 treatment groups. The first group received 2.5 mg nebulized salbutamol plus 1 mg (4 puffs) of beclomethasone dipropionate (BDP) at baseline, 30 minutes, and at 1, 2, and 4 hours, delivered by a metered-dose inhaler (MDI) attached to a spacer device (Vent-AH-aler, Glaxo). The second group was given the same salbutamol regimen plus MDI placebo through the Vent-AH-aler. The primary endpoint was improvement in FEV1 %predicted at 6 hours. RESULTS: Of 54 patients enrolled, 28 were assigned to the BDP group and 26 to the placebo group. Spirometry improved significantly in both groups over the 6 hours compared with baseline (ANOVA, P <.001). At 6 hours, the mean absolute improvement in FEV1 % predicted for BDP was 18% versus 17% for placebo (95% confidence interval for the absolute difference of 1% [-8% to 10%]). The proportion of patients in the BDP group who were hospitalized was 7% compared with 19% for patients in the placebo group (95% confidence interval for the difference of 12% [-6%, 30%]). CONCLUSION: In this group of patients with mild to moderately severe asthma, 5 mg BDP delivered by MDI during the initial 4 hours of an emergency visit was of no added benefit over standard therapy, as measured by improvement in FEV1 % predicted at 6 hours. However, a trend toward a difference in admission favoring BDP was observed. [Afilalo M, Guttman A, Colacone A, Dankoff J, Tselios C, Stern E, Wolkove N, Kreisman H: Efficacy of inhaled steroids (beclomethasone dipropionate) for treatment of mild to moderately severe asthma in the emergency department: A randomized clinical trial.     

Asthma mortality, inhaled steroids, and changing asthma therapy in Argentina (1990-1999)

BACKGROUND: The asthma managing strategy has evolved and inhaled corticosteroids (ICS) are now the cornerstone of asthma treatment. Their effect on symptoms and exacerbations are well ascertained, whereas their effects on asthma mortality are still matter of debate. This ecological study evaluated asthma mortality rates and drug sales in the decade 1990-1999 in Argentina. METHODS: Mortality (overall and adjusted for 5-34 years) was obtained from the Argentinean Epidemiological Institute, and data on the sales of antiasthma drugs were provided by the International Marketing Survey. RESULTS: There was a significant change in drug sales in the spanned period: ICS +479%, inhaled beta2 agonists +32%, theophylline -63%. The crude and adjusted mortality rates were 3.38 and 0.72 in the 1980-1989 decade, and 2.58 (P<0.05) and 0.38 (P<0.01) in the subsequent one. There was inverse correlation between inhaled corticosteroid sale and age-adjusted (5-34) asthma mortality (r=-0.84; P=0.003), and the same with global mortality rates (r=-0.81; P=0.005). A positive correlation was also seen between theophylline sales and mortality. CONCLUSION: The increased sale of ICS and possibly the decrease of theophylline use seem to be the more relevant factors associated with decreased asthma mortality in Argentina.     

Efficacy of inhaled budesonide and oral theophylline in asthmatic subjects.

The aim of present study was to evaluate clinical, functional, and anti-inflammatory effects of inhaled budesonide and oral theophylline treatments in patients with mild to moderate asthma. The study included 38 patients. After a 10-day run-in period, the patients were randomly assigned into two groups. Group 1 received inhaled budesonide (Pulmicort Turbuhaler) 800 microg/day for 4 weeks. Group 2 received oral theophylline (Talotren tablets, 200 mg twice daily) for 4 weeks. Inhaled budesonide therapy was accompanied by a significant decrease in serum interleukin (IL)-5 levels (p < 0.0005) and blood, sputum, and nasal eosinophil counts (p < 0.005). It produced a significant reduction in daytime (p < 0.01) and nighttime (p < 0.005) symptom scores and an increase in morning (p < 0.005) and evening (p < 0.05) peak expiratory flow (PEF) and forced expiratory volume in I sec (FEV1) values (p < 0.01). Theophylline therapy was associated with a significant decrease in blood (p < 0.02) and nasal (p < 0.01) eosinophil counts and serum IL-5 levels (p < 0.01). It resulted in significant improvements in daytime and nighttime symptom scores (p < 0.05), and morning PEF and FEV1 values (p < 0.05). These changes were more significant in group I than in group 2. There was no statistically significant difference between the two groups with respect to post-treatment values. Our results confirm the role of inhaled corticosteroids in the treatment of asthma and are consistent with the recommendation that theophylline exerts an anti-inflammatory effect. Further studies should be conducted to determine long-term benefits of theophylline.     

Anabolic steroids in COPD: a review and preliminary results of a randomized trial

Patients with severe chronic obstructive pulmonary disease (COPD) commonly develop weight loss, muscle wasting, and consequently poor survival. Nutritional supplementation and anabolic steroids increase lean body mass, improve muscle strength, and survival in patients enrolled in comprehensive rehabilitation programs. Whether anabolic steroids are effective outside an intensive rehabilitation program is not known. We conducted a prospective, double-blind, placebo-controlled, 16-week trial to study the benefits of anabolic steroids in patients with severe COPD who did not participate in a structured rehabilitation program. Biweekly intramuscular injections of either the drug (nandrolone decanoate) or placebo were administered. Sixteen patients with severe COPD were randomized to either placebo or nandrolone decanoate. The placebo group weighed 55.32 +/- 11.33 kg at baseline and 54.15 +/- 10.80 kg at 16 weeks; the treatment group weighed 68.80 +/- 6.58 at baseline and 67.92 +/- 6.73 at 16 weeks. Lean body mass remained unchanged, 71 +/- 6 vs. 71 +/- 7 kg in placebo group and 67 +/- 7 vs. 67 +/- 7 in treatment group, at baseline and 16 weeks respectively. The distance walked on 6 min was unchanged at baseline, 8 weeks, and 16 weeks in placebo (291.17 +/- 134.83, 282.42 +/- 115.39, 286.00 +/- 82.63 m) and treatment groups (336.13 +/- 127.59, 364.83 +/- 146.99, 327.00 +/- 173.73 m). No improvement occurred in forced expiratory volume in one second, forced vital capacity, maximal inspiratory pressure, maximal expiratory pressure, VO(2) max or 6-min walk distance or health related quality of life. Administration of anabolic steroids (nandrolone decanoate) outside a dedicated rehabilitation program did not lead to either weight gain, improvement in physiological function, or better quality of life in patients with severe COPD.     

Low-dose inhaled corticosteroids and the risk of acute myocardial infarction in COPD.

Inflammation plays a major role in the development and complications of atherosclerosis. Here, the dose-related impact of inhaled corticosteroids (ICS), used for their anti-inflammatory properties, on the risk of acute myocardial infarction (AMI) is studied in a cohort of chronic obstructive pulmonary disease (COPD) patients. Saskatchewan (Canada) health services databases were used to form a population-based cohort of 5,648 patients, > or =55 yrs, who received a first treatment for COPD between 1990 and 1997. A nested case-control analysis was conducted, where 371 cases presenting with a first AMI were matched with 1,864 controls, based on the date of cohort entry and age. A conditional logistic regression was used to estimate the effect of ICS, after adjusting for use of oral corticosteroids, severity of COPD, sex, systemic hypertension, diabetes and cardiovascular disease. ICS were used in the prior year by 42.2% of cases and 46.4% of controls. Overall, current use of ICS was not associated with a significant decrease in the risk of AMI. However, a 32% reduction in the risk of AMI was observed for doses ranging 50-200 microg x day(-1). In conclusion, very low doses of inhaled corticosteroids may be associated with a reduction in the risk of acute myocardial infarction.     

Effects of inhaled steroids on methacholine-induced bronchoconstriction and gas trapping in mild asthma.

According to a recent hypothesis, airway smooth muscle regulates airway calibre mostly at high lung volume, whereas the mucosa and adventitia dimensions dominate at low lung volumes. It was thought that if inhaled steroids decrease the thickness of airway wall in asthma, then forced vital capacity (FVC), which reflects the functional changes at low lung volume, should decrease less during induced bronchoconstriction than flow at high volume. The study was conducted in 31 mild asthmatics under control conditions and during a methacholine challenge before and after 4-weeks treatment with inhaled fluticasone dipropionate (1.5 mg daily, 16 patients) or placebo (15 patients). After fluticasone dipropionate treatment, control forced expiratory volume in one second (FEV1), and maximal flow at 50% of control FVC during forced expiration after a maximal (V'max,50) and a partial inspiration (V'p,50) significantly increased. During methacholine challenge, FVC decreased less than did FEV1 or V'max,50, and so did inspiratory vital capacity compared to V'p,50. Both the provocative dose of methacholine causing a 20% fall in FEV1 and the bronchodilator effect of deep inhalation significantly increased. The latter was assessed by means of the regression coefficient of all V'max,50 plotted against V'p,50. No significant changes in these parameters occurred after placebo. These data show that inhaled steroids remarkably blunt the occurrence of gas trapping during induced bronchoconstriction in mild bronchial asthma, possibly due to their effect on airway wall remodelling.     

Early effects of inhaled steroids on airway hyperreactivity and pulmonary function in asthma.

While inhaled steroids (IS) are increasingly recognized as having a more rapid onset of action than was once thought, little is known about the early changes in objective measures of respiratory function that follow the inhalation of repeated doses. These early effects were examined in a randomized, double-blind, placebo-controlled, crossover study of 20 children aged 10-16 years with stable mild asthma. Beclomethasone dipropionate (BDP) 2,000 mcg, fluticasone propionate (FP) 400 mcg, and placebo were given twice daily for three doses. Airway hyperreactivity (AHR) to methacholine (PC20), pulmonary function tests (PFT: FVC, FEV1, FEF25-75%), and the rate of recovery from methacholine-induced bronchospasm following administration of salbutamol were determined at 8 h (after 1 dose) and at 32 h (after three doses). At 8 h, minor improvements in AHR were demonstrated, averaging 0.32 doubling doses in PC20. At 32 h, significant improvements in AHR and PFTs were present, averaging 0.92 doubling doses in PC20, 3.96% of predicted values in FEV1, and 7.74% of predicted values in FEF25-75%. No significant changes occurred in FVC. There were no significant differences between the effects of BDP and FP. Inhaled steroids were associated with a slower response to salbutamol following methacholine challenge testing at 32 h. We conclude that IS, given in repeated high doses, result in significant improvements within 32 h in both AHR and PFTs, along with changes in response to beta2 agonists. These effects are likely to be the result of the topical activity of IS.     

Low-dose inhaled corticosteroid therapy and risk of emergency department visits for asthma

BACKGROUND: Patients who visit the emergency department (ED) because of asthma frequently have a relapse. While the use of inhaled corticosteroids has been demonstrated to improve asthma symptoms and lung function, it is not clear whether their use after discharge from the ED reduces asthma relapse rates. OBJECTIVE: To determine whether inhaled corticosteroid therapy reduces ED asthma relapse rates. METHODS: We analyzed ED visit and medication data on patients 5 to 60 years of age who were enrolled in a government-sponsored drug plan and who visited an ED because of asthma between April 1, 1997, and March 31, 1999, in Alberta, Canada (N = 1293). Using a Cox proportional hazards model, we determined the relative risk (RR) of relapse ED visits among users and nonusers of inhaled corticosteroids after discharge from the ED. We also compared the RR of relapse ED visits across different dose categories. RESULTS: Users of inhaled corticosteroids after ED discharge had 45% fewer relapse ED visits than did nonusers (adjusted RR, 0.55; 95% confidence interval [CI], 0.44-0.69). Low-, medium-, and high-dose therapies were associated with similar reductions in the risk of relapse ED visits: low-dose therapy (RR, 0.52; 95% CI, 0.39-0.68), medium-dose therapy (RR, 0.51; 95% CI, 0.34-0.76), and high-dose therapy (RR, 0.67; 95% CI, 0.47-0.94). CONCLUSIONS: Inhaled corticosteroid therapy after ED discharge is associated with a significant reduction in the risk of subsequent ED visits. Low-dose therapy appears to be as effective as high-dose therapy. However, further studies are needed to determine the optimal dosing regimen for inhaled corticosteroid therapy for asthma.     

Skin manifestations of inhaled corticosteroids in COPD patients: results from Lung Health Study II

OBJECTIVE: To define the relationship between skin bruising (as well as other cutaneous manifestations) and inhaled corticosteroid (ICS) therapy vs placebo in subjects with COPD who were participating in a clinical trial. To explore the relationship between easy skin bruising and other systemic effects of ICS therapy, including adrenal suppression and loss of bone mineral density (BMD). DESIGN: Double-blind, randomized, placebo-controlled clinical trial of triamcinolone acetonide (1200 microg daily) vs placebo in participants with mild-to-moderate COPD. SETTING: Lung Health Study II, a clinical trial to assess the effect of ICS compared to placebo in 1,116 participants in 10 centers over > 3.5 to 4.5 years. PARTICIPANTS: A total of 1,116 smokers or recent ex-smokers with mild-to-moderate COPD (age range, 40 to 69 years; mean age, 56.3 years; 37.2% female). MEASUREMENTS AND RESULTS: Every 6 months, a structured questionnaire was administered to elicit reports of any bruising and/or skin rashes, slow healing of cuts or sores, or other skin changes. Compliance with inhaler use was assessed by canister weighing. A significantly higher proportion of ICS than placebo participants who complied with using their inhaler reported easy bruising (11.2% vs 3.5%, respectively) and the slow healing of skin cuts or sores (2.4% vs 0.5%, respectively). Older men in the ICS group with good inhaler compliance appeared to be at the greatest risk of bruising. In those participants undergoing serial measurements of adrenal function and BMD, no association was noted between skin bruising and either the suppression of adrenal function or the loss of BMD as systemic complications of ICS use. CONCLUSION: These findings indicate that moderate-to-high doses of ICSs result in an increased incidence of easy bruising and impairment in skin healing in middle-aged to elderly persons with COPD. No association was noted between skin bruising and other markers of systemic toxicity from the use of ICSs.