A comparison of medication adherence/persistence for asthma and chronic obstructive pulmonary disease in the United Kingdom.

AIM: To describe and compare adherence and persistence with maintenance therapies in patients with asthma or chronic obstructive pulmonary disease (COPD) in the United Kingdom (UK). METHODS: A retrospective prescribing database cohort was obtained from 44 general practitioner surgeries in National Health Service Forth Valley Scotland. Patients with physician-diagnosed asthma or COPD who received maintenance therapy between January 2008 and December 2009 were included. Five classes of therapy were assessed: inhaled corticosteroids, long-acting beta-agonists, combination therapy inhalers, theophyllines and long-acting muscarinic antagonists. Adherence was calculated using the medication possession ratio (MPR) and persistence was determined using Kaplan-Meier survival analysis for the time to discontinuation (TTD) over 1 year. Two step-wise logistic regressions were performed to assess the contribution of diagnosis to adherence/persistence. RESULTS: A total of 13,322 patients were included in the analysis: 10,521 patients with asthma and 2801 patients with COPD. 25.2% of medication episodes for asthma and 45.6% of medication episodes for COPD were classified as having an adequate medication supply (MPR of 80-120%). The overall median TTD was 92 days (IQR, interquartile range: 50-186 days) for patients with asthma and 116 days (IQR: 58-259 days, comparison p < 0.001) for patients with COPD. Patients with COPD were found to be more likely to achieve an MPR of at least 80% (OR: 1.27, 95% CI: 1.15-1.40), but had a similar likelihood of persistence at 1 year to patients with asthma. CONCLUSION: Adherence and persistence with respiratory therapies in the UK is relatively low. There is suggestion that patients with COPD may display more adherent behaviours than patients with asthma.

Atopy influences exhaled nitric oxide levels in adult asthmatics.

STUDY OBJECTIVE: To examine whether atopy influences exhaled nitric oxide (NO) levels in adults with established asthma. SETTING: Specialist respiratory unit in a university teaching hospital. PATIENTS: Twenty-eight asthmatics (mean FEV(1), 85.7%) receiving short-acting inhaled bronchodilators and a range of inhaled steroids (0 to 4,000 microg/d). INTERVENTIONS: Subjects were studied on two occasions, 5 to 7 days apart, between September and March. MEASUREMENTS AND RESULTS: On the first day, FEV(1), exhaled NO, and histamine challenge were performed. On the second day, exhaled NO, total IgE, and skin-prick testing to six common allergens were conducted. Exhaled NO was measured with the single exhalation method. We found exhaled NO levels to correlate positively with total IgE (r = 0.43, p = 0.02) and number of positive skin-prick tests (p = 0. 002). By contrast, there was no significant correlation between exhaled NO and FEV(1) or the provocative concentration causing a 20% fall in FEV(1). Subanalyses of steroid-treated and steroid-naive patients in this group revealed the same findings. CONCLUSION: Exhaled NO levels in asthmatics correlate more closely with atopy than with bronchial hyperreactivity and lung function.

The current single exhalation method of measuring exhales nitric oxide is affected by airway calibre.

The authors have observed that some patients with acute exacerbations of asthma do not have substantially higher levels of exhaled nitric oxide (NO). The study examined whether this could be explained by the effect of airway calibre on exhaled NO. Exhaled NO, height and forced expiratory volume in one second (FEV1) were measured in 12 steroid-naive asthmatics and 17 normal subjects. For comparison, another group of patients with airways disease (34 cystic fibrosis patients) were also studied. In 20 asthmatics (on various doses of inhaled steroids, 0-3,200 microg x day-1), exhaled NO was measured before and after histamine challenge (immediately after reaching the provocative concentration causing a 20% fall in FEV1) and in 12 of these patients, also after nebulized salbutamol to restore FEV1 to baseline. Studies were also conducted to examine possible confounding effects of repeated spirometry (as would occur in histamine challenge) and nebulized salbutamol alone in exhaled NO levels. Exhaled NO was measured using a single exhalation method with a chemiluminescence analyser at a constant flow rate and mouth pressure. There was a significant correlation between FEV1 and exhaled NO in steroid naive asthmatics (r=0.9, p<0.001) and cystic fibrosis patients (r=-0.48, p<0.05) but not in normal subjects (r=-0.13, p=0.61). Exhaled NO decreased significantly after histamine challenge and returned to baseline after bronchodilation by nebulized salbutamol (mean+/-SEM: 23.6+/-3.6 parts per billion (ppb) (prehistamine), 18.2+/-2.7 ppb (posthistamine) and 23.6+/-3.8 ppb (postsalbutamol) p=0.001). Repeated spirometry and nebulized salbutamol did not affect exhaled NO measurements significantly. Exhaled nitric oxide levels appear to be lower in circumstances of smaller airway diameter. Hence, within a subject nitric oxide levels may be artefactually decreased during bronchoconstriction. This may be caused by increased airflow velocity in constricted airways when the exhalation rate is kept constant.

Virulence of avian influenza A viruses for squirrel monkeys.

Ten serologically distinct avian influenza A viruses were administered to squirrel monkeys and hamsters to compare their replication and virulence with those of human influenza A virus, A/Udorn/307/72 (H3N2). In squirrel monkeys, the 10 avian influenza A viruses exhibited a spectrum of replication and virulence. The levels of virus replication and clinical response were closely correlated. Two viruses, A/Mallard/NY/6874/78 (H3N2) and A/Pintail/Alb/121/79 (H7N8), resembled the human virus in their level and duration of replication and in their virulence. At the other end of the spectrum, five avian viruses were restricted by 100- to 10,000-fold in replication in the upper and lower respiratory tract and were clearly attenuated compared with the human influenza virus. In hamsters, the 10 viruses exhibited a spectrum of replication in the nasal turbinates, ranging from viruses that replicated as efficiently as the human virus to those that were 8,000- fold restricted. Since several avian viruses were closely related serologically to human influenza viruses, studies were done to confirm the avian nature of these isolates. Each of the avian viruses plaqued efficiently at 42 degrees C, a restrictive temperature for replication of human influenza A viruses. Avian strains that had replicated either very efficiently or very poorly in squirrel monkeys still grew to high titer in the intestinal tracts of ducks, a tropism characteristic of avian, but not mammalian, influenza viruses. These observations indicate that some avian influenza A viruses grow well and cause disease in a primate host, whereas other avian viruses are very restricted in this host. These findings also provide a basis for determining the gene or genes involved in the restriction of replication that is observed with the attenuated avian viruses. Application of such information may allow the preparation of reassortant viruses derived from a virulent human influenza virus and an attenuated avian virus for possible use in a live attenuated vaccine for prevention of influenza in humans.

Characterization of the temperature sensitive phenotype of the A/Ann Arbor/6/60 cold-adapted virus and its recombinants.

The A/Ann Arbor/6/60 cold-adapted (ca) donor virus had a 38 degrees C shutoff temperature when tested in MDCK tissue culture. ca recombinant viruses bearing all six "internal genes" of the A/Ann Arbor/6/60 ca donor virus and the surface antigens of wild-type virus can manifest a 1,000-fold difference in plaquing efficiency at 38 degrees C. These observations suggest that the A/Ann Arbor/6/60 ca donor genes that specify the temperature sensitive phenotype of the ca recombinants can undergo genetic modification during the production and passage of the recombinants. The NS gene in the ca recombinant virus could be inherited from either parent without influencing the level of temperature sensitivity of the ca recombinant.

Temperature-sensitive mutants of influenza A virus. Transfer of the two ts-1A2 ts lesions present in the Udorn/72-ts-1A2 donor virus to the influenza A/Alaska/6/77 (H3N2) wild type virus.

The Udorn/72-ts-1A2 temperature-sensitive influenza A virus has a 37 degrees C shutoff temperature and a ts mutation on the genes coding for the P1 and P3 proteins. This ts donor virus was produced with the expectation that the transfer of its two ts genes would regularly and predictably attenuate each new variant of influenza A virus. It had previously been mated with the A/Victoria/75 (H3N2) virus and five Vic/75-ts-1A2 rcombinants were isolated that had both ts-1A2 ts genes and in vitro and in vivo genetic and biological properties similar to their Udorn/72-ts-1A2 parent. The present study was designed to determine if the acquisition of the two ts-1A2 ts genes would also confer a specific level of attenuation on the influenza A/Alaska/6/77 (H3N2) wild type virus. Fifteen recombinant Alaska/77-ts-1A2 viruses were isolated and characterized genetically for the number and location of ts mutations. These clones were also studied for their level of replication and genetic stability in hamsters. Four recombinants possessed both of the ts-1A2 mutations and had a 37 degrees C shutoff temperature for plaque formation. Two recombinants possessed only a ts P1 gene and had either a 38 degrees C or 39 degrees C shutoff temperature. The remaining nine clones had the ts P3 gene and a shutoff temperature of 37 degrees C, 38 degrees C or 39 degrees C. Each of the four 37 degrees C shutoff temperature recombinants that possessed both ts P1 and P3 genes were restricted at least 10,000-fold in replication in the hamster's lung and approximately 100-fold in the nasal turbinates compared to the level of replication of wild type virus in these sites. All isolates from these animals retained the ts phenotype. The level of replication in vivo of the ts P1 and P3 segregants was related to their shutoff temperature of plaque formation in vitro, e.g. the 38 degrees C ts P3 segregant was less restricted in replication in the lungs than a 37 degrees C ts P3 segregant. All isolates from animals infected with the ts P3 segregants were ts, whereas a low level of genetic instability was detected for one of the ts P1 segregants. Since ten independent ts-1A2 recombinants (one Udorn/72, 5 Victoria/75 and 4 Alaska/77) with both ts-1A2 mutations exhibited the same genetic and biologic properties, it is likely that these ts P1 and P3 genes were the prime determinants of attenuation and could effect a similar level of attenuation in other influenza A viruses within the H3N2 subtype.

Radioactive labeling of proteins with an iodinated amidination reagent.

An iodinated phenolic imidoester has been synthesized for the labeling of proteins to high specific activities with radioactive iodine. The main advantage of this two-step labeling method is that it obviates direct contact of the protein with deleterious oxidizing agents, such as chloramine-T, pressent in direct methods of iodinating proteins.