Inhalation delivery systems with compliance and disease management capabilities

Non-compliance with prescribed medication is a major reason for poor therapeutic outcomes, leading to unnecessary contributions to healthcare costs. Poor technique in self-administration of inhalation therapy is a special type of non-compliance associated with this route of administration. However, pulmonary drug delivery has fundamental advantages for therapy of diseases of the respiratory tract because it is site-directed. The lung is also a promising portal for drug delivery into the systemic circulation. Incorporation of microprocessors into pulmonary drug delivery systems facilitates sophisticated compliance management of chronic diseases such as asthma and diabetes. Microprocessor-assisted systems afford control of patients' administration technique during the therapeutic inhalation event, thus leading to efficient and reproducible regional deposition of the inhaled drug or diagnostic agent. SmartMist is a hand-held asthma disease management device that aids patients to use optimally metered dose inhalers. It also measures pulmonary lung function and provides a long term downloadable electronic record of the therapeutic and diagnostic events. The AERx pulmonary delivery system utilizes similar microprocessor capabilities; however, it employs a novel means of generating aqueous aerosols from unit dose packages, thus providing a broad inhalation technology base for delivery of a wide variety of therapeutic and diagnostic agents into the respiratory tract, and via the lung into the systemic circulation.     

Oesophageal dysfunction in male patients with angina-like pain

The value of betamethasone valerate by inhalation in the prophylactic therapy of severe childhood asthma has been established. To determine whether the efficacy of this drug is due to a local or a systemic action a double-blind crossover study of 28 days' treatment with oral betamethasone valerate and 28 days' treatment with inhaled steroid was carried out in 10 asthmatic children. Daily doses used were 1 mg orally and 800 mug by inhalation. Nine patients had fewer symptoms, higher peak expiratory flow rates, and a lower bronchodilator requirement on inhaled than on oral therapy. Exercise-induced bronchoconstriction was diminished on inhaled therapy. Five children requested early termination of the oral therapy period because of unacceptable symptoms. Nine parents stated a preference for the period of inhaled therapy. It is concluded that betamethasone valerate is highly effective by inhalation but that a comparable oral dose has no appreciable clinical effect.     

Parental criticism and treatment outcome in adolescents hospitalized for severe, chronic asthma

This pilot study investigated the relationship between parental criticism and medical treatment outcome across an inpatient hospitalization in 19 adolescents with severe, chronic asthma. Parental criticism toward their asthmatic adolescent was assessed using the Five Minute Speech Sample technique (FMSS) at the beginning of the adolescent's inpatient stay at a national asthma referral center. Those adolescents whose parents were rated as high in criticism on the FMSS were found to have greater improvement in their overall asthma severity, greater reduction in their steroid medication dose, and shorter lengths of stay in the hospital than those whose parents were rated as low in criticism. The adolescents whose parents were rated as high in criticism also showed lower compliance with their prescribed theophylline and oral steroid medication at admission than the low criticism group. These findings do not appear to be due to misdiagnosis secondary to the presence of vocal cord dysfunction or to the allergy status of the children. Clinical implications and possible causal mechanisms underlying these findings are discussed.     

Education of parents of infants and very young children with asthma: a developmental evaluation of the Wee Wheezers program

A randomized control trial of the Wee Wheezers asthma education program was conducted with 76 children < 7 years of age, 31% of whom were on a medication regimen consistent with mild, 51% with moderate, and 18% with moderately severe/severe asthma. Treatment children showed improved morbidity at 3-month follow-up relative to the changes in the controls: increased symptom-free days in the preceding 2 weeks (mean change of +2.2 vs. -2.6 in the controls; p = .004) and month (+2.0 vs. -3.8; p < .02), fewer nights of parental sleep interruption in a typical week (+0.7 vs. +1.8; p < or = .05), and a trend toward fewer asthma sick days (-0.2 vs +0.7; p = ns). These improvements were accompanied by significantly better parental asthma management compared with controls (more consistent use of preventive medications, p < or = .01; early symptom intervention, [corrected] p < or = .05) and trends toward more restrictions on smoking in the home (p < .07) and decreased parental confusion about asthma treatment (p < .11). This study provides evidence that a multisession program of asthma education for parents can improve parental asthma management and clinical outcomes in very young children and provides information on the validity and sensitivity of various asthma outcome measures in this age group.     

The Scandinavian laboratory--a goldmine for public health research

The incidence of asthma appears to have doubled since the 1970s. 15% of children in the UK are now estimated to have the condition. Children's asthma needs to be taken seriously by parents, health professionals and teachers. Its severity varies and it is a potentially life-threatening condition. The reason why children develop asthma is not known. Theories include a family tendency to asthma and allergy, house-dust mite and parental smoking. There is no clear evidence of a link between asthma and traffic fumes and air pollution. The vast majority of people with asthma take inhaled steroids, and these produce little or no side-effects. Tablet forms of the drug also have few side-effects if used for short courses of a few days. Only a minority need to take steroid tablets regularly, and need to discuss the issue of side-effects versus improvements in symptoms with their doctor. Most children use a preventer and a reliever medication. It is important that parents and child understand how and when to use each. Research suggests that two-thirds of children may grow out of their asthma symptoms, though asthma that is triggered by an allergic response may recur in later life. The prognosis for pre-school children is good.     

Fluid-bed microencapsulation of ascorbic acid

Epidemiological studies suggest the prevalence of asthma is increasing, though some remain sceptical as to the magnitude or indeed the presence of an increase. However, despite improved diagnosis and the availability of the potent drugs now available there remains considerable respiratory morbidity associated with asthma. It is clear from a number of studies that failure to deliver drugs to the lungs when using inhaler devices is a factor contributing to this high level of morbidity. Failure of drug delivery may result from the prescribing of inappropriate devices, failure to use devices appropriately or failure to comply with a treatment regimen. For most of the currently available forms of asthma therapy there are significant advantages to be gained from administering them in aerosol form. The benefits to be derived from administering these drugs as an aerosol include a rapid onset of action for drugs such as beta-agonists and a low incidence of systemic effects from drugs such as beta-agonists and corticosteroids. Over the past 25 years our understanding of the nature of asthma has changed. Though this has been reflected in the emphasis on inhaled corticosteroid therapy in recent guidelines, it has not been reflected in the range of inhaler devices available. Manufacturers continue to place drugs such as corticosteroids in the same devices as short acting beta-agonists even though the requirements for these different drug classes are very different. It is likely that this contributes to suboptimal therapeutic responses with inhaled corticosteroids. However, the variability associated with current delivery systems is relatively small compared with the variability introduced by poor compliance. There is no work currently available to indicate how the use of cheap disposable devises which do not incorporate any form of positive feedback influence compliance with inhaled steroids. Optimising aerosolised drug delivery in childhood involves consideration of the class of drugs, the particular drug within a class but more importantly, the age and abilities of the child. Devices must be selected to suit a particular child's needs and abilities. Devices utilising tidal breathing are generally used such as spacing chambers or, less commonly these days, nebulisers. A screaming or struggling child, or failure to use a closely fitting mask, reduces drug delivery to the lungs enormously. Failure to respond to inhaled therapy in early childhood may be attributable to failure of drug delivery. Drug delivery in early childhood using current devices remains more an art than a science.     

Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction

Adherence with inhaled beta-agonists and corticosteroids in 24 asthmatic children was tracked over 3 months utilizing the metered-dose inhaler chronolog (MDIC). Patients seldom took all of their medications as prescribed, and failed to take any inhaled corticosteroid doses on a median of 41.8% of days or inhaled beta-agonists on 28.1% of days despite prescribed daily use. Medication nonadherence was correlated with lower levels of asthma knowledge (Asthma Knowledge Questionnaire) and family dysfunction (Family Assessment Device), but not child behavior disorder (Child Behavior Checklist). Patients tended to dramatically over-report medication use. Improved identification of the markers of nonadherence can directly facilitate more efficient targeting of behavioral interventions, resulting in improved adherence, better illness control, and less requirement of urgent medication intervention.     

Delirium risk factors in elderly hospitalized patients

BACKGROUND: The relation of parental smoking to wheezing and asthma occurring after the first year of life was assessed by a systematic quantitative review of case-control and longitudinal studies, complementing earlier reviews of cross sectional surveys and wheezing in early childhood. METHODS: Fifty one relevant publications were identified after consideration of 1593 abstracts selected by electronic search of the Embase and Medline databases using keywords relevant to passive smoking in children. The search was completed in April 1997 and identified six studies of asthma incidence, seven of prognosis, 22 case-control studies, and 10 case series addressing disease severity. RESULTS: Maternal smoking was associated with an increased incidence of wheezing illness up to age 6 (pooled odds ratio 1.31, 95% CI 1.22 to 1.41), but less strongly thereafter (1.13, 95% CI 1.04 to 1.22). The long term prognosis of early wheezing illness was better if the mother smoked. The pooled odds ratio for asthma prevalence from 14 case-control studies was 1.37 (95% CI 1.15 to 1.64) if either parent smoked. Four studies suggest that parental smoking is more strongly associated with wheezing among non-atopic children. Indicators of disease severity including symptom scores, attack frequency, medication use, hospital attendance, and life threatening bronchospasm were in general positively related to household smoke exposure. CONCLUSIONS: The excess incidence of wheezing in smoking households appears to be largely non-atopic "wheezy bronchitis" with a relatively benign prognosis, but among children with established asthma, parental smoking is associated with more severe disease. This apparent paradox may be reconciled if environmental tobacco smoke is considered a co-factor provoking wheezing attacks, rather than a cause of the underlying asthmatic tendency.     

Common measures of asthma severity lack association for describing its clinical course

BACKGROUND AND OBJECTIVE: To address the problems of increasing asthma morbidity and mortality rates, reliable severity measures must be identified. Accordingly, we compared three measures and their relationship to beclomethasone compliance. METHODS: Three clinical measures (symptom scores, morning peak expiratory flow rates, and number of as needed albuterol inhalations with Nebulizer Chronologs [Forefront Technologies, Inc., Lakewood, Colo.]) were assessed daily in 13 adults with asthma for 8.9 +/- 2.1 weeks. The relationships among these three variables were analyzed in terms of Pearson correlation coefficients. These were evaluated for each of the three possible pairs of the three clinical measures for each of the 13 patients. The relationship between inhaled beclomethasone compliance and the pairwise correlations was studied with the use of nonparametric statistical procedures. RESULTS: In four of the 13 patients, no pairwise correlations between any of the three severity measures were observed. The peak expiratory flow rate-symptom score relationship was observed in eight patients, whereas peak expiratory flow rate-albuterol use and albuterol use-symptom score correlations were each seen in four patients. Mean beclomethasone compliance was 64% and was greatest in those patients whose albuterol use increased concurrently with symptom scores (94% vs 50%, p = 0.02). CONCLUSIONS: The commonly used measures of asthma severity, symptom scores, peak flow rate, and beta-agonist use may not be interchangeable in describing the clinical course. Patients whose beta-agonist use is driven by symptoms tend to be more compliant with use of inhaled corticosteroids.     

Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients

BACKGROUND: Misunderstanding of the role of asthma medication and fear of untoward side effects may reduce compliance to therapy, potentially resulting in poor asthma control and increased risk of severe asthma events. METHODS: We report the results of a recent Canadian survey of 603 asthmatic patients recruited from the general population, aimed at determining their perception of the role and potential side effects of inhaled corticosteroids (ICS). RESULTS: The survey revealed that a large proportion of asthmatic patients do not understand the role of their medications and have many misconceptions and fears in regard to ICS, reducing their willingness to use them. Among the most common fears are those concerning troublesome side effects, particularly in regard to corporeal image, bone density, and a reduction in efficacy of medication over time. More than half of the population said they were very or somewhat concerned using ICS on a regular basis; two thirds of patients had not discussed their concerns about ICS with their physicians or other health-care professionals. Finally, in a large number of asthma patients, asthma was not adequately controlled, according to recent asthma consensus guidelines. CONCLUSIONS: These observations stress the importance for those involved in asthma care of questioning patients about their understanding of the role of asthma medications, particularly ICS, their fears and misconceptions, and what they consider to be adequate asthma control, in order to provide appropriate education and counseling.     

Compliance and adverse drug reactions: a prospective study with ethinylestradiol using continuous compliance monitoring

This study examined the relationship between adverse reactions and patient compliance with ethinylestradiol at 40 micrograms twice daily versus 20 micrograms four times daily. In a randomized study 61 female patients with primary infertility were prescribed the drug twice daily (n = 31) or four times daily (n = 30). Ethinylestradiol was administered for 7 days before the sperm cervical mucus penetration-test was performed for hormonal standardization of the cervical mucus quality. Drug compliance was measured by continuous monitoring using the Medication Event Monitoring System. Two parameters were evaluated: percentage of prescribed doses taken (administration compliance) and adherence to the prescribed dose schedule (regimen compliance, number of days with two or four dosing events recorded). Adverse drug reactions were assessed using a standardized questionnaire. Fourty-four women experienced side effects, of which 81% were rated by patients as being mild. Patient compliance was higher with the twice daily than with the four times daily regimen: 85% versus 65% prescribed doses taken (P < 0.05). There was no significant difference in compliance comparing patients with and without adverse reactions (82% versus 72%, respectively), but compliance was lower and more irregular with at least 3 versus one or two adverse reactions reported: 54% versus 84% in administration compliance and 31% versus 58% in regimen compliance (P < 0.05). Compliance was also lower in patients with nausea and vomiting than in those without these symptoms, 59% versus 91% and 34% versus 66% (P < 0.005), respectively, and lower with moderate or severe compared to mild side effects; 48% versus 85% and 25% versus 59% (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder

OBJECTIVES: To determine whether readmission to hospital for children aged 1-7 years with asthma can be predicted; and to discover whether factors related to the severity of the attack and past pattern of asthma, assessment of the parents' intention to treat the child with inhaled therapy, perceived consequences of treatment, habits of treatment and self-efficacy show a difference between those children subsequently readmitted and those who were not. METHODS: A specifically developed questionnaire was administered to parents of 121 children admitted with asthma. Clinical assessment was made of severity of the acute attack and past pattern of the asthma. One year after admission subjects were reviewed to determine those who had been readmitted. RESULTS: On univariate analysis, the negative perceived consequences of treatment with inhaled therapy were associated with an increased risk of readmission over a one-year period (P = 0.04). After adjusting for confounders (place of birth of mother, two- or one-parent family) and the effect-modifier of past pattern of the asthma (infrequent episodic, frequent episodic, persistent), the greater the negative perceived consequences of treatment, the more likely there would be readmission in children with infrequent episodic asthma. After adjusting for potential confounders, using logistic regression a decrease of one standard deviation in the negative perceived consequences score resulted in a one-third decrease in the odds of readmission (odds ratio (OR) = 0.31, 95% CI 0.12-0.83). CONCLUSIONS: Parents whose children are readmitted see greater negative perceived consequences of treatment. If asthma is infrequent episodic, the negative perceived consequences may be an inhibitor of treatment, whereas for more severe past patterns of asthma the severity is the controller of treatment. If parental negative consequences could be decreased, admissions for asthma may decrease.     

Studies on the stereoselective internal acyl migration of ketoprofen glucuronides using 13C labeling and nuclear magnetic resonance spectroscopy

BACKGROUND: To improve asthma disease management, the National Asthma Education Program (NAEP) Expert Panel published Guidelines for the Diagnosis and Management of Asthma in 1991. OBJECTIVES: To compare the current status of asthma disease management among patients in a large health maintenance organization with the NAEP guidelines and to identify the factors that may be associated with medical care (eg, emergency department visits and hospital admissions) and adherence to the guidelines. METHODS: Analyses of 1996 survey data from 5580 members with asthma (age range, 14 to 65 years) covered by a major health maintenance organization in California (Health Net). RESULTS: In general, adherence to NAEP guidelines was poor. Seventy-two percent of respondents with severe asthma reported having a steroid inhaler, and of those, only 54% used it daily. Only 26% of respondents reported having a peak flowmeter, and of those, only 16% used it daily. Age (older), duration of asthma (longer), increasing current severity of disease, and treatment by an asthma specialist correlated with daily use of inhaled steroids. Ethnicity (African American and Hispanic) correlated negatively with inhaled steroid use but positively with emergency department visits and hospital admissions for asthma. Increasing age and treatment by an asthma specialist were also identified as common factors significantly related to the daily use of a peak flowmeter and, interestingly, to overuse of beta2-agonist metered-dose inhalers. CONCLUSIONS: Although the NAEP guidelines were published 7 years ago, compliance with the guidelines was low. It was especially poor for use of preventive medication and routine peak-flow measurement. Furthermore, the results showed that asthma specialists provided more thorough care than did primary care physicians in treating patients with asthma. Combining the results of the regression analyses revealed that some of the variation in rates of emergency department visits and hospitalizations among some subpopulations can be explained by the underuse of preventive medication. This study serves the goal of documenting the quality of care and services currently provided to patients with asthma through a large health maintenance organization and provides baseline information that can be used to design and assess effective population-based asthma disease management intervention programs.     

Asthma treatment during pregnancy. What can be safely taken?

'Safe' pharmacological therapy for gestational asthma is defined as therapy during which the apparent risks of the drug appear to be lower than the maternal and potential fetal risks of uncontrolled asthma that could result if the drug were not used. Major malformations occur in 2 to 4% of all newborns, 1% of which can be attributed to medication in general. Information regarding the effects of drugs administered during pregnancy may come from animal studies, human case reports, and prospective cohort studies. Based on a review of the available information, it is recommended that mild asthma during pregnancy be managed with inhaled beta 2-agonists, as required; step therapy for moderate asthma would include inhaled sodium cromoglycate (cromolyn sodium), inhaled beclomethasone dipropionate and oral theophylline. Severe gestational asthma should be treated with oral corticosteroids at the lowest effective dosage. The pharmacological management of acute asthma during pregnancy should include nebulised beta 2-agonists and ipratropium bromide, and intravenous methylprednisolone. Intravenous aminophylline would not generally be recommended, unless the patient requires hospitalisation. Optimal medical practice medico-legal considerations demand that the patient's informed consent be obtained for that recommended gestational management programme.     

Accuracy of asthma treatment in schoolchildren in NSW, Australia

Insufficient use of anti-inflammatory drugs, such as inhaled corticosteroids and cromoglycate, may contribute to the disease burden associated with asthma. Conversely, aggressive treatment of mild disease may result in avoidable costs and/or adverse drug effects. The aim of this study was to determine the relationship between asthma severity and inhaled corticosteroid/cromoglycate use in a large (n=4,909) random sample of children, aged 8-11 yrs, in NSW, Australia. Asthma and its treatment were assessed by questionnaire responses. Asthma, defined as diagnosis plus current wheeze, was present in 901 children (18% of the sample), of whom 225 (5%) had moderate asthma, defined as asthma plus additional symptoms (sleep disturbance), utilization (hospital, casualty), or disability (reduced activity, school absence). Use of inhaled corticosteroid/cromoglycate was reported by 636 children (13% of the sample). Determinants of use included: asthma diagnosis, current wheeze, and troublesome dry nocturnal cough. There was also a strong relationship between anti-inflammatory treatment and a multicomponent asthma severity score constructed for each child. Inhaled corticosteroids and/or cromoglycate were used by 56% of the children with asthma (24% daily) and by 76% of children with moderate asthma (42% daily). Undertreatment, defined as less than daily inhaled corticosteroids/cromoglycate in moderate asthma, was identified in 130 children (14% of those with asthma or 3% of the sample). Conversely, apparently aggressive treatment, defined as inhaled corticosteroid/cromoglycate use in children with persistent minimal symptoms (asthma severity score of less than 3) was identified in 101 children (2% of the sample). Although there were significant differences between regions in the choice of anti-inflammatory drugs and in the prevalence both of undertreatment and apparently aggressive treatment, there was no clear relationship to regional utilization of emergency and hospital services for asthma. Nevertheless, the frequency of undertreatment suggests an opportunity to reduce asthma morbidity by more consistent application of current therapeutic guidelines.