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PubMed2003

Inhaled insulin in diabetes mellitus.

BACKGROUND: Insulin therapy often relies on multiple daily injections of insulin. However this is a considerable burden to many people with diabetes and adherence to such an insulin regimen can be difficult to maintain, hence compromising optimal glycaemic control. Also, short acting injected insulin is absorbed more slowly than insulin released by the normal pancreas in response to a meal. Inhaled insulin has the potential to reduce the number of injections to perhaps one long-acting insulin per day, and provide a closer match to the natural state, by more rapid absorption from the lung. OBJECTIVES: To compare the efficacy, adverse effects and patient acceptability of inhaled versus injected insulin. SEARCH STRATEGY: A sensitive search strategy for randomised controlled or cross-over trials was combined with key terms for inhaled insulins. Databases searched were: The Cochrane Library, MEDLINE, PubMed, EMBASE, Science Citation Index, BIOSIS, Web of Science Proceedings, National Research Register UK, Current Controlled Trials, ClinicalTrials.gov, Conference Papers Index, LexisNexis, and web sites of the ADA and EASD were searched for recent meeting abstracts. Reference lists and journals were handsearched. There were no language restrictions on searching. Manufacturers of inhaled insulin were also contacted. Date of last search October 2002. SELECTION CRITERIA: Only randomised controlled trials with parallel groups or controlled cross-over trials, including type 1 or type 2 diabetic patients of any age treated with insulin, were considered eligible. The minimum trial duration considered was 10 weeks, as this is the time taken for glycated haemoglobin to reliably reflect changes in glycaemic control. DATA COLLECTION AND ANALYSIS: Trial selection and evaluation of study quality was performed independently by two reviewers. The quality of reporting of each trial was assessed according to a modification of the criteria outlined in Centre for Reviews and Dissemination (CRD) Report 4, Spitzer; and Jadad. MAIN RESULTS: Six randomised controlled trials were found and the overall number of participants was 1191. Three trials included patients with type 1 diabetes and three with type 2 diabetes. Three trials had a duration of 24 weeks, and three of 12 weeks. All were open label. There was insufficient information to determine the study quality. Results for HbA1c were similar for all trials, in that all showed comparable glycaemic control for inhaled insulin compared to an entirely subcutaneous regimen. All trials that reported patient satisfaction and quality of life showed that these were significantly greater in the inhaled insulin group. Overall there was no difference in total hypoglycaemic episodes between the groups, but one trial showed a statistically significant increase in severe hypoglycaemic episodes for the inhaled insulin group. No adverse pulmonary effects were observed in any of the studies, but longer follow-up will be required to be sure that there are no adverse side-effects. Cavets include: few studies published in full (so quality could not be assessed), and only two studies used the same basal regimen in both the inhaled and injected groups. REVIEWER'S CONCLUSIONS: Inhaled insulin taken before meals, in conjunction with an injected basal insulin, has been shown to maintain glycaemic control comparable to that of patients taking multiple daily injections. The key benefit appears to be that patient satisfaction and quality of life are significantly improved, presumably due to the reduced number of daily injections required. However, the patient satisfaction data is based on five trials, of which only two have been published in full; also the three trials containing quality of life data are all only published in abstract form at present. In addition, longer term pulmonary safety data are still needed. Also, the lower bioavailability, and hence higher doses of inhaled insulin required, may make it less cost-effective than injected insulin.

Administration, Inhalation↗
PubMed2004

Inhaled insulin in diabetes mellitus.

BACKGROUND: Insulin therapy often relies on multiple daily injections of insulin. However this is a considerable burden to many people with diabetes and adherence to such an insulin regimen can be difficult to maintain, hence compromising optimal glycaemic control. Also, short acting injected insulin is absorbed more slowly than insulin released by the normal pancreas in response to a meal. Inhaled insulin has the potential to reduce the number of injections to perhaps one long-acting insulin per day, and provide a closer match to the natural state, by more rapid absorption from the lung. OBJECTIVES: To compare the efficacy, adverse effects and patient acceptability of inhaled versus injected insulin. SEARCH STRATEGY: A sensitive search strategy for randomised controlled or cross-over trials was combined with key terms for inhaled insulins. Databases searched were: The Cochrane Library, MEDLINE, PubMed, EMBASE, Science Citation Index, BIOSIS, Web of Science Proceedings, National Research Register UK, Current Controlled Trials, ClinicalTrials.gov, Conference Papers Index, LexisNexis, and web sites of the ADA and EASD were searched for recent meeting abstracts. Reference lists and journals were handsearched. There were no language restrictions on searching. Manufacturers of inhaled insulin were also contacted. Date of last search October 2002. SELECTION CRITERIA: Only randomised controlled trials with parallel groups or controlled cross-over trials, including type 1 or type 2 diabetic patients of any age treated with insulin, were considered eligible. The minimum trial duration considered was 10 weeks, as this is the time taken for glycated haemoglobin to reliably reflect changes in glycaemic control. DATA COLLECTION AND ANALYSIS: Trial selection and evaluation of study quality was performed independently by two reviewers. The quality of reporting of each trial was assessed according to a modification of the criteria outlined in Centre for Reviews and Dissemination (CRD) Report 4, Spitzer; and Jadad. MAIN RESULTS: Six randomised controlled trials were found and the overall number of participants was 1191. Three trials included patients with type 1 diabetes and three with type 2 diabetes. Three trials had a duration of 24 weeks, and three of 12 weeks. All were open label. There was insufficient information to determine the study quality. Results for HbA1c were similar for all trials, in that all showed comparable glycaemic control for inhaled insulin compared to an entirely subcutaneous regimen. All trials that reported patient satisfaction and quality of life showed that these were significantly greater in the inhaled insulin group. Overall there was no difference in total hypoglycaemic episodes between the groups, but one trial showed a statistically significant increase in severe hypoglycaemic episodes for the inhaled insulin group. No adverse pulmonary effects were observed in any of the studies, but longer follow-up will be required to be sure that there are no adverse side-effects. Cavets include: few studies published in full (so quality could not be assessed), and only two studies used the same basal regimen in both the inhaled and injected groups. REVIEWERS' CONCLUSIONS: Inhaled insulin taken before meals, in conjunction with an injected basal insulin, has been shown to maintain glycaemic control comparable to that of patients taking multiple daily injections. The key benefit appears to be that patient satisfaction and quality of life are significantly improved, presumably due to the reduced number of daily injections required. However, the patient satisfaction data is based on five trials, of which only two have been published in full; also the three trials containing quality of life data are all only published in abstract form at present. In addition, longer term pulmonary safety data are still needed. Also, the lower bioavailability, and hence higher doses of inhaled insulin required, may make it less cost-effective than injected insulin.

Administration, Inhalation↗
PubMed2005

Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma.

BACKGROUND: Long-acting inhaled beta2-adrenergic agonists are recommended as 'add-on' medication to inhaled corticosteroids in the maintenance therapy of asthmatic adults and children aged two years and above. OBJECTIVES: To quantify in asthmatic patients the safety and efficacy of the addition of long-acting beta2-agonists to inhaled corticosteroids on the incidence of asthma exacerbations, pulmonary function and other measures of asthma control. SEARCH STRATEGY: We identified randomised controlled trials (RCTs) through electronic database searches (the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE and CINAHL), bibliographies of RCTs and correspondence with manufacturers, until April 2004. SELECTION CRITERIA: RCTs were included that compared the addition of inhaled long-acting beta2-agonists to corticosteroids with inhaled corticosteroids alone for asthma therapy in children aged two years and above and in adults. DATA COLLECTION AND ANALYSIS: Studies were assessed independently by two review authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible. The primary endpoint was rate of asthma exacerbations requiring systemic corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), symptom scores, adverse events and withdrawal rates. MAIN RESULTS: Of 594 identified citations, 49 trials met the inclusion criteria: 27 full-text publications, one unpublished full-text report and 21 abstracts. Twenty-three citations (21 abstracts and two full-text publications) provided data in insufficient detail, 26 trials contributed to this systematic review. All but three trials were of high methodological quality. Most interventions (N = 26) were of four-month duration or less. Eight trials focused on children and 18 on adults, with participants generally symptomatic with moderate airway obstruction despite their current inhaled steroid regimen. If a trial had more than one intervention or control group, additional control to intervention comparisons were considered separately. Formoterol (N = 17) or salmeterol (N = 14) were most frequently added to low-dose inhaled corticosteroids (200 to 400 microg/day of beclomethasone (BDP) or equivalent). The addition of a daily long-acting beta2-agonist (LABA) reduced the risk of exacerbations requiring systemic steroids by 19% (relative risk (RR) 0.81, 95% CI 0.73 to 0.90). The number needed to treat for one extra patient to be free from exacerbation for one year was 18 (95% CI 13 to 33). The addition of LABA significantly improved FEV1 (weighted mean difference (WMD) 170 mL, 95% CI 110 to 240) using a random-effects model, increased the proportion of symptom-free days (WMD 17%, 95% CI 12 to 22, N = 6 trials) and rescue-free days (WMD 19%, 95% CI 12 to 26, N = 2 trials). The group treated with LABA plus inhaled corticosteroid showed a reduction in the use of rescue short-acting beta2-agonists (WMD -0.7 puffs/day, 95% CI -1.2 to -0.2), experienced less withdrawals due to poor asthma control (RR 0.5, 95% CI 0.4 to 0.7) and less withdrawals due to any reason (RR 0.9, 95% CI 0.8 to 0.98), using a random-effects model. There was no group difference in risk of overall adverse effects (RR 0.98, 95% CI 0.92 to 1.05), withdrawals due to adverse health events (RR 1.29, 95% CI 0.96 to 1.75) or specific adverse health events. AUTHORS' CONCLUSIONS: In patients who are symptomatic on low to high doses of inhaled corticosteroids, the addition of a long-acting beta2-agonist reduces the rate of exacerbations requiring systemic steroids, improves lung function, symptoms and use of rescue short-acting beta2-agonists. The similar number of serious adverse events and withdrawal rates in both groups provides some indirect evidence of the safety of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids.

Administration, Inhalation↗
PubMed1994

Acute and subchronic inhalation toxicity of tetraethoxysilane (TEOS) in mice.

To clarify the acute and subchronic inhalation toxicity of tetraethoxysilane [TEOS, Si(OC2H5)4], groups of ten male ICR mice (SPF grade) were exposed to 1000 ppm TEOS for 1,2,4 or 8 h (acute inhalation study), or to 200 ppm of TEOS for 6 h/day, 5 days/week, for 2 or 4 weeks (subchronic inhalation study). The numbers of mice that died during 2 weeks of observation were 0, 1, 1 and 6 in the 1-, 2-, 4- and 8-h inhalation experiments and zero in the subchronic inhalation study. In the acute inhalation study, body weight decreased after TEOS exposure and did not reach the level of control mice during 2 weeks of observation except in the 1-h inhalation study. In the subchronic exposure study, weight gain was suppressed during the exposure period. Body weight in mice exposed for 2 weeks reached the level of non-exposed mice during the 2-week observation period, but did not do so in mice exposed for 4 weeks. Acute tubular necrosis (ATN) and acute splenic atrophy (ASA) were observed in all dead mice in the acute inhalation study, and tubulointerstitial nephritis (TIN) was frequently found in the surviving mice in both the acute and subchronic studies. However, blood biochemical examinations revealed no evidence of renal dysfunction. The olfactory epithelium was necrotic in all dead mice. In the subchronic inhalation study, infiltration of polymorphonuclear neutrophils in the nasal mucosa was observed in all mice killed 1 day after exposure. These results indicate that the LCL0 for 1-h exposure to TEOS and LC50 for 4-h exposure are greater than 1000 ppm, and that the kidney and nasal mucosa are the target organs for TEOS inhalation.

Administration, Inhalation↗
PubMed1995

Regional deposition of inhaled 11C-nicotine vapor in the human airway as visualized by positron emission tomography.

The deposition of 11C-nicotine in the respiratory tract from a nicotine vapor inhaler was studied by means of positron emission tomography (PET) in an intrasubject comparison of six healthy smokers using two modes of inhalation: one with shallow, frequent inhalations ("buccal mode") and one with deep inhalations ("pulmonary mode"). An average of 15% of the radioactivity was released from the vapor inhaler after 5 minutes of inhalation. Approximately 45% of the dose released was found in the oral cavity. A significant amount of radioactivity, 10%, was observed in the esophagus, suggesting transfer of a major fraction of the dose to the stomach. Only a minor fraction, 5%, was found in the lungs, followed by 2% in the bronchi and 1% in the trachea. The deposition in the oral cavity closely followed a linear pattern during the 5 minutes of inhalation and was followed by a rapid elimination from the oral cavity, with an average half-life of 18 minutes. Only 8% of the dose released remained in the oral cavity 45 minutes after the end of inhalation. On the other hand, the dose fraction of about 14% distributed into the body tissue compartment at the end of inhalation had risen to 60% at that late time point. No statistically or clinically important differences were observed between the buccal and the pulmonary mode of inhalation in either deposition pattern or elimination rates.

Administration, Inhalation↗
PubMed1989

The uptake and elimination of 1,1,1-trichloroethane during and following inhalation exposures in rats.

The pharmacokinetics of 1,1,1-trichloroethane (TRI) was studied in male Sprague-Dawley rats in order to characterize and quantify TRI uptake and elimination oby direct measurements of the inhaled and exhaled compound. Fifty or 500 ppm TRI was inhaled for 2 hr through a one-way breathing valve by unanesthetized rats of 325-375 g. Repetitive samples of the separate inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently both during and following TRI inhalation and analyzed for TRI by gas chromatography. Respiratory rates and volumes were continuously monitored during and following exposure and were used in conjunction with the pharmacokinetic data to characterize profiles of uptake and elimination. TRI was very rapidly absorbed from the lung, in that substantial levels were present in arterial blood at the first sampling time (i.e., 2 min). Blood and exhaled breath concentrations of TRI increased rapidly after the initiation of exposure, approaching but not reaching steady state during the 2-hr exposures. The blood and exhaled breath concentrations were directly proportional to the exposure concentration during the exposures. Percentage uptake of TRI decreased 30-35% during the first hour of inhalation, diminishing to approximately 45-50% by the end of the exposure. Total cumulative uptake in the 50 and 500 ppm groups over the 2-hr inhalation exposures was determined to be 6 and 48 mg/kg body wt, respectively. By the end of the exposure period, 2.1 and 20.8 mg, respectively, of inhaled TRI was eliminated from rats inhaling 50 and 500 ppm TRI. A physiological pharmacokinetic model for TRI inhalation was utilized to predict blood and exhaled breath concentrations for comparison with observed experimental values. Overall, values predicted by the physiological pharmacokinetic model for TRI levels in the blood and exhaled breath were in close agreement with measured values both during and following TRI inhalation.

Administration, Inhalation↗
PubMed1992

Bronchodilator properties of an inhaled leukotriene D4 antagonist (verlukast--MK-0679) in asthmatic patients.

The safety, tolerability and bronchodilator properties of inhaled verlukast (MK-0679), a new potent and selective LTD4-receptor antagonist, were studied in 12 asthmatic subjects with more than 15% increase in FEV1 after salbutamol inhalation. On three separate study days the patients inhaled placebo, verlukast 2 mg and verlukast 8 mg from a metered dose inhaler according to a randomized, double-blind, cross-over allocation schedule. Pulmonary function and tolerability were assessed regularly and after 8 h a second dose of test drug was inhaled. Thirty minutes later a beta 2-agonist dose-response curve was performed by inhaling salbutamol in cumulative doses of 200, 400 and 800 micrograms. Verlukast (8 mg) caused significant improvement in mean FEV1 from 1.5 through 8 h after inhalation as compared to placebo (P less than 0.05). The maximum change in FEV1 occurred at 2 h after inhalation with mean percent increases above baseline of 3.5, 7.7, and 9.2% after placebo, verlukast 2 mg and 8 mg, respectively. The bronchodilator response to inhaled salbutamol was significantly larger after verlukast 8 mg than after placebo pretreatment (P less than 0.05), whereas verlukast 2 mg afforded no additive bronchodilator effect. We conclude that inhalation of the LTD4-antagonist verlukast induces modest but significant bronchodilatation and may be beneficial in the treatment of asthma.

Administration, Inhalation↗
PubMed2006

Dry powder inhalation of colistin sulphomethate in healthy volunteers: A pilot study.

BACKGROUND: Pulmonary administration of the antimicrobial drugs colistin sulphomethate and tobramycin has been shown to be effective in slowing down pulmonary deterioration in cystic fibrosis (CF) patients. Both drugs are administered by liquid nebulisation, a technique known to have disadvantages. Dry powder inhalation may be an attractive alternative. We investigated inhalation of colistin sulphomethate dry powder using a newly developed Twincer device in healthy volunteers. METHODS: Eight healthy volunteers inhaled a single dose of 25mg colistin sulphomethate dry powder each, using the Twincer inhaler. The median diameter (X(50)) of the dry powder was 1.6 microm (X(10)=0.7 microm, X(90)=3.1 microm), measured by laser diffraction technique. Pulmonary function tests were performed before, 5 and 30 min after inhalation. Serum samples were drawn at t=15 min, 45 min, 1.5h, 2.5h, 3.5h, 5.5h, 7.5h and 24h after inhalation. RESULTS: The colistin sulphomethate dry powder inhaler was well tolerated: no clinically relevant effect on FEV(1) was observed nor did the volunteers experience adverse effects. CONCLUSION: Dry powder inhalation of colistin sulphomethate using the Twincer inhaler is well tolerated by healthy volunteers. A pilot study in cystic fibrosis patients is therefore considered safe in developing a dry powder inhalation of colistin for everyday CF treatment.

Administration, Inhalation↗
PubMed2005

Inhaled but not intravenous milrinone prevents pulmonary endothelial dysfunction after cardiopulmonary bypass.

OBJECTIVE: Cardiopulmonary bypass triggers a systemic inflammatory response that alters pulmonary endothelial function, which can contribute to pulmonary hypertension. Milrinone is a type III phosphodiesterase inhibitor. The objective of this study was to compare the effects of inhaled and intravenous milrinone on the pulmonary endothelium-dependent relaxations and hemodynamic and oxygenation parameters after cardiopulmonary bypass in a porcine model. METHODS: Five groups of Landrace swine were compared: (1) control group, no cardiopulmonary bypass; (2) bypass group, 90 minutes of normothermic bypass and 60 minutes of reperfusion; (3) inhaled milrinone group, bypass preceded by a 1.8-mg bolus of inhaled milrinone followed by a continuous milrinone nebulization; (4) intravenous milrinone group, bypass preceded by 2 mg of intravenous milrinone; and (5) inhaled NaCl group, bypass preceded by inhaled saline solution. After sacrifice, pulmonary arterial endothelium-dependent relaxations to acetylcholine and bradykinin were studied in organ chambers. RESULTS: Inhaled milrinone caused less hypotension ( P < .05), a lesser decrease in peripheral vascular resistances ( P < .01), and a lower heart rate ( P < .05) than intravenous milrinone. Inhaled milrinone prevented the alterations in relaxations of pulmonary arteries to acetylcholine caused by cardiopulmonary bypass, and relaxations to bradykinin were improved in the inhaled milrinone group ( P < .05) compared with the cardiopulmonary bypass and control groups. CONCLUSIONS: Inhaled milrinone prevents the occurrence of the pulmonary endothelial dysfunction seen after cardiopulmonary bypass. The hemodynamic and oxygenation profiles obtained with inhaled milrinone are safer than with intravenous milrinone. These strategies might be useful in preventing pulmonary hypertension after cardiac surgery.

Acetylcholine↗
PubMed2006

The need to improve inhalation technique in Europe: a report from the Aerosol Drug Management Improvement Team.

Although the principles of asthma management are well established in Europe, the available data indicate that asthma in patients is not well controlled. Many patients derive incomplete benefit from their inhaled medication because they do not use inhaler devices correctly and this may compromise asthma control. The Aerosol Drug Management Improvement Team (ADMIT), incorporating clinicians from the UK, Germany, France, Italy, Spain and The Netherlands, reviewed published evidence to examine ways to improve the treatment of reversible airways disease in Europe. Data indicate that there is a clear need for specific training of patients in correct inhalation technique for the various devices currently available, and this should be repeated frequently to maintain correct inhalation technique. Devices which provide reassurance to patients and their physicians that inhalation is performed correctly should help to improve patient compliance and asthma control. Educational efforts should also focus on primary prescribers of inhaler devices. ADMIT recommends dissemination of information on the correct inhalation technique for each model of device by the use of an accessible dedicated literature base or website which would enable to match the appropriate inhaler to the individual patient. There is also a need for standardisation of prescribing practices throughout Europe. Regular checking of inhalation technique by prescribers is crucial as correct inhalation is one of the keystones of successful asthma management.

Administration, Inhalation↗
PubMed1997

Evaluation of single-dose inhaled corticosteroid activity with an allergen challenge model.

BACKGROUND: Inhaled corticosteroids are the most commonly used antiinflammatory agents for asthma. There is no simple way to compare objectively the relative potency of inhaled corticosteroids. The allergen-induced late asthmatic response (LAR) can be suppressed by a single dose of inhaled corticosteroid. OBJECTIVE: This study was undertaken to evaluate LAR as a model for the determination of the relative potency of single doses of inhaled corticosteroids. METHODS: We compared doses of 200 and 800 microg of a highly active inhaled corticosteroid (budesonide) with placebo and a marginally active investigational inhaled corticosteroid (D5159). Ten atopic patients with asthma completed a randomized, double-blind, double-dummy, multicenter, four-way, crossover trial. A standardized allergen challenge with the identical dose of allergen was performed 10 minutes after each of four blinded, single-dose treatments: 200 microg of budesonide, 800 microg of budesonide, 8 mg of D5159, and placebo, all administered from Turbuhaler. The LAR was recorded as the maximum percent fall in FEV1 between 4 and 7 hours, and the allergen-induced increase in methacholine airway responsiveness at 24 hours was recorded as the A log PC20 from the day before to the day after allergen challenge. RESULTS: There were no significant differences in the early asthmatic responses during the 4 days; the mean maximum percent in FEV1 fall ranged between 19.5% and 22%. D5159 produced a slight inhibition of the LAR with maximum percent fall in FEV1 recorded as 28.8% +/- 5.0% for D5159 versus 34.1% +/- 4.8% for placebo (p < 0.05). There was a greater reduction recorded after administration of the two doses of budesonide. The mean LAR was 15.1% +/- 3.8% for 200 microg of budesonide and 11.2% +/- 2.3% for 800 microg of budesonide (p < 0.01 compared with placebo and D5159). The two doses of budesonide were not statistically different. Airway responsiveness to methacholine increased by 1.07 doubling doses 24 hours after allergen challenge. This increased airway responsiveness was slightly, but not significantly, reduced by the three active treatments (0.6 to 0.91 doubling doses). CONCLUSION: The allergen-induced LAR model was able to differentiate a single dose of an active inhaled corticosteroid from placebo and a highly potent inhaled corticosteroid from a weak inhaled corticosteroid. The model did not differentiate between 2 fourfold doses of the highly active inhaled corticosteroid (at the doses used in this study), neither for the fall in FEV1 nor for the increase in airway hyperresponsiveness.

Administration, Inhalation↗
PubMed1997

Quantitative bronchial challenge tests with wheat flour dust administered by spinhaler: comparison with aqueous wheat flour extract inhalation.

BACKGROUND: Quantitative bronchial challenge tests with flour dust for the diagnosis of bakers' asthma may be performed by inhalation of flour delivered to the patient's respiratory tract by sophisticated equipment. OBJECTIVE: This study was carried out to assess the diagnostic value of bronchial challenge tests with flour dust inhalation from capsules administered by a Spinhaler (Fisons Inc., Loughborough, U.K.) and to compare this method quantitatively with bronchial challenge tests with a commercially available wheat flour extract. METHODS: A highly selected group of 36 bakers with work-related symptoms of rhinitis or asthma were referred to our department, a tertiary referral center, from 1992 to 1995. Thirty-four of the subjects and 10 atopic control subjects were included in this study. After the assessment of bronchial hyperresponsiveness on day 1, subjects were randomized to inhale an aqueous wheat flour extract at concentrations of 0.01, 0.1, 1, 10, and 100 mg/ml by tidal volume breathing for 10 minutes or to inhale wheat flour dust filled in capsules on days 2 and 3. One, two, and four capsules (maximum of 7 cumulative capsules) of flour dust were administered by a Spinhaler. In addition, skin prick tests were performed with a battery of environmental and occupational allergens. Total serum IgE and specific IgE to wheat flour were measured by standard procedures. RESULTS: Seventeen bakers and two control subjects demonstrated a positive skin test response to wheat flour (wheal > or = 3 mm). Fifteen bakers demonstrated a fall of 50% or more in specific airway conductance after inhalation of the commercial wheat flour extract, and 11 demonstrated such a fall in specific airway conductance after inhalation of wheat dust. Three control subjects had a positive bronchial challenge response to the extract, but dust inhalation from the capsule did not cause positive bronchial reactions in control subjects. When a 50% fall of specific airway conductance was used as criterion for a positive bronchial provocation test result, sensitivity for the extract or dust inhalation was 0.44 and 0.32, respectively, and specificity was 0.7 and 1.0, respectively. If only subjects with a positive skin test response to wheat flour were considered, sensitivity of both tests was 0.65. With more stringent criteria for the gold standard, there was a trend for a higher sensitivity but a lower specificity of the extract inhalation. Both methods were safe. CONCLUSION: The validity of bronchial challenge tests with wheat flour dust inhaled from Spinhaler capsules was superior to that of tests done with a commercially available aqueous wheat flour extract. The higher specificity of the Spinhaler method might be an advantage if bronchial challenge tests are used as confirmation tests.

Administration, Inhalation↗
PubMed2000

[Inhalation technique in patients with chronic respiratory diseases].

OBJECTIVE: To determine how inhalers are used by patients with chronic respiratory diseases in the Community of Valencia (Spain) and to identify the factors associated with correct use. MATERIAL AND METHODS: We carried out a prospective study of 554 patients (331 men, 223 women, mean age 50.5 +/- 21.5 years) who underwent spirometric testing (292 with bronchial asthma, 192 with COPD, 15 with bronchiectasis and 55 with other diagnoses). The patients were asked what type of inhaler they used. Pressurised canisters (PC) were used by 39.9%, inhalation chambers (IC) by 37.9% and dry powder inhalers (Turbuhalers) (DP) by 22.2%. They were also asked what instructions they had received; the inhalation techniques recommended by the Spanish Society of Pneumologists and Chest Surgeons (SEPAR) was reviewed step by step. RESULTS: a) Four hundred thirty-two patients (78%) reported having received instruction in how to use the inhaler; b) One hundred seventy-five (31.6%) used the correct technique: 25.3% using PC, 32.4% using IC and 41.5% using DP (p = 0.008); c) The most common errors were not holding the breath after inhaling in the case of PC users, not waiting 30 seconds between inhalation maneuvers and the lack of synchrony with inspiration among PC users; d) Use of correct inhalation technique was associated with prior instruction (rs = 0.249; p < 0.001) and younger age (rs = 0.92; p = 0.03). CONCLUSIONS: A high percentage of patients, particularly those using PC and those who received no instruction, use inhalers incorrectly in the Community of Valencia. We therefore recommend health education programs that target the main errors identified.

Administration, Inhalation↗
PubMed2003

Oral candidiasis associated with inhaled corticosteroid use: comparison of fluticasone and beclomethasone.

BACKGROUND: Inhaled steroids such as fluticasone propionate and beclomethasone dipropionate play a central role in the treatment of bronchial asthma. Fluticasone exhibits excellent clinical effectiveness; however, oral adverse effects can occur. OBJECTIVE: To compare the frequency of oral candidiasis in asthmatic patients treated with fluticasone and beclomethasone, to evaluate the effect of gargling with amphotericin B, and to measure the inhalation flow rate on candidiasis. METHODS: The study consisted of 143 asthmatic patients who were treated with inhaled steroids, 11 asthmatic patients not treated with inhaled steroids, and 86 healthy volunteers. Quantitative fungal culture was performed by aseptically obtaining a retropharyngeal wall swab from these patients. Patients with positive results were treated with gargling using a 1:50 dilution amphotericin B solution. In asthmatic patients treated with fluticasone, the inhalation flow rate was measured using an inspiratory flow meter. RESULTS: The amount of Candida spp. was significantly greater in asthmatic patients taking inhaled steroids compared with those who were not. It was also significantly greater in patients with oral symptoms than asymptomatic patients and significantly greater in asthmatic patients treated with fluticasone than in those treated with beclomethasone. Although the presence of Candida did not correlate with the inhaled dose of beclomethasone, it did increase with the dose of fluticasone. Gargling with amphotericin B was effective in most asthmatic patients with candidiasis. Candidiasis was not due to inappropriate flow rates during inhalation of steroids. CONCLUSIONS: Fungal culture of a retropharyngeal wall swab may be useful for predicting the risk of developing oral candidiasis in asthmatic patients treated with inhaled steroids. The amount of isolated Candida was significantly greater in asthmatic patients treated with fluticasone than in those treated with beclomethasone. Attention to dosage is required as the amount of Candida increased with dose of fluticasone. Gargling with a 1:50 dilution of amphotericin B is effective in treating oral candidiasis of asthmatic patients treated with inhaled steroids.

Administration, Inhalation↗
PubMed1999

Inhalant use among urban American Indian youth.

AIMS: To assess the prevalence of inhalant use among urban American Indian youth and to examine differences between inhalant users and non-users. DESIGN: Baseline (T1) self-report questionnaires completed in 5th-6th grade and at seven annual follow-up assessments (T2-T8). SETTINGS: Seattle metropolitan area. PARTICIPANTS: Two hundred and twenty-four Indian youth. MEASUREMENTS: Youth-completed measures of substance use, ethnic self-identity, involvement in traditional Indian activities, family conflict, family history of alcoholism, peer and sibling deviance, self-esteem, delinquency, aggression, anxiety, depression, sensation seeking, conduct disorder and alcohol dependence. FINDINGS: Lifetime inhalant use was reported by 12.3% of adolescents. At T1, inhalant users had significantly lower perceived self-worth and average annual household incomes and significantly greater density of familial alcoholism and expression of aggressive and delinquent conduct than non-users. Aggressive behavior was the most important T1 predictor of inhalant use. Lifetime conduct and alcohol dependence disorders were 3.3 and 2.6 times more prevalent among inhalant users than non-users at T5. Inhalant users had more extensive deviant peer networks, were more sensation-seeking, and evidenced lower perceived self-worth than non-users at T8. CONCLUSIONS: Inhalant use was less prevalent in this particular sample of urban Indian adolescents than in most studies of reservation Indian youth. As with other studies of inhalant abuse, aggressive and delinquent males of low SES and low-perceived self-worth with family histories of alcohol dependence, were at highest risk for inhalant use.

Administration, Inhalation↗
PubMed2001

Does the mode of inhalation affect the bronchodilator response in patients with severe COPD?

Spacing devices improve lung deposition of aerosols from metered dose inhalers (MDI) but it is sometimes difficult for dyspnoeic patients to perform maximal breaths with breath-holds needed to inhale the aerosols from them. Our aim was to determine whether the response to bronchodilators (BD) depended on the method of inhalation. We studied 20 patients with moderately severe chronic obstructive pulmonary disease (COPD) with a mean age of 68 years and a mean of forced expiratory volume in 1 sec (FEV1) of 41% predicted. In a randomized, cross-over fashion they inhaled terbutaline 1.5 mg (six puffs) followed by ipratropium 120 microg (six puffs) via MDI and nebuhaler with either two inspirations to total lung capacity and a 10-sec breath-hold per puff or with six tidal breaths per puff. Before and after BDs we measured FEV1, forced vital capacity (FVC), airways resistance using interrupter method (Rint) and 6-min walking distance (6MWD). Subsequently, we re-tested nine of these patients with the two methods of inhalation, before and after conventional doses (terbutaline 500 microg+ipratropium 40 microg), then after terbutaline 1 mg and ipratropium 80 microg and finally after nebulized terbutaline 5 mg and ipratropium 500 microg to sec whether there was a dose-dependent difference in effect between the two methods. Spirometry, slow vital capacity (SVC). inspiratory capacity and shuttle walking tests were monitored. In the original 20 patients there were highly significant improvements in all parameters after inhalers, with no significant difference between methods of inhalation. Median improvements after BDs were: FEV1 0.221 and 0.191, FVC 0.501 and 0.381 and 6MWD 40 m and 44 m, for maximal breaths and tidal breathing, respectively. For nine patients, tidal and maximal breaths produced similar effects on lung function and exercise tolerance at both doses of BDs. Nebulized BDs only improved shuttle distances slightly when compared with either method of inhalation from MDI and spacer but had no additional effect on lung function. In conclusion, in patients with moderately severe COPD, BDs given by metered dose inhaler via nebuhaler have similar effects whether given by six easy tidal breaths or the more difficult two maximal breaths with breath-hold. This holds true at small or larger doses of BD. Either method of inhaling six puffs of the BDs can be used as an effective alternative to nebulized aerosol.

Administration, Inhalation↗
PubMed2003

Inhalation profiles in asthmatics and COPD patients: reproducibility and effect of instruction.

Turbuhaler and Salbutamol-Diskus produce therapeutic doses at peak inspiratory flow (PIF) of >30 L/min. However, the optimum flow for Fluticasone-Diskus and Turbuhaler, in terms of total emitted dose and fine particle mass, is >60 L/min. The Turbuhaler achieved a higher output at this flow, as compared to Diskus. For pMDI 25 < PIF < 90 L/min, an actuation time of 0.0-0.2 sec is optimal. The aim of this study was to examine the incidence of optimum inhalation profiles, the effect of instruction, reproducibility, and the relationship between inhalation profiles and patient characteristics in stable asthmatics and mild/moderate/severe COPD patients. For each device, triplicate inhalation profiles were recorded during 6 sessions in a 10-week period. All patients achieved PIF > 30 L/min using Diskus. After instruction, all Diskus inhalations were performed with >60 L/min, except 7% of the inhalations of the severe COPD patients. At least 95% of the Turbuhaler inhalations was also performed with the minimum flow; however, 19% of the inhalations of the severe COPD patients were not optimally performed. The hand-lung coordination was inadequate in 40% of pMDI inhalation profiles, and 80% was performed with a too high flow. The reproducibility of PIF of both dry powder inhalers (DPIs) was very high (coefficient of variation = 4-10%). The reproducibility of the pMDI variables was lower (coefficient of variation = 9-18%). The major lung function variables predictive for PIF(diskus) and PIF(turbuhaler) were maximal inspiratory mouth pressure (MIP), PIF, and inspiratory capacity. No significant predictive lung function variables for PIF(pMDI) were found. Most patients performed reproducible optimum inhalation profiles through Diskus and Turbuhaler. However, in the severe COPD group, 7-19% of the patients were not able to generate the optimum flows through the DPIs. For these patients, a flow-independent aerosol delivery system might be more suitable. The majority of patients were using the pMDI incorrectly. Instruction had no effect. So, we concluded that the pMDI should not be used in these patient groups because of the coordination problems.

Administration, Inhalation↗
PubMed2004

Impact of particle size and aerosolization time on the metabolic effect of an inhaled insulin aerosol.

The effects were compared of varying aerosol particle size and aerosolization time within each breath on the metabolic effect elicited by inhalation of a liquid insulin aerosol in comparison with that after subcutaneous injection (s.c.) of regular insulin. In this single-center, open-label euglycemic glucose clamp study, 13 healthy non-smoking subjects received five administrations of insulin in randomized order on separate study days, once by s.c. (0.15 U/kg of regular insulin) and four times by inhalation. Subjects inhaled 1.5 U/kg of liquid insulin aerosol administered by the Aerodose Insulin Inhaler (Aerogen Inc., Mountain View, CA) configured to deliver two aerosol particle sizes--fine [F, 4.4 +/- 0.3 microm (mean +/- SD)] or very fine (VF, 3.5 +/- 0.2 microm)--and two aerosolization times (aerosol released for the first 2 or 4 s after the start of each 5-s inhalation). Glucose infusion rate (GIR) values necessary to keep blood glucose concentrations constant at 5.0 mmol/L were determined over a 6-h period following insulin administration. After inhalation of insulin, the onset of action was substantially more rapid on all four inhalation study days than after s.c. insulin, and the time to maximal action [t(GIRmax) (min)] was reached earlier: F/2 s, 127 +/- 54; F/4 s, 128 +/- 55; VF/2 s, 158 +/- 91; VF/4 s, 132 +/- 72; s.c., 175 +/- 69 (P < 0.0001). The longer aerosolization time (4 vs. 2 s) resulted in higher maximal metabolic action [GIR(max) (mg/kg/min), F/4 s 8.1 +/- 3.6, VF/4 s 8.4 +/- 2.7 vs. F/2 s 6.6 +/- 2.4, VF/2 s 7.2 +/- 2.4 (P = 0.01 for 4 s vs. 2 s, grouped data)], total metabolic activity [area under the curve of GIR 0-6 h (g/kg), F/4 s 1.97 +/- 0.92, VF/4 s 2.14 +/- 0.86 vs. F/2 s 1.56 +/- 0.68, VF/2 s 1.78 +/- 0.60 (P = 0.01)], and relative biopotency [F/4 s 10.6 +/- 4.0%, VF/4 s 11.7% +/- 4.1% vs. F/2 s 8.5 +/- 3.2%, VF/2 s 9.7 +/- 2.4% (P = 0.01)]. None of these summary measures was significantly affected by particle size. No drug- or device-related adverse events were observed. This study shows that aerosolization time, but not particle size, in the ranges studied, had an impact on the metabolic effect elicited by inhaled insulin, allowing rational selection of delivery parameters for further clinical testing. Based on the observed biopotency and the rapid onset of action, inhalation of a liquid insulin aerosol generated by the Aerodose Insulin Inhaler shows promise for covering prandial insulin requirements.

Administration, Inhalation↗