What the pulmonary specialist should know about the new inhalation therapies.

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

Experimental and theoretical screening of nanoscale oxide reactivity with LiBH4.

Experimentation, thermodynamic modeling, and atomic modeling were combined to screen the reactivity of SiO2, Al2O3, and ZrO2 nanoscale oxides with LiBH4. Equilibrium thermodynamic modeling showed that the reactions of oxides with LiBH4 could lead to formation of stable Li-bearing oxide and metal boride phases. Experimentation was conducted to evaluate the discharge/recharge reaction products of nanoscale oxide-LiBH4 mixtures. Thermal gravimetric analyses-mass spectroscopy and x-ray diffraction revealed significant SiO2 destabilization of LiBH4 dehydrogenation, resulting in the formation of lithium silicate and boric acid. A smaller amount of lithium metaborate and boric acid was formed with Al2O3. No destabilization products were observed with ZrO2. Density functional theory atomic modeling predicted much stronger LiBH4 interfacial adsorption on the SiO2 and Al2O3 surfaces than on the ZrO2 surface, which was consistent with the experimental findings. Following dehydrogenation, interfacial Li atoms were predicted to strongly adsorb on the oxide surfaces effectively competing with LiH formation. The interfacial Li interactions with Al2O3 and ZrO2 were equal in strength in the fully hydrided and dehydrided states, so that their predicted net effect on LiBH4 dehydrogenation was insignificant. Zirconia was selected for nanoframework development based on the combined observations of compatibility and weaker associative interactions with LiBH4.

Early pulmonary response to allergen is attenuated during acute emotional stress in females with asthma.

Some asthma patients and physicians who treat asthma have reported that stress worsens their disease. It has also recently been shown that chronic stressful life events increase airway inflammation 6-24 h after inhalation of antigen in patients with allergic asthma. However, there is no data regarding the effect of an acute stressor on the airway constriction that occurs within minutes of antigen inhalation (early pulmonary response) in this same population. The aim of this study was to examine this effect in eight females with allergic asthma. Each subject was challenged with increasing concentrations of inhaled allergen on a control visit (no stress) and on a stress visit, when they were asked to verbally recount an emotionally stressful situation between each concentration. Systolic (SP) and diastolic (DP) blood pressure, cardiac frequency (fC) and forced expiratory volume in one second (FEV1) were measured on both visits. SP, DP and fC were statistically increased on the stress visit as compared to control. Per cent decrease in FEV1 at the same last dose of allergen was significantly less on the stress visit (11.2 +/- 7.0%) compared to control (15.0 +/- 8.7%). These findings suggest that the early pulmonary response to inhaled allergen is attenuated while verbally re-experiencing an acute emotional stressor in females with allergic asthma.

A pilot study examining the relationship between stress and serum cortisol concentrations in women with asthma.

The mechanism (s) by which stress exacerbates asthma is unknown. One explanation could be a reduction in endogenous serum cortisol concentrations as a result of stress. Our objective was to determine if a reduction in morning serum cortisol concentrations is associated with higher levels of stress in women with asthma. In this pilot study, seven women with a history of allergic-asthma were prospectively assigned to either low, moderate, or high stress groups based on a combination of their level of current stress and their resources to cope with the stress. After stress group assignment, women donated a morning blood sample, which was analyzed for serum cortisol concentration by an independent laboratory whose personnel were blinded to the subjects' stress status. Three women were assigned to the low stress group, two to the moderate stress group and two to the high stress group. Serum cortisol concentrations ranged from 8 to 23 microg/dl, averaging 14 +/- 6 microg/dl. A Spearman rank correlation indicated that serum cortisol concentrations were significantly inversely related to the stress groupings (r(s) = -0.915; P = 0.025). These results suggest that a reduction in morning serum cortisol concentration may be associated with higher levels of stress and lower resources to cope with the stress in women with allergic-asthma.

Mouthpiece diameter affects deposition efficiency in cast models of the human oral airways.

We examined the effect of altering mouthpiece diameter to 1.5, 2.0, and 2.7 cm on the deposition efficiency of inertial size particles (2, 4, and 8 microm) in adult human oral-pharyngeal-laryngeal (OPL) airway cast models at various inspiratory flow rates (30, 60, 90, and 120 L/min). Deposition efficiency of 2-microm particles was unaffected by changes in mouthpiece diameter at all flow rates. Deposition of 4-microm particles decreased significantly with the 2.0- and 2.7-cm mouthpieces compared to the 1.5 cm mouthpiece at 60, 90, and 120 L/min (p < 0.01). Deposition of 4-microm particles was significantly reduced with the 2.7-cm mouthpiece compared to the 2.0-cm mouthpiece at 90 and 120 L/min (p < 0.05). Deposition efficiency of 8 microm particles decreased significantly with the 2.0- and 2.7-cm mouthpieces compared to the 1.5-cm mouthpiece at 60 L/min (p < 0.05), and with the 2.7-cm mouthpiece compared to the 1.5-cm mouthpiece at 120 L/min (p < 0.05). These results suggest that the effect of mouthpiece diameter varies with particle size, with 2- and 8-microm particles least affected. However, our findings may have important implications for improving the future design of mouthpieces of devices that deliver particles with 4-microm diameters and require inspiratory flow rates of > or = 60 L/min (i.e., DPIs) for adequate drug delivery.

Treating diabetes with aerosolized insulin.

Because of the pain, inconvenience, and disruption of lifestyle associated with the injection of insulin, many patients with diabetes are noncompliant in terms of treatment regimens that require daily multiple injections. To eliminate the pain and to improve treatment outcome, there has been increasing interest in the development of aerosolized insulin to replace subcutaneously (SC) delivered formulations. Recent studies in human volunteers have shown that when aerosolized insulin is effectively delivered to the alveolar region of the lung, absorption rates and decreases in glucose levels are similar to those achieved with SC-delivered insulin during the fasting state. Other human trials have shown that inhaled insulin also effectively controls postprandial glucose levels. Aerosolized insulin is well-tolerated, and there is no evidence of irritation, hypoglycemia, or changes in pulmonary function when administered over short periods. At present, limitations in the delivery device result in less efficient administration of insulin aerosol compared to SC dosing. However, new devices and different formulations of insulin, which are currently under development, should improve the efficiency. It is likely that the treatment of diabetes with aerosolized insulin will provide an effective alternative means for controlling plasma glucose levels in diabetic individuals. Aerosolized insulin also will serve as a developmental model for this route of administration for a number of other therapeutic peptides that are currently administered by injection only.

Gene therapy in cystic fibrosis.

Theoretically, cystic fibrosis transmembrane conductance regulator (CFTR) gene replacement during the neonatal period can decrease morbidity and mortality from cystic fibrosis (CF). In vivo gene transfers have been accomplished in CF patients. Choice of vector, mode of delivery to airways, translocation of genetic information, and sufficient expression level of the normalized CFTR gene are issues that currently are being addressed in the field. The advantages and limitations of viral vectors are a function of the parent virus. Viral vectors used in this setting include adenovirus (Ad) and adeno-associated virus (AAV). Initial studies with Ad vectors resulted in a vector that was efficient for gene transfer with dose-limiting inflammatory effects due to the large amount of viral protein delivered. The next generation of Ad vectors, with more viral coding sequence deletions, has a longer duration of activity and elicits a lesser degree of cell-mediated immunity in mice. A more recent generation of Ad vectors has no viral genes remaining. Despite these changes, the problem of humoral immunity remains with Ad vectors. A variety of strategies such as vector systems requiring single, or widely spaced, administrations, pharmacologic immunosuppression at administration, creation of a stealth vector, modification of immunogenic epitopes, or tolerance induction are being considered to circumvent humoral immunity. AAV vectors have been studied in animal and human models. They do not appear to induce inflammatory changes over a wide range of doses. The level of CFTR messenger RNA expression is difficult to ascertain with AAV vectors since the small size of the vector relative to the CFTR gene leaves no space for vector-specific sequences on which to base assays to distinguish endogenous from vector-expressed messenger RNA. In general, AAV vectors appear to be safe and have superior duration profiles. Cationic liposomes are lipid-DNA complexes. These vectors generally have been less efficient than viral vectors but do not stimulate inflammatory and immunologic responses. Another challenge to the development of clinically feasible gene therapy is delivery mode. Early pulmonary delivery systems relied on the direct instillation of aerosolized vectors, which can result in the induction of adverse reactions because vector is delivered into the lung parenchyma. More recent studies have examined the potential for using spray technologies to target aerosolized AAV vectors to the larger central airways, thereby avoiding alveolar exposure and adverse effects. Comparisons of lung deposition with nebulized delivery of aerosol and spray delivery indicate that spraying results in a more localized deposition pattern (predominantly in the proximal airways) and significantly higher deposition fractions than nebulization. These findings could lead to more efficient and targeted lung delivery of aerosolized gene vectors in the future.

Targeting aerosol deposition in patients with cystic fibrosis: effects of alterations in particle size and inspiratory flow rate.

STUDY OBJECTIVE: To determine if aerosolized medications can be targeted to deposit in the smaller, peripheral airways or the larger, central airways of adult cystic fibrosis (CF) patients by varying particle size and inspiratory flow rate. DESIGN: Randomized clinical trial. SETTING: Outpatient research laboratory. PATIENTS: Nine adult patients with CF. INTERVENTIONS: Patients inhaled an aerosol comprised of 3.68+/-0.04 microm saline solution droplets (two visits) or 1.01+/- 0.2 microm saline solution droplets (two visits) for 30 s, starting from functional residual capacity and breathing at a slow or faster inspiratory flow rate. On all visits, the saline solution was admixed with the radioisotope (99m)Tc. Immediately after inhalation, a gamma camera recorded the deposition pattern of the radioaerosol in the lungs. Deposition images were analyzed in terms of the inner:outer zone (I:O) ratio, a measure of deposition in an inner zone (large, central airways) vs. an outer zone (small airways and alveoli). MEASUREMENTS AND RESULTS: For the 3.68-microm aerosol, I:O ratios averaged 2.29+/-1.45 and 2.54+/-1.48 (p>0.05), indicating that aerosol distribution within the lungs was unchanged while breathing at 12+/-2 L/min vs. 31+/-5 L/min, respectively. For the 1.01-microm aerosol, I:O ratios averaged 2.09+/-0.96 and 3.19+/-1.95 (p<0.05), indicating that deposition was predominantly in the smaller airways while breathing at 18+/-5 L/min and in the larger airways while breathing at 38+/-8 L/min, respectively. CONCLUSIONS: These results suggest that the targeted delivery of an aerosol to the smaller, peripheral airways or the larger, central airways of adult CF patients may be achieved by generating an aerosol comprised of approximately 1.0-microm particles and inspiring from functional residual capacity at approximately 18 L/min and approximately 38 L/min, respectively.

The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma.

BACKGROUND: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS: Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes.

STUDY OBJECTIVES: To determine the efficacy of the lung as an alternative route of delivery for insulin in controlling glucose below diabetic levels (11.2 mmol/L) 2 h after the ingestion of a meal in patients with type 2 diabetes mellitus. DESIGN: Single-blinded, nonrandomized, placebo-controlled pilot study consisting of two visits. SETTING: A primary care facility. PATIENTS: Seven patients with type 2 diabetes mellitus. INTERVENTIONS: On the first study visit, fasting glucose levels were normalized. Then, patients inhaled 1.5 U/kg insulin by aerosol into the lungs 5 min before ingesting a test meal. On the second visit, patients inhaled placebo aerosol 5 min before ingesting the same meal. On both visits, plasma samples were collected and analyzed for glucose levels for 3 h during the postprandial state. MEASUREMENTS AND RESULTS: No one coughed after inhalation of insulin aerosol or demonstrated hypoglycemia. During the postprandial period, glucose levels were significantly lower at 20 min (5.12+/-1.08 mmol/L), 1 h (7.87+/-0.73 mmol/L), 2 h (8.05+/-1.24 mmol/L) and 3 h (7.50+/-1.43 mmol/L) following inhalation of insulin than when the placebo was used. Data for the placebo were 10.36+/-1.23 mmol/L at 20 min, 14.0+/-1.68 mmol/L at 1 h, 16.18+/-1.45 mmol/L at 2 h, and 14.37+/-2.11 mmol/L at 3h (for all comparisons, p < 0.05). On the insulin visit, glucose levels were < 11.2 mmol/L 2 h after the meal in six of seven patients. None attained this level at the placebo visit. In addition, glucose levels were within the normal postprandial range of < 7.84 mmol/L in four of seven patients 2 h after eating on the insulin visit. CONCLUSIONS: These results suggest that, once plasma glucose levels are normalized, postprandial glucose levels can be maintained below diabetic levels by delivering 1.5 U/kg insulin into the lungs 5 min before the ingestion of a meal.

Time to peak insulin level, relative bioavailability, and effect of site of deposition of nebulized insulin in patients with noninsulin-dependent diabetes mellitus.

Seven fasting patients with noninsulin-dependent diabetes mellitus (NIDDM) inhaled 1.0 U/kg of body weight of nebulized regular pork insulin by mouth or were subcutaneously (sc) injected with 0.1 U/kg of body weight of insulin in the upper arm on two different occasions. The time to peak insulin level was compared for the two treatment modalities. Insulin bioavailability after inhalation was quantified relative to sc injected insulin. Deposition of a radiolabeled insulin surrogate aerosol (insulin diluent) in the larger central airways versus the peripheral airways, expressed as the inner-to-outer (I:O) ratio, and in the lung apex versus the lung base, expressed as the apex-to-basal (A:B) ratio, was quantified with gamma scintigraphy. Ratios were related to glucose responses after inhalation of insulin. Times to peak insulin level were similar for the two methods of treatment, averaging 43 +/- 16 and 64 +/- 40 minutes after inhalation and sc injection of insulin, respectively. The bioavailability of inhaled insulin averaged 14.7% +/- 5.8% relative to sc injected insulin. This was significantly less than the average bioavailability of deposited drug (18.9% +/- 5.3%) relative to sc injected insulin (P < 0.05). I:O and A:B ratios for the surrogate aerosol averaged 1.3 +/- 0.4 and 0.7 +/- 0.2, respectively. Linear regression analysis revealed that the maximum percentage of decrease in glucose after insulin inhalation was significantly related to the A:B ratio such that percentage decrease in glucose was greater in patients who demonstrated a lower A:B ratio (P = 0.003). Percentage decrease in glucose was not related to the I:O ratio. These results indicate that the bioavailability of nebulized insulin inhaled by mouth is approximately 20% when calculated in terms of drug deposited and suggest that increasing the distribution of insulin aerosol to the base of the lung enhances the glucose response in patients with NIDDM during the fasting state.

Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis.

We tested the hypothesis that recombinant human deoxyribonuclease 1 (rhDNase) reduces airflow obstruction and improves mucociliary clearance in patients with cystic fibrosis (CF), and that improvements seen in FEV1 and FVC after rhDNase treatment are independent of chest physical therapy (CPT). CF patients inhaled placebo (10 patients) or 2.5 mg rhDNAse aerosol (10 patients) twice a day for six consecutive days. Compared with baseline, there were no statistically significant differences between the two study groups by Day 6 for indices of airflow obstruction obtained from gamma-camera images of the right lung following inhalation of 99mTc aerosol, or for mucociliary clearance or the rate of clearance of the radioaerosol, quantified over a 6-h period. By Day 6, FEV1 and FVC were significantly higher in the rhDNase-treated group than in the placebo group, increasing by an average of 9.4 +/- 3.5% and 12.7 +/- 2.6%, respectively, as compared with a decrease of 1.8 +/- 1.7% and an increase of 0.4 +/- 1.1%, respectively (p < 0.05). There was no significant change in the FEV1/FVC ratio on Day 6 (0.68 +/- 0.05) compared with baseline (0.70 +/- 0.05) in the rhDNase group. On Day 6, FEV1 and FVC decreased after CPT in both study groups, but the decreases were not significant. Our results indicate that aerosolized rhDNase improves FEV1 and FVC independent of CPT. We were unable to demonstrate that rhDNase reduces airflow obstruction or improves mucociliary clearance.

In vivo measurements of aerosol dose and distribution: clinical relevance.

Mathematical and in vitro models, that incorporate particle diameter, normal breathing frequencies and tidal volumes, have been used to predict the deposition fraction of respirable aerosols within the lungs. Although very useful in drug development, determinations of dose and the distribution of dose based solely on such models may be less accurate than in vivo measurements, which are performed under conditions that combine the effects of all the factors that determine aerosol deposition, including the effect of disease. Gammascintigraphy provides a method for in vivo quantification of the total deposited fraction and the distribution of the dose within the lower respiratory tract. Using this technology, it has been shown that deposition fraction in the lower respiratory tract may vary between 1-30% of the dose actuated from an MDI or nebulizer. This wide range in deposited dose suggests that variations in the clinical response to inhaled aerosols may be explained by alterations in the dose delivered, especially if the aerosolized medication has a narrow therapeutic range. Alterations in the distribution of inhaled drugs within the lungs may also affect the clinical response, such that some disorders may best be treated by targeting drug to specific locations of the lung, while others may respond best to homogeneous distribution of aerosolized drug. In vivo measurements would provide confirmation of the dose deposited as well as the pattern of distribution, which should improve the therapeutic outcome of most aerosolized medications.

Acute exposure to acid fog: influence of breathing pattern on effective dose.

Concern about the possible adverse health effects of acid fog has been fed by two observations: air pollution disasters earlier in this century were typically associated with fog, and current samples of fog water can be strongly acid. To study the acute effects of acid fog on the lung, the authors generated a monodisperse 10 microM MMAD aerosol of H2SO4 with a pH of 2.0 and a nominal concentration of 500 micrograms/m3. They exposed seven healthy young men on alternate days to acid or control equiosmolar NaCl aerosol during 40 min of resting ventilation and 20 min of exercise; the latter was sufficiently intense to induce oronasal breathing. Exposure was by means of a head dome, a head-only exposure device that permitted continuous measurement (unfettered breathing) of Vr, f, VE, and the onset and persistence of oronasal breathing. In this article the authors compare the relative importance of parameters contributing to the between-subject variability in estimated hydrogen ion dose to the lower airways (H+LAW), based on analysis of variance. Physiologic parameters accounted for 70% of the variability, of which 34% was due to differences in duration of oronasal breathing (tON) and 36% to differences in ventilation rate during oronasal breathing (VE(ON)); inhaled hydrogen ion concentration [H+], the environmental parameter, contributed only 30%. Minute ventilation at the time of transition from nasal to oronasal breathing varied significantly among subjects even if normalized to FVC, an index of lung size.

Bronchodilator pretreatment improves aerosol deposition uniformity in HIV-positive patients who cough while inhaling aerosolized pentamidine.

OBJECTIVE: To determine the effect of bronchodilator pretreatment on deposition uniformity of aerosolized pentamidine (AP) in HIV-positive patients who coughed while inhaling AP. DESIGN: Nonrandomized control trial. SETTING: A university hospital. PATIENTS: Ten HIV-positive patients who were using AP prophylactically. INTERVENTION: Four patients who coughed during AP administration were pretreated with 10 mg metaproterenol aerosol prior to a second inhalation of AP. MEASUREMENTS: Skew, a measure of overall deposition symmetry, deposition in the apex vs the base of the right lung (A:B ratio), and percentage of change from baseline in peak expiratory flow rate (PEFR). RESULTS: At baseline, the average (+/- SD) skew value for four subjects who coughed (0.89 +/- 0.19) was significantly higher than for six control subjects (0.58 +/- 0.07) (p < 0.01), indicating enhanced nonuniformity of AP distribution. After bronchodilator, no one coughed and the average skew value was normalized to 0.57 +/- 0.13. The A:B ratios at baseline and after metaproterenol were not significantly different, suggesting that deposition of AP in the apex, relative to basal deposition, was not enhanced by bronchodilator treatment. When no bronchodilator was administered, average PEFR decreased to 330 +/- 162 from baseline (410 +/- 84). Average PEFR increased to 429 +/- 85 from baseline (395 +/- 116) after bronchodilator pretreatment. CONCLUSIONS: These results suggest that in addition to relieving cough in patients receiving AP prophylactically, pretreatment with metaproterenol enhances uniformity of distribution of AP and improves PEFR.

Acute exposure to acid fog. Effects on mucociliary clearance.

Submicrometric sulfuric acid (H2SO4) aerosol can affect mucociliary clearance without eliciting irritative symptoms or changes in pulmonary function. The effect of larger fog droplets containing H2SO4 on mucociliary clearance is unknown. We quantified mucociliary clearance from the trachea (n = 4) and small airways (n = 7) of young healthy male adults after an acute exposure to H2SO4 fog (MMAD = 10.3 microns; pH = 2.0; liquid water content = 481 +/- 65 mg/m3; osmolarity = 30 mOsm). Acid fog (AF) or saline fog (SF) (10.9 microns; 492 +/- 116 mg/m3; 30 mOsm) was administered for 40 min of unencumbered breathing (no mouth-piece) at rest and for 20 min of exercise sufficient to produce oronasal breathing. Fog exposures were followed by a methacholine (MCh) challenge (a measure of airway reactivity) or inhalation of technetium-99M radioaerosol (MMAD = 3.4 microns) on 2 study days each. Changes in symptoms and forced ventilatory function were also assessed. Clearance was quantified from computer-assisted analyses of gamma camera images of the lower respiratory tract in terms of %removal/min of the radiolabel from the trachea 25 min after inhalation and from the outer zone of the right lung after 1.9 to 3 h. Symptoms, forced ventilatory function, and MCh response were unaffected by either fog. Tracheal clearance was more rapid in four of four subjects after AF (0.83 +/- 1.58% removal/min) compared with that after SF (-0.54 +/- 0.85% removal/min). Outer zone clearance was more rapid in six of seven subjects after AF (0.22 +/- 0.15% removal/min) compared with that after SF (0.01 +/- 0.09% removal/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients.

OBJECTIVE: To maximize deposition of an aerosolized dose of insulin (mean +/- SD = 0.99 +/- 0.06 U/kg of body weight) in the lungs of subjects with non-insulin-dependent diabetes mellitus (NIDDM), and investigate its efficacy in normalizing plasma glucose levels during the fasting state. DESIGN: Nonrandomized, placebo-controlled trial. SETTING: A primary care facility. PATIENTS OR OTHER PARTICIPANTS: Six nonobese, nonsmoking volunteers with NIDDM. No subjects withdrew from the study. INTERVENTION: Aerosolized insulin was administered by oral inhalation after a 12-hour period of fasting. Aerosol was generated by a raindrop nebulizer from regular 500 U/mL pork insulin. During inhalation, inspiratory flow was regulated at 17 L/min. Plasma samples were collected after inhalation and analyzed for insulin and glucose levels. MAIN OUTCOME MEASURES: Plasma insulin and glucose levels. RESULTS: Deposition of the aerosol was maximized within the lungs, with 79% +/- 17% of the inhaled dose depositing below the larynx. Geometric mean fasting plasma insulin level was 71 pmol/L (11.8 microU/mL), rising to 269 pmol/L (44.8 microU/mL) after insulin inhalation. Average time to peak insulin level was 40 +/- 34 minutes. The mean fasting plasma glucose level (12.63 +/- 2.59 mmol/L [225.5 +/- 46.3 mg/dL]) was reduced to within the normal range in five subjects and was almost normal in the sixth subject (5.52 +/- 0.89 mmol/L [98.6 +/- 15.9 mg/dL]). Average maximum decrease in plasma glucose from baseline was 55% +/- 10% (n = 6) vs 13% +/- 9% after placebo aerosol inhalation (n = 3). No side effects were reported following insulin or placebo aerosol inhalation. CONCLUSIONS: These preliminary results indicate that a dose of approximately 1.0 U of aerosolized insulin per kilogram of body weight, delivered by oral inhalation and deposited predominantly within the lungs, is well tolerated and can effectively normalize plasma glucose levels in patients with NIDDM.