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Intensive therapy with inhaled insulin via the AERx insulin diabetes management system: a 12-week proof-of-concept trial in patients with type 2 diabetes.

OBJECTIVE: To compare the glycemic control of inhaled insulin via the AERx insulin diabetes management system (iDMS) with that of subcutaneous (SC) insulin, both combined with NPH insulin at bedtime, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The AERx iDMS uses a liquid insulin formulation to achieve flexible precise mealtime dosing (with increments corresponding to 1 IU administered subcutaneously) and ensures insulin delivery only when the breathing technique is optimal. This trial in patients with type 2 diabetes compared the glycemic control (HbA(1c)) achieved by inhaled insulin administered via AERx iDMS with that using SC insulin. This was a randomized, 12-week, open-label, parallel, multicenter, multinational trial in 107 nonsmoking patients with type 2 diabetes (mean age 59 years, mean duration of diabetes 11.9 years). Patients were randomized to receive either inhaled fast-acting human insulin via AERx iDMS immediately before meals or SC fast-acting human insulin administered 30 min before meals, both in combination with evening NPH insulin. RESULTS: Baseline and demographic characteristics were similar between the two groups. There was no statistically significant difference in HbA(1c) between the AERx and SC groups after 12 weeks of treatment (7.84 +/- 0.77 vs. 7.76 +/- 0.77%, P = 0.60). Fasting serum glucose was significantly lower in the AERx group compared with the SC group by the end of the trial (8.9 +/- 3.8 vs. 10.8 +/- 3.7 mmol/l, P = 0.01) with a similar NPH dose in the two groups (0.23 vs. 0.23 IU/kg, P = 0.93). There were no statistically significant differences between the two groups in the intra-subject variability of fasting or prandial blood glucose increment. Adverse events were similar in the two groups. No major safety concerns were raised during the trial. CONCLUSIONS: In patients with type 2 diabetes, preprandial inhaled insulin via AERx iDMS is as effective as preprandial SC insulin injection in achieving glycemic control with similar tolerability.

Administration, Inhalation↗

[Treatment of chronic inflammation of the upper respiratory airways by inhalation thermal therapy with sulfur-sulfate-bicarbonate- carbonate-alkaline earth mineral water: a study of nasal cytology].

The purpose of the paper is to better characterise changes occurred in nose cytology in a group of 50 subjects affected by chronic inflammation of upper respiratory airway. The patients were random shared in two groups: group A 40 subjects treated using sulphurous thermal water and a group B (control), 10 cases, treated using placebo saline solution. The post-therapy evaluation of nasal cytology showed an improvement of the chronic inflammation in 65% of group A patients (diminution of bacterial dust 65%, diminution of PMN cells in 60% of cases and disappearance of metaplasy notes in all the cases of group A. No statistical modifications were observed in control group. Moreover were observed a increase of plasma-cell number much more in group A. The author conclusion is that a period of thermal therapy using sulphur-sulphate-alkaline-earth metals water in chronic inflammation of the nose, throw pharmacological and physical actions, cause an improvement of the chronic inflammation and a normalisation of nose cytology.

Adult↗

Inhaled nitric oxide therapy after Fontan-type operations.

PURPOSE: Inhaled nitric oxide (NO) therapy is a newly developed strategy designed to reduce pulmonary vascular resistance after the Fontan-type operation. We reviewed our experience to evaluate its efficacy and true indications. METHODS: We retrospectively examined 47 children who received inhaled NO therapy after the Fontan-type operation between August 1996 and December 2002. The maximal dose of NO ranged from 5 to 30 ppm (median 10 ppm), and the duration of inhaled NO therapy ranged from 5 h to 52 days (median 2 days). RESULTS: Inhaled NO significantly decreased the central venous pressure (CVP), from 16.2 +/- 2.2 to 14.6 +/- 2.2 mmHg (P < 0.0001), and the transpulmonary pressure gradient between the CVP and left atrial pressure, from 9.9 +/- 2.9 to 8.4 +/- 2.7 mmHg (P < 0.0001). It also increased the systolic systemic arterial pressure from 71.9 +/- 15.2 to 76.8 +/- 14.5 mmHg (P < 0.05). In 26 patients with additional fenestration, inhaled NO led to a significant improvement in SaO(2) from 90.1% +/- 9.6% to 93.3% +/- 7.9% (P < 0.01). However, patients with a CVP <15 mmHg or a transpulmonary pressure gradient <8 mmHg, or both, after the Fontan-type operation, showed no significant changes in hemodynamics during inhaled NO therapy. CONCLUSIONS: We propose that a CVP >/=15 mmHg or a transpulmonary pressure gradient >/=8 mmHg, or both, after Fontan-type operations are appropriate indications for inhaled NO therapy.

Administration, Inhalation↗

[Biophysical basics of aerosol therapy in bronchial asthma].

For an effective inhalation therapy with aerosols the drug itself but also the inhalation device have to be considered. Several biophysical parameters influence the deposition in different regions of the respiratory tract. Particle size and the breathing pattern of the patient are the most important factors and have to be considered.

Aerosols↗

Deposition and clearance of inhaled 18FDG powder in patients with chronic obstructive pulmonary disease.

As freon is limited in its use as a generator for aerosol inhalation, powder particles are used as an alternative for inhalation therapy. The pulmonary deposition and clearance of inhaled powder particles was studied by positron emission tomography (PET) in ten patients with chronic obstructive pulmonary disease (COPD) and in five normal controls. The powder, 5 microm in mean diameter, was water soluble and labelled with 2-deoxy-2-[18F]-fluoro-D-glucose (18FDG). Powder inhalation was done with single deep inspiration from residual volume to total lung capacity. The initial deposition ratio in the right or left lung field to total inhaled dose, measured by an anteroposterior rectilinear scan, did not differ between normals and COPD patients. Ratios of radioactivity detected within the central and peripheral regions (the central to peripheral ratio) measured by the PET scan was not significantly different between COPD patients (4.8+/-2.6, mean+/-SD) and normals (2.6+/-0.8, mean+/-SD). However, the regional powder deposition in peripheral lung fields measured by the PET scan was significantly more uneven in COPD patients than in normal patients. The clearance rate of 18FDG, defined as the retention ratio of 18FDG activity to the initially deposited 18FDG at 60 and 120 min after inhalation, in the trachea, large bronchi or peripheral lung fields measured by tomographic scan showed a wider variation in COPD patients than in normals. To conclude, inhaled powder tended to be deposited more centrally and was distributed more unevenly in the peripheral lung in chronic obstructive pulmonary disease patients than in normals. This could be a limitation of powder inhalation used for therapy in chronic obstructive pulmonary disease patients.

Administration, Inhalation↗

Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy.

Our previous studies have demonstrated that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity in vivo and that this inhibition is associated with rebound pulmonary hypertension upon acute withdrawal of inhaled NO. We have also demonstrated that inhaled NO elevates plasma endothelin-1 (ET-1) levels and that pretreatment with PD156707, an ETA receptor antagonist, blocks the rebound hypertension. The objectives of this study were to further elucidate the role of ET-1 in the rebound pulmonary hypertension upon acute withdrawal of inhaled NO. Inhaled NO (40 ppm) delivered to thirteen 4-week-old lambs decreased NOS activity by 36.2% in control lambs (P<0.05), whereas NOS activity was preserved in PD156707-treated lambs. When primary cultures of pulmonary artery smooth muscle cells were exposed to ET-1, superoxide production increased by 33% (P<0.05). This increase was blocked by a preincubation with PD156707. Furthermore, cotreatment of cells with ET-1 and NO increased peroxynitrite levels by 26% (P<0.05), whereas preincubation of purified human endothelial nitric oxide synthase (eNOS) protein with peroxynitrite generated a nitrated enzyme with 50% activity relative to control (P<0.05). Western blot analysis of peripheral lung extracts obtained after 24 hours of inhaled NO revealed a 90% reduction in 3-nitrotyrosine residues (P<0.05) in PD156707-treated lambs. The nitration of eNOS was also reduced by 40% in PD156707-treated lambs (P<0.05). These data suggest that the reduction of NOS activity associated with inhaled NO therapy may involve ETA receptor-mediated superoxide production. ETA receptor antagonists may prevent rebound pulmonary hypertension by protecting endogenous eNOS activity during inhaled NO therapy.

Administration, Inhalation↗

History of aerosol therapy: liquid nebulization to MDIs to DPIs.

Inhaled therapies have been used since ancient times and may have had their origins with the smoking of datura preparations in India 4,000 years ago. In the late 18th and in the 19th century, earthenware inhalers were popular for the inhalation of air drawn through infusions of plants and other ingredients. Atomizers and nebulizers were developed in the mid-1800s in France and were thought to be an outgrowth of the perfume industry as well as a response to the fashion of inhaling thermal waters at spas. Around the turn of the 20th century, combustible powders and cigarettes containing stramonium were popular for asthma and other lung complaints. Following the discovery of the utility of epinephrine for treating asthma, hand-bulb nebulizers were developed, as well as early compressor nebulizers. The marketing of the first pressurized metered-dose inhaler for epinephrine and isoproterenol, by Riker Laboratories in 1956, was a milestone in the development of inhaled drugs. There have been remarkable advances in the technology of devices and formulations for inhaled drugs in the past 50 years. These have been influenced greatly by scientific developments in several areas: theoretical modeling and indirect measures of lung deposition, particle sizing techniques and in vitro deposition studies, scintigraphic deposition studies, pharmacokinetics and pharmacodynamics, and the 1987 Montreal Protocol, which banned chlorofluorocarbon propellants. We are now in an era of rapid technologic progress in inhaled drug delivery and applications of aerosol science, with the use of the aerosolized route for drugs for systemic therapy and for gene replacement therapy, use of aerosolized antimicrobials and immunosuppressants, and interest in specific targeting of inhaled drugs.

Administration, Inhalation↗

[Diagnosis and therapy of hemodynamic disorders. A contribution to the management of pregnancies with threatened premature labor].

114 pregnant women (without multiple pregnancies) with premature labour were examined in a randomized prospective study. Pulsatility index (PI) in the uterine artery and fetal thoracic aorta was the parameter we used for the examination, the determination of which was done with doppler sonography at the time of hospital admission. Therapy with beta-sympathomimetics alone or additionally either Oxygen inhalation therapy or transcutaneous dorsal nerve stimulation were conducted and the pulsatility index was controlled at intervals of one and two weeks after initiation of the aforementioned therapy. The negative correlations which we determined between pulsatility index and prolongation of duration of pregnancy, gestational age at the time of delivery and birth weight were significant. This confirms the clinical importance of maternal perfusion already at the time of admission for the clinical end-results. Similarly significantly negative correlations between pulsatility index of uterine vessels, weight percentile of the corresponding newborns and antenatal CTG scores (Fischer) verify the close connections between the hemodynamic, nutritional and respiratory partial functions of the fetoplacento-maternal unit. The clinical results after normalization of an impaired perfusion were found to be improved significantly after a combined therapy with beta-sympathomimetics and transcutaneous dorsal nerve stimulation (TNS) as compared with beta-sympathomimetic therapy alone. These results justify the recommendation that doppler sonographic measurements of utero-placental perfusion can be used for the diagnostic and therapeutic concept in pregnancies with premature labour.

Cardiotocography↗

Randomised placebo-controlled trial of inhaled sodium cromoglycate in 1-4-year-old children with moderate asthma.

BACKGROUND: Inhalation therapy with sodium cromoglycate is recommended as the first-line prophylactic treatment for moderate asthma in children. The availability of spacer devices with face-masks has extended the applicability of metered-dose inhalers to younger children. We studied the feasibility and effects of this therapy compared with placebo in children aged 1-4 years. METHODS: 218 children aged 1-4 years with moderate asthma were recruited through 151 general practitioners between March, 1995, and March, 1996. They were randomly assigned sodium cromoglycate (10 mg three times daily) or placebo, given by inhaler with spacer device and face-mask for 5 months. Rescue medication (ipratropium plus fenoterol aerosol) was available during the baseline period of 1 month and the intervention period. Parents completed a daily symptom-score list. The primary outcome measure was the proportion of symptom-free days in months 2 to 5. Analysis was by both intention to treat and on treatment. FINDINGS: 167 (77%) children completed the trial. 131 (78%) of these children used at least 80% of the recommended dose. Of the 51 children who stopped prematurely, 23 had difficulties with inhaled treatment. The mean proportion of symptom-free days for both groups was greater for the treatment period than for the baseline period (95% CI for mean difference 5.1 to 17.5 cromoglycate, 11.9 to 23.3 placebo). However there were no differences between the sodium cromoglycate and placebo groups in the proportion of symptom-free days (mean 65.7 [SD 25.3] vs 64.3 [24.5]%; 95% CI for difference -8.46 to 5.70) or in any other outcome measure. INTERPRETATION: Our study in a general practice setting shows that inhalation therapy with a spacer device and face-mask is feasible in a majority of children below the age of 4 years. However, long-term prophylactic therapy with inhaled sodium cromoglycate is not more effective than placebo in this age-group.

Administration, Inhalation↗

[Efficacy and safety of inhaled drugs].

In the paper the foundations are presented of current inhalation therapy, particularly of that applied in childhood. The problems are discussed, concerning deposition of aerosols in the tracheobronchial tree achieved by various methods of aerosol generation. Various factors affecting the bioavailability of the inhaled drugs are defined. Particular attention is paid to the problems of safety of inhaled corticosteroid therapy, stability of the inhaled drugs and their influence on the pulmonary surfactant.

Administration, Inhalation↗

Contamination of hospital compressed air with nitric oxide: unwitting replacement therapy.

BACKGROUND: Inhaled nitric oxide (NO) at levels between 5 and 80 ppm has been used experimentally to treat a variety of conditions. NO also is a common environmental air pollutant in industrial regions. As compressed hospital air is drawn from the local environment, we speculated that it may contain NO contamination, which, if present, would provide unwitting inhaled NO therapy to all subjects respiring this compressed gas. METHODS: NO levels were measured twice daily from ambient hospital air and compressed gas sources driving positive pressure ventilation from two adjacent hospitals and compared with NO levels reported daily by local Environmental Protection Agency sources. An NO chemiluminescence analyzer (Sievers 270B; Boulder, Colo) sensitive to > or =2 parts per billion was used to measure NO levels in ambient air and compressed gas. RESULTS: NO levels in ambient air and hospital compressed air covaried from day to day, and absolute levels of NO differed between hospitals with the difference never exceeding 1.4 ppm (range, 0 to 1.4 ppm; median, 0.07 ppm). The hospital with the highest usage level of compressed air had the highest levels of NO, which approximated ambient levels of NO. NO levels were lowest on weekends in both hospitals. We also documented inadvertent NO contamination in one hospital occurring over 5 days, which corresponded to welding activity near the intake port for fresh gas. This contamination resulted in system-wide NO levels of 5 to 8 ppm. CONCLUSION: Hospital compressed air contains highly variable levels of NO that tend to covary with ambient NO levels and to be highest when the rate of usage is high enough to preclude natural degradation of NO in 21% oxygen. Assuming that inhaled NO may alter gas exchange, pulmonary hemodynamics, and outcome from acute lung injury, the role of unwitting variable NO of hospital compressed air needs to be evaluated.

Air↗