[Recent achievements in inhalation therapy].
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The inhalation route is widely used for the treatment of obstructive lung diseases, because administered drugs have a high therapeutic index as they reach their target directly; this requires that they be of adequate size to penetrate the conducting airways, i.e. 2-5 microns. Pressurized inhalers were the first reliable metered-dose devices available, and are still the most frequently used. However, metered-dose inhaler (MDI) suspensions will have to be reformulated: they contain chlorofluorocarbons (CFCs), whose production has to be stopped within a few years, as they affect the stratosphere. Another limitation of MDI usage is paradoxical bronchospasm; this phenomenon, however, occurs in a low number of patients and is rarely clinically relevant. The main cause of concern with MDIs is their misuse by more than 50% of patients, which leads to a reduced lung deposition and clinical efficacy. Therefore, other inhalation devices have been developed: spacers, dry-powder inhalers (DPIs), and breath-actuated MDIs have been shown to increase lung deposition of drugs in poor coordinators. However, all have limitations which may have varying consequences on clinical efficacy: cumbersome dimensions of spacers, effect of inspiratory flow rate and humidity on lung deposition of dry powders, need for reformulation with CFC-free gases for breath-actuated pressurized inhalers. Reformulation of MDI aerosols is a complex procedure, which may not be feasible for all drugs. The new products need extensive toxicological and clinical testing, as some of their characteristics may differ from those of their predecessors.
Binding of NO to heavy metal-containing proteins probably accounts for many of its physiologic actions. NO inhalation is a promising new treatment for various disorders of neonates. The therapy is most likely to benefit premature neonates who are hypoxemic despite breathing pure oxygen and those who suffer from impaired carbon dioxide elimination. Newborn infants who have congenital heart disease may benefit from inhaled NO therapy if their disease involves some form of pulmonary venous hypertension or if they have recently undergone surgery involving cardiopulmonary bypass grafting. The use of NO in infants with PPHN might obviate the need for ECMO or other invasive treatment methods. Neonates with CDH seem likely to benefit marginally from NO therapy. Minimizing the toxicities of NO inhalation therapy requires that the physicians understand the nuances of infant care. The therapeutic value of increasing carbon dioxide elimination with NO inhalation warrants further investigation.
BACKGROUND: The extent to which inhaled glucocorticoids increase the risk of intraocular pressure elevation has been controversial. OBJECTIVE: The authors attempt to assess such risk attributable to budesonide, an inhaled glucocorticoid for asthma therapy. METHODS: Data were pooled from four prospective, randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trials of 12 to 20 weeks in duration. One thousand two hundred and fifty-five patients, 6 to 70 years of age whose intraocular pressures (IOPs) were less than 23 mmHg at screening were randomized to receive placebo or inhaled budesonide at doses ranging from 100 to 800 microg, administered twice daily. Intraocular pressure was measured at screening and at the end of double-blind treatment. Intraocular change was compared between budesonide and placebo, accounting for the confounding effects of gender, race, age, history of diabetes, history of hypertension, clinical trial, systemic glucocorticoid use during the trials, ophthalmic glucocorticoid use during the trials, and prior oral glucocorticoid use. RESULTS: No budesonide treatment effect on the IOP was evident either in the crude analysis or after adjustment for possible confounding factors. For patients exposed to budesonide at a total daily dose of 1600 microg for 20 weeks, there was no difference in IOP change compared with the placebo controls. CONCLUSIONS: No association with an increased IOP was observed in asthmatic patients treated with budesonide at daily doses ranging from 200 to 1600 microg for durations of 12 to 20 weeks. The subgroup analysis, which focused on the highest dose and longer term therapy was reassuring, as was the overall result.
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The humble origins of the propellant driven metered dose inhaler, as a response to a child's enquiry, initiated an industry which supplies approximately a half billion inhalers globally for the treatment of asthma. These inhalers fall into three major groups: nebulizers; propellant driven metered dose inhalers and dry powder inhalers. Each requires drug formulation, metering and device technology to be successful. In recent years there have been several new developments in the field including auxiliary systems to improve drug delivery from the device to the patient and new categories of device, notably single breath aqueous systems. As device technology improves and our understanding of the disease leads to new drugs the only barrier to therapy is the patient. Patient training and compliance will continue to be important factors in the success, or failure, of inhaled therapy and the role of health care professionals will depend on who sponsors their intervention.
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The authors designed a low-deadspace system to deliver inhaled nitric oxide from a high-concentration (10%) source. Nitric oxide, nitrogen dioxide, and O2 concentrations were compared under simulated inhaled nitric oxide therapy (in vitro) from low (0.08%, 800 ppm) and high (10%, 100,000 ppm) sources of nitric oxide in nitrogen. O2 concentrations remained above 99% and nitrogen dioxide below 3 ppm for nitric oxide delivered at dosages up to 180 ppm from the 10% source. An acute toxicity trial (in vivo) was also performed in nine rabbits mechanically ventilated with 100% O2 for four hours. Six rabbits received 80 ppm nitric oxide from a 10% source and three control rabbits received only O2. Nitric oxide, nitrogen dioxide, and O2 concentrations were monitored in the ventilator circuit. Methemoglobin, arterial blood gases, arterial blood pressure, and heart rate were sampled every hour. At the 80-ppm nitric oxide dose, an average of 1.1 +/- 0.2 ppm of nitrogen dioxide was produced within the ventilator circuit. Arterial methemoglobin in rabbits that received nitric oxide rose by 0.5% from baseline, compared with a 0.2% rise for controls (p = 0.001). The authors conclude that inhaled nitric oxide therapy can be provided from a high-concentration source. Because this system does not reduce inspired O2 fraction, it may be more appropriate than low-source-concentration nitric oxide delivery systems for testing the efficacy of inhaled nitric oxide as an adjunct to optimal conventional medical therapy.