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Administration, Inhalation↗
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Considerations for toxicology studies of respiratory drug products.
The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intended patient population is often particularly susceptible. Current and former representatives of the Division of Pulmonary Drug Products (CDER, U.S. FDA) present this article to describe general principles of preclinical development for respiratory drug indications. The article addresses drugs intended for administration by the intranasal or inhalation routes. The article describes the types of studies recommended, considers the initial human dose, and discusses dose-escalation strategies in clinical trials. Other areas of special concern with intranasal or inhalation administration include immunotoxicity, reproductive toxicity, types of dosing apparatus, excipients and extractables, and formulation changes. The approaches described in this article are intended as general information and should be adapted to the scientific considerations and circumstances of a particular drug under development.
Humans↗
The distribution of dust in the rat lung following administration by inhalation and by single intratracheal instillation.
A comparison was made of the distribution of dust in the rat lung following its administration by inhalation and by a single intratracheal instillation. Due to the wide variety of instillation techniques, an "average" method was adopted based on the results from a survey of 15 laboratories in Europe and the USA. Novel techniques were developed to quantify the distribution of dust within the lung both microscopically and macroscopically. The distribution of dust obtained by instillation was shown to be much less homogeneous that that obtained by inhalation and penetration to the periphery was minimal. The effects of (a) changing the volume of suspension, (b) changing the concentration of the suspension, and (c) introducing air into the syringe were investigated. Although the use of air in the syringe was beneficial, none of the other modifications effected any improvement in the distribution. The difference in distribution following inhalation and instillation leads to the conclusion that the latter may be of use in establishing the nature and comparative response of the lung to different dusts, but not for establishing an absolute dose-response relationship. It is recommended that no more than 1 mg of fibrous or 5 mg of nonfibrous dust be given in a single instillation to adult rats.
Animals↗
Two cases of asthma in handicapped elderly persons in which assisted inhalation therapy was effective.
BACKGROUND: Chronic airway inflammation is a basic pathology of bronchial asthma and it is important to control the inflammation by anti-inflammatory therapy mainly with steroids. However, in asthma in the elderly, there are cases where physicians hesitate to introduce the inhaled corticosteroid (ICS) therapy based on the diagnosis that the use of inhalants is difficult due to the existence of a functional lesion accompanying asthma. METHODS & RESULTS: In cases where self-administrated inhalation therapy is difficult to execute due to the accompaniment of a functional lesion and in cases where sufficient curative effects of steroids are not produced in self-inhalation, administration of assisted inhalation resulted in improvement of clinical symptoms and pulmonary function and was proven effective. CONCLUSIONS: Assisted inhalation therapy is expected to be useful in general and also in terms of expanding the application of ICS in the asthma in the elderly.
Administration, Inhalation↗
Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates.
BACKGROUND: Chronic lung disease remains a common complication amongst preterm infants. There is increasing evidence that inflammation play an important role in the pathogenesis of CLD. Due to their strong anti-inflammatory properties corticosteroids is an attractive intervention strategy. However, there are growing concerns regarding short and long term effects of systemic corticosteroids. Theoretically, administration of inhaled corticosteroids may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects. OBJECTIVES: To determine the impact of inhaled corticosteroids administered to ventilated very low birth weight preterm neonates in the first two weeks of life for the prevention of chronic lung disease(CLD). SEARCH STRATEGY: Systematic search in accordance with Cochrane Neonatal Review Group. Randomized and quasi-randomized trials were identified by searching MEDLINE, Embase, CINAHL, the Cochrane Library, reference lists of published trials and abstracts published in Pediatric Research. SELECTION CRITERIA: Randomized controlled trials of inhaled corticosteroid therapy initiated within the first 2 weeks of life in ventilated preterm infants with birth weight 1500 grams or less were included in this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including chronic lung disease at 28 days or 36 weeks corrected gestational age (CGA), mortality, combined outcome of death or CLD at 28 days of age and at 36 weeks CGA, the need for systemic corticosteroids, failure to extubate within 14 days and adverse effects of corticosteroids were evaluated. All data were analyzed using Revman 3.1. When possible, meta-analysis was performed using relative risk (RR), risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, number needed to treat (NNT) was calculated. MAIN RESULTS: Eight trials assessing the impact of inhaled corticosteroid for the prevention of CLD were identified. The study by Kovacs 1998 was excluded as investigators evaluated the impact of a combination of systemic and inhaled corticosteroid for prevention of CLD. Seven trials qualified for inclusion in this review but data from two of these studies are awaiting assessment. Thus, the present review includes data analyses based on five qualifying trials. There was no statistically significant effect of inhaled steroids on CLD either at 28 days or at 36 weeks CGA, when analyzed either for all randomized infants or amongst survivors. No statistically significant differences were noted for mortality or for the combined outcome of mortality and CLD either at 28 days of age or at 36 weeks CGA. The meta-analysis supports a reduction in the need for systemic steroids, RR 0.78 (95% CI 0.62, 0.99), RD -0. 097 (95% CI -0.187, -0.008); however statistical heterogeneity was noted. The number needed to treat (NNT) to reduce the need for systemic steroid was 10 (95% CI 5.3, 125). There were no statistically significant differences in adverse events between groups. REVIEWER'S CONCLUSIONS: There is no evidence from the trials reviewed that early administration (in the first 2 weeks of life) of inhaled steroids to ventilated preterm neonates was effective in reducing the incidence of CLD. There was a reduction in the need for systemic steroids. Although this difference was statistically significant, there was significant heterogeneity between studies and the upper limit of the 95% CI for this outcome was very close to no effect. Currently, use of inhaled steroids in this population cannot be recommended. Studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short-term and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.
Administration, Inhalation↗
Model-based administration of inhalation anaesthesia. 1. Developing a system model.
This paper is the first of a series of reports on a system model for the administration of inhalation anaesthesia. We present the development and basic testing of the model. It is a multiple-gas model; it covers fresh-gas flow rates from basal to more than total ventilation and includes an actual, not an idealized, circle-absorber breathing system featuring a standing bellows ventilator. Kinetics of nitrogen, oxygen, carbon dioxide, nitrous oxide, inhaled anaesthetic agents and helium are described. Their partial pressures sum to the total pressure. Ventilation and cardiac output are treated as continuous, not cyclical. The model of the breathing system was empirically matched to the chosen one (a GMS absorber and 7850 ventilator (Datex-Ohmeda)). Predictions for the wash-in of isoflurane and the uptake of desflurane and isoflurane agree well with observed data. The results obtained by continuously checking total gas pressures, calculating mass balances and simulating the measurement of alveolar space by the closed-circuit helium dilution method support the mathematical credibility of the model. It thus merits further exploration.
Algorithms↗
Toluene-induced ototoxicity by subcutaneous administration.
Inhalation exposure of rats to toluene causes irreversible hearing loss (e.g., Pryor et al.). To determine whether noise emanating from the inhalation system was a major contributing factor and whether exposure by a noninhalation route would cause a similar effect, weanling, male Fischer-344 rats were injected SC twice daily in a quiet environment with PEG-300 (control) or with 1.5 or 1.7 g/kg of toluene for 7 days. After being trained to perform a multisensory conditioned avoidance response (CAR) task, tone intensity-response functions were generated at 4, 8, 12, and 20 kHz, and behavioral auditory response thresholds were estimated. Toluene caused a dose-related hearing loss at frequencies of 8 kHz and above, with no effect on performance of the CAR in response to light, nonaversive footshock, or the 4-kHz tone. The similarity of this effect to that observed following inhalation exposure indicates that noise is not a major factor in the toluene-induced hearing loss, although possible interactions between noise and toluene remain to be investigated. These results also demonstrate that direct penetration of the toluene vapors through the external ear structure, as might occur during inhalation exposure, is not a necessary condition for inducing the hearing loss.
Air Pollutants↗
The pharmacokinetics of levosalbutamol: what are the clinical implications?
Salbutamol (albuterol) is a beta2-adrenoceptor agonist used as a bronchodilator for the treatment of asthma and as a uterine relaxant for the suspension of premature labour. Salbutamol has been marketed as a racemic mixture, although beta2-agonist activity resides almost exclusively in the (R)-enantiomer. The enantioselective disposition of salbutamol and the possibility that (S)-salbutamol has adverse effects have led to the development of an enantiomerically pure (R)-salbutamol formulation known as levosalbutamol (levalbuterol). Salbutamol is metabolised almost exclusively by sulphotransferase (SULT) 1A3 to an inactive metabolite. (R)-Salbutamol is metabolised up to 12 times faster than (S)-salbutamol. This leads to relatively higher plasma concentrations of (S)- salbutamol following all routes of administration, but particularly following oral administration because of extensive metabolism by the intestine. Enantiomer concentrations are similar for the first hour following an inhaled dose, reflecting the fact that salbutamol in the lung probably undergoes little metabolism. Subsequently, (S)-salbutamol predominates due to absorption and metabolism of the swallowed portion of the inhaled dose. Following oral or inhaled administration of enantiomerically pure salbutamol, a small amount (6%) is converted to the other enantiomer, probably by acid-catalysed racemisation in the stomach. Tissue binding of salbutamol is not enantioselective and plasma protein binding is relatively low. Both enantiomers are actively excreted into the urine. Compared with healthy individuals, patients with asthma do not have substantially different pharmacokinetics of the salbutamol enantiomers, but they do appear to have less drug delivered to the lung following inhaled administration because of their narrowed airways. Levosalbutamol elicits an equal or slightly larger response than an equivalent dose of the racemic mixture. This is probably due to competitive inhibition between the enantiomers at beta-adrenoceptors. Pharmacokinetic-pharmacodynamic relationships for levosalbutamol show relatively large interindividual variations. Functionally significant genetic polymorphisms have been identified for beta2-adrenoceptors, SULT1A3 and organic action transporters, all of which affect the disposition or action of levosalbutamol. Animal, in vitro and some clinical studies have reported deleterious effects of (S)-salbutamol on smooth muscle contractility or lung function. However, well-designed clinical studies in patients with asthma have failed to find evidence of significant toxicity associated with (S)-salbutamol. The clinical consequences of relatively higher plasma concentrations of (S)-salbutamol following administration of racemate remain unclear, but in the absence of clear evidence of toxicity the clinical superiority of levosalbutamol over racemic salbutamol appears to be small.
Administration, Inhalation↗
Mass balance and metabolism of [(3)H]Formoterol in healthy men after combined i.v. and oral administration-mimicking inhalation.
Mass balance and metabolism of formoterol were investigated in six healthy men in an open study. Mean age was 49.7 years (range: 40-63). Simultaneous oral (mean dose 88.6 nmol, 49.3 MBq) and i.v. (mean dose 38.2 nmol, 21.4 MBq) doses of tritium-labeled formoterol were administered. The combination of these two administrations was aimed at simulating the fate of inhaled formoterol. Total radioactivity was monitored for 24 h in blood plasma and for at least 4 days in urine and feces. Formoterol and metabolites were determined using liquid chromatography plus radiodetection, directly after centrifugation in urine and after sample workup in blood plasma and feces. Metabolites were identified in urine, sampled from two subjects, using liquid chromatography-electrospray ionization mass spectrometry. Mean total recovery was 86% of the administered formoterol dose, 62% in urine and 24% in feces. Tritiated water was generated and because its in vivo turnover is slow, the terminal decline of total radioactivity was slow and dose recovery was incomplete during the sampling period. Formoterol was conjugated to inactive glucuronides and a previously unidentified sulfate. The phenol glucuronide of formoterol was the main metabolite in urine. Formoterol was also O-demethylated and deformylated. Plasma exposure to these pharmacologically active metabolites was low. O-demethylated formoterol was seen mainly as inactive glucuronide conjugates and deformylated formoterol only as an inactive sulfate conjugate. Intact formoterol and O-demethylated formoterol dominated recovery in feces. Mean recovery of unidentified metabolites was 7. 0% in urine and 2.0% in feces.
Administration, Inhalation↗
Simultaneous administration of inhaled nitric oxide in two children with pulmonary hypertension.
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Administration, Inhalation↗
Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis.
Pseudomonas aeruginosa endobronchial infection causes significant morbidity and mortality among cystic fibrosis patients. Microbiology results from two multicenter, double-blind, placebo-controlled trials of inhaled tobramycin in cystic fibrosis were monitored for longitudinal changes in sputum microbial flora, antibiotic susceptibility, and selection of P. aeruginosa isolates with decreased tobramycin susceptibility. Clinical response was examined to determine whether current susceptibility standards are applicable to aerosolized administration. Treatment with inhaled tobramycin did not increase isolation of Burkholderia cepacia, Stenotrophomonas maltophilia, or Alcaligenes xylosoxidans; however, isolation of Candida albicans and Aspergillus species did increase. Although P. aeruginosa tobramycin susceptibility decreased in the tobramycin group compared with that in the placebo group, there was no evidence of selection for the most resistant isolates to become most prevalent. The definition of resistance for parenteral administration does not apply to inhaled tobramycin: too few patients had P. aeruginosa with a tobramycin MIC >/=16 microgram/mL to define a new break point on the basis of clinical response.
Administration, Inhalation↗
Administration of inhaled medication via a tracheostomy in infants with chronic lung disease of prematurity.
Four cases of infants with chronic lung disease of prematurity in whom a tracheostomy was performed for acquired subglottic stenosis are reported. The feasibility of administration of inhaled drugs and supplemental oxygen are discussed.
Aerosols↗
Guidelines for the safe administration of inhaled nitric oxide.
Inhaled nitric oxide (NO) is a selective pulmonary vasodilator, potentially useful in the treatment of pulmonary hypertension and ventilation-perfusion mismatch. High doses of inhaled NO and its oxidative product nitrogen dioxide (NO2) may cause acute lung injury. Using a standard infant ventilator, ventilator circuit and test lung, an administration and monitoring strategy has been defined for inhaled NO and these observations validated in eight ventilated infants. In 90% oxygen, doses of inhaled NO > or = 80 parts per million may result in toxic NO2 concentrations.
Administration, Inhalation↗
Is the administration of inhaled nitric oxide (NO) associated with electroencephalogram abnormalities? There is NO harm in looking.
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Administration, Inhalation↗
Contemporary opinions on administration of inhaled glucocorticosteroids in the treatment of chronic obstructive pulmonary disease.
The contemporary medicine is looking for new, more effective methods of treatment for patients suffering from chronic obstructive pulmonary disease (COPD), whose number is systematically increasing. It seems that main challenges involve improving treatment efficiency, preventing exacerbations and inhibiting the progression of the disease. The aim of this paper is to briefly present the contemporary knowledge of the application of inhaled glucocorticosteroid in COPD treatment, their effectiveness and side-effects. According to the present state of knowledge, inhaled glucocorticosteroid do not inhibit the neutrophil inflammation in COPD. However, they significantly restrict the inflammatory response in severe forms of the disease, which, practically, means decrease of exacerbation frequency, life quality improvement and mortality reduction in these patients. Inhaled glucocorticosteroids, just like systemic glucocorticosteroids, do have many side-effects, but they can be effectively prevented.
Administration, Inhalation↗
[The immediate response to the administration of inhaled nitric oxide in a newborn infant with congenital diaphragmatic hernia and pulmonary hypertension].
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Administration, Inhalation↗
A comparison of different intervals of administration of inhaled terbutaline in children with acute asthma.
Thirty asthmatic children, 5 to 14 years of age, 20 boys and 10 girls, were studied while having acute asthmatic attacks. Each group of 10 children received either a single dose of 6 puffs (1500 micrograms) or 3 doses of 2 puffs (500 micrograms) at 5-minute or 15-minute intervals of terbutaline pressurized aerosol inhaler through a 750-ml volumetric spacer. The onset of bronchodilatation was observed within 2 minutes in all. The 3 doses at 15-minute intervals gave the greatest bronchodilatation throughout the 6-hour study period in comparing with the other two regimens. Slightly insignificant increases in systolic blood pressure and heart rate were observed in all groups and there were no statistically significant differences among them. No serious side effects were observed.
Acute Disease↗
Early administration of inhaled nitric oxide to children with acute respiratory distress syndrome and its effects on oxygenation and ventilator settings: prospective preliminary report of ten patients.
AIM: To establish a protocol for the early introduction of inhaled nitric oxide (iNO) therapy in children with acute respiratory distress syndrome (ARDS) and to assess its acute and sustained effects on oxygenation and ventilator settings. PATIENTS AND METHODS: Ten children with ARDS, aged 1 to 132 months (median, 11 months), with arterial saturation of oxygen <88% while receiving a fraction of inspired oxygen (FiO2) >or=0.6 and a positive end-expiratory pressure of >or=10 cm H2O were included in the study. The acute response to iNO was assessed in a 4-hour dose-response test, and positive response was defined as an increase in the PaO2/FiO2 ratio of 10 mm Hg above baseline values. Conventional therapy was not changed during the test. In the following days, patients who had shown positive response continued to receive the lowest iNO dose. Hemodynamics, PaO2/FiO2, oxygenation index, gas exchange, and methemoglobin levels were obtained when needed. Inhaled nitric oxide withdrawal followed predetermined rules. RESULTS: At the end of the 4-hour test, all the children showed significant improvement in the PaO2/FiO2 ratio (63.6%) and the oxygenation index (44.9%) compared with the baseline values. Prolonged treatment was associated with improvement in oxygenation, so that FiO2 and peak inspiratory pressure could be quickly and significantly reduced. No toxicity from methemoglobin or nitrogen dioxide was observed. CONCLUSION: Administration of iNO to children is safe. iNO causes rapid and sustained improvement in oxygenation without adverse effects. Ventilator settings can safely be reduced during iNO treatment.
Administration, Inhalation↗