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PubMed2005

Toluene inhalation-induced adrenocortical hypertrophy and endocrinological changes in rat.

Rats were exposed to toluene (1,500 ppm for 4 hr per day) for 7 days. The body weight of the rats was significantly lower and the weight of the adrenal gland was significantly higher in the toluene inhalation group compared to the controls. Microscopically, there was no obvious change in the medulla, but hypertrophy of the cortex was observed in the toluene inhalation group. And, the size of adrenocortical cells in treated-rats was also significantly enlarged than the control. Immunohistochemical staining did not show a clear difference in localization of aldosterone-positive cells between the control and inhalation groups. Expansion of the corticosterone-positive area consistent with the cortical hypertrophy was recognized in the inhalation group. Enhancement of 72 kD-heat-shock protein (HSP70)-expression in the toluene inhalation group was not observed. Neither stress nor damage to cortical cells due directly to toluene exposure was observed in the cortex. Also, there was no obvious difference in the anti-proliferating cell nucleus antigen (PCNA)-immunostaining between control and inhalation groups. Thus, it is suspected that cortical hypertrophy was the result of cell enlargement due to the stimulation of the cortical cells. Corticotropin-releasing factor (CRF) immunoreactivity in the paraventricular nucleus (PVN) was increased in the inhalation group. Concentration of plasma ACTH was elevated significantly by toluene exposure. The amounts of mRNA of adrenocortical steroid metabolism gene, cytochrome side-chain cleavage (P450scc), was also increased by toluene inhalation. Toluene exposure might induce adrenocortical hypertrophy via the hypothalamus-pituitary-adrenal gland (HPA) axis.

Administration, Inhalation↗
PubMed2005

A rat model of smoke inhalation injury: influence of combustion smoke on gene expression in the brain.

Acute smoke inhalation causes death and injury in victims of home and industrial fires as well as victims of combat situations. The lethal factors in combustion smoke inhalation are toxic gases and oxygen deficiency, with carbon monoxide (CO) as a primary cause of death. In survivors, inhalation of smoke can result in severe immediate and delayed neuropathologies. To gain insight into the progression of molecular events contributing to smoke inhalation sequelae in the brain, we developed a smoke inhalation rat model and conducted a genome-wide analysis of gene expression. Microarray analysis revealed a modified brain transcriptome with changes peaking at 24 h and subsiding within 7 days post-smoke. Overall, smoke inhalation down regulated genes associated with synaptic function, neurotransmission, and neurotrophic support, and upregulated genes associated with stress responses, including nitric oxide synthesis, antioxidant defenses, proteolysis, inflammatory response, and glial activation. Notably, among the affected genes, many have been previously implicated in other types of brain injury, demonstrating the usefulness of microarrays for analysis of changes in gene expression in complex insults. In accord with previously described modulations of nitric oxide homeostasis in CO poisoning, microarray analysis revealed increased brain expression of nitric oxide synthase (NOS) and NOS ligand after inhalation of smoke. Furthermore, immunostaining showed significant elevations in perivascular NOS and in protein nitration, corroborating the involvement of nitric oxide perturbations in post-smoke sequelae in the brain. Thus, the new rat model, in combination with microarray analyses, affords insight into the complex molecular pathophysiology of smoke inhalation in the brain.

Animals↗
PubMedDate not supplied

A novel propellant-free inhalation drug delivery system for cardiovascular drug safety evaluation in conscious dogs.

INTRODUCTION: Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. This paper describes a new strategy for treating conscious labrador dogs with drugs by inhalation using a specially designed mask and a novel inhaler device. METHODS: Labrador dogs (male or female) were used that had transducers implanted for the measurement of left ventricular and descending aortic blood pressures and an ECG for use together with a telemetry system. Administration by inhalation was achieved using a novel delivery device. The Respimat device is a propellant-free inhaler to deliver aerosols from solutions. The new system was evaluated using Formoterol with four dogs using a 4 x 4 Latin square design. Three doses of Formoterol (0.6, 1.2, and 2.4 microg/kg, dissolved in 60% ethanol) were administered by inhalation together with a vehicle (60% ethanol) treatment by applying three inhalations, each consisting of 10 microl solution. RESULTS: Formoterol increased HR, QRS-interval, QT-interval, and LVPdP/dtmax and dose-dependently decreased systolic and diastolic BP. This effect lasted up to 14 h. DISCUSSION: Drug administration by inhalation in the conscious labrador dog using the Respimat is a useful new model for safety pharmacology studies of new drug candidates that are intended to be given by inhalation in the clinic.

Administration, Inhalation↗
PubMed1994

Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response.

To determine the role of inhaled nitric oxide (NO) in a population of critically ill hypoxic near-term infants and to determine the dose response to inhaled NO, we examined a consecutive group of 23 infants referred for neonatal extracorporeal membrane oxygenation (ECMO) who had an oxygen index of 20 or greater after treatment with bovine surfactant. Inhaled NO was administered in concentrations from 5 to 80 ppm in random order to 23 infants. Overall, 13 infants had a significant response (an improvement in arterial oxygen pressure > 10 mm Hg or arterial oxygen saturation > 10%) to the first administration of inhaled NO, and one infant had a late response. There was no significant difference in the response to inhaled NO as measured by changes in arterial oxygen pressure or in the alveolar-arterial difference in partial pressure of oxygen, for any of the doses from 5 to 80 ppm. Thirteen infants had echocardiographic evidence of persisted pulmonary hypertension; 11 of these infants responded, compared with 3 responders among the 10 infants without persistent pulmonary hypertension of the newborn (p < 0.01). Overall, 11 infants required ECMO; there were two deaths in this group. Seven infants had congenital diaphragmatic hernia; five of those had a response to NO inhalation and four required ECMO. Our study demonstrates that there is no significant difference in response between low and high doses of inhaled NO and that this treatment may prevent the need for ECMO in some infants referred for this therapy, especially in infants with pulmonary hypertension. Prospective, controlled, randomized, and blinded trials of low doses of inhaled NO are needed to determine the clinical role of this potentially useful therapy.

Administration, Inhalation↗
PubMed1997

Inhaled nitric oxide is not a negative inotropic agent in a porcine model of pulmonary hypertension.

BACKGROUND: Reports of pulmonary edema complicating inhaled nitric oxide therapy in patients with chronic heart failure and pulmonary hypertension have raised the concern that inhaled nitric oxide may have negative inotropic effects. METHODS AND RESULTS: We investigated the effect of multiple doses of inhaled nitric oxide (20, 40 and 80 ppm) on left ventricular contractile state in 10 open-chest pigs. Pressure-volume loops were generated during transient preload reduction to determine the end-systolic pressure-volume relationship and the stroke work-end-diastolic volume relation. Inhaled nitric oxide had no effect on systemic vascular resistance, cardiac output, end-systolic pressure volume relationship or stroke work-end-diastolic volume relation under normal conditions. After induction of pulmonary hypertension (intravenous thromboxane A2 analog), inhalation of nitric oxide (80 ppm) resulted in a reduction in pulmonary vascular resistance (mean +/- standard error of the mean) from 10.4 +/- 3 to 6.5 +/- 2 Wood units (p < 0.001) and in pulmonary artery pressure from 44 +/- 4 to 33 +/- 4 mm Hg (p < 0.05). Left ventricular end-diastolic volume rose from 53 +/- 9 ml to 57 +/- 10 ml (p = 0.02). No statistically significant change in cardiac output or systemic vascular resistance was observed. Inhaled nitric oxide had no effect on end-systolic pressure-volume relationship or stroke work-end-diastolic volume relation. CONCLUSIONS: In a porcine model of pulmonary hypertension, inhaled nitric oxide does not impair left ventricular contractile function. Therefore the cause of pulmonary edema observed in some patients receiving inhaled nitric oxide is not due to a negative inotropic action of this therapy.

Administration, Inhalation↗
PubMed1992

A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial.

We compared the effect of an inhaled corticosteroid, budesonide, and an inhaled beta 2-agonist, terbutaline, on clinical symptoms, lung function, and airway inflammation in 14 adult patients with newly diagnosed asthma. The study was conducted as a randomized, double-blind, parallel-group trial. Seven patients inhaled 600 micrograms, twice daily, of budesonide, the other seven patients inhaled 375 micrograms, twice daily, of terbutaline via identical metered-dose inhalers with a spacer. Bronchial biopsy specimens, obtained before randomization and after 3 months of treatment, were analyzed by electron microscopy. Both groups improved clinically budesonide was more effective than terbutaline in improving morning and evening peak expiratory flow rates, as well as bronchial responsiveness to inhaled histamine. Treatment with budesonide was accompanied by increased numbers of ciliated airway cells and intraepithelial nerves and fewer inflammatory cells, including eosinophils, especially in the epithelium, these changes were not observed in specimens from terbutaline-treated patients. We conclude that, in contrast to inhaled terbutaline, inhaled budesonide improved lung function and bronchial hyperreactivity in adult subjects with asthma treated for 3 months and that this corticosteroid was more effective in ameliorating abnormalities of the bronchial epithelium and decreasing inflammation in the airways.

Administration, Inhalation↗
PubMed1997

Effectiveness of prophylactic inhaled steroids in childhood asthma: a systemic review of the literature.

BACKGROUND: There has been no systematic appraisal of the evidence regarding the effectiveness of prophylactic inhaled steroids in childhood asthma. OBJECTIVE: We sought to evaluate the effectiveness of prophylactic inhaled steroids in childhood asthma. METHODS: A MEDLINE search from January 1966 through December 1996 was used to identify pertinent English-language publications. All randomized, double-blind, placebo-controlled trials of prophylactic inhaled steroid therapy for childhood asthma that included data on clinical outcomes (symptom scores and concomitant drug use) or laboratory outcomes (peak expiratory flow rate) were included. RESULTS: In total, 24 of 93 studies retrieved met the inclusion criteria. The overall weighted relative improvement in mean total symptom score (inhaled steroid vs placebo) was 50% (95% confidence interval [CI]: 49%, 51%), the overall weighted relative decrease in mean concomitant beta2-agonist use (inhaled steroid vs placebo) was 37% (95% CI: 36%, 38%), and the overall weighted relative decrease in mean concomitant oral steroid use (inhaled steroid vs placebo) was 68% (95% CI: 66%, 70%). The overall weighted absolute improvement in mean peak expiratory flow rate (inhaled steroid vs placebo) was 38 L/min (95% CI: 34.3 L/min, 41.7 L/min). CONCLUSIONS: Prophylactic inhaled steroids are effective, compared with placebo, in improving both clinical and laboratory outcomes in childhood asthma.

Child↗
PubMedDate not supplied

Inhaled nitric oxide for severe acute respiratory distress syndrome: a blessing or a curse?

The effects of inhaled nitric oxide (NO) in two young adults who developed severe acute respiratory distress syndrome are presented. Modest improvements in gas exchange and reductions in pulmonary artery pressures occurred after the initiation of treatment with inhaled NO. However, both patients became "dependent" on the inhaled NO for stabilization of their cardiopulmonary function. Repeated attempts to discontinue the inhaled NO resulted in life-threatening deterioration in gas exchange and hemodynamic instability. Prolonged family discussions were held regarding the withdrawal of inhaled NO and other life-sustaining therapies, when the irreversible nature of the patients' lung disease became apparent. However, both families were strong in their desire to continue all therapies--due in large part to the single organ nature of the disease process. Both patients died while receiving inhaled NO and escalating doses of sedative and analgesics. Based on this experience, it is recommended that clearly defined goals or endpoints for the discontinuation of inhaled NO should be established before its initial administration. If these goals are not achieved, then the therapy should be considered a failure and withdrawn. A similar strategy should be applied to all life-sustaining therapies in the intensive care unit setting (e.g., mechanical ventilation, vasopressors, dialysis). This requires that critical care clinicians effectively communicate the difference between aggressive supportive care and definitive treatment of the underlying disease process to patients or their families, or both. Furthermore, until the results of ongoing clinical trials of inhaled NO become available, it is recommended that its administration be restricted to medical centers examining its use in clinical trials.

Acute Disease↗
PubMed1999

Inhaled corticosteroids, family history, and risk of glaucoma.

OBJECTIVE: Until recently, inhaled corticosteroids were not considered to cause elevated intraocular pressure (IOP), although topical and oral corticosteroids have been shown to do so in susceptible individuals. The authors aimed to (1) identify whether an association existed between inhaled corticosteroid use and elevated IOP or open-angle glaucoma and (2) determine whether this effect may have a genetic basis. DESIGN: Cross-sectional, population-based study of 3654 persons 49 to 97 years of age attending the Blue Mountains Eye Study, near Sydney, Australia. METHODS: A series of questions assessed use of inhaled and other corticosteroids as well as family history of glaucoma. Elevated IOP was assessed using applanation tonometry. Diagnosis of glaucoma was based on automated perimetry defects and optic disc signs but without reference to IOP. MAIN OUTCOME MEASURE: Statistical analysis of associations between inhaled corticosteroid use and elevated IOP or glaucoma, by family history, adjusting for other risk factors. RESULTS: Open-angle glaucoma was diagnosed in 108 subjects, and elevated IOP was found in 160 subjects. In persons with a glaucoma family history, there was a strong association between inhaled corticosteroid use and presence of either glaucoma or elevated IOP (odds ratio [OR], 2.6; 95% confidence interval, 1.2-5.8). The risk increased with higher doses (OR, 6.3; 95% CI, 1.0-38.6) for persons who used more than four puffs per day. These findings were not explained by concurrent use of oral or ocular corticosteroids. In persons without a family history of glaucoma, no association was found between use of inhaled corticosteroids and glaucoma or elevated IOP. CONCLUSIONS: These findings suggest an association between ever use of inhaled corticosteroids and a finding of elevated IOP or glaucoma in subjects with a glaucoma family history. Patients being treated with inhaled corticosteroids need review by an ophthalmologist if they report a glaucoma family history.

Administration, Inhalation↗
PubMed1997

A toxicological review of lactose to support clinical administration by inhalation.

Although lactose is widely used in the pharmaceutical industry as an excipient in preparations given by several routes of administration, including by inhalation, there is no comprehensive review of its toxicological properties. This document seeks to review the available oral preclinical and clinical safety data from the literature, together with that generated by Fisons in animals using the inhalation route. In animal toxicity studies, lactose has been administered primarily by the inhalation and dietary routes to the rat, dog and/or primate. Adverse findings, such as abdominal distension and diarrhoea, have been demonstrated in rodent feeding studies. However, these changes are considered to be due to non-specific effects associated with high dietary doses of lactose, with a subsequent production of a dietary imbalance which results in physiological disturbances and an overload in the metabolic processes particularly involving calcium. These changes at high dietary intakes of lactose are considered to be of little relevance for man under the normal conditions of use of the material as an excipient in pharmaceutical formulations. No adverse local effects to the lung have been demonstrated in the animal studies using the inhalation route. Although the inhalation dose of lactose in the animal studies, of which most is subsequently swallowed, is markedly higher than the clinical dose, it is considerably less than consumed in animal studies using the dietary route. Consequently, it is not surprising that lactose is well tolerated by the inhalation route. In a small number of susceptible humans, intolerance to lactose is generally observed with oral intake of lactose, usually as a constituent of milk and is associated with lactase deficiency. Swallowed lactose at the levels present in inhaled preparations is unlikely to present any significant problems in patients with lactase deficiency. In conclusion, lactose is well recognized as a safe pharmaceutical excipient for use in oral or inhalation formulations and is not likely to constitute any significant toxicological hazard to man.

Administration, Inhalation↗
PubMedDate not supplied

Inhalant use among antisocial youth: prevalence and correlates.

The current (2.9%), annual (19.6%), and lifetime (34.3%) prevalence of inhalant use among 475 youth (M age = 15.5; SD = 1.5; 87.4% male) on probation in a western state of the United States was assessed. Inhalant users reported significantly less family support and cohesiveness and lower self-esteem, and significantly more lifetime thoughts of suicide and suicide attempts, neighborhood gang activity, peer and parental substance abuse, intentions to engage in illegal behavior, substance-related criminality, and substance abuse than did nonusers. Ethnicity, self-esteem, suicidality, number of substance-using peers, and extent of substance-related criminality significantly discriminated inhalant users from nonusers in a logistic regression analysis. Multiple linear regression analyses indicated that age, perceived school ability, age at initiation of alcohol use, self-esteem, and substance-related criminality significantly predicted age at onset of inhalant use (R2 = .30). Age at initiation of inhalant use, gang membership, truancy, and substance-related criminality significantly predicted lifetime frequency of inhalant use (R2 = .20). Study findings indicate that inhalant-using delinquents evidence significantly greater antisocial attitudes, personal and familial dysfunction, and substance abuse, than do their non-inhalant-using counterparts.

Administration, Inhalation↗
PubMed1998

Inhalant abuse in pregnancy.

Information from a variety of sources suggests the possibility of adverse effects of maternal inhalant abuse, although a well-controlled, prospective study in this area has not been conducted. One source of this concern is the data from occupational exposure to some of the abused solvents, specifically toluene and TCE, with numerous reports suggesting increased spontaneous abortion and fetal malformations. There are also data suggesting decreased fertility and an increased risk for spontaneous abortion in health care workers exposed to nitrous oxide. The relevance of these studies to problems of inhalant abuse is not clear. Although the chemicals involved are the same, there are many differences in the exposure parameters, the populations exposed, and the types of associated risk factors. Nonetheless, there are more than 100 cases reported in the literature of children born to solvent-abusing mothers. Many of these children were small at birth, and some have craniofacial abnormalities not unlike that seen in children with FAS. In the few studies reporting the findings of follow-up in these children, some evidence has been obtained for retardation in growth and development and for residual deficits in cognitive, speech, and motor skills. Clearly, more research is needed to rule out the concomitant risk factors and to identify specific chemicals and patterns of use associated with adverse effects. Animal studies provide more direct evidence that prenatal exposure to toluene or TCE can produce reduced birth weights, occasional skeletal abnormalities, and delayed neurobehavioral development, even under conditions designed to mimic inhalant abuse patterns. Additional research is needed to identify other chemicals with adverse effects, critical periods of exposure, effects of combinations of inhalants, or interactions with drugs of abuse. The research literature seems sufficient to alert clinicians to possible problems in patients who abuse inhalants while pregnant. Diagnosis and good prenatal care for these women are important. The evidence for neonatal withdrawal is limited at this time; however, infants born to women who have recently used inhalants should be observed carefully for an alcohol-like withdrawal syndrome. Although it is not possible to link a specific birth defect or developmental problem in the child of an inhalant abuser to prenatal exposure to a specific chemical, it is clear that inhalant abuse and its associated lifestyle place children at increased risk. A wider appreciation of this is needed among health care professionals and the general public.

Anesthetics, Inhalation↗
PubMed1998

Household insecticides: evaluation and assessment of inhalation toxicity: a workshop summary.

Particularly in tropical countries household insecticides are used on a day-by-day basis to control mosquitoes, other crawling and flying insects to prevent the spread of vector-borne diseases. The products used most often are spray-cans, oil-sprays, mosquito coils as well as slow-release vaporising systems such as mats and liquid vaporiser. The extent and duration of exposure of humans is highly dependent on the type of product used. The objective of this workshop was to analyse the necessity and feasibility of inhalation studies with household insecticides taking into account the specific constrains associated with each type of end-use product. The standardisation of inhalation studies with regard to the generation of test atmospheres, mode and duration of exposure, and selection of adequate toxicological endpoints were addressed. Due to the complex nature of exposure atmospheres generated by some household insecticides, viz. mosquito coils, it is scientifically challenging to characterise the pathomechanism of most concern, since irritant combustion gases, volatile and semi-volatile organic substances, particulates (soot), condensation aerosols and re-condensed substances onto particulates may act independently, synergistically or mixture specific. It has been concluded that for the comparative safety evaluation and risk assessment of indoor insecticide end-use products generally recognised guidance for harmonised inhalation testing is required: 1) For high-dose release products, such as spray-cans, acute inhalation testing appears to be most relevant. 2) For low-dose, slow-release devices, subchronic inhalation studies of 13-weeks, duration of exposure 6 hours/day for 5 consecutive days per week, should be performed on rats preferably with the end-use product. A dose-range finding study of 2-weeks duration, daily exposure, should be available for the justification of dose selection and to demonstrate that the findings of 5 days/week exposure is not different from that utilising a daily exposure. 3) In certain instances, inhalation testing of shorter duration, for example 2 or 4 weeks, may be appropriate if the inhalation toxicity of the basic formula has already been characterised or the major constituents contained in the formulation have been examined in extant studies. The duration of study should also depend on actual use and exposure pattern, the accumulation potential and the mode of action of the ingredients of concern. 4) Particularly for mosquito coil smokes, the possible physico-chemical interactions of particulates, potentially irritant water soluble or nonsoluble vapours and aerosol or vapours of the active ingredient(s) are virtually impossible to predict without appropriate inhalation testing. 5) Physiological measurements may be useful for the detection and quantification of the respiratory tract sensory irritation potency. Biochemical endpoints in lung lavage and conventional histopathology of the lungs and extrathoracic airways are considered to be important. 6) It has been agreed that the nose-only exposure technique provides the most cost-effective and controlled means to expose small laboratory animals to well defined atmospheres as long as the limitations of this technique are taken into account.

Air Pollution, Indoor↗
PubMed2005

Effects of inhaled corticosteroids on bone.

OBJECTIVE: To discuss the effects of inhaled corticosteroids on bone and their potential public health implications. DATA SOURCES: The MEDLINE and EMBASE databases were searched to identify articles published between 1966 and January 2004 with the following keywords in the title: inhaled corticosteroid, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, triamcinolone plus bone, fracture, osteoporosis, osteocalcin, growth, or height. STUDY SELECTION: Key studies of adequate size and duration that allowed for potential confounding factors where required were selected. RESULTS: Inhaled corticosteroids are absorbed into the systemic circulation and therefore have the potential to cause adverse effects on bone. Several of the larger studies showed that inhaled corticosteroids cause a dose-related reduction in bone mineral density. Three cross-sectional studies found a dose-related increase in fractures in people taking an inhaled corticosteroid compared with controls. Prospective studies found a short-term reduction in growth velocity in children taking an inhaled corticosteroid, although target adult height is usually achieved. CONCLUSION: Since osteoporotic fracture is common in elderly patients and up to 5% of the population in more developed countries take an inhaled corticosteroid, these findings have public health implications. Strategies are needed to reduce the systemic effects of inhaled corticosteroids.

Administration, Inhalation↗
PubMed2006

Dose counting and the use of pressurized metered-dose inhalers: running on empty.

BACKGROUND: Pressurized metered-dose inhalers (pMDIs) are the cornerstone of asthma treatment. The pMDI is an economic and portable medication delivery system, but the device does not indicate how much medicine remains in the canister once a patient starts using it. OBJECTIVE: To determine how patients evaluate the contents of their pMDI and whether they are either discarding inhalers when medication remains or using inhalers beyond the indicated number of doses. METHODS: This study was conducted in April 2003 via a 6.5-minute telephone interview with a random sample of 500 families with asthma from across the United States. RESULTS: Of the 500 respondents participating in the telephone interview, nearly one third (31.6%) named an inhaled corticosteroid or bronchodilator and inhaled corticosteroid combination as the inhaler used when wheezing, coughing, or short of breath. Respondents using a bronchodilator (n = 342) varied in the frequency with which they use their pMDIs: 31.9% daily, 18.7% weekly, 23.4% monthly, and 23.1% less than once per month. More than half (53.8%) of bronchodilator users refill their prescriptions more frequently than recommended by national guidelines. Only 36% of bronchodilator users reported ever having been told to keep track of pMDI doses used. Of those, 79% had been advised to do so by a physician, 6% by a pharmacist, and 3% by a nurse. Eighty-seven (25%) of the 342 respondents who named a bronchodilator reported having found their pMDI empty during an asthma exacerbation. Seven of those patients had to call 911. Of these 87 patients, 71 (82%) considered their pMDI empty when absolutely nothing came out. CONCLUSIONS: Patients do not have a reliable means of monitoring the contents of their metered-dose inhalers, which is causing serious problems that need to be addressed. Given the necessity of a reliable dose counting method, it is clear that manufacturers should include dose counters as a standard feature of every metered-dose inhaler.

Adolescent↗
PubMed2004

Safety profile of budesonide inhalation suspension in the pediatric population: worldwide experience.

OBJECTIVE: To review the worldwide safety data for budesonide inhalation suspension (Pulmicort Respules) to provide a budesonide inhalation suspension pediatric tolerability profile. DATA SOURCES: Clinical study data were obtained from AstraZeneca safety databases used by the US Food and Drug Administration to support the approval of budesonide inhalation suspension and from postmarketing surveillance reports (January 1, 1990, through June 30, 2002). STUDY SELECTION: Completed parallel-group studies of patients with asthma 18 years and younger. RESULTS: Safety data for budesonide inhalation suspension were pooled from 3 US, 12-week, randomized, double-blind, placebo-controlled studies (n = 1,018); data from their open-label extensions (n = 670) were pooled with data from a fourth US open-label study (n = 335). Data for 333 patients 18 years and younger enrolled in 5 non-US studies also were analyzed. No posterior subcapsular cataracts were reported in any study, and the frequencies of oropharyngeal events and infection with budesonide inhalation suspension were comparable with those of reference treatments. No increased risk of varicella or upper respiratory tract infection was apparent, and budesonide inhalation suspension did not cause significant adrenal suppression in studies assessing this variable. There were small differences in short-term growth velocity between children who received budesonide inhalation suspension and those who received reference treatment in 2 of 5 trials that evaluated this variable. No increased risk of adverse events was apparent from postmarketing reports. CONCLUSIONS: Short- and long-term treatment with budesonide inhalation suspension, using a wide range of doses, is safe and well tolerated in children with asthma.

Administration, Inhalation↗
PubMed1999

Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children.

BACKGROUND: Inhaled glucocorticosteroids (GCS) are the most effective long-term controller medications for the treatment of persistent asthma. Currently, however, available delivery devices limit their use in young children. A nebulized formulation of budesonide has been developed to address the needs of infants and young children. OBJECTIVE: To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS. METHODS: Three hundred fifty-nine children were randomized to receive once-daily budesonide inhalation suspension (0.25 mg, 0.50 mg, or 1.0 mg) or placebo via a Pari LC-Jet Plus nebulizer for 12 weeks. Efficacy assessments included nighttime/daytime asthma symptoms, pulmonary function (subset of patients), rescue medication use, and treatment discontinuations. Safety was based on adverse events and assessment of HPA-axis function. RESULTS: Demographics, baseline characteristics, asthma symptoms, and pulmonary function were similar across treatment groups. Mean nighttime/daytime asthma symptom scores were 1.19 +/- 0.63 and 1.34 +/- 0.53, respectively. Mean duration of asthma was 36.3 months and mean FEV1 was 81.3% of predicted with 27.7% reversibility. Following 12 weeks of treatment, all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms (P < or = .049) and significant decreases in rescue medication use (P < or = .038) compared with placebo. Significant improvements (P < or = .044) in FEV1 were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups. There were no differences between doses of budesonide inhalation suspension. Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups. CONCLUSION: Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments.

Administration, Inhalation↗
PubMed2002

Quantification of terbutaline in urine by enzyme-linked immunosorbent assay and capillary electrophoresis after oral and inhaled administrations.

The International Olympic Committee and World AntiDoping Agency restricts the use of beta2-agonists and only the inhaled administration of terbutaline, salbutamol, formoterol and salmeterol is permitted for therapeutic reasons. The aim of this study was to develop a test for the quantitation of terbutaline in urine and evaluate different parameters to distinguish between oral and inhaled administration of the drug. Urine samples were collected from asthmatic and non-asthmatic recreational swimmers who had received repeated doses of oral (3x2.5 mg plus 1x5 mg during 24 h) and inhaled (12x0.5 mg in 24 h with half of it being in the last 4 h) racemic terbutaline, and single oral (5 mg) or single inhaled doses (1 mg). Total terbutaline concentrations (free+conjugated) were determined by enzyme-linked immunosorbent assay. Results showed that after oral administrations urinary terbutaline concentrations were higher than those detected after inhalation. For confirmation purposes, a chiral capillary electrophoretic procedure was established and validated. A solid-phase extraction with Bond-Elut Certify cartridges was undertaken, separation performed using a 50 mM phosphate buffer (pH 2.5) containing 10 mM of (2-hydroxypropyl)-beta-cyclodextrin as running buffer and diode-array UV detection set at 204 nm. The proposed procedure is rapid, selective and sensitive allowing quantitation of free terbutaline enantiomers in urine. No statistical differences were found between total free terbutaline concentrations [S-(+)+R-(-)] in urine collected after oral and inhaled administrations of the drug. After oral doses enantiomeric [S-(+)]/[R-(-)] ratios lower than those obtained after inhalation were observed probably due to an enantioselective metabolism that take place in the intestine, but differences between both routes of administration were not statistically significant. Although different trends were observed after oral and inhaled doses in total terbutaline, total free terbutaline concentrations and in ratios between its enantiomers, differences observed were not sufficiently significant to establish cut-off values to clearly distinguish between both routes of administration.

Administration, Inhalation↗