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PubMed2003

Assessment of handling of inhaler devices in real life: an observational study in 3811 patients in primary care.

The correct use of inhalation devices is an inclusion criterion for all studies comparing inhaled treatments. In real life, however, patients may make many errors with their usual inhalation device, which may negate the benefits observed in clinical trials. Our study was undertaken to compare inhalation device handling in real life. A total of 3811 patients treated for at least 1 month with an inhalation device (Aerolizer, Autohaler, Diskus, pressurized metered dose inhaler (pMDI), or Turbuhaler) were included in this observational study performed in primary care in France between February 1st and July 14th, 2002. General practitioners had to assess patient handling of their usual inhaler device with the help of a checklist established for each inhaler model, from the package leaflet. Seventy-six percent of patients made at least one error with pMDI compared to 49-55% with breath-actuated inhalers. Errors compromising treatment efficacy were made by 11-12% of patients treated with Aerolizer, Autohaler, or Diskus compared to 28% and 32% of patients treated with pMDI and Turbuhaler, respectively. Overestimation of good inhalation by general practitioners was maximal for Turbuhaler (24%), and lowest for Autohaler and pMDI (6%). Ninety percent of general practitioners felt that participation in the study would improve error detection. These results suggest that there are differences in the handling of inhaler devices in real life in primary care that are not taken into account in controlled studies. There is a need for continued education of prescribers and users in the proper use of these devices to improve treatment efficacy.

Adult↗
PubMed2004

Inhalant use, abuse, and dependence among adolescent patients: commonly comorbid problems.

OBJECTIVE: Little is known about adolescents with DSM-IV-defined inhalant abuse and dependence. The aim of this study was to compare comorbidity among (1) adolescents with inhalant use disorders, (2) adolescents who reported using inhalants without inhalant use disorder, and (3) other adolescent patients drawn from an adolescent drug and alcohol treatment program. METHOD: The authors examined 847 admissions of patients who had completed structured diagnostic assessments. The three groups were compared for noninhalant substance use disorders, posttraumatic stress disorder, conduct disorder, major depression, previous suicide attempts, and physical/sexual abuse and neglect. RESULTS: Adolescents with inhalant abuse or dependence (group 1; n = 28) were significantly more likely to meet lifetime criteria for abuse or dependence on alcohol, hallucinogens, nicotine, cocaine, and amphetamines, to have had major depression, and to have attempted suicide compared with other adolescent patients who reported never using inhalants (group 3); adolescents with inhalant use disorders also reported significantly more abuse and neglect. Adolescents with inhalant abuse or dependence (group 1) did not differ significantly on any measure compared with adolescents who reported using inhalants without an inhalant use disorder (group 2). CONCLUSIONS: Adolescent patients with a history of inhalant use, abuse, or dependence entering treatment should be carefully screened for noninhalant substance use disorders, major depression, suicidality, and abuse and neglect.

Adolescent↗
PubMed1992

Effect of an inhaled thromboxane mimetic (U46619) on in vivo pulmonary resistance and airway hyperresponsiveness in dogs.

1. We investigated the role of thromboxane A2 in the airway hyperresponsiveness that follows the inhalation of ozone in dogs by examining the responses to an inhaled thromboxane analogue (U46619). 2. Measurements of pulmonary resistance were made in anaesthetized dogs; the concentration of inhaled agonist causing an increase of 5 cmH2O l-1 s was calculated (provocative concentration). The effect of inhaled U46619 was studied on in vivo canine airway resistance, on airway responsiveness and on airways made hyperresponsive following the inhalation of ozone. 3. Inhaled thromboxane is a potent constrictor of the canine airway. The mean provocative concentration was 2.13 x 10(-4) M, compared to acetylcholine which was 3.23 x 10(-2) M. 4. Inhaled thromboxane did not result in the development of airway hyperresponsiveness to acetylcholine. Following U46619 inhalation the mean provocative concentration to acetylcholine was 3.92 x 10(-2) M. 5. Canine airway was not hyperresponsive to inhaled thromboxane following the inhalation of ozone. This was not due to an inhibition of acetylcholinesterase as the dogs were hyperresponsive to carbachol (a muscarinic agonist not degraded by endplate cholinesterase). 6. These experiments do not support a role for thromboxane in the development of airway hyperresponsiveness following the inhalation of ozone in dogs.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Nasal inhalation of l-menthol reduces respiratory discomfort associated with loaded breathing.

To test the hypothesis that stimulation of cold receptors in the upper airway may alleviate the sensation of respiratory discomfort, we investigated the effects of nasal inhalation of l-menthol (a specific stimulant of cold receptors) on the respiratory sensation and ventilation during the loaded breathing in 11 normal subjects. Subjects were asked to rate their sensation of respiratory discomfort using a visual analog scale (VAS) while breathing on a device with a flow-resistive load (180 cm H2O/L/s) or with an elastic load (75.5 cm H2O/L). The effects of inhalation of l-menthol on ventilation and respiratory sensation were evaluated by comparing the steady-state values of ventilatory variables and VAS scores obtained before, during, and after l-menthol inhalation. In 8 of 11 subjects inhalation of strawberry-flavored air instead of l-menthol was performed during loaded breathing. Both during the flow-resistive loading and the elastic loading, inhalation of l-menthol caused a significant reduction in sensation of respiratory discomfort (flow-resistive loading: 62 +/- 14 [mean +/- SD] VAS units before inhalation versus 36 +/- 16 during inhalation, p < 0.01; elastic loading: 68 +/- 13 before inhalation versus 55 +/- 17 during inhalation, p < 0.01) without a significant change in breathing pattern and ventilation. Comparison of the effects between the flow-resistive loading and the elastic loading also revealed that the reduction in VAS score was more during the flow-resistive loading than during the elastic loading (p < 0.01). Inhalation of strawberry-flavored air caused neither changes in VAS score nor changes in breathing pattern and ventilation, indicating that olfaction is not a contributing factor in the relief of respiratory discomfort. We concluded that stimulation of cold receptors in the upper airway with nasal inhalation of l-menthol reduces the sensation of respiratory discomfort associated with loaded breathing. This effect is more effective during the flow-resistive loading than during the elastic loading.

Adult↗
PubMed1995

The reversibility of airway obstruction to an inhaled beta 2-adrenergic agent is less satisfactory after methacholine testing in asthmatic subjects.

AIMS: The aim of this work was to compare the response to an inhaled beta 2-adrenergic agent in two situations: (1) spontaneous airway obstruction in asthmatic subjects who had withheld treatment with the medication for more than 12 hs; and (2) after methacholine-induced airway obstruction once airway caliber had recovered to the premethacholine test value. SUBJECTS AND METHODS: Sixteen asthmatic subjects who showed a 20% or more improvement in FEV1 after inhaled beta 2-adrenergic agent (B2) (salbutamol, 200 micrograms) entered a double-blind crossover randomized trial in which the following tests were carried out: (1) FEV1 response after inhaling a placebo or active B2; (2) FEV1 response after inhaling a placebo or active B2 after a methacholine test that had induced a 20% or more reduction in FEV1, once FEV1 had recovered to the premethacholine value after inhaling salbutamol in an open fashion. RESULTS: As expected, the mean percent improvement in FEV1 in the spontaneous airway obstruction situation was 21.7 +/- 8.5% after inhaling the active B2 and 2.2 +/- 1.8% after placebo B2 (p < 0.001). Following recovery after methacholine challenge, the FEV1 was slightly superior (mean difference of 146 mL) to the premethacholine value before inhaling the active or placebo B2. In this situation, the percent improvement in FEV1 after inhaling the active B2 was only 7.5 +/- 4.4% and not significantly different from after inhaling placebo B2 (4.9 +/- 5.4%). Consequently, the end FEV1 value after inhaling active B2 was significantly higher in a situation of spontaneous airway obstruction than after methacholine-induced airway obstruction (mean difference = 110 mL; p = 0.02). CONCLUSION: After a methacholine test, the reversibility of an inhaled beta 2 agent is not significantly different from a placebo and is less satisfactory than in a situation of spontaneous airway obstruction. The mechanism for this needs to be explored but it is not secondary to persisting airway obstruction.

Adult↗
PubMed2003

Inhaled salmeterol/fluticasone propionate combination: a pharmacoeconomic review of its use in the management of asthma.

UNLABELLED: Asthma guidelines recommend an inhaled corticosteroid plus a long-acting inhaled beta(2)-agonist (beta(2)-adrenoceptor agonist) as the preferred maintenance therapy for moderate and severe persistent asthma. Advair/Seretide Diskus also registered as Accuhaler is fixed-dose salmeterol (a long-acting inhaled beta(2)-agonist) and fluticasone propionate (a corticosteroid) administered via a single powder inhalation device. The clinical effectiveness of salmeterol/fluticasone propionate in patients with persistent asthma symptoms has been established in comparative clinical trials. Pharmacoeconomic analyses, based on data from these clinical trials, have been conducted from a healthcare payer perspective in various countries. In patients with asthma not controlled with inhaled corticosteroids, salmeterol/fluticasone propionate was associated with more favourable (lower) cost-effectiveness ratios than fluticasone propionate monotherapy, oral montelukast plus inhaled fluticasone propionate, inhaled budesonide, and inhaled formoterol plus budesonide. As the initial maintenance therapy in patients with persistent asthma symptoms while receiving short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate was cost effective relative to montelukast monotherapy. Although the total cost of asthma management tended to be slightly higher with salmeterol/fluticasone propionate than with fluticasone propionate or montelukast monotherapy, salmeterol/fluticasone propionate consistently had a more favourable cost-effectiveness ratio in terms of per successfully treated week or symptom-free day and/or was associated with small incremental costs to achieve significant additional clinical benefits. In clinical practice, salmeterol plus fluticasone propionate was associated with lower asthma-related costs than treatment with other maintenance therapies.In patients with asthma symptoms despite treatment with inhaled corticosteroids, salmeterol/fluticasone propionate produced clinically meaningful improvements in overall Asthma Quality of Life Questionnaire (AQLQ) scores relative to salmeterol or placebo monotherapy, in emotional function domain scores relative to fluticasone propionate or budesonide, and in asthma symptoms domain scores relative to budesonide. In patients with persistent asthma symptoms while receiving short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate produced clinically meaningful improvements in overall AQLQ scores compared with fluticasone propionate or montelukast. CONCLUSIONS: Pharmacoeconomic analyses indicate that salmeterol/fluticasone propionate administered via a single inhaler represents a cost-effective treatment option (relative to fluticasone propionate at the same nominal dosage, budesonide, formoterol plus budesonide and montelukast plus fluticasone propionate) in patients with asthma not controlled with inhaled corticosteroid therapy. In patients with asthma not controlled with short-acting beta(2)-agonists alone, salmeterol/fluticasone propionate is a cost effective treatment relative to monotherapy with montelukast. Importantly, salmeterol/fluticasone propionate is also associated with improvements in health-related quality of life.

Albuterol↗
PubMed1997

NTP Toxicology and Carcinogenesis Studies of Nitromethane (CAS No. 75-52-5) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Nitromethane is used as a rocket and engine fuel; as a synthesis intermediate for agricultural fumigants, biocides, and other products; as a solvent; and as an explosive in mining, oil-well drilling, and seismic exploration. It has been detected in air, in surface and drinking water, and in cigarette smoke. Nitromethane was studied because of the potential for widespread human exposure and because it is structurally related to the carcinogens 2-nitropropane and tetranitromethane. Male and female F344/N rats and B6C3F1 mice received nitromethane (purity 98% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood erythrocytes of mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived until the end of the study. The mean body weight gain of male rats in the 1,500 ppm group was slightly but significantly less than that of the controls; the final mean body weights and mean body weight gains of exposed females were similar to those of the controls. Clinical findings in all male and female rats in the 1,500 ppm groups included increased preening, rapid breathing, hyperactivity early in the study, and hypoactivity and loss of coordination in the hindlimbs near the end of the study. The relative liver weights of all exposed groups of male rats and the absolute and relative liver weights of females exposed to 375 ppm or greater were significantly greater than those of the controls. Minimal to mild degeneration of the olfactory epithelium was observed in the nose of males and females exposed to 375 ppm or greater. Sciatic nerve degeneration was present in all male and female rats exposed to 375 ppm or greater; rats exposed to 750 or 1,500 ppm also had reduced myelin around sciatic axons. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All mice survived to the end of the study. The final mean body weights and weight gains of exposed males and females were similar to those of the controls. Clinical findings included hypoactivity and tachypnea in male and female mice in the 1,500 ppm groups. Absolute and relative liver weights of male mice in the 750 and 1,500 ppm groups and female mice in all exposed groups and the relative liver weight of males in the 375 ppm group were significantly greater than those of the controls. Degeneration of the olfactory epithelium of the nose was observed microscopically in all males and females exposed to 375 ppm or greater; this lesion was of minimal severity in males and minimal to mild severity in females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 13 weeks. All rats survived to the end of the study. The final mean body weight and weight gain of male rats in the 1,500 ppm group were significantly less than those of the controls. Clinical findings included hindlimb paralysis in rats in the 750 and 1,500 ppm groups. Inhalation exposure of rats to nitromethane resulted in an exposure concentration-dependent, microcytic, responsive anemia; anemia was most pronounced in males and females exposed to 375 ppm or greater. The presence of schistocytes, Heinz bodies, and spherocytes and increased mean cell hemoglobin concentration and methemoglobin concentration were evidence that a hemolytic process was occurring; this hemolytic process could have accounted, in part, for the anemia. Thrombocytosis accompanied the anemia and would be consistent with a reactive bone marrow or could have been due to the erroneous inclusion of small erythrocyte fragments as part of the platelet count. On day 23, transient decreases in serum triiodothyronine, thyroxine, and fr and free thyroxine were observed in male rats exposed to 375 ppm or greater and female rats exposed to 750 or 1,500 ppm. There was little or no pituitary response to the thyroid hormone decreases, as evidenced by the lack of significantly increased concentrations of thyroid-stimulating hormone in exposed rats. No biologically significant differences in organ weights were observed. The forelimb and hindlimb grip strengths of males in the 1,500 ppm group were significantly less than those of the controls. The hindlimb grip strengths of females in the 750 and 1,500 ppm groups were also significantly less than the control value. Minimal to mild hyperplasia of the bone marrow was observed microscopically in male rats in the 750 and 1,500 ppm groups and in females exposed to 188 ppm or greater. Nasal lesions in exposed males and females included olfactory epithelial degeneration in males and females exposed to 375 ppm or greater and in one female exposed to 188 ppm and respiratory epithelial hyaline droplets and goblet cell hyperplasia in males and females in the 750 and 1,500 ppm groups; the severity of nasal lesions in males and females was minimal to mild. Males and females exposed to 375 ppm or greater had minimal to mild degeneration of the sciatic nerve and the lumbar spinal cord. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weights and weight gains of exposed mice were generally similar to those of the controls. There were no treatment-related clinical findings. The absolute right kidney weights of all groups of exposed male mice except the 1,500 ppm group and of females exposed to 188 ppm or greater and the relative right kidney weights of all groups of exposed males and of females in the 750 and 1,500 ppm groups were significantly greater than those of the controls. The absolute liver weight of male mice in the 750 ppm group and the relative liver weights of males exposed to 375 ppm or greater were significantly greater than those of the controls. Olfactory epithelial degeneration and respiratory epithelial hyaline droplets were observed microscopically in all male and female mice exposed to 375 ppm or greater. Degeneration also occurred in females in the 188 ppm group, and hyaline droplets occurred in females in the 94 and 188 ppm groups. The average severity of the nasal lesions ranged from minimal to mild in males. In females, the average severity of olfactory epithelial degeneration ranged from minimal to mild and the severity of respiratory epithelial hyaline droplets ranged from minimal to moderate. All males and nine females in the 1,500 ppm groups also had minimal extramedullary hematopoiesis of the spleen. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 94, 188, or 375 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival,Body Weights, and Clinical Findings: There were no significant differences in survival rates between exposed and control male or female rats. The mean body weight of females in the 375 ppm group was slightly greater than that of the control group; the mean body weights of exposed males were generally similar to the mean body weight of the controls throughout the study. Clinical findings were consistent with incidences of mammary gland neoplasms in females exposed to 188 or 375 ppm; no hindlimb paralysis, as occurred in rats in the 13-week study, was observed in male or female rats in the 2-year study. Pathology Findings: The incidences of mammary gland fibroadenoma and fibroadenoma, adenoma, or carcinoma (combined) in female rats in the 188 and 375 ppm groups were significantly greater than those in the controls. Additionally, the incidences of mammary gland carcinoma in the 375 ppm group were significantly greater than those in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 0, 188, 375, or 750 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival,Body Weights, and ClinicalFindings The survival rate of females in the 750 ppm group was marginally greater than that of the controls. The mean body weights of exposed females were generally slightly greater than the mean body weights of the controls during the study but were generally similar to the mean body weight of the controls at the end of the study. The mean body weights of exposed males were similar to those of the controls throughout the study. Clinical findings included swelling around the eyes and exophthalmos in exposed males and females; these findings were coincident with harderian gland neoplasms. Pathology Findings: The incidences of harderian gland adenoma and adenoma or carcinoma (combined) in exposed mice increased with increasing exposure concentration and were significantly greater in males and females in the 375 and 750 ppm groups than those in the controls. The incidences of harderian gland carcinoma in males and females in the 375 and 750 ppm groups were also slightly greater than those in the controls. Female mice in the 188 and 750 ppm groups had significantly greater incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) than the controls. The incidences of liver eosinophilic focus increased with increasing exposure concentration, and the incidences in the 375 and 750 ppm groups were significantly greater than the control incidence. The incidences of alveolar/bronchiolar carcinoma in male mice in the 750 ppm group and female mice in the 375 ppm group were significantly greater than those in the controls. Females in the 750 ppm group also had a significantly greater incidence of alveolar/bronchiolar adenoma or carcinoma (combined) and a slightly greater incidence of alveolar/bronchiolar adenoma than the controls. Females in the 375 ppm group had a significantly greater incidence of cellular infiltration of histiocytes in the lung than the controls. The incidences of degeneration and metaplasia of the olfactory epithelium and hyaline degeneration of the respiratory epithelium were significantly greater in exposed male and female mice than those in the controls. Additionally, males in the 375 and 750 ppm groups had significantly greater incidences of inflammation of the nasolacrimal duct than did the controls. GENETIC TOXICOLOGY: Nitromethane was not mutagenic in any tests performed by the NTP. It did not induce mutations in Salmonella typhimurium, with or without S9 metabolic activation, and no induction of sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells exposed to nitromethane was noted with or without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male and female mice at the end of the 13-week inhalation study of nitromethane. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of nitromethane in male F344/N rats exposed to 94, 188, or 375 ppm. There was clear evidence of carcinogenic activity of nitromethane in female F344/N rats based on increased incidences of mammary gland fibroadenomas and carcinomas. There was clear evidence of carcinogenic activity of nitromethane in male B6C3F1 mice based on increased incidences of harderian gland adenomas and carcinomas. There was clear evidence of carcin ogenic activity in female B6C3F1 mice, based on increased incidences of liver neoplasms (primarily adenomas) and harderian gland adenomas and carcinomas. Increased incidences of alveolar/bronchiolar adenomas and carcinomas in male and female mice exposed to nitromethane were also considered to be related to chemical administration. Exposure to nitromethane by inhalation for 2 years resulted in increased incidences of nasal lesions including degeneration and metaplasia of the olfactory epithelium and degeneration of the respiratory epithelium in male and female mice. Synonym: Nitrocarbol

Journal Article↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of Methyl Bromide (CAS: 74-83-9) in B6C3F1 Mice (Inhalation Studies).

Methyl bromide is widely used as a fumigant and pesticide. Toxicology and carcinogenesis studies were conducted by exposing groups of male and female B6C3F1 mice to methyl bromide (99.8% pure) by inhalation 6 hours per day, 5 days per week, for 14 days, 6 weeks, 13 weeks, or 2 years. Six-week and 13-week inhalation toxicity studies in F344/N rats were conducted concurrently with the mouse studies. Hematology parameters were measured during the 6-week, 13-week, and 2-year studies. Quantitative neurobehavioral testing was performed during the 14-day, 13-week and 2-year studies. Genetic toxicology studies were conducted for gene mutation induction in Salmonella typhimurium and for induction of sister chromatid exchanges in mouse bone marrow cells and of micronuclei from peripheral blood erythrocytes. 14-Day Studies: Groups of five B6C3F1 mice of each sex were exposed to 0, 12, 25, 50, 100, or 200 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 2 weeks. Only four female mice and one male mouse survived 10 exposures at 200 ppm. No deaths occurred at the lower doses. Neurobehavioral effects including trembling and paralysis were noted in all groups, but were most pronounced in the three highest dose groups. Red urine was noted in the mice exposed to 200 ppm. 13-Week Studies : Groups of 10 mice of each sex were exposed to 0, 10, 20, 40, 80, or 120 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 13 weeks. Additional groups of eight to 17 mice were concurrently exposed for neurobehavioral and genetic toxicology studies. The final mean body weight of males exposed to 120 ppm was significantly (12%) lower than that of the controls. Four of 24 males exposed to 120 ppm died during the study. Groups of 10 rats of each sex were exposed to 0, 30, 60, or 120 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 13 weeks. Additional groups of eight rats were concurrently exposed for neurobehavioral studies. Final mean body weights of rats exposed to 120 ppm were 12% lower than those of the controls for males and 13% lower for females. No rats died as a result of methyl bromide exposure during the studies. Special 6-Week Target Organ Toxicity Studies: Neither the 14-day nor the 13-week studies provided strong evidence for specific organ toxicity. Six-week studies were therefore conducted to identify target organs for the 2-year studies. Groups of 20 rats and mice of each sex were exposed to methyl bromide by inhalation for 6 hours per day, 5 days per week for 6 weeks at a dose of 160 ppm. Mortality rates exceeded 50% in the male mice after eight exposures, in female mice after six exposures, and in male rats after 14 exposures. Only the female rat group survived 30 exposures with less than 50% mortality. The study identified the brain, kidney, nasal cavity, heart, adrenal gland, liver, and testis as the primary organs to examine for toxicity in the 2-year methyl bromide inhalation studies. 2-Year Studies: Groups of 70 B6C3F1 mice of each sex were exposed to methyl bromide by inhalation at 0, 10, 33, or 100 ppm for 6 hours per day, 5 days per week for up to 103 weeks. Additional groups of 16 mice were included for neurobehavioral evaluations throughout the 2-year studies. By 20 weeks (139 days), 27 males and 7 females exposed to 100 ppm had died and methyl bromide exposure was discontinued for the remaining mice in this dose group. Ten female mice from the 100 ppm group predesignated for the 15-month interim evaluation were killed on schedule and all other high-dose animals were allowed to live to term (24 months) for evaluation of chronic toxicity and carcinogenicity. Clinical signs indicative of neurotoxicity, including tremors, abnormal posture, tachypnea, and hind leg paralysis, persisted in these high-dose mice until the end of the studies. Final mean body weights of surviving 100 ppm males and females were markedly lower (33% and 31%) than those of the controls. Neurobehavioral changes occurred in male and female mice initially exposed to 100 ppm methyl bromide, with more prnitially exposed to 100 ppm methyl bromide, with more pronounced changes observed in males. In general, these animals were less active and manifested a heightened sensitivity in the startle response than mice in other dose groups. Exposure to methyl bromide was not carcinogenic under the conditions of these studies. However, there was an increase in the incidence of several nonneoplastic lesions in the brain, heart, bone (sternum), and nose. Degenerative changes in the cerebellum and cerebrum occurred in males and females exposed to 100 ppm. Myocardial degeneration and cardiomyopathy were observed in the hearts of mice exposed to 100 ppm. An increased incidence of sternal dysplasia was seen in treated animals, particularly in those exposed to 100 ppm. An increased incidence of olfactory epithelial necrosis and metaplasia within the nasal cavity was seen in the mice exposed to 100 ppm, particularly males. Genetic Toxicology: Methyl bromide was positive for induction of gene mutations in Salmonella typhimuriumstrain TA100, with and without exogenous metabolic activation; negative results were obtained with TA98 in this assay. In vivo, methyl bromide induced sister chromatid exchanges in bone marrow cells and micronuclei in peripheral erythrocytes of female mice exposed by inhalation for 14 days. No significant increase in either sister chromatid exchanges or micronuclei was observed in male or female mice exposed to methyl bromide by inhalation for 4, 8, or 12 weeks. Conclusions: Under the conditions of these 2-year inhalation studies, methyl bromide caused degenerative changes in the cerebellum and cerebrum, myocardial degeneration and cardiomyopathy, sternal dysplasia, and olfactory epithelial necrosis and metaplasia. Toxic effects persisted although exposure to methyl bromide in the 100 ppm group terminated after 20 weeks. There was no evidence of carcinogenic activity of methyl bromide in male or female B6C3F1 mice exposed to 10, 33, or 100 ppm. Synonym: Bromomethane

Journal Article↗
PubMed1991

[The role of 5-lipoxygenase products in the development of airway responsiveness induced by platelet activating factor inhalation in dogs].

To determine whether 5-lipoxygenase products are involved in the development of airway responsiveness and in the infiltration of inflammatory cells into the airway after platelet activating factor (PAF) inhalation, we studied the effect of a selective 5-lipoxygenase inhibitor, AA-861 on PAF-induced airway hyperresponsiveness and on the increase of neutrophil and eosinophil counts in bronchoalveolar lavage fluid (BALF) after PAF inhalation in seven dogs. Airway responsiveness to inhaled methacholine was determined by modified Astograph (7Hz oscillation method). PAF (1000 mu/ml) was delivered as an aerosol, generated from a Devilbiss 646 nebulizer for ten minutes. Airway responsiveness to inhaled methacholine increased significantly 3 hr after PAF inhalation (p less than 0.01). After PAF inhalation, neutrophil and eosinophil counts in BALF increased significantly (p less than 0.01), and the levels of thromboxane (Tx)B2 in BALF also increased (p less than 0.05). Pretreated AA-861 significantly inhibited the increase of airway responsiveness after PAF inhalation (p less than 0.01). The increase of neutrophil and eosinophil counts in BALF after PAF inhalation was also inhibited significantly by pretreated AA-861 (p less than 0.01). The levels of TxB2 in BALF did not change after PAF inhalation following pretreatment with AA-861. These results suggest that 5-lipoxygenase products play important roles in the increase of airway responsiveness and in the infiltration of inflammatory cells into the airway after PAF inhalation in dogs. TxA2 released from inflammatory cells may be involved in the increase of airway responsiveness induced by PAF inhalation.

Animals↗
PubMed1990

In vivo evaluation of the new multiple dose powder inhaler and the Rotahaler using the gamma scintigraphy.

Deposition of 99mTc-labelled particles of disodium cromoglycate in the respiratory tract was evaluated after inhalation from two dry powder inhalers. The inhalers tested were a new multiple dose powder device (Chiesi Farmaceutici) and the Rotahaler powder device (Glaxo). Fractional deposition in the whole lung area, the upper respiratory passages and the stomach, as well as in the inhaler, was measured using a gamma camera. Ten healthy volunteers participated in the inhalation test. The mean, whole lung deposition of the inhaled disodium cromoglycate particles was about 9 per cent of the dose for the both devices. The deposition patterns of the inhaled drug doses in the lung area given by the devices were, however, clearly different. The Chiesi powder inhaler was more efficient in dispersing the drug particles into the therapeutically important alveolar regions of the lungs. The fraction of the dose retained in the inhaler was significantly higher for the Rotahaler than for the Chiesi powder device. On the other hand, the deposition in the upper passages was somewhat larger for the Chiesi device than for the Rotahaler. According to the deposition results of this study, a new multiple dose powder inhaler can be useful in inhalation therapy.

Animals↗
PubMed1980

Effect of cigarette smoke inhalation during pregnancy in Sprague-Dawley rats.

Pregnant 9 weeks old Sprague-Dawley rats were exposed to the smoke of different research cigarettes (C1-C7). The cigarettes were different in smoke nicotine, condensate and carbon monoxide. The animals were divided in groups inhaling different smoke concentrations, numbers of inhalations per day and time periods per pregnancy. Carbon monoxide and dioxide content in the inhalation chamber increased dependent on time and concentration of smoke inhalation. Both parameters were highest after inhalation of smoke from cigarette C2. The weight of the pregnant rats was reduced after inhalation of high concentrations of smoke from cigarette C1 and c2. Weight and length of fetuses were reduced dependent on number and duration of smoke inhalation. High concentrations of cigarette smoke, twice daily for 21 days were more effective than smoke inhalation in the second part of the pregnancy. Inhalation of cigarette smoke during the second half of the pregnancy was more effective than smoke inhalation in the first ten days of pregnancy. cigarette C1 reduced the length and weight of fetuses more than cigarette C2 when concentration and number of inhalations per day were the same. The vapor phase in both cigarettes was not as effective as the total smoke. Resorptions and stillbirths were independent of treatment. Malformations were diagnosed only in one fetus.

Air↗
PubMed1994

Assessing fullness of asthma patients' aerosol inhalers.

BACKGROUND: The importance of regular medication in order to control asthma symptoms is recognized. However, there is no accurate mechanism for assessing the fullness of aerosol inhalers. The contribution to asthma morbidity of unexpectedly running out of inhaled medication is unknown. AIM: A study was undertaken to determine how patients assess inhaler fullness and the accuracy of their assessments, and to evaluate the floatation method of assessing inhaler fullness. METHOD: An interview survey of 98 patients (51% of those invited to take part), using 289 inhalers, was completed at one general practice in Hampshire. RESULTS: One third of participants said they had difficulty assessing aerosol inhaler fullness and those aged 60 years and over were found to be more inaccurate in assessing fullness than younger participants. Shaking the inhaler to feel the contents move was the commonest method of assessment. When placed in water, an inhaler canister floating on its side with a corner of the canister valve exposed to air indicates that the canister is less than 15% full (sensitivity 90%, specificity 99%). CONCLUSION: Floating a canister in water provides an objective measurement of aerosol inhaler fullness. Providing the method is recommended by the aerosol inhaler manufacturer, general practitioners should demonstrate the floatation method to patients experiencing difficulty in assessing inhaler fullness.

Adolescent↗
PubMed1994

A novel multiple dose powder inhaler. Salbutamol powder and aerosol give equal bronchodilatation with equal doses.

Twenty adult patients with stable asthma were treated with cumulatively increasing doses of salbutamol delivered from a metered dose inhaler (MDI) and from a novel multiple dose powder inhaler (MDPI), Easyhaler, in a randomized 3-period crossover study. Four doses of salbutamol (delivered doses to the patient: 90, 90, 180, 360 micrograms; cumulative dose of 720 micrograms) were administered during each of the three study days and were inhaled every 30 minutes. Drug doses were released from the powder inhaler either before or during inhalation. Spirometry was performed at the beginning of each study day and 20 minutes after each dose. The lung function parameters after cumulative dosing of salbutamol were equal during each study day. The maximal percentage changes in forced expiratory volumes in one second after 720 micrograms of salbutamol were 24% with the MDI and 23% and 24% with the Easyhaler inhaler, respectively. Ten patients reported mild side effects when using the MDI, three when the powder was released before inhalation and five when the MDPI was actuated during inhalation. No significant changes in heart rate or blood pressure were observed during the study. We conclude that the novel multiple dose powder inhaler is clinically equally effective and slightly better tolerated than conventional metered dose inhaler when equal doses of salbutamol are inhaled by asthmatic patients.

Adult↗
PubMed1998

[Investigation of the effects of puff times and spacer devices on the distribution pattern of a Becotide 100 inhaler in the twin impinger].

In order to investigate the dispersion pattern and compare the effect of spacer devices (Volumatic, Volumatic Soft and InspirEase), the Becotide 100 inhaler actuating 100 micrograms of beclomethasone dipropionate (BDP) per shot was studied with respect to its distribution ratio in a twin impinger and also compared with that of the Becotide 50 inhaler. The distribution patterns of BDP during each stage of the twin impinger were not affected by the puff times of the Becotide 100 inhaler. No significant difference was observed when the distribution ratios between the Becotide 50 inhaler and Becotide 100 inhaler were compared. All of these three spacer devices reduced the deposition ratio in stage I which is assumed to be the oral cavity and oropharynx. As the puff times of the Becotide 100 inhaler increased, the BDP deposited in the spacer increased and that of stage II assumed to be the lung decreased. These results suggested that the inhalation volume of BDP would depend on the puff times during clinical use and the inhalation volume of BDP for the Becotide 100 inhaler would be double that of the Becotide 50 inhaler. The spacer devices could decrease the local adverse effects caused by deposited BDP in the oral cavity. When using large spacer devices, one or two puff times into the spacer would be recommended for the best clinical effectiveness. The Volumatic could be expected to produce a superior BDP inhalation volume by reducing the deposition in the oral cavity in the 3 spacer devices examined in this study.

Beclomethasone↗
PubMed2003

Optical feedback training of inhalation with Autohaler and Turbuhaler in COPD patients.

The success of inhalation therapy depends on patients inhalation technique and correct handling of the inhalation device. In this study the effort to train correct handling and optimal inhalation technique of patients using Autohaler and Turbuhaler was assessed. The Bad-Reichenhall-Aerosol-Therapy-Trial (BREATH) was a prospective, randomized, cross-over trial in 200 patients who were not familiar with either of the test systems. The correct handling of Autohaler and Turbuhaler was assessed by means of a checklist (observation score). An optimal inhalation maneuver was used evaluated with the computer-based Inhalation Manager (optical feedback, computer score). The Autohaler reached 6.58 +/- 3.64 (mean +/- SD) out of nine points in the observation score and 66.85 +/- 29.84% in the computer score before training. After training the scores increased significantly to 8.33 +/- 2.08 points and 86 +/- 23.40% respectively. The use of the Turbuhaler also significantly improved from 4.28 +/- 4.24 points and 56.67 +/- 42.97% to 7.78 +/- 2.74 points and 85.80 +/- 27.63%, respectively. The significant improvement of patients inhalation technique after training emphasizes the importance of training in inhalation therapy. In addition, it could be demonstrated that the optical feedback given by the Inhalation Manager was a useful tool for improving the inhalation technique of patients using Autohaler and Turbuhaler.

Administration, Inhalation↗
PubMed2004

Adherence logger for a dry powder inhaler: a new device for medical adherence research.

BACKGROUND: Adherence to inhaled steroid regimens is frequently poor. Finding ways to improve adherence depends on the ability to measure time and date of inhaler use reliably and to detect deliberate dose dumping. There is no such monitor for the popular new dry powder inhalers. OBJECTIVE: To develop and test an electronic monitor for a dry powder inhaler that will provide information on the time and date of use. METHODS: An electronic adherence monitor for the Advair Diskus dry powder inhaler was developed and tested. In this device, inhaler use is determined by detecting and recording the motion of the drug delivery lever in the inhaler with a magnetic sensor. An additional electronic interface and software were also developed to allow the adherence data to be uploaded to a computer for display and analysis. RESULTS: System and reliability tests involving multiple-day and repeated-use tests of the adherence monitor demonstrate the overall performance and reliability of the device, and specifically its ability to record the time and date of dose delivery. In the repeated-use test, 300 successive actuations of the dose delivery lever were correctly sensed and recorded without error. CONCLUSION: The simple-to-use, low-cost, reusable adherence monitor accurately records time and date of inhaler use and thus allows clinical monitoring and adherence studies in patients using the Advair Diskus dry powder inhaler. The same technology should be adaptable to other dry powder inhalers, including the Pulmicort Tubuhaler and the Symbicort Tubuhaler.

Administration, Inhalation↗
PubMed2005

In vitro evaluation of an asthma dosing device: the smart-inhaler.

Monitoring devices attached to pressurised metered dose inhalers provide an important objective measurement of patient adherence with asthma medications in clinical and research settings. The Smart-inhaler is a relatively new device that has not been previously validated. This study examines the accuracy of the Smart-inhaler in a bench-top experiment and compares it with a previously validated device, the Doser. Ten Smart-inhalers and five Dosers were actuated twice on two occasions per day for 30 days (120 doses). Six Smart-inhalers were also actuated 30 times in rapid succession to examine the ability of the Smart-inhaler to detect "dumping". Five Smart-inhalers failed to detect the first one or two doses. However, when the aerosol canister was placed more firmly in the device, actuating the device in the process, the following two doses were recorded accurately in all ten devices. Otherwise all ten Smart-inhalers and five Dosers recorded all actuations faithfully and there were no spurious recordings. The six Smart-inhalers recorded all 30 doses delivered in rapid succession. The Smart-inhaler and Doser are both highly accurate at measuring actuated doses and no spurious doses were recorded in an in vitro setting.

Administration, Inhalation↗
PubMed2006

Efficacy and safety of budesonide and formoterol in one pressurised metered-dose inhaler in adults and adolescents with moderate to severe asthma: a randomised clinical trial.

BACKGROUND: Inhaled corticosteroids (ICSs) are the preferred maintenance therapy for adults and children with mild, moderate and severe persistent asthma, with the addition of a long-acting beta(2)-adrenoceptor agonist to ICS therapy recommended for patients with moderate or severe persistent asthma. The efficacy and safety of the combination of budesonide and formoterol delivered via dry powder inhaler (DPI) is well documented. OBJECTIVE: To compare the efficacy and safety of budesonide/formoterol pressurised metered-dose inhaler (budesonide/formoterol pMDI; Symbicort pMDI, AstraZeneca LP, Wilmington, DE, USA) with budesonide pMDI (Pulmicort pMDI, Astra [corrected] Zeneca, Lund, Sweden), formoterol DPI (Oxis Turbuhaler, AstraZeneca, Lund, Sweden), budesonide plus formoterol in separate inhalers (budesonide pMDI + formoterol DPI) and placebo. STUDY DESIGN: This was a 12-week randomised, double-blind, double-dummy, placebo-controlled study. SETTING: This multicentre study was conducted in the respiratory specialty clinical practice setting. PATIENTS: The study included 596 patients > or =12 years of age with moderate to severe persistent asthma previously receiving ICSs. INTERVENTIONS: After 2 weeks on budesonide pMDI 80 microg x two inhalations (160 microg) twice daily, patients received budesonide/formoterol pMDI 160 microg/4.5 microg x two inhalations (320 microg/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) + formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo twice daily. MAIN OUTCOME MEASURES: There were two prespecified primary efficacy variables: mean change from baseline in morning predose forced expiratory volume in 1 second (FEV(1)), obtained approximately 12 hours after the most recent administration of study medication at home and immediately before the next administration of study medication at the clinic; and mean change from baseline in 12-hour FEV(1), assessed as the average change in FEV(1) from serial spirometry over the 12-hour period after administration of the morning dose of study medication at the clinic. RESULTS: Mean changes from baseline in morning predose FEV(1) at end of treatment were greater (p < or = 0.049) with budesonide/formoterol pMDI (0.19L) versus budesonide pMDI (0.10L), formoterol DPI (-0.12L) and placebo (-0.17L). Mean changes from baseline in 12-hour FEV(1) were greater (p < or = 0.001) with budesonide/formoterol pMDI after 1 day (0.37L), 2 weeks (0.34L) and at end of treatment (0.37L) versus budesonide pMDI (0.11, 0.15 and 0.15L) and placebo (0.09, -0.03 and -0.03L), and after 2 weeks and at end of treatment versus formoterol DPI (0.19 and 0.17L). Fewer (p < or = 0.025) patients receiving budesonide/formoterol pMDI versus monoproducts or placebo met worsening asthma criteria. Results were similar in the budesonide/formoterol pMDI group and the budesonide pMDI + formoterol DPI group on all measures. All treatments were well tolerated with similar safety profiles. CONCLUSIONS: In this population, twice-daily budesonide/formoterol pMDI provides asthma control significantly greater than the monocomponents or placebo and comparable with budesonide pMDI + formoterol DPI. Safety profiles were similar for all treatments.

Administration, Inhalation↗