Venous thromboembolism in paediatric practice.
Explore the source record for details and available documents.
Child↗
Biomedical subjects
D J Clark
Publications and source records attributed to D J Clark.
Adrenocortical activity with repeated administration of one-daily inhaled fluticasone propionate and budesonide in asthmatic adults.
OBJECTIVE: The aim of this study was to evaluate the steady-state effects of once-daily inhaled fluticasone propionate (FP) and budesonide (BUD) on adrenocortical activity in asthmatic patients. METHODS: Ten asthmatic patients with a mean age of 31.2 years, a mean forced expiratory volume in 1 s (FEV1) of 91% predicted and a forced mid-expiratory flow (FEF25-75) of 62.3% predicted were studied in a single-blind randomised crossover design comparing placebo (PL), FP (375 microg per day and 750 microg per day) and BUD (400 microg per day and 800 microg per day) all given once daily for 4 days at each dose via a pressurised metered dose inhaler (pMDI) at 0800 hours. After 4 days of treatment, plasma cortisol was measured at 0800 hours (24 h after the last dose) and a 10-h overnight urine collection was taken, 14 h after the last dose (2200-0800 hours) for analysis of cortisol and creatinine excretion. RESULTS: Plasma cortisol levels (nmol.l(-1), as geometric mean) at 0800 hours demonstrated a significant difference between the highest doses of FP and BUD (424.1 vs 510.3 nmol.l(-1), respectively) but not between the low doses (506.8 vs 514.9 nmol.l(-1); PL 532.2 nmol.l(-1)). For the highest dose FP (750 microg) this equated to 20% suppression of 0800 hours plasma cortisol. Likewise, for overnight urinary cortisol output (nmol.10 h(-1) as geometric mean), there was a significant difference at the high doses of FP and BUD (25.5 vs 38.2 nmol.10 h(-1)), but not at the low doses 31.3 vs 34.8 nmol.10 h(-1); PL 32.0 nmol.10 h(-1). For the overnight urinary cortisol/creatinine ratio (nmol.mmol(-1), as geometric mean) there was a similar trend; 4.5 vs 6.1 nmol.mmol(-1) for high dose and 5.6 vs 6.3 nmol.mmol(-1) for low dose; PL 5.9 nmol.mmol(-1). CONCLUSION: Repeated doses of FP 750 microg once daily caused greater adrenal suppression than BUD 800 microg once daily, when comparing effects on plasma cortisol levels at 0800 hours, 24 h after the last dose, as well as effects on overnight urinary cortisol output. Neither FP 375 microg once daily nor BUD 400 microg once daily produced detectable adrenal suppression.
Adult↗
Early lung absorption profile of non-CFC salbutamol via small and large volume plastic spacer devices.
AIMS: To evaluate the lung dose of a non-CFC salbutamol metered dose inhaler (MDI) formulation via three commonly used plastic spacer devices, of both large and small volume, compared with the MDI used on its own. METHODS: Ten healthy volunteers were studied in a randomized single (investigator) blind crossover design. Single 1200 microg nominal doses of salbutamol from a non-CFC MDI (Airomir), as 12 sequential 100 microg puffs over 6 min, were delivered from the MDI alone and via two large volume spacer devices (Nebuhaler, Volumatic), and a small volume spacer (Aerochamber). All spacers were prewashed prior to each study day and mouth rinsing was performed after each drug sequence. Plasma salbutamol was measured at 5, 10, 15 and 20 min, with calculation of maximum (Cmax) and average (Cav) concentrations. This lung dose was assessed using the early lung absorption profile of salbutamol in the first 20 min after inhalation. RESULTS: Both of the large volume spacers, the Nebuhaler and the Volumatic, delivered significantly more salbutamol than the MDI alone. For Cav this amounted to a 2.07-fold difference (95% CI 1.48-2.90) between Nebuhaler vs MDI, and a 1.49-fold difference (95%CI 1.19-1.87) between Volumatic vs MDI. The Nebuhaler also produced greater deposition than either the Volumatic or the Aerochamber spacers; Nebuhaler vs Volumatic: 1.39-fold difference (95% CI 1.09-1.76), Nebuhaler vs Aerochamber: 1.63-fold difference (95% CI 1.20-2.21). There were no significant differences between the Aerochamber and the MDI alone. CONCLUSIONS: Using the early lung absorption profile, for administration of the same nominal dose, both of the large volume spacers (Nebuhaler and Volumatic) but not the small volume spacer (Aerochamber) delivered significantly more salbutamol than the MDI alone. The Nebuhaler also produced greater delivery than either the Volumatic or the Aerochamber spacer devices. Our results show that whilst lung delivery of non-CFC salbutamol MDI is improved by the use of a plastic spacer, there may be appreciable differences in performance, particularly between large and small volume devices.
Absorption↗
Lung delivery of non-CFC salbutamol via small volume metal spacer and large volume plastic spacer devices compared with an open vent jet nebulizer.
AIMS: To compare the lung delivery of salbutamol from a commonly used constant output open vent jet nebuliser (Sidestream) with use of both a conventional large volume plastic spacer (Volumatic) and a novel small volume metal spacer (NebuChamber). This was assessed using the early lung absorption profile of salbutamol over the first 20 min after inhalation. METHODS: Twelve healthy volunteers were studied in a randomized single (investigator) blind crossover design. Single 1200 microg nominal doses salbutamol from a CFC-free metered-dose inhaler (12 sequential 100 microg puffs of Airomir) were delivered via the Volumatic and NebuChamber spacers. A single 1200 microg nominal dose of salbutamol was given as a 4 ml fill volume from a Sidestream nebuliser with mouthpiece. Mouth rinsing was performed after each drug sequence. Plasma salbutamol was measured at 5, 10, 15 and 20 min after the last dose of each inhalation sequence, with calculation of maximal concentration (Cmax) and average concentration over 20 min (C[av]). Systemic beta2-responses were measured as plasma potassium, tremor and heart rate. RESULTS: Both the Volumatic and the NebuChamber spacers produced significantly greater salbutamol concentration than the Sidestream nebuliser. For C(av) this amounted to a 7.34-fold difference (95%CI 5.31 to 9.38) between Volumatic vs Sidestream, and a 7.04-fold difference (95%CI 4.91 to 9.17) for NebuChamber vs Sidestream. Similar differences were found for the extrapulmonary beta2-responses. There were no significant differences in either salbutamol concentration or extrapulmonary beta2-responses between the Volumatic and NebuChamber spacers. CONCLUSIONS: We found that, in vivo, both the Volumatic and the NebuChamber spacers produced seven-fold greater lung delivery of salbutamol than the Sidestream nebuliser when comparing microgram equivalent nominal doses, in terms of the early lung absorption profile.
Administration, Inhalation↗
Evaluation of corticotropin releasing factor stimulation and basal markers of hypothalamic-pituitary-adrenal axis suppression in asthmatic patients.
PURPOSE: The aim of our study was to compare basal unstimulated levels of plasma cortisol and adrenocorticotropic hormone (ACTH) with stimulated levels produced by the corticotropin releasing factor (CRF) test in asthmatics taking high-dose inhaled steroid therapy. In theory, the CRF test would appear to be a suitable replacement for tetracosactrin (cosyntropin) (synthetic ACTH) as a test of hypothalamic-pituitary-adrenal (HPA) axis suppression. PATIENTS AND METHODS: Ten patients with stable asthma and a mean age of 28.8 years, FEV1 of 88.9% predicted, and forced expiratory flow between 25% and 75% of FVC of 57.0% predicted, were studied in a double-blind placebo-controlled crossover design comparing 4 days with budesonide, 1,000 microg bid, and placebo. Each dose was given at 8 AM and 10 PM for 4 days by metered-dose inhaler. Measurements were made at steady-state of basal 8 AM plasma cortisol and ACTH 10 h after the eighth dose, and CRF test (100-microg i.v. bolus) was then performed. RESULTS: The results for 8 AM plasma cortisol (nmol/L, means and 95% confidence interval [CI] for difference) showed that budesonide produced significant suppression compared with placebo: budesonide (284.1) vs placebo (360.9) (95% CI, 9.3 to 144.3). Suppression also occurred for peak plasma cortisol in response to CRF: budesonide (375.9) vs placebo (470.2) (95% CI, 27.0 to 161.6). ACTH (ng/L, means and 95% CI for difference) demonstrated a similar nonsignificant trend to cortisol, with suppression in both basal and stimulated forms: 8 AM ACTH, budesonide (36.6) vs placebo (42.2) (95% CI, -2.6 to 13.8); CRF peak response, budesonide (49.9) vs placebo (62.8) (95% CI, -3.6 to 29.5). CONCLUSION: In asthmatic patients receiving inhaled budesonide, 1,000 microg bid, the suppression of basal unstimulated 8 AM plasma cortisol was mirrored by the suppression of the CRF stimulation response. These results highlight the point that when basal 8 AM plasma cortisol levels are suppressed, a comparable degree of dynamic impairment of HPA axis response is also likely to be found with physiologic testing.
Administration, Inhalation↗
Lung delivery of salbutamol given by breath activated pressurized aerosol and dry powder inhaler devices.
Poor inhalation technique is prevalent in asthmatics using standard metered dose inhalers (MDI). Both dry powder inhalers (DPI) and breath activated MDIs offer a solution to this problem. Our aim was to compare the lung delivery of salbutamol from two DPIs, Diskhaler and Diskus (Accuhaler), and the Easi-Breathe breath activated MDI. Ten healthy volunteers mean (SEM) age 24.0 years (1.7) were studied in a randomized single (investigator) blind crossover design. Single 1200 micrograms nominal doses of salbutamol via Diskhaler and Diskus (6 sequential 200 micrograms puffs) and Easi-Breathe (12 sequential 100 micrograms puffs) were given over 6 min. Mouth rinsing was performed after every inhalation sequence. Lung delivery was evaluated by measuring the early lung absorption profile of salbutamol at 5, 10, 15 and 20 min after inhalation, with calculation of peak (Cmax) and average over 20 min (Cav) concentration (ng/ml). Both the Diskhaler and the Easi-Breathe produced significantly greater salbutamol Cmax and Cav than Diskus (as mean and 96% CI for difference vs. Diskus): [Cmax] Diskus 3.22 vs. Diskhaler 4.35 (95% CI 0.19 to 2.08), vs. Easi-Breathe 3.98 (95% CI -0.18 to 1.71). [Cav] Diskus 2.62 vs. Diskhaler 3.95 (95% CI 0.52 to 2.14), vs. Easi-Breathe 3.52 (95% CI 0.09 to 1.71). For Cav this amounted to a 1.51-fold difference (95% CI 1.35 to 1.68) between Diskhaler vs. Diskus, and a 1.36-fold difference (95% CI 1.03 to 1.69) for Easi-Breathe vs. Diskus. In conclusion we found that, in vivo, the Diskus DPI produced significantly lower lung delivery for the same nominal dose of salbutamol than either Diskhaler DPI or the Easi-Breathe pressurised aerosol. This shows that breath activated inhaler devices may have different in vivo deposition characteristics for delivering the same drug.
Adult↗
Adrenal suppression with high doses of inhaled fluticasone propionate and triamcinolone acetonide in healthy volunteers.
STUDY OBJECTIVE: This study was conducted to compare the adrenal suppression of inhaled fluticasone propionate and triamcinolone acetonide in healthy volunteers, both given via their respective pressurised metered dose inhaler (pMDI) devices at high doses within the manufacturers recommended dose range. DESIGN: We used a single (investigator) blind, randomised, crossover design comparing a total daily dose of 1.625 mg fluticasone propionate delivered via a pMDI, 1.60 mg daily of triamcinolone acetonide delivered via a pMDI with integrated spacer, or placebo pMDI; each drug was given in two divided doses at 0800 hours and 2200 hours over a 24-h period. Each drug treatment was separated by a 1-week washout. PATIENTS: Twelve normal subjects mean age 27.5 years were studied. MEASUREMENTS: Blood samples were taken for 0800 hours plasma cortisol, i.e. 10 h following the second dose. Ten hour urine collections (2200 hours until 0800 hours) were taken for urinary cortisol and creatinine excretion. RESULTS: For the 0800 hours plasma cortisol (geometric mean, nmol.1(-1) compared with placebo (353) fluticasone propionate (138) produced significant (P < 0.05) suppression (2.57-fold difference), whereas triamcinolone acetonide (263) did not (1.34-fold difference). Fluticasone propionate produced a 1.91-fold greater adrenal suppression than triamcinolone acetonide (95% CI 1.10 to 3.33). Individual subjects with abnormally low 0800 hours cortisol values < 150 nmol.1(-1) (< 5.4 micrograms/dl) were n = 4 for fluticasone propionate and n = 0 for triamcinolone acetonide. Overnight urinary cortisol/creatinine ratio (geometric mean, nmol/mmol) did not show any difference between fluticasone propionate (1.48) and triamcinolone acetonide (1.60), with both producing significant suppression versus placebo (4.01): triamcinolone acetonide 2.50-fold difference (95% CI 1.45-4.24); fluticasone propionate 2.71-fold difference (95% CI 1.57-4.69). CONCLUSION: Fluticasone propionate 1.625 mg/day (pMDI) produced an approximately two-fold greater adrenal suppression of 0800 hours plasma cortisol than triamcinolone acetonide 1.60 mg per day (Oral Inhaler) when given twice daily, and one third of subjects with fluticasone had abnormally low 0800 hours cortisol values < 150 nmol.1(-1) (< 5.4 micrograms.dl-1. There were no differences between the drugs for urinary cortisol excretion. Further dose-ranging studies are required at steady-state in asthmatic subjects in order to see whether differences occur at lower doses on the steep part of the dose-response curve for both plasma and urinary cortisol suppression.
Administration, Inhalation↗
Comparative lung delivery of salbutamol given via Turbuhaler and Diskus dry powder inhaler devices.
OBJECTIVE: The environmental concerns surrounding the use of chlorofluorocarbons (CFC) have led to a resurgence of interest in dry powder inhaler devices. The aim of our study was to compare two commonly used dry powder inhaler devices, namely the Turbuhaler and Diskus. METHODS: Eight healthy volunteers with a mean (SEM) age of 21 years (0.8) were studied using a randomised single-investigator blind crossover design. Single doses of 1.2 mg salbutamol as Turbuhaler (12 x 100 micrograms) and Diskus (6 x 200 micrograms) were administered over 6 min. Mouth rinsing was performed after every inhalation. Lung delivery from each device was assessed by measuring the early plasma salbutamol profile at 5, 10, 15 and 20 min after inhalation. RESULTS: Significant differences in lung delivery were found between the Diskus and the Turbuhaler for salbutamol Cmax 3.21 vs 4.04 ng.ml-1, respectively and Cav 2.65 vs 3.73 ng.ml-1, respectively. This amounted to a 1.28-fold difference (95% CI 1.09 to 1.45) between these devices for Cmax and a 1.42-fold difference (95% CI 1.57 to 1.66) for Cav. CONCLUSION: We have demonstrated that, in vivo, the Turbuhaler dry powder inhaler produces significantly greater lung delivery of salbutamol than the Diskus. This illustrates that dry powder inhaler devices may have different in vivo deposition characteristics.
Adrenergic beta-Agonists↗
Generation of cytotoxic T lymphocytes against immunorecessive epitopes after multiple immunizations with adenovirus vectors is dependent on haplotype.
Currently, adenovirus (Ad) is being considered as a vector for the treatment of cystic fibrosis as well as other diseases. However, the cytotoxic T lymphocyte (CTL) response to Ad could limit the effectiveness of such approaches. Since the CTL response to virus infection is often focused on one or a few immunodominant epitopes, one approach to circumvent this response is to create vectors that lack these immunodominant epitopes. The effectiveness of this approach was tested by immunizing mice with human group C adenoviruses. Three mouse strains (C57BL/10SnJ [H-2b], C3HeB/FeJ [H-2k], and BALB/cByJ [H-2d]) were immunized with wild-type Ad or Ad vectors lacking the immunodominant antigen(s), and the CTL responses were measured. In C57BL/10 (B10) mice, a single inoculation intraperitoneally (i.p.) led to the recognition of an immunodominant antigen in E1A. When B10 mice were inoculated multiple times either i.p. or intranasally with wild-type Ad or an Ad vector lacking most of the E1 region, subdominant epitopes outside this region were recognized. In contrast, C3H mice inoculated with wild-type Ad recognized an epitope mapping within E1B. When inoculated twice with Ad vectors lacking both E1A and E1B, no immunorecessive epitopes were recognized. The immune response to Ad in BALB/c mice was more complex. CTLs from BALB/c mice inoculated i.p. with wild-type Ad recognized E1B in the context of the major histocompatibility complex (MHC) class I Dd allele and a region outside E1 associated with the Kd allele. When BALB/c mice were inoculated with E1-deleted Ad vectors, only the immunodominant Kd-restricted epitope was recognized, and Dd-restricted CTLs did not develop. This report indicates that the emergence of CTLs against immunorecessive epitopes following multiple administrations of Ad vectors lacking immunodominant antigens is dependent on haplotype and could present an obstacle to gene therapy in an MHC-diverse human population.
Adenovirus E1A Proteins↗
Adrenal suppression with chronic dosing of fluticasone propionate compared with budesonide in adult asthmatic patients.
BACKGROUND: In a previous single dosing comparison between fluticasone propionate and budesonide differences in cortisol levels measured at 08.00 hours were observed at doses in excess of 1000 micrograms. The aim of this study was to compare the adrenal suppression caused by chronic twice daily dosing with inhaled fluticasone propionate (FP) and budesonide (B) given on a microgram equivalent basis by metered dose inhaler to asthmatic patients. METHODS: Twelve stable asthmatic patients of mean age 29.7 years with forced expiratory volume in one second (FEV1) 89.0% predicted and mid forced expiratory flow (FEF25-75) 58.9% predicted, on 400 micrograms/day or less of inhaled corticosteroid, were studied in a double blind, placebo controlled, crossover design comparing inhaled budesonide and fluticasone propionate in doses of 250 micrograms, 500 micrograms, and 1000 micrograms twice daily. Each dose was given at 08.00 hours and 22.00 hours for four days by metered dose inhaler with mouth rinsing. Measurements were made of overnight urinary cortisol excretion and plasma cortisol levels at 08.00 hours, 10 hours after the eighth dose. RESULTS: The plasma cortisol levels (nmol/ l) at 08.00 hours showed that fluticasone propionate produced lower cortisol levels than budesonide at all three dose levels: F500 333.8, B500 415.2 (95% CI 28.9 to 134.0); F1000 308.3, B1000 380.3 (95% CI 10.5 to 133.5); F2000 207.3, B2000 318.5 (95% CI 5.8 to 216.7); placebo 399.9. Fluticasone produced greater effects than budesonide on the overnight urinary cortisol/creatinine ratio (nmol/mmol) at all three dose levels: F500 3.12, B500 5.55 (95% CI 0.16 to 3.79); F1000 2.54, B1000 6.12 (95% CI 1.25 to 5.91); F2000 2.07, B2000 6.09 (95% CI 0.88 to 7.18); placebo 5.23. CONCLUSIONS: With repeated dosing across a dose range of 250-1000 micrograms twice daily, fluticasone propionate produced significantly greater adrenal suppression than budesonide for both plasma and urinary cortisol. It was therefore possible to demonstrate differences between fluticasone and budesonide at lower doses with chronic dosing from those previously found with single dosing when given on a microgram equivalent basis in asthmatic patients. Factors contributing to the systemic adverse activity profile of fluticasone comprise enhanced receptor potency, prolonged receptor residency time, greater tissue retention, and a longer elimination half life.
Adrenal Glands↗
Pharmacokinetics and extrapulmonary beta 2 adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers.
BACKGROUND: Racemic salbutamol remains one of the most commonly used bronchodilators in the treatment of reversible airways obstruction. Data from animal and human studies suggest that the S-isomer, whilst contributing no bronchodilator activity, may induce increased bronchial hyperreactivity and may explain the adverse effects of regular racemic salbutamol on asthmatic disease control. The purpose of this study was to evaluate the dose-response effects of racemic (+/-) salbutamol and its R(-) and S(+) isomers in terms of pharmacokinetics and pharmacodynamics at extrapulmonary beta 2 adrenoceptors when given by the inhaled route to healthy volunteers. METHODS: Twelve healthy volunteers of mean age 20.6 years were studied in a double blind, placebo controlled, crossover design comparing cumulative doubling doses of nebulised R-salbutamol (R) and S-salbutamol (S) isomers (200 micrograms/400 micrograms/800 micrograms/1600 micrograms/3200 micrograms) and racemic salbutamol (RS) (400 micrograms/800 micrograms/1600 micrograms/3200 micrograms/6400 micrograms). Doses were administered at 20 minute intervals (t0/t20/t40/t60/t80) and measurements were made of extrapulmonary beta 2 responses as an increase in finger tremor and heart rate and fall in plasma potassium at baseline and each dose level (t0/t20/t40/t60/t80/t100). Plasma levels of salbutamol were measured at 15 minutes after each dose with a further sample at 30 minutes after the last dose (t110). RESULTS: Pharmacodynamics showed dose related beta 2 responses for R-salbutamol and RS-salbutamol but not for the S isomer, and a plateau in response was not reached within the administered dose range. No differences in responses were found between R-salbutamol and RS-salbutamol when compared on a 1:2 microgram basis. The effects of the S isomer were indistinguishable from those of placebo. For all beta 2 responses there were differences between R-salbutamol and S-salbutamol (for t100 response as change from placebo); tremor (log units): R 0.74 vs S 0.03 (95% CI 0.39 to 1.03); fall in potassium (mmol/ 1): R 0.35 vs S -0.02 (95% CI 0.03 to 0.71). Pharmacokinetics showed consistently higher levels for S-salbutamol than R-salbutamol at 15 minutes after each dose, with R-salbutamol already being cleared and S-salbutamol reaching peak levels at 30 minutes after the last dose (at t110). There were higher plasma levels of R-salbutamol and S-salbutamol following administration of the respective isomers alone compared with their levels after administration of the racemate, suggesting an influence of each isomer on the clearance of the opposite isomer when given as a racemate. CONCLUSIONS: The S-isomer of salbutamol has no detectable activity at extrapulmonary beta 2 adrenoceptors whilst exhibiting higher plasma levels than the R-isomer, in keeping with greater clearance of R-salbutamol than S-salbutamol. Inhalation of R-salbutamol and RS-salbutamol produced dose-related beta 2 responses which were equivalent when compared on a 1:2 microgram basis, despite higher plasma levels of R-salbutamol after administration of the R isomer than after administration of the racemate. Further dose ranging studies are required at steady state to evaluate the pharmacokinetics of R- and S-salbutamol and their relative effects on bronchial hyperreactivity when given on a regular basis to asthmatic subjects.
Adult↗
Effects of airway calibre on lung delivery of nebulised salbutamol.
BACKGROUND: A study was undertaken to test the hypothesis that airway calibre may alter lung deposition and therefore lung bioavailability of inhaled drugs as a result of narrowed airways reducing peripheral drug delivery. This was evaluated using the early lung absorption profile of salbutamol over the first 30 minutes after inhalation. METHODS: Three groups were compared: (1) 10 normal subjects with mean forced expiratory volume in one second (FEV1) 109.5% predicted and mid forced expiratory flow (FEF25-75) 103.0%, (2) 10 mild asthmatic patients with FEV1 102.0% and FEF25-75 82.6%, and (3) 10 severe asthmatic patients with FEV1 49.2% and FEF25-75 27.5% predicted. Each subject had one study visit where a single dose of nebulised salbutamol was given (40 micrograms/kg) via a Ventstream nebuliser with mouthpiece followed by mouth rinsing. Plasma salbutamol levels were measured at five, 10, 20, and 30 minutes after the end of nebulisation with calculation of maximal (Cmax) and average (Cav) concentration over 0-30 minutes. Systemic beta 2 responses (plasma potassium, tremor and heart rate) and airway responses (FEV1, FEF25-75) were measured before and 30 minutes after nebulisation. RESULTS: For Cav over 0-30 minutes the severe asthmatic patients had a lower plasma salbutamol concentration (1.31 ng/ml) than either the normal subjects (2.40 ng/ml) or those with mild asthma (2.45 ng/ml): normal subjects versus severe asthmatics 95% CI 0.30 to 1.88, mild versus severe asthmatics 95% CI 0.07 to 2.21. Airway responses as delta FEF25-75 were lower in the severe asthmatic subjects (0.30 l/s) than in either the normal subjects (0.69 l/s) or those with mild asthma (0.74 l/s): normal subjects versus severe asthmatic subjects 95% CI 0.09 to 0.88, mild versus severe asthmatics 95% CI 0.04 to 0.93. Values for delta log tremor also showed attenuated responses in those with severe asthma (1.22 mg2/s) compared with normal subjects (2.00 mg2/s) or those with mild asthma (2.02 mg2/s): normal subjects versus those with severe asthma 95% CI -0.02 to 3.30, mild versus severe asthmatics 95% CI 0.02 to 3.30. CONCLUSIONS: These results show that baseline airway calibre significantly alters the early lung absorption profile of salbutamol in patients with severe asthma. This may have implications in terms of optimising dose and delivery of inhaled beta 2 agonists in these patients.
Absorption↗
Adrenocortical activity with repeated twice daily dosing of fluticasone propionate and budesonide given via a large volume spacer to asthmatic school children.
BACKGROUND: In a previous single dosing study in asthmatic school children fluticasone propionate produced significantly greater suppression of overnight urinary cortisol excretion than budesonide at high doses of 800 micrograms/day or greater. The aim of this study was to assess whether conventional lower doses of both drugs cause adrenal suppression when given at steady state twice daily by large volume spacer on a microgram equivalent basis in asthmatic school children. METHODS: Eight school children of mean age 12.1 years with stable asthma of mild to moderate severity (forced expiratory volume in one second (FEV1) 78.6% predicted, mid forced expiratory flow rate (FEF25-75) 72.5% predicted), on 400 micrograms/day or less of inhaled corticosteroid, were studied in a single blind (investigator blind), placebo controlled, crossover design comparing inhaled budesonide and fluticasone propionate 100 micrograms bid and 200 micrograms bid. Each dose was given at 08.00 hours and 20.00 hours for four days by metered dose inhaler via their respective large volume spacers with mouth rinsing. Measurements were made of overnight urinary cortisol and creatinine excretion after the eighth dose. RESULTS: Neither drug produced significant suppression of overnight urinary cortisol or cortisol/creatinine excretion compared with pooled placebo and there were no differences between the drugs. Only one subject with each drug at 200 micrograms twice daily had abnormally low urinary cortisol excretion of < 10 nmol/12 hours. Ratios for the fold difference between active treatment versus placebo for urinary cortisol excretion were (as means and 95% confidence intervals for difference): budesonide 100 micrograms b.i.d 1.03 (95% CI 0.46 to 1.61), budesonide 200 micrograms b.i.d 1.04 (95% CI 0.62 to 1.46); fluticasone 100 micrograms b.i.d 1.11 (0.45 to 1.77), fluticasone 200 micrograms b.i.d 1.12 (0.78 to 1.47). Likewise, there were no significant differences in overnight urinary cortisol/creatinine excretion. CONCLUSIONS: With repeated twice daily administration at steady state across a dose range of 200-400 micrograms/day no evidence of significant adrenal suppression was found using the sensitive marker of overnight urinary cortisol excretion for either fluticasone propionate or budesonide given via a large volume spacer. These results emphasise the good safety profile in children of these inhaled steroids at conventional dose levels, which have proven antiasthmatic efficacy.
Adrenal Cortex↗
Lung delivery of salbutamol by dry powder inhaler (Turbuhaler) and small volume antistatic metal spacer (Airomir CFC-free MDI plus NebuChamber).
As a worldwide ban on the use of chlorofluorocarbons (CFCs) in inhaler devices approaches, considerable attention has been focused on the production of CFC-free delivery devices. The aim of our study was to compare the delivery of salbutamol by dry powder inhaler (DPI), Turbuhaler and a CFC-free metered-dose inhaler (MDI), Airomir, used with a novel small volume metal spacer (NebuChamber). Ten healthy volunteers, mean (SEM) age 21 (0.7) yrs were studied in a randomized, single (investigator)-blind cross-over design. Single doses of 1,200 microg salbutamol, from Turbuhaler DPI and Airomir CFC-free MDI via a NebuChamber, were given as 12 sequential 100 microg inhalations over 6 min. The lung delivery of salbutamol was assessed by measuring the plasma salbutamol profile over the first 20 min after inhalation. Plasma salbutamol concentration was expressed as maximal (Cmax) and average (Cav) value. Significant differences (p<0.001) were found between the NebuChamber (N) and the Turbuhaler (T) for salbutamol Cmax and Cav. This amounted to a 1.89 fold difference (95% CI 1.56-2.22) between these devices for Cmax, and a 1.78 fold difference (95% CI 1.42-2.15) for Cav. We have demonstrated that, in vivo, salbutamol from a chlorofluorocarbon-free metered-dose inhaler given via a small volume metal spacer (NebuChamber) produces significantly greater delivery than from an efficient dry powder inhaler (Turbuhaler).
Administration, Inhalation↗
Dose-response of inhaled drugs in asthma. An update.
The demographic characteristics of patients used in clinical trials (such as the severity of airway obstruction) can significantly influence the results of dose-response studies, emphasising the need to evaluate effects on the steep part of the dose-response curve. Differences in inhaler devices can also influence study outcomes, as for inhaled drugs both airway efficacy and adverse effect profiles are primarily determined by lung deposition and hence bioavailability. Dose-response studies with short- and long-acting beta 2-agonists show an excellent therapeutic ratio at conventional doses used in everyday clinical practice (i.e. 2 to 4 puffs). Dose-related systemic effects of beta 2-agonist occur at higher doses, for salbutamol (albuterol) > 500 micrograms. Fenoterol is a beta 2-agonists with higher intrinsic activity than salbutamol and produces greater systemic effects at higher than conventional doses on a microgram equivalent basis, although even at 4000 micrograms such differences are unlikely to be clinically relevant. No differences between fenoterol and salbutamol have been shown in terms of bronchodilator potency on a microgram equivalent basis. The long-acting beta 2-agonist salmeterol, as a partial agonist, has the potential to attenuate the acute bronchodilator response to a higher activity beta 2-agonist such as salbutamol or fenoterol, although there is no evidence to date on whether this is relevant in the setting of acute asthma. When comparing inhaled corticosteroids, attention should be focused on their respective risk-benefit ratios for antiasthmatic versus systemic activity. In terms of detecting systemic activity, it is important to use sensitive measures, such as urinary cortisol excretion, rather than insensitive parameters, such as a single morning plasma cortisol measurement between 0800h and 1000h. For fluticasone, a greater in vitro potency results in only marginal differences in antiasthmatic efficacy, particularly on the flatter part of the dose-response curve above 1000 micrograms/day in adults and 400 micrograms/day in children. However, the same enhanced potency translates directly into commensurate differences in systemic adverse effects on the steep part of the systemic dose-response curve above 1000 micrograms/day in adults and 400 micrograms/day in children, respectively. Furthermore, with repeated twice-daily administration, a longer elimination half-life and prolonged systemic tissue retention due to enhanced lipophilicity will result in greater systemic activity observed at steady-state in long term administration studies. This dissociation of airway and systemic dose-response curves results in a J-shaped curve for benefit: risk ratio, with a watershed area above 1000 microgram/day in adults. This fall in the benefit: risk ratio is likely to be greater for fluticasone than for budesonide or beclomethasone. Further studies are needed to clearly define the dose-response relationships of higher potency steroids such as fluticasone, particularly on the steep part of the curve (for clinical efficacy), using the appropriate back-titration design along with sensitive measures of antiasthmatic and systemic activity.
Administration, Inhalation↗
The International Classification for Nursing Practice: a progress report.
This paper will review and report progress on the development of the International Classification for Nursing Practice. This project, begun in 1990 by the International Council of Nurses, aims to develop a standardised vocabulary and classification of nursing phenomena (nursing diagnoses), nursing interventions, and nursing outcomes which can be used in both electronic and paper records to describe and compare nursing practice across clinical settings. An Alpha Version of the Classification of Nursing Phenomena and Nursing Interventions was released for further development and field testing in 1996 and an outline for a Classification of Nursing Outcomes in 1997. Nurses around the world, and other classification experts, have been invited to participate in the development of the Beta Version which it is hoped will be ready for release in 1999.
Classification↗
Microsatellite analysis of recurrent chromosome 2 deletions in acute myeloid leukaemia induced by radiation in F1 hybrid mice.
Deletions and/or rearrangements involving one copy of chromosome 2 are consistent and early events in the development of murine acute myeloid leukaemia (AML) by radiation. More than 90% of AMLs induced in the CBA strain of mice express such cytogenetic alterations, with chromosome 2 breakpoints clustering in the C and F regions of the chromosome. In inbred mouse strains, the molecular resolution of these breakpoints is problematic. However, by using x-ray-induced AMLs in FI progeny of genetically divergent CBA/H x C57BI, it has been possible to show region-specific loss of heterozygosity (LOH) in genetically linked sets of chromosome 2 microsatellite alleles from one of the two parental chromosomes. In the majority of cases, an acceptable concordance was shown for AML chromosome 2 deletion, as defined by microsatellites and as revealed by G-band cytogenetics. A degree of breakpoint clustering was found, but the identification of a number of deletion types, based on the position of proximal and distal breakpoints as defined by microsatellite analysis, strongly supports a leukaemogenic mechanism involving gene deletion. No bias towards loss of CBA or C57BI alleles was observed, and the gender of AML-presenting animals did not appear to influence the parental origin of the deletions. A molecular map of chromosome 2 breakpoints has now been established in FI AMLs as a first step towards the molecular cloning of breakpoint sequences.
Acute Disease↗