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Biomedical subjects

B J Lipworth

Publications and source records attributed to B J Lipworth.

At least 19 recordsLinked to original sources
PubMed1998

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↗
PubMed1998

Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma.

OBJECTIVE: We have previously found that beta2-adrenoceptor downregulation and bronchodilator desensitization to albuterol occurred at 36 hours after stopping regular treatment with twice daily salmeterol. In this study we have evaluated these same effects with formoterol given once or twice daily on a regular basis. METHODS: In a randomized, placebo-controlled, double-blind, double-dummy crossover study, 16 subjects with mild-to-moderate stable asthma (mean [SD] age, 32.5 [15.3] years; mean [SD] FEV1, 73.2 [12.1] percent predicted) receiving regular inhaled corticosteroid therapy received 1 week of treatment with formoterol dry powder (24 microg twice daily [8 AM/8 PM]), formoterol (24 microg once daily [8 PM]), or identical placebo. Lymphocyte beta2-adrenoceptor parameters and a dose-response curve to inhaled albuterol (200 to 1600 microg) were evaluated at 36 hours after the last dose of each treatment period. RESULTS: There were no significant differences in the mean values for albuterol dose-response effects among the three treatment regimens. Comparison of maximal bronchodilator responses between treatments (mean and SEM as change from baseline) revealed no significant differences between treatments for FEV1 (0.47 L [0.06 L] for placebo vs 0.48 L [0.07 L] for 24 microg once daily formoterol vs 0.51 L [0.08 L] for 24 microg twice daily formoterol) or for forced expiratory flow, mid-expiratory phase (FEF25-75) (0.80 L/sec [0.12 L/sec] for placebo vs 0.80 L/sec [0.16 L/sec] for 24 microg once daily formoterol vs 0.89 L/sec [0.14 L/sec] for 24 microg twice daily formoterol). Formoterol also had no significant effect on mean lymphocyte beta2-adrenoceptor density. However, in five of seven patients with the homozygous Gly-16 polymorphism, beta2-adrenoceptor density was downregulated by twice daily formoterol, whereas only two such cases exhibited a reduction in maximal FEV1 response to albuterol. CONCLUSIONS: The results of this study showed that for patients taking inhaled corticosteroids, overall beta2-adrenoceptor regulation and associated bronchodilator sensitivity to inhaled albuterol were unaltered at 36 hours after stopping regular treatment with formoterol. However, in a subset of patients who were Gly-16 homozygous, there was a tendency towards downregulation but not desensitization. Further studies in subjects with more severe asthma are required to assess the clinical relevance of these findings.

Administration, Inhalation↗
PubMed1998

Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal-axis activity.

BACKGROUND: Intranasal corticosteroids are regarded as the first-line treatment for allergic rhinitis, but few studies have directly compared their systemic effects. OBJECTIVE: We sought to compare the hypothalamic-pituitary-adrenal (HPA)-axis suppression with three intranasal corticosteroids in terms of basal and dynamic adrenocortical activity. METHODS: Sixteen healthy volunteers (mean age, 30.7 years) were studied in a single-blind, randomized, four-way crossover study comparing placebo with 200 microg/day fluticasone propionate (FP), 220 microg/day triamcinolone acetonide (TAA), and 336 microg/day beclomethasone dipropionate (BDP). After 4 days of treatment, an overnight urine collection was taken for cortisol and creatinine excretion starting at 10 PM (14 hours after the fourth dose), and blood was taken for serum cortisol at 8 AM (24 hours after the fourth dose) and after stimulation with adrenocorticotrophic hormone (ACTH) (0.5 microg). RESULTS: For overnight urinary cortisol excretion compared with placebo (20.8 nmol), there was a significant (p < 0.05) degree of suppression with FP (11.8 nmol) but not with TAA (16.0 nmol) or BDP (16.5 nmol). In terms of fold difference (95% CI for difference) from placebo, this amounted to 1.75-fold (1.01 to 3.03) for FP (43% suppression), 1.30-fold (0.75 to 2.25) for TAA (23% suppression), and 1.26-fold (0.73 to 2.18) for BDP (21% suppression). There was also a trend towards suppression of overnight urinary cortisol/creatinine excretion, but this was not statistically significant (placebo, 5.2 nmol/mmol; TAA, 5.0 nmol/mmol; BDP, 4.3 nmol/mmol; and FP, 4.3 nmol/mmol). Values for serum cortisol before and after ACTH stimulation showed no significant suppression. CONCLUSION: Suppression of overnight urinary cortisol occurred with intranasal FP (43%), TAA (23%), and BDP (21%), although this was only statistically significant with FP. None of the drugs were associated with blunting of the response to ACTH stimulation. Further studies are indicated to establish whether the systemic effects of inhaled and intranasal corticosteroids are additive.

Administration, Intranasal↗
PubMed1998

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↗
PubMed1998

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↗
PubMed1998

Effects of low and high doses of inhaled flunisolide and triamcinolone acetonide on basal and dynamic measures of adrenocortical activity in healthy volunteers.

The objective of this study was to evaluate the effects of inhaled flunisolide (FN) and triamcinolone acetonide (TAA) on basal and dynamic adrenocortical activity. A randomized cross-over design was used, comparing placebo (PL), low (L) and high (H) doses of FN (Aerobid; 250 microg/actuation; without spacer; L, 1000 microg; H, 2000 microg/day), and TAA (Azmacort; 100 microg/actuation; with integrated actuator/spacer; L, 800 microg; H, 1600 microg/day). Each dose was given at 0800 and 2200 h for 3 days, and treatments were separated by a 10-day washout. Twelve normal volunteers (mean +/- SE age, 24.2 +/- 2.4 yr) were studied. After 3 days of treatment, blood samples were taken before ACTH stimulation at 0800 h (10 h after the sixth dose) and after ACTH (0.5 microg) stimulation for determination of serum cortisol. Overnight (starting at 2200 h on the third day of treatment) and early morning urine collections were taken for measurements of urinary cortisol corrected for creatinine excretion. For serum cortisol (pre- and post-ACTH stimulation), there was no significant difference compared with placebo for either drug. Post-ACTH cortisol (nanomoles per L) values were: PL, 666.3; H FN, 617.0; H TAA, 591.4; L FN, 699.2; and L TAA, 686.0. For overnight corrected urinary cortisol/creatinine excretion (nanomoles per mmol) compared with PL (6.4), there was a significant suppression (P < 0.05) at the high dose of both drugs (H FN, 2.6; H TAA, 2.3) but not at the low dose (L FN, 4.2; L TAA, 4.5). Likewise, values for early morning corrected urinary cortisol/creatinine (nanomoles per mmol) showed significant suppression (P < 0.05) only with high doses of both drugs (PL, 39.0; H FN, 26.5; H TAA, 26.6; L FN, 37.2; L TAA, 36.5). The following conclusions were reached. 1) Overnight and early morning corrected urinary cortisol/creatinine excretion was more sensitive at detecting adrenocortical suppression than basal 0800 h serum cortisol or response to 0.5 microg ACTH stimulation. 2) There were no significant differences between inhaled FN (without spacer) and TAA (with integrated actuator/spacer), which only produced detectable adrenocortical suppression at the highest recommended doses and was not associated with impaired adrenal reserve. 3) Even at the high dose, the suppression observed with both drugs is unlikely to be of clinical relevance.

Administration, Inhalation↗
PubMed1998

Concomitant administration of low-dose prednisolone protects against in vivo beta2-adrenoceptor subsensitivity induced by regular formoterol.

STUDY OBJECTIVES: To assess whether concomitant administration of low-dose prednisolone (PRED) with regular inhaled formoterol (FM) might prevent the occurrence of beta2-adrenoceptor (beta2-AR) tachyphylaxis. DESIGN: Eleven healthy male subjects (mean age, 29 years) were randomized to receive 1 week with either inhaled FM, 24 microg bid, and placebo tablets (PL), or inhaled FM, 24 microg bid, and oral PRED, 15 mg daily, in double-blind, crossover fashion, with a 2-week washout between treatments. A dose-response curve (DRC) for systemic beta2-responses to inhaled salbutamol (800 to 3,200 microg) was constructed before and after each treatment period (ie, FM + PL or FM + PRED). Lymphocyte beta2-AR density (Bmax) and maximal cyclic adenosine monophosphate response to isoproterenol (isoprenaline) (Emax) were evaluated ex vivo at each visit; 8 AM serum cortisol level was also evaluated as a marker of systemic glucocorticoid activity. Comparisons for DRC were made as peak responses and area under curve (AUC). RESULTS: There was significant (p < 0.05) subsensitivity of systemic beta2-AR responses (as AUC) following FM + PL: for heart rate (before vs after), 760 vs 340 beats (95% confidence interval [CI], 160 to 680), for tremor 0.39 vs 0.19 log units/h (95% CI, 0.01 to 0.41), and for potassium, -0.34 vs -0.19 mmol x h/L (95% CI, -0.04 to -0.28). With PRED, there was protection against subsensitivity induced by FM with no significant difference in values before vs after FM: heart rate, 740 vs 640; tremor, 0.35 vs 0.34; and potassium, -0.30 vs -0.25. FM + PL induced significant downregulation of lymphocyte beta2-AR density (log Bmax; fmol/10(6) cells) (before vs after): 0.25 vs 0.11 (95% CI, 0 to 0.22; p < 0.05) and this was not altered by PRED (before vs after): 0.21 vs 0.10 (95% CI, 0.01 to 0.27; p < 0.05). FM + PL also caused desensitization of Emax (pmol/10(6) cells) (before vs after): 6.21 vs 2.29 (95% CI, 1.19 to 6.64; p < 0.05) and this was attenuated by PRED with no significant difference between before and after values: 4.60 vs 3.28. CONCLUSIONS: Concomitant administration of a low dose of PRED produced protection against FM-induced subsensitivity of systemic beta2-AR, as assessed by the response to inhaled salbutamol. In contrast, prednisolone did not prevent ex vivo beta2-AR downregulation despite causing significant cortisol suppression. This, in turn, suggests that there is a dissociation in the dose of PRED required to protect against beta2-AR downregulation and subsensitivity, following continuous exposure to long-acting beta2-agonist.

Administration, Inhalation↗
PubMed1998

Beta2-adrenoceptor regulation and function in female asthmatic patients receiving the oral combined contraceptive pill.

STUDY OBJECTIVES: Previously it has been shown that there is abnormal hormonal control of beta2-adrenoceptors in asthmatic women. Exogenous progesterone but not estradiol produces paradoxic downregulation and desensitization of beta2-adrenoceptors in asthmatic women when compared with nonasthmatic subjects. This study investigates the effect of the oral combined contraceptive pill (OCP) on beta2-adrenoceptor regulation and function in female asthmatic patients. PATIENTS: The study population was comprised of 11 women with stable mild to moderate asthma. The mean age was 25 years; the FEV1 was 89% of predicted, and the forced expiratory flow, mid-expiratory phase (FEF25-75%) was 69% of predicted. DESIGN: Patients were evaluated while on (day 20 to 21) and off (day 5 to 7) the OCP during a 28-day calendar period. MEASUREMENTS: Serum sex hormones, lymphocyte beta2-adrenoceptor parameters, and bronchodilator and systemic dose-response curves (DRCs) to albuterol (Salbutamol) (100 to 1,600 microg) were measured at both on and off periods. RESULTS: Serum levels of endogenous estradiol and progesterone were both suppressed by the OCP. Baseline FEV1 were not different while patients were on (2.70 L) and off (2.72 L) the OCP. There were no significant differences in lymphocyte beta2-adrenoceptor parameters between the two phases of the cycle. Receptor density (geometric mean Bmax) was 1.78 (on OCP) vs 1.86 (off OCP) fentomole/10(6) cells, maximal cyclic adenosine monophosphate response to isoprenaline was 6.60 (on OCP) vs 7.58 (off OCP) pmol/10(6) cells, and binding affinity was 14.0 (on OCP) and 13.6 (off OCP) pmol/L. Likewise, there were no significant differences in the bronchodilator and systemic DRCs constructed at both phases of the cycle as evaluated: area-under-curve (AUC) FEV1 was 0.53 (on OCP) vs 0.56 (off OCP) L.h; and AUC FEF25-75% was 3,130 (on OCP) vs 3,640 (off OCP) L. Potassium (K) and finger tremor responses were unaltered between the two periods: AUC K was 0.50 (on OCP) vs 0.44 (off OCP) mmol . h/L and AUC tremor was 0.72 (on OCP) vs 0.89 (off OCP) log units.h. CONCLUSION: The OCP did not alter beta2-adrenoceptor regulation and function in stable female asthmatic patients. Further studies are required in patients who have premenstrual asthma.

Adrenergic beta-Agonists↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

Effect of exogenous female sex-steroid hormones on beta 2-adrenoceptors in healthy males.

OBJECTIVE: We have previously demonstrated that exogenous progesterone, but not oestrogen, upregulated lymphocyte beta 2-adrenoceptors (beta 2-AR) when given during the follicular phase in healthy females. In the present study, we were interested to see whether this facilitatory effect of female sex-steroid hormones could be demonstrated in healthy males. METHODS: Nine healthy male volunteers with a mean age of 24 years completed this randomised, double-blind, placebo-controlled, cross-over study. They were randomised to receive either oral placebo, oestradiol valerate (4 mg) or medroxyprogesterone (40 mg). The study medication was given in two divided doses 12 h apart. Subjects attended the laboratory at baseline (T0 is baseline), 1 h after ingestion of the second dose of study medication (T1) and 24 h later (T24). At each visit, 60 ml of peripheral blood was withdrawn for measurement of serum oestradiol, progesterone and testosterone levels, and for lymphocyte beta 2-AR parameters; density (Bmax), binding affinity (Kd) and maximal cyclic AMP response to isoprenaline (Emax). RESULTS: Baseline levels of sex-steroid hormones were comparable for each of the treatment periods. Serum oestradiol levels increased significantly, twofold, 1 h after ingestion of oestradiol but there was no significant change in levels of serum progesterone and testosterone. Lymphocyte beta 2-AR parameters following treatment with oestradiol and progesterone did not change significantly from baseline and were not different from placebo. CONCLUSION: In contrast to previously reported effects in women, female sex-steroid hormones did not appear to have any significant facilitatory effects on lymphocyte beta 2-AR parameters when given exogenously to healthy males. This lack of effect may be due either to the absence of receptors for female sex hormones in beta 2-AR or to reduced efficacy of female hormone-receptor coupling in male lymphocytes.

Adult↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale.

OBJECTIVES: Angiotensin II (ANG II) is known to be a potent vasoconstrictor agent in the pulmonary circulation. Furthermore, type 1 ANG II receptor blockade with losartan attenuates acute hypoxic pulmonary vasoconstriction in normal subjects. The aim of this study was therefore to evaluate the haemodynamic and endocrine sequelae of type 1 ANG II receptor blockade in patients with hypoxaemic cor pulmonale. METHODS: Nine patients with chronic obstructive pulmonary disease (COPD) age 67 +/- 3 years with pulmonary hypertension and normal left ventricular systolic function were studied on two separate occasions in a double-blind, placebo-controlled, crossover study. They were randomised to receive either 50 mg of oral losartan or matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Haemodynamic measurements and venous blood samples were taken at baseline and after 2 and 4 h. RESULTS: Maximal effects were observed at 4 h where losartan compared to placebo resulted in a significant reduction in both MPAP (28.6 +/- 2.0 vs 32.4 +/- 1.5 mmHg) and TPR (428 +/- 40 vs 510 +/- dyn.s.cm-5), respectively. Similarly losartan compared to placebo resulted in a significant reduction in MAP (87 +/- 4.5 vs 93 +/- 3.2 mmHg) and SVR (1293 +/- 94 vs 1462 +/- 112 dyn.s.cm-5), and significantly increased CO (5.58 +/- 0.43 vs 5.31 +/- 0.42 l/min). In addition, plasma aldosterone was significantly lower after treatment with losartan compared to placebo: 76 +/- 23 vs 164 +/- 43 pg/ml respectively. CONCLUSIONS: Thus, selective type 1 ANG II receptor blockade appears to have beneficial pulmonary and endocrine effects, suggesting a possible therapeutic role in the management of hypoxaemic cor pulmonale.

Aged↗
PubMed1997

Cardiopulmonary effects of endothelin-1 in man.

OBJECTIVES: Endothelin-1 levels are elevated in a number of conditions characterised by impaired cardiovascular performance and abnormal vasoconstriction such as congestive cardiac failure and primary and secondary pulmonary hypertension. The aim of the present study was to assess the effects of the vasoconstrictor peptide endothelin-1 on pulmonary and systemic haemodynamics and cardiovascular performance in normal man. METHODS: Ten healthy male volunteers were studied on two occasions in a randomised, double-blind, placebo-controlled, cross-over study and received systemic infusions of either endothelin-1 (0.75, 1.5 and 3 pmol.kg-1.min-1 for 30 min each) or saline placebo. Systemic and pulmonary haemodynamic parameters were monitored non-invasively by pulsed-wave Doppler, as were parameters of left and right ventricular diastolic filling and inotropic state. Effects on renin-angiotensin and natriuretic peptide system activity were also measured. RESULTS: Endothelin-1 infusion produced dose-related falls in heart rate, stroke volume and cardiac output. Systemic vascular resistance (SVR) increased from 1156 +/- 57 to 1738 +/- 115 dyn.s.cm-5, and total pulmonary vascular resistance (TPR) increased from 142 +/- 12 to 329 +/- 22 dyn.s.cm-5. Endothelin-1 caused significant impairment of left and right ventricular diastolic filling, even at a low dose which had no pulmonary or systemic pressor effects. Electromechanical and Doppler acceleration indices of inotropic state were also significantly impaired. Activity of the renin-angiotensin system was suppressed by endothelin-1 whilst plasma levels of atrial natriuretic peptide (ANP) were unchanged. CONCLUSIONS: Thus, in addition to systemic and pulmonary pressor effects our results suggest that endothelin-1 impairs overall cardiovascular performance by causing diastolic dysfunction and acting as a negatively inotropic agent. These effects were associated with compensatory changes in the renin-angiotensin system.

Adult↗
PubMed1997

Effects of frusemide and hypoxia on the pulmonary vascular bed in man.

AIMS: Diuretic therapy is conventionally used to treat oedema in patients with hypoxic cor pulmonale. This condition is associated with activation of the renin angiotensin system (RAS) with elevated levels of angiotensin II (ANG II), a potent pulmonary pressor agent. We explored the hypothesis that RAS activation by diuretic therapy might therefore worsen hypoxic pulmonary vasoconstriction via the effects of ANG II on the pulmonary vascular bed. METHODS: Eight normal volunteers were studied on 2 separate days. They either received 40 mg frusemide daily or placebo for 4 days and were then rendered hypoxaemic, by breathing an N2/O2 mixture for 20 min to achieve an SaO2 of 85-90% adjusted for a further 20 min to achieve an SaO2 of 75-80%. Pulsed wave doppler echocardiography was used to measure mean pulmonary artery pressure, cardiac output and hence pulmonary vascular resistance (PVR). RESULTS: Plasma renin activity (PRA) was significantly (P < 0.01) increased after prior treatment with frusemide compared with placebo at all time points. Prior treatment with frusemide significantly (P < 0.05) increased PVR compared with placebo at baseline: 185 +/- 17 vs 132 +/- 10 dyn s cm-5 at an SaO2 of 85-90%: 291 +/- 18 vs 229 +/- 16 dyn s cm-5 and at SaO2 of 75-80%: 356 +/- 12 vs 296 +/- 17 dyn s cm-5 respectively. However, the delta-PVR response to hypoxaemia was not significantly altered by frusemide compared with placebo. In contrast to its effect on the pulmonary vasculature prior treatment with frusemide did not significantly alter systemic haemodynamic parameters either at baseline or during hypoxia. CONCLUSIONS: Thus, prior treatment with frusemide increased baseline pulmonary vascular resistance and significantly augmented the hypoxaemic pulmonary vascular response in additive fashion. It is hypothesised that this effect of frusemide may be due to RAS activation with ANG II mediated pulmonary vasoconstriction.

Adult↗