Biomedical subjects
Publications and source records attributed to A M Wilson.
The lung bioavailability (as adrenal suppression) of fluticasone propionate was about twofold greater with chlorofluorocarbons than hydrofluoroalkane as propellant. Direct switching between formulations on a microg equivalent may therefore be inadvisable.
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BACKGROUND: Current guidelines recommend anti-leukotriene agents as alternative treatments for mild persistent asthma; however, information on their long-term safety and efficacy is needed. OBJECTIVE: To evaluate long-term safety and efficacy of and compliance with oral zafirlukast (Z; 20 mg BID) during the first 39 weeks of ongoing, multicenter, open-label extension (OLE) of a previously reported 13-week, randomized (2:1), double-blind (DB), placebo (P)-controlled trial in mild-to-moderate asthmatic patients treated previously with beta2-agonists alone. METHODS: Patients (12 to 76 years; FEV1 > or = 55% predicted) elected to enter OLE after completing the DB trial. Safety evaluated by adverse events (AEs), laboratory tests, and physical and electrocardiographic examinations. Efficacy assessed by spirometry measurements [FEV1, FEV1 % predicted, personal-best (post-bronchodilator) FEV1] and treatment failure rates. Compliance was calculated as percentage of treatment dispensed. After a visit at OLE week 3 (week 16), patients had visits every 12 weeks. RESULTS: A total of 443 patients (nz-->z = 310, np-->z = 133) entered the OLE. Results through the OLE period showed that 80% of patients overall reported AEs. Of patients randomized to Z and P during DB period, 68% and 67%, respectively, reported AEs during quarter I (Q1); percentage of Z-treated patients reporting AEs during the OLE ranged from 66% (Q2) to 44% (Q4). Review by quarters showed occurrence of AEs in Z-treated groups (Q2-4) was similar to that in P group (Q1). Compared with baseline (week 0), modest yet significant improvements (P < or = .02) in all spirometry measurements were noted in Z --> Z and P --> Z groups at OLE week 3, with sustained effects noted during OLE period. Treatment failure rates during OLE ranged from 7.2% (Q2) to 3.3% (Q4). Mean compliance ranged from 98% (OLE week 3) to 95% (OLE week 39). CONCLUSIONS: Long-term treatment with zafirlukast was safe and well tolerated in asthmatic patients. Sustained efficacy and asthma control and good compliance were observed over extended treatment period. Results demonstrate long-term safety and effectiveness of and compliance with this anti-leukotriene agent.
AIMS: To determine the systemic dose-response relationships with oral prednisolone and inhaled fluticasone propionate administered in a putative 11:1 mg equivalent basis, in terms of effects on adrenal, bone and haematological markers. METHODS: Twelve asthmatic patients mean (s.e.) age, 28.8 [3.3] years, FEV1 94.7 [3.6]% predicted, FEF(25-75) 65.5 [6.1]% predicted were studied in a double-blind, double dummy randomised crossover design comparing placebo, inhaled fluticasone propionate via volumatic spacer given twice a day (ex actuator dose 0.44 mg day-1, 0.88 mg day-1, 1.76 mg day-1 ) and oral prednisolone given once daily (5 mg day-1, 10 mg day-1, 20 mg day-1 ). All treatments were for 4 days at each dose level with a 7-day washout at crossover. Measurements were made at 08.00 h after the last dose of each dose level for plasma cortisol, serum osteocalcin and blood eosinophil count. RESULTS: There were significant dose-related effects for suppression of all three endpoints with both prednisolone and fluticasone propionate. Parallel slope analysis revealed a calculated dose ratio for relative potency of 8. 5:1 mg (95% CI 5.7-11.2) comparing Pred with FP for morning cortisol. The magnitude of suppression with FP was less for osteocalcin and eosinophils than for cortisol. CONCLUSIONS: Systemic tissues exhibit different dose-response relationships for the effects of inhaled and oral corticosteroids with suppression of cortisol being greater than osteocalcin or eosinophils. For cortisol suppression we observed an 8.5:1 mg relative potency ratio comparing prednisolone with fluticasone propionate. Patients taking high dose inhaled fluticasone propionate should therefore be screened for evidence of impaired adrenal reserve.
AIMS: A new formulation, low dose microencapsulated aspirin, permits slow absorption of aspirin and presystemic acetylation of platelet cyclo-oxygenase within the portal circulation, potentially avoiding deleterious effects on gastric and systemic prostaglandin synthesis. The objective of this study was to determine whether the administration of microencapsulated aspirin was as effective as enteric coated (EC) aspirin as an inhibitor of platelet function in patients with atherosclerosis. METHODS: One hundred and four patients were enrolled and randomised after a run in period of at least 14 days on aspirin EC 75 mg (day 0), to receive either microencapsulated aspirin 162.5 mg (n=34), aspirin EC 150 mg (n=36) or continue on aspirin EC 75 mg (n=34) for 28 days. Serum thromboxane B2 and collagen-induced platelet aggregation and release of 5-hydroxytryptamine (EC50 values) were measured on days 0 and 28. Aggregation/release EC50s were then repeated in the presence of a large dose of aspirin added in vitro to determine the EC50 at the maximum level of platelet inhibition. RESULTS: Median thromboxane B2 levels were low after 14 days run-in therapy with aspirin EC 75 mg, but significant further reductions were seen on day 28 in patients randomised to microencapsulated aspirin 162.5 mg (P=0.0368) and aspirin EC 150 mg (P=0.0004) compared with those remaining on aspirin EC 75 mg. Median EC50 s on day 28 showed small but significant increases from baseline (day 0) in aggregation in patients randomised to microencapsulated aspirin 162.5 mg (0.62-0.85, P=0.0482) and in both aggregation and release in patients randomised to aspirin EC 150 mg (0.95-1.20, P=0.0002, 8.4-11.7, P<0. 0001, respectively) signifying enhanced antiplatelet activity. No changes were seen in patients continuing on aspirin EC 75 mg. Results following addition of high dose aspirin in vitro suggest that mechanisms other than thromboxane synthesis may be operative in the long term effects of microencapsulated aspirin 162.5 mg and aspirin EC 150 mg over aspirin EC 75 mg. CONCLUSIONS: The results show good inhibition of thromboxane B2 synthesis and subsequent platelet activity by all preparations of aspirin, although both microencapsulated aspirin 162.5 mg and aspirin EC 150 mg are slightly more effective than aspirin EC 75 mg. A randomised trial is now required to determine whether microencapsulated aspirin is associated with fewer gastric side-effects.
OBJECTIVE: To evaluate the dose-response relationship for adrenocortical activity with fluticasone propionate (FP) and to assess basal and dynamic markers after stopping treatment for 3 days. PATIENTS AND DESIGN: Fourteen asthmatic patients were recruited: mean age 33.3 years, forced expiratory volume in 1 s (FEV1): 91.3% predicted, forced mid expiratory flow rate (FEF25-75): 58.1% predicted. A single blind study design was used comparing a placebo run-in with sequentially low, medium and high doses of FP and a placebo washout. All active treatments, placebo and washout were each for 3 days. FP was given at steady-state with twice daily divided dosing at 0800 h and 2200 h at doses of 375 micrograms, 875 micrograms, and 1750 micrograms per day. MEASUREMENTS: A 100 micrograms i.v. bolus hCRF test was performed at 0800 h after the run-in and washout periods. Blood samples were taken for 0800 h serum cortisol and osteocalcin as well as an overnight 10 h urine collection for cortisol/creatinine excretion after the run-in period, each dose of active treatment and washout. RESULTS: For serum cortisol (pre and post hCRF stimulation) there was no significant difference between placebo and washout values. Mean (SE) cortisol (nmol/1) values pre hCRF were run-in: 644.5 (59.7), washout: 550.3 (42.8) and post hCRF were run-in: 690.9 (42.9), washout: 719.1 (43.8). There was a significant (P < 0.05) difference between run-in vs medium and high doses for 0800 h serum cortisol, overnight urinary cortisol and overnight urinary cortisol/creatinine excretion; and vs high dose for serum osteocalcin. The fold difference (95% CI for difference) between run-in and high dose was: 2.2 (1.5-3.2) for overnight urinary cortisol, 2.5 (1.5-4.1) for overnight urinary cortisol/creatinine, 2.0 (1.1-3.6) for serum cortisol, and 1.2 (1.1-1.3) for serum osteocalcin. CONCLUSION: Fluticasone propionate exhibited dose related adrenal suppression with treatment. The suppressive effects of fluticasone propionate on adrenocortical activity were greater than those observed on osteocalcin.
Hoof wall cracks need mechanical stabilisation to allow healing. Common techniques are fixation with screws, wires and plates or bonding of a patch across the crack. An in vitro system to determine the shear properties of equine hoof crack repairs is described. The force and displacement at yield, stiffness and ultimate force were determined for 4 repair techniques based on an acrylic material, polyurethane patch attached with cyanoacrylate adhesive, steel plate attached with screws and a transverse metal bar cut into the hoof wall. The cyanoacrylate bonded patch repair had lower values for all parameters measured (n = 8, P<0.05) and the other 3 repairs had similar mechanical properties. This study demonstrates that acrylic adhesive repairs can resist similar shear forces to traditional screw plate repairs without risk of penetrating into the sensitive structures of the foot. The transverse bar mounted across the crack had similar resistance to shear as the much larger screw plate and plain bonding repair techniques. This novel technique may be a useful adjunct to other repair methods.
A radiological study was performed to test the hypothesis that osteoarthritis of the scapulohumeral joint in Shetland ponies is secondary to shoulder dysplasia. Animals were selected into 3 groups: Group 1: Shetland ponies with a radiological and clinical diagnosis of scapulohumeral osteoarthritis (n = 8); Group 2: Shetland ponies without forelimb lameness (n = 12); Group 3: Horses/ponies without a history or clinical signs of forelimb lameness (n = 22). Anatomical indices were measured from mediolateral radiographs of a scapulohumeral joint from each animal. There was a significant difference in the mean radius of curvature of the glenoid cavity of the scapula (RCG) between the 3 groups (MANOVA test, P = 0.003). The mean RCG of both Group 1 (P = 0.001) and Group 2 (P = 0.022) was significantly greater than that of Group 3. There was no significant effect of group on the radius of curvature of the humeral head or on the Conformity Index. There was a significant effect of group on the Glenoid Ratio (MANOVA test, P = 3 x 10(-6)). The mean Glenoid Ratio was significantly lower in both Group 1 (P = 2 x 10(-6)) and in Group 2 (P = 0.006) than in Group 3. These results indicate that the glenoid cavity of the scapula is 'flatter' and 'shallower' in Shetland ponies which we postulate to be a primary dysplasia in this breed.
BACKGROUND: As both rhinitis and asthma are allergic conditions, they frequently occur together. The objective of this study was to assess the diurnal adrenocortical activity in asthmatics receiving inhaled (inh) and intranasal (n) formulations of two different corticosteroids, fluticasone propionate (FP) and triamcinolone acetonide (TAA), both given at clinically recommended doses. METHODS: Twelve stable moderately severe asthmatic subjects of mean age 23.9 years and mean forced expiratory volume in one second (FEV1) 84% predicted were recruited into a randomised placebo (PL) controlled two-way crossover study comparing nPL + inhPL, nPL + inhFP (880 micrograms bid), and nFP (200 micrograms once daily) + inhFP (880 micrograms bid) with nPL + inhPL, nPL + inhTAA (800 micrograms bid) and nTAA (220 micrograms once daily) + inhTAA (800 micrograms bid), each given for five days with a 10 day washout period. Twenty four hour integrated and fractionated (overnight, 08.00 hours, daytime) serum cortisol levels and urinary cortisol/creatinine excretion were measured. RESULTS: For 24 hour and fractionated serum cortisol levels and corrected urinary cortisol/creatinine excretion there were significant (p < 0.05) differences between all active treatments and placebo. For 24 hour integrated serum cortisol levels the ratio between inhaled TAA and FP was 2.3 fold (95% CI 1.2 to 4.3), and for 24 hour urinary cortisol/creatinine excretion the ratio was two-fold (95% CI 1.2 to 3.4). For 24 hour urinary cortisol excretion, with all active treatments, individual abnormal low values of < 40 nmol (< 14.4 micrograms) occurred in 17/24 with FP compared with 4/24 with TAA (p < 0.0005). The 24 hour serum cortisol profile was flattened by FP but not with TAA. The addition of nasal corticosteroid did not produce further significant suppression of mean cortisol values, although with intranasal FP there were three more abnormal values for 24 hour urinary cortisol excretion than with inhaled FP alone. CONCLUSIONS: Both inhaled FP and TAA caused significant suppression of adrenocortical activity which was twice as great with FP, the latter being associated with significantly more individual abnormal values and loss of the normal diurnal circadian rhythm. Fractionated serum cortisol levels and urinary cortisol/creatinine excretion were as sensitive as the respective integrated 24 hour measurements. Although the addition of intranasal formulations did not produce further significant suppression of mean values, there were more individual abnormal cortisol values associated with the addition of intranasal FP.
BACKGROUND: Inhaled corticosteroids have dose related systemic effects determined by oral (swallowed or oropharyngeal absorption) and lung bioavailability. A study was undertaken to evaluate the significance of oropharyngeal absorption for fluticasone propionate. METHODS: Sixteen healthy volunteers of mean age 29.3 years were studied using an open randomised, placebo controlled, four way crossover design. Treatments were: (a) fluticasone metered dose inhaler (pMDI) 250 microg, 8 puffs; (b) fluticasone pMDI 250 microg, 8 puffs + mouth rinsing/gargling (water); (c) fluticasone pMDI 250 microg, 8 puffs + mouth rinsing/gargling (charcoal); and (d) placebo pMDI, 8 puffs + mouth rinsing/gargling (water). Overnight (ONUC) and early morning (EMUC) urinary cortisol/creatinine ratios and 8 am serum cortisol (SC) levels were measured. RESULTS: Significant (p<0. 05) suppression of ONUC, EMUC, and SC occurred with each active treatment compared with placebo. The mean values (95% CI for difference from placebo) were: (a) ONUC (nmol/mmol): fluticasone (2. 8, 95% CI 3.6 to 7.9), fluticasone + water (3.1, 95% CI 3.3 to 7.7), fluticasone + charcoal (2.3, 95% CI 4.1 to 8.5); placebo (8.6); (b) EMUC (nmol/mmol): fluticasone (5.6, 95% CI 8.4 to 24.5), fluticasone + water (7.6, 95% CI 6.6 to 22.4); fluticasone + charcoal (5.6, 95% CI 8.7 to 24.5); placebo (22.1). There were no significant differences between active treatments. The numbers of subjects with an overnight urinary cortisol of <20 nmol/10 hours were 0 (placebo), 11 (fluticasone), 12 (fluticasone + water), and 13 (fluticasone + charcoal). CONCLUSIONS: Oropharyngeal absorption of fluticasone does not significantly contribute to its overall systemic bioactivity as assessed by sensitive measures of adrenal suppression. In view of almost complete hepatic first pass inactivation with fluticasone, there is no rationale to employ mouth rinsing to reduce its systemic effects although it may be of value for reducing oral candidiasis.
BACKGROUND: Inhaled corticosteroids such as fluticasone propionate (FP) have dose-related systemic effects, including adrenal suppression. We have therefore investigated the effect of adding a large volume spacer on the systemic bioactivity of FP given via a pressurized metered-dose inhaler (pMDI). METHODS: Fourteen healthy volunteers (mean age, 29.9 years old) were studied using an open, randomized, placebo-controlled, three-way crossover design. Single doses of the following were given at 5:00 PM in a randomized sequence: (1) eight puffs of FP by pMDI, 1.76 mg (250 microg ex-valve, 220 microg ex-actuator); (2) eight puffs of FP by pMDI, 250 microg, with 750-mL spacer (Volumatic; Allen & Hanburys; Uxbridge, UK); and (3) eight puffs of placebo by pMDI. Measurements were made after each dose, including overnight and early morning urinary cortisol/creatinine ratios and 8:00 AM serum cortisol. RESULTS: Significant (p < 0.05) suppression of all three end points occurred with each active treatment compared to treatment with placebo. Furthermore, significant (p < 0.05) additional suppression occurred when comparing FP by pMDI alone to FP by pMDI with spacer. Geometric mean fold differences (95% confidence interval for fold difference) between FP by pMDI alone and FP by pMDI with spacer were 1.94-fold (1.00-3.78) for overnight urinary cortisol/creatinine ratio and 1.98-fold (1.26-3.10) for 8:00 AM serum cortisol. This was mirrored by a twofold rise in the number of values for uncorrected overnight urinary cortisol < 10 nmol/10 h: placebo treatment (none of 14 subjects); FP by pMDI (6 of 14 subjects; 43%); and FP by pMDI with spacer (12 of 14 subjects; 86%). CONCLUSIONS: The use of a large volume spacer with FP by pMDI results in a twofold increase in the systemic bioavailability as assessed by sensitive measures of adrenal suppression. This, in turn, reflects a twofold improvement in respirable dose delivery with the spacer device.
Two studies were designed to replicate the finding that people scoring high on aesthetic motivation, as measured by Wann's Sport Fan Motivation Scale, tend to prefer nonaggressive sports. Study 1 correlated 75 college students' scores on aesthetic motivation with their enjoyment of watching aggressive sports. Study 2 correlated 44 college students' scores on aesthetic motivation with their enjoyment of watching a series of aggressive football plays. Neither study replicated the previous finding that people high on aesthetic motivation tend to prefer nonaggressive sports, suggesting that the earlier finding was an artifact of the method used.
OBJECTIVE: To assess the force plate as a diagnostic aid in equine locomotor abnormalities, particularly for abnormalities such as navicular disease that do not have specific diagnostic criteria. ANIMALS: 17 Thoroughbreds without observable locomotor abnormalities (group A), 6 Thoroughbreds with superficial digital flexor tendon injury (group B), and 8 Thoroughbreds with navicular disease (group C). PROCEDURE: Using a force plate, ground reaction force patterns were recorded at the trot. Peak limb vertical force and force/time curve parameters were derived from 4 identifiable points at the beginning and end of vertical and craniocaudal horizontal plots. Principal component analysis (PCA) of group-A data was undertaken on beginning and end of stride data, and the first 2 components were represented graphically. The PCA rotation matrices were applied to equivalent data for horses of groups B and C. RESULTS: Asymmetry of peak vertical force (PVF) could not be differentiated among groups A, B, and C. Values for group-B horses, however, were significantly outside mean group-A values on the PCA plot for beginning of stride phase variables. Group-B data were within the group-A range for end of stride phase variables. Values for group-C horses were significantly outside the group-A range for beginning of stride phase variables and were outside mean group-A values for end of stride phase variables. CONCLUSIONS: PCA of force/time data provides a sensitive method to evaluate the force/time curve associated with 2 specific injury/disease processes. CLINICAL RELEVANCE: Horses alter weight-bearing in biomechanically distinct ways, thus creating potential for the force plate to become an important diagnostic and prognostic tool.
Treating schizophrenia is expensive. Preventing rehospitalization of patients with schizophrenia provides an attractive opportunity for cost savings, especially for patients with 'revolving-door' or multiple-episode schizophrenia. Reducing the occurrence of extrapyramidal symptoms and other adverse events associated with standard antipsychotic agents may increase compliance and reduce the rate of rehospitalization of patients with schizophrenia. Quetiapine ('Seroquel', ICI 204,636, Zeneca Pharmaceuticals) is a new dibenzothiazepine antipsychotic agent with a low propensity for extrapyramidal symptoms. We describe here a unique methodology to compare quetiapine with usual-care medications in real-world treatment settings. The trial objective is to determine if therapy with this new atypical antipsychotic agent can reduce the rate of rehospitalization and, therefore, treatment costs. Using two secondary medical-claims databases, we defined the minimal threshold for revolving-door status as 1.0 admission per year; this definition allows our trial to focus on the subpopulation of schizophrenic patients with the greatest potential for cost savings by either the new atypical antipsychotic quetiapine or usual-care therapy. We describe here the approach used in our trial.
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.
BACKGROUND: Budesonide (BUD) has recently been licensed for treatment of asthma in the United States, whereas triamcinolone acetonide (TAA) has been used for many years. OBJECTIVE: We sought to evaluate the dose-response effect of inhaled BUD and TAA in terms of adrenal, bone, and blood markers. METHODS: Twelve asthmatic subjects (mean age, 32 years; mean FEV1, 91% of predicted value) were studied in a randomized design comparing 3 days of treatment with placebo and low (200 micrograms twice daily), medium (400 micrograms twice daily), and high (800 micrograms twice daily) doses of BUD (Pulmicort Turbuhaler, 100 micrograms) and TAA (Azmacort integrated actuator/spacer, 100 micrograms) with a 7-day period at crossover, when patients received their usual inhaled corticosteroid therapy. Measurements were made at 8 am for serum cortisol, osteocalcin, and blood eosinophils. Measurements were also made for overnight urinary cortisol/creatinine excretion. RESULTS: For all measurements there were no significant differences between the 2 treatments at any dose level. Ratios between BUD and TAA (95% CI) at the highest dose levels were as follows: 8 am serum cortisol, 1.08-fold (0.63 to 1. 85); urinary cortisol, 1.09-fold (0.63 to 1.86); eosinophils, 0. 98-fold (0.69 to 1.38); and osteocalcin 1.05-fold (0.78 to 1.41). There was no evidence of a significant overall dose-response effect for any parameter of hypothalamo-pituitary-adrenocortical axis activity, with neither drug being significantly different from placebo at any dose. For the 3 dose levels of both drugs, total abnormal low values for 8 am serum cortisol (ie, <5.4 micrograms/dL [<150 nmol/L]) showed 2 of 36 for BUD and 2 of 36 for TAA. There was also no significant overall dose-response effect for eosinophils or osteocalcin, although both drugs were significantly (P <.05) different from placebo at the highest dose: eosinophils (x10(9)/L), placebo: 0.36, TAA: 0.24, and BUD: 0.23; and osteocalcin (nmol/L), placebo: 1.04, TAA: 0.73, and BUD: 0.77. CONCLUSION: There were no significant differences in the systemic bioactivity profiles, in terms of adrenal, blood, and bone markers, between BUD administered by means of Turbuhaler and TAA administered by means of an integrated actuator/spacer in a dose range of 400 micrograms to 1600 micrograms/day. Both drugs exhibited a significant degree of detectable systemic bioactivity but only at the highest dose of 1600 micrograms/day for effects on eosinophil count and osteocalcin.