The efficacy of fluticasone furoate administered in the morning or evening is comparable in patients with persistent asthma.

BACKGROUND: The inhaled corticosteroid fluticasone furoate (FF) is efficacious as a once-daily treatment for the management of asthma. Asthma is associated with circadian changes, with worsening lung function at night. We compared the efficacy of once-daily FF in the morning or evening for the treatment of asthma. METHODS: Adults with persistent bronchial asthma were enrolled into this randomised, repeat-dose, double-blind, double-dummy, placebo-controlled, three-way crossover study. After a 14-day run-in period, patients received either: FF 100 µg in the morning (AM); FF 100 µg in the evening (PM); or placebo, via the ELLIPTA(®) dry powder inhaler. Patients received all three treatments (14 ± 2 day duration) separated by a 14- to 21-day washout period. The primary endpoint was 24-h weighted mean forced expiratory volume in 1 s (FEV1) measured at the end of each 14-day treatment. RESULTS: A total of 28 patients aged between 19 and 67 years were randomised and 21 (75%) completed all three study arms. Once-daily administration of FF 100 µg resulted in an increased 24-hour weighted mean FEV1; differences between the adjusted means for AM and PM FF dosing versus placebo were 0.077 L (90% confidence interval [CI]: 0.001, 0.152) and 0.105 L (90% CI: 0.029, 0.180), respectively (adjusted mean difference: -0.028 L [90% CI: -0.102, 0.045]). AM or PM doses had comparable incidences of adverse events (AEs; 18/23 versus 18/24, respectively), no serious AEs occurred. CONCLUSION: AM and PM doses of once-daily FF 100 µg produced comparable improvements in lung function relative to placebo.

Duration of effect of single-dose inhaled fluticasone propionate on AMP-induced bronchoconstriction.

Airway hyperresponsiveness induced by adenosine-5'-monophosphate (AMP) is regarded as a reliable model for allergic asthma and for the evaluation of anti-asthmatic drugs. Single-dose inhaled corticosteroids (ICS) are known to be protective in this model, but the duration of action of these drugs in this model has never been studied. The duration of ICS protection was determined by administration of single-dose fluticasone propionate (FP; 1,000 micrograms) up to 26 h before AMP challenge. A randomised, double-blind, placebo-controlled, four-way crossover study was performed in 13 mild asthmatics (mean +/- SD predicted forced expiratory volume in one second (FEV1) 98 +/- 7%). Each subject received placebo and FP (at 26, 14 or 2 h prior to the AMP challenge). Furthermore, the marker exhaled nitric oxide (eNO) was studied after administration at these time points to investigate whether eNO also demonstrates the duration of action of ICS. The doubling concentrations difference (DCD) of AMP causing a 20% fall in FEV1, when FP was administered 26, 14 or 2 h prior to challenge, was significantly increased as compared with placebo: DCD (95% confidence interval) at 26 h, 0.73 (0.20-1.26), p = 0.008; 14 h, 1.50 (0.99-2.01), p < 0.001; and 2 h, 2.89 (2.37-3.40), p < 0.001. However, eNO was not significantly affected at these time points. In conclusion, a single dose of 1,000 micrograms inhaled fluticasone propionate protects against adenosine-5'-monophosphate airway hyperresponsiveness up to 26 h after dosing. This study suggests that adenosine-5'-monophosphate challenge can be used as a sensitive marker to study the duration of action of inhaled corticosteroids.

Pharmacokinetics of naratriptan in adolescent subjects with a history of migraine.

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12-lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients--3 males and 4 females, 12 to 16 years of age--received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9-10.7), elimination half-life (t1/2) was 4.9 hours (4.5-5.4), area under the concentration-time curve (AUC) was 74.6 ng.h/mL (56.6-98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3-735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses.

Oxygen supply and oxygen demand in the isolated working rabbit heart perfused with asanguineous crystalloid solution.

STUDY OBJECTIVE: It has been suggested that oxygenation of the isolated, crystalloid perfused, Langendorff rabbit heart is inadequate and that consequent hypoxia limits mechanical performance. The isolated working rabbit heart, which has a higher oxygen requirement than the Langendorff preparation, was used to investigate the relationships between the ability of the heart to perform external work, myocardial oxygen consumption, and tissue high energy phosphate content. DESIGN: Hearts from adult rabbits (1.5-2.2 kg), paced at 200 beats.min-1, were perfused in the working mode with bicarbonate buffer (1.8 mmol.litre-1 Ca2+; PO2 greater than 85 kPa, 630 mm Hg). MEASUREMENTS AND MAIN RESULTS: The effects of (a) increasing preload (10, 14, 18, 22, 26 cm H2O) at fixed afterload (80 cm H2O) and (b) increasing afterload (60, 80, 100, 120 cm H2O) at fixed preload (18 cm H2O) on left ventricular power and myocardial oxygen consumption were determined. Increasing preload (from 10 to 26 cm H2O) resulted in linear increases in left ventricular power [from 1.36(SEM 0.06) to 2.81(0.19) J.min-1] and myocardial oxygen consumption [from 554(37) to 801(59) microliters.g dry wt-1.min-1]; this was made possible by increased oxygen supply secondary to increased coronary flow. Increasing afterload (from 60 to 120 cm H2O) also increased left ventricular power [from 1.76(0.05) to 2.16(0.09) J.min-1] and myocardial oxygen consumption [from 617(48) to 903(30) microliters.g dry wt-1.min-1]. For a given increase in left ventricular power, the increase in myocardial oxygen consumption was greater if the increased workload was due to an increased afterload than if it was due to an increased preload, suggesting that increasing afterload resulted in a reduced external mechanical efficiency. Prolonged perfusion under conditions of low and high workload (80 and 120 cm H2O afterload for 60 min) was associated with comparable myocardial contents of adenosine triphosphate [22.5(1.4) and 21.7(0.4) mumols.g dry wt-1] and creatine phosphate [21.8(4.5) and 23.7(1.9) mumols.g dry wt-1] and comparable rates of lactate efflux [34.7(13.0) and 36.7(12.5) mumols.g dry wt-1.60 min-1]. CONCLUSION: Our observation of increased myocardial oxygen consumption and comparable contents of high energy phosphates with increased workload would suggest that the crystalloid perfused working rabbit heart is adequately oxygenated.

Transient hypothermic reperfusion and postischemic recovery in isolated rat heart.

The potential benefit of transient hypothermic reperfusion of the ischemic myocardium was investigated in isolated working rat hearts (n = 6/group) subjected to 25 min of global ischemia at 37 degrees C. Hearts were reperfused in the Langendorff mode at 5, 10, 20, 30, or 37 degrees C for 10 min plus 5 min at 37 degrees C before assessment of functional recovery (working mode). Compared with normothermic reperfusion (recovery of cardiac output = 42.3 +/- 6.1%), transient hypothermia failed to improve the recovery of cardiac output, which was 47.9 +/- 12.7 (P = NS), 54.3 +/- 11.5 (P = NS), 25.3 +/- 2.7 (P = NS), and 6.4 +/- 3.8% (P less than 0.05) in the 30, 20, 10, and 5 degrees C groups, respectively. Reduced recovery in the 5 degrees C group was reflected in increased creatine kinase leakage from 0.26 +/- 0.04 IU.ml-1.g dry wt-1 (37 degrees C reperfusion) to 0.62 +/- 0.12 IU. ml-1.g dry wt-1 (5 degrees C reperfusion; P less than 0.05). Brief periods (3 x 1 min) of hypothermic (5 degrees C) perfusion during normothermic Langendorff reperfusion (15 min) also reduced recovery of cardiac output to 12.1 +/- 7.2% (P less than 0.01). In additional studies, hearts were subjected to a 2-min preischemic infusion with the St. Thomas' Hospital cardioplegic solution before either 25 or 35 min of normothermic ischemia and reperfusion with transient hypothermia at 5, 10, 20, or 30 degrees C. Once again hypothermic reperfusion failed to improve recovery but detrimental effects were not observed in the 5 degrees C group. These results indicate no beneficial effect of transient hypothermic reperfusion on recovery of function measured following global normothermic ischemia.

Protection of the immature heart. Temperature-dependent beneficial or detrimental effects of multidose crystalloid cardioplegia in the neonatal rabbit heart.

There are conflicting reports of the detrimental or beneficial effects of hypothermic cardioplegia in the immature heart. We therefore investigated the temperature-dependence of myocardial protection and the ability of single-dose and multidose infusions of cardioplegic solution to protect the immature heart during hypothermic ischemia. Isolated, working hearts (n = 6 per group) from neonatal rabbits (aged 7 to 10 days) were perfused aerobically (37.0 degrees C) for 20 minutes before infusion (2 minutes) with either perfusion fluid (noncardioplegia control) or St. Thomas' Hospital cardioplegic solution and ischemic arrest (for 4, 6, and 18 hours) at various temperatures between 10.0 degrees and 30.0 degrees C. Hearts arrested with cardioplegic solution received either one preischemic infusion only (single-dose cardioplegia) or repeated infusions at intervals of 60 or 180 minutes (multidose cardioplegia). Ischemic arrest with single-dose cardioplegia for 4 hours at 10.0 degrees, 20.0 degrees, 22.5 degrees, 25.0 degrees, 27.5 degrees, and 30.0 degrees C resulted in 96.0% +/- 4.3%, 96.6 +/- 2.5%, 87.0% +/- 3.8%, 71.8% +/- 10.0% (p less than 0.05 versus 10.0 degrees C group), 35.1% +/- 10.3% (p less than 0.01 versus 10.0 degrees C group), and 3.0% +/- 1.9% (p less than 0.04 versus 10.0 degrees C group) recovery of preischemic cardiac output, respectively. With 6 hours of ischemia at 20.0 degrees C, single-dose cardioplegia significantly (p less than 0.01) increased the recovery of cardiac output from 20.9% +/- 13.1% (control) to 76.4% +/- 4.4%, whereas multidose cardioplegia (infusion every 60 minutes) further increased recovery to 97.8% +/- 3.8% (p less than 0.01 versus control and single-dose cardioplegia). In contrast, after 6 hours of ischemia at 10.0 degrees C, cardiac output recovered to 93.4% +/- 1.2% (control) and 92.3% +/- 3.1% (single-dose cardioplegia), whereas multidose cardioplegia reduced recovery to 76.9% +/- 2.2% (p less than 0.01 versus both groups). This effect was confirmed after 18 hours of ischemia at 10.0 degrees C; single-dose cardioplegia significantly increased the recovery of cardiac output from 24.5% +/- 10.9% (control) to 62.9% +/- 13.3% (p less than 0.05), whereas multidose cardioplegia reduced recovery to 0.8% +/- 0.4% (p less than 0.01 versus single-dose cardioplegia) and elevated coronary vascular resistance from 8.90 +/- 0.56 mm Hg.min/ml (control) to 47.83 +/- 9.85 mm Hg.min/ml (p less than 0.01). This effect was not reduced by lowering the infusion frequency (from every 60 to every 180 minutes).(ABSTRACT TRUNCATED AT 400 WORDS)

Age-dependent changes in the tolerance of the rabbit heart to ischemia.

Many studies in several species have demonstrated an enhanced ischemic tolerance in the immature myocardium when compared with the adult. Little is known about the rate at which these changes occur. We have compared the extent of post-ischemic recovery using isolated working hearts from rabbits of various ages (7-90 days). Hearts (n = 8/group) from rabbits of 7, 14, 21, 28, 31, 40 and 60-90 days of age were perfused aerobically (37 degrees C) for 20 min and control indices of cardiac function were recorded. The hearts were then arrested (2 min infusion) with the St. Thomas' Hospital cardioplegic solution and subjected to global ischemia for 45 min (37 degrees C). The hearts were then reperfused for 15 min in the Langendorff mode and 20 min in the working mode. Leakage of creatine kinase (CK) during Langendorff reperfusion and the recovery of cardiac function during working perfusion were measured. Pre-ischemic cardiac output (CO) was 58.6 +/- 2.6, 80.1 +/- 2.9, 117.5 +/- 4.5, 131.9 +/- 3.2, 134.1 +/- 2.1, 152.0 +/- 1.6 and 165.8 +/- 4.6 ml/min in the 7, 14, 21, 28, 31, 40 and 60-90 day-old groups, respectively. Following ischemia, CO recovered to 82.9 +/- 3.6, 79.2 +/- 3.1, 77.9 +/- 3.4, 72.3 +/- 2.7, 55.3 +/- 2.1, 35.7 +/- 2.9 and 33.1 +/- 6.9%, respectively. CK leakage correlated poorly with recovery and was 31.5 +/- 4.7, 32.0 +/- 8.5, 33.6 +/- 7.9, 35.8 +/- 7.0, 37.3 +/- 4.4, 38.7 +/- 4.8 and 30.4 +/- 5.9 IU/15 min per gram dry weight, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Protection of the immature myocardium during global ischemia. A comparison of four clinical cardioplegic solutions in the rabbit heart.

Controversy surrounds the reported beneficial effects of crystalloid cardioplegic solutions in the immature myocardium. In the present study we have investigated the efficacy of four clinical cardioplegic solutions in the immature myocardium to determine (1) whether cardioplegic protection could be demonstrated and, if so, (2) the relative efficacy of the four solutions. Isolated, working hearts (n = 6 per group) from neonatal rabbits (aged 5 to 8 days) were perfused aerobically (37 degrees C) for 20 minutes before a 2-minute infusion of one of four cardioplegic solutions: The St. Thomas' Hospital No. 2, Tyers, Bretschneider, and Roe solutions. Hearts were then rendered globally ischemic for 50 minutes at 37 degrees C before reperfusion for 15 minutes in the Langendorff mode and 20 minutes in the working mode. The postischemic recovery of cardiac function and leakage of creatine kinase were compared with results in noncardioplegic control hearts. Good protection was observed with the St. Thomas' Hospital and Tyers solutions: The postischemic recovery of cardiac output was increased from 21.2% +/- 12.7% in the cardioplegia-free group to 79.4% +/- 6.2% and 72.9% +/- 4.4%, respectively, in the St. Thomas' Hospital and Tyers groups (p less than 0.01). In contrast, no protection was observed with either the Bretschneider or Rose solutions: Cardiac output recovered to 31.7% +/- 10.3% and 5.1% +/- 3.2%, respectively, in these groups. Postischemic creatine kinase leakage was 72.4 +/- 12.3 and 92.1 +/- 18.6 IU/15 min/gm dry weight in the St. Thomas' Hospital and Tyers groups compared with 125.6 +/- 28.6 IU/15 min/gm dry weight in control hearts (p = no significant difference). In the Bretschneider group, creatine kinase leakage increased to 836.9 +/- 176.8 IU/15 min/gm dry weight (p less than 0.01 versus noncardioplegic control hearts), and with the Roe solution the value was 269.0 +/- 93.0 IU/15 min/gm dry weight (p = no significant difference). In conclusion, cardioplegic protection can be achieved in the immature rabbit myocardium with both St. Thomas' Hospital and Tyers solutions, but acalcemic solutions such as Bretschneider and Roe solutions (which may be effective in the adult heart) increased damage in this preparation. The reported lack of cardioplegic efficacy in the immature myocardium may therefore reflect the choice of cardioplegic solution rather than a greater vulnerability to injury in the neonatal heart.

Assessment of the antiarrhythmic activity of nicorandil during myocardial ischemia and reperfusion.

The potential pro- and antiarrhythmic effects of nicorandil (1-100 microM) were assessed in isolated rat hearts subjected to coronary artery ligation and reperfusion under conditions of normal (5.9 mM) and lowered (3.2 mM) perfusate K+. Nicorandil dose dependently increased coronary flow, induced a moderate negative inotropic effect but had no chronotropic effects. During ligation (15 min), only high concentrations of nicorandil (50 and 100 microM) significantly reduced the incidence of ventricular premature beats and ventricular tachycardia in normal perfusate, but ventricular fibrillation was observed in 2/9 hearts. No antiarrhythmic effects were observed with hypokalemic conditions. During reperfusion, nicorandil was associated with a more rapid degeneration into ventricular fibrillation in normal perfusate while the incidence of ventricular fibrillation was only reduced by 100 microM nicorandil. No antiarrhythmic effects were observed during reperfusion with lowered K+ and all drug-treated hearts demonstrated irreversible ventricular fibrillation. Nicorandil perfusion (50 microM; 5.9 mM K+) did not affect the depression of ATP or elevation of lactate within the ischemic tissue during coronary artery ligation. These data do not support an effect of nicorandil against ischemia- or reperfusion-induced arrhythmias in the intact heart in vitro and may suggest a proarrhythmic effect particularly at lowered K+ concentrations.