Double-masked, placebo-controlled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye.

PURPOSE: To investigate the safety and efficacy of diquafosol tetrasodium, a P2Y2 receptor agonist that stimulates fluid and mucin secretion on the ocular surface, as a novel topical treatment of dry eye disease. METHODS: Subjects with dry eye (n=527) were evaluated in a randomized, double-masked, parallel-group trial comparing 24 weeks of treatment with 2 concentrations of diquafosol (1% and 2%) versus placebo instilled 4 times daily. Corneal staining, conjunctival staining, Schirmer tests, and subjective symptoms of dry eye were evaluated. Use of artificial tears was permitted as necessary. RESULTS: Subjects treated with 2% diquafosol had significantly lower corneal staining scores compared with placebo at the 6-week, primary efficacy time point (P<0.001), and superiority continued throughout the 24-week study. Reductions in corneal staining were observed as early as after 2 weeks of treatment, were maintained throughout the 24-week study, and were observed to worsen slightly (toward baseline) when diquafosol treatment was discontinued (week 25). Results for conjunctival staining were consistent with those observed for corneal staining. Schirmer scores at week 6 were significantly higher with diquafosol treatment than with placebo (P

Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects.

Objectives of this study were to compare the pharmacokinetics, pharmacodynamics and safety of single cumulative doses of active (R)-salbutamol given either as the single enantiomer or racemic mixture by inhalation to subjects with mild to moderate asthma. This was a double-blind, crossover, cumulative-dose, randomized study where all subjects received either four doses of 1.25 mg of (R)-salbutamol or 2.5 mg of racemic (RS-) salbutamol by nebulization. The pharmacokinetic parameters were determined by noncompartmental analysis and model-fitting. Changes in FEV(1), plasma potassium, plasma glucose, heart rate, and QTc interval were measured. The potassium and glucose data were fitted to indirect response pharmacodynamic models. The heart rate and QTc data were evaluated using data descriptors. No significant differences in pharmacokinetics of (R)-salbutamol given as either (R)- or (RS)-salbutamol were found with AUC values of 11.90 +/- 4.37 and 11. 47 +/- 2.88 ng.h/ml. The t(max)of about 2 h reflected serial dosing rather than delayed absorption. The t(1/2)averaged about 3.5 h. The (S)-salbutamol showed AUC of 48.46 +/- 12.11 ng.h/ml with a t(1/2)of about 5 h. The changes in FEV(1)reached a plateau after an initial increase and did not return to pre-drug values for 10 h. All pharmacodynamic parameters were similar whether (R)- or (RS)-salbutamol was given. The exposure to (R)-salbutamol was identical after inhalation of (R) -and (RS)-salbutamol by subjects with asthma. Several pharmacological responses including FEV(1)were also similar and there were no unique safety concerns with either treatment.

Fluticasone propionate powder and lack of clinically significant effects on hypothalamic-pituitary-adrenal axis and bone mineral density over 2 years in adults with mild asthma.

BACKGROUND: Although inhaled corticosteroids are widely used for the treatment of inflammation in asthma, prospective, long-term, placebo-controlled trials characterizing their systemic safety with chronic use are lacking. OBJECTIVE: This study was designed to prospectively evaluate the long-term safety of inhaled fluticasone propionate therapy. METHODS: Fluticasone propionate powder, 500 microgram, or placebo was administered twice daily by means of the Diskhaler for 104 weeks to 64 adults with mild persistent asthma in a randomized, double-blind, parallel-group study. Primary safety variables were measured at baseline and every 6 months thereafter. Although evaluation of efficacy was not an objective of this study, pulmonary function testing was performed at monthly intervals. RESULTS: Two years of treatment with fluticasone propionate had no significant effects on the skeletal system. No clinically significant changes were observed in ophthalmic parameters (glaucoma and posterior subcapsular cataracts). Mean change from baseline in lumbar spine (L1 to L4 ) bone density at week 104 was not significantly different between fluticasone propionate (-0.006 +/- 0.008 g/cm2) and placebo (-0.007 +/- 0.010 g/cm2). Markers of bone formation (serum osteocalcin) and resorption (urinary N-telopeptide) did not differ significantly between treatment groups. The effects of fluticasone propionate treatment on the hypothalamic-pituitary-adrenal axis were minimal, with no alterations in morning plasma cortisol concentrations and minor but statistically significant decreases in poststimulation mean peak plasma cortisol concentrations (P =.021) and 8-hour plasma cortisol area under the curve values (P =.020) at week 104. Drug-related adverse events were primarily topical effects of inhaled corticosteroids. Pulmonary function improved significantly during 2 years of fluticasone propionate treatment. CONCLUSION: Fluticasone propionate powder, 500 microgram twice daily for up to 2 years, was efficacious and well tolerated, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis, bone density, or ophthalmic parameters in adults with mild asthma.

Dose-related response to inhaled fluticasone propionate in patients with methacholine-induced bronchial hyperresponsiveness: a double-blind, placebo-controlled study.

Dose-response relationships with inhaled corticosteroids in the treatment of asthma have been difficult to establish. A multicenter, double-blind, parallel-group study was conducted to evaluate the clinical efficacy and safety of low doses of inhaled fluticasone propionate (FP) in patients with mild to moderate asthma. Methacholine challenge testing was conducted in addition to measurement of traditional efficacy variables. After a single-blind screening period, 138 patients > or = 12 years of age were randomly assigned to receive placebo, FP 50 microg, or FP 100 microg, twice daily for 8 weeks. The results of methacholine challenge testing averaged over all visits favored FP 200 microg/day over placebo and FP 100 microg/day (p < 0.05); there were no significant differences between placebo and FP 100 microg/day. Mean changes from baseline to endpoint favored each dose of FP over placebo based on forced expiratory volume in 1 sec (FEV1), patient-measured peak expiratory flow (PEF), total symptom scores, and rescue bronchodilator use (p < 0.05); there were no differences in these parameters between the two doses of FP. The addition of methacholine challenge testing allowed definition of a dose-response relationship that was not apparent with traditional efficacy variables.

Pharmacokinetic and pharmacodynamic characteristics and safety of inhaled albuterol enantiomers in healthy volunteers.

The pharmacokinetics and pharmacodynamics of inhaled albuterol given as single or multiple doses of racemate (RS-) or single enantiomers (R-, S-) were determined. In an open-label, three-way crossover, parallel-dose study, 1.25 and 5 mg of (R)- and (S)-albuterol and 2.5 and 10 mg of (RS)-albuterol were given via nebulization to 15 healthy volunteers. The pharmacokinetic parameters of each enantiomer were determined by noncompartmental and model-fitting analyses. Both (R)- and (S)-albuterol showed rapid absorption and biexponential decline, with half-lives (t1/2) averaging 4 and 6 hours, respectively. There were no differences in pharmacokinetics of (R)-albuterol when administered as (R)- or (RS)-albuterol at the 5-mg dose with equivalent relative bioavailability as seen from maximum concentration (Cmax) and area under the concentration-time curve (AUC). The same was true for (S)-albuterol at the 1.25-mg and 5-mg doses. The data from 5-mg doses were considered to be more reliable due to assay sensitivity limitations, and indicated equivalent absorption and disposition of the individual enantiomers. There was no evidence of in vivo racemization, and (R)-albuterol did not interconvert to (S)-albuterol. Plasma potassium, plasma glucose, heart rate, and QTc interval were used in linear and Emax models to assess responses relating to (R)-albuterol concentrations. The Emax for potassium change was 1.32 meq/L, with an EC50 of 0.59 and 0.94 ng/mL after administration of (R)- and (RS)-albuterol, respectively. The slopes and intercepts for glucose and heart rate changes were similar after administration of (R)- and (RS)-albuterol. No concentration-effect relationships were evident for QTc interval or for (S)-albuterol. The extrapulmonary responses of (R)-albuterol and adverse effects were similar for single R-enantiomer or the racemic mixture.

Comparative efficacy and safety of twice daily fluticasone propionate powder versus placebo in the treatment of moderate asthma.

BACKGROUND: Fluticasone propionate, an inhaled corticosteroid with negligible systemic bioavailability via the oral route, is efficacious in the treatment of asthma when administered via metered-dose inhaler. OBJECTIVE: To evaluate the efficacy and safety of inhaled fluticasone propionate powder in patients with moderate asthma previously treated with an inhaled corticosteroid. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of 342 adolescent and adult patients with moderate asthma [forced expiratory volume in 1 second (FEV1) between 50% and 80% of predicted] treated previously by beclomethasone dipropionate or triamcinolone acetonide. Patients received fluticasone propionate powder 50 micrograms, 100 micrograms, 250 micrograms, or placebo via a breath-actuated inhalation device, the Diskhaler, twice daily for 12 weeks. RESULTS: Patients in the fluticasone propionate groups experienced a mean increase from baseline to endpoint in FEV1 ranging from 0.43 L to 0.47 L. Patients in the placebo group experienced a mean decrease from baseline of 0.22 L (P < .001). The probability of patients remaining in the study over time without developing signs of exacerbating asthma was significantly greater in the fluticasone propionate groups than in the placebo group (P = .001). Asthma symptom scores, supplemental rescue albuterol use, and number of nighttime awakenings due to asthma requiring treatment also improved significantly with all fluticasone propionate treatment regimens compared with placebo (P < .001). There were no statistically significant differences at endpoint among the three fluticasone propionate groups. No serious drug-related adverse events occurred. CONCLUSIONS: Fluticasone propionate powder (50, 100, and 250 micrograms) was well-tolerated and significantly improved lung function in patients with moderate asthma.

Fluticasone propionate compared with theophylline for mild-to-moderate asthma.

BACKGROUND: The inhaled corticosteroid, fluticasone propionate, was compared with the oral bronchodilator theophylline in the maintenance treatment of asthma. OBJECTIVE: The objective of the present study was to compare the efficacy and safety of twice-daily inhaled fluticasone propionate, 50 micrograms, and fluticasone propionate, 100 micrograms, with that of theophylline in the maintenance treatment of mild-to-moderate asthma. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, 353 adult and adolescent patients with asthma inadequately controlled with inhaled beta-agonist therapy alone received fluticasone propionate, 50 micrograms, or fluticasone propionate, 100 micrograms, by metered-dose inhaler; theophylline capsules; or placebo twice daily for 12 weeks. Only inhaled albuterol was permitted as needed for acute symptoms. RESULTS: Both fluticasone propionate groups had a significantly greater probability of remaining in the study (ie, meeting asthma stability criteria) than did either the theophylline or placebo group (P < or = .008); 39% and 51% in the theophylline and placebo groups, respectively, were withdrawn due to lack of treatment efficacy compared with 14% and 21% in the fluticasone propionate, 50 micrograms, and fluticasone propionate, 100 micrograms, groups. Both fluticasone propionate groups experienced significantly greater improvement in FEV1 and PEF compared with patients in the theophylline or placebo group (P < or = .004). The incidence of potentially drug-related adverse events was significantly greater in the theophylline group (25%) than in the placebo group (11%) (P = .031), while there were no differences between placebo and fluticasone propionate, 50 micrograms, (18%) or fluticasone propionate 100 micrograms, (22%). CONCLUSION: Twice daily treatment with inhaled fluticasone propionate 50 micrograms or 100 micrograms was significantly more effective than theophylline in the treatment of mild-to-moderate asthma.

Fluticasone propionate improves quality of life in patients with asthma requiring oral corticosteroids.

BACKGROUND: Fluticasone propionate is a potent inhaled corticosteroid that is effective in improving pulmonary function and symptoms in patients with asthma. OBJECTIVE: To evaluate the effects of fluticasone propionate on quality of life in patients with severe asthma requiring oral corticosteroids. METHODS: A total of 96 patients with severe asthma participated in a randomized, double-blind, placebo-controlled, parallel-group, oral steroid-sparing study. Patients received fluticasone propionate aerosol, 750 or 1000 micrograms bid, or placebo for 16 weeks; 91 of these patients continued in a 1-year open-label study, in which everyone initially received fluticasone propionate, 1000 micrograms bid. At regular intervals, patients completed the Medical Outcomes Study Short Form-36 (SF-36), a general health status questionnaire measuring eight dimensions of quality of life, plus one question on change in health from the previous year. RESULTS: Compared with the US population, patients scored significantly lower at baseline for five of eight SF-36 dimensions (P < .01). After 16 weeks, patients receiving fluticasone propionate, 1000 micrograms, improved significantly (P < or = .02) in physical functioning, role-physical, general health, and change in health, compared with the placebo group. After 1 year of open-label treatment with fluticasone propionate, these improvements were maintained. SF-36 scores in the placebo group during the double-blind period either worsened or remained unchanged; however, when these patients were switched to fluticasone propionate during the open-label period, their SF-36 scores also improved. Forced expiratory volume in 1 second (FEV1) at the end of the double-blind period was positively correlated with mean quality of life scores on physical functioning, role-physical, vitality, social functioning, and change-in-health status. CONCLUSION: Health-related quality of life improved in patients with severe asthma following 16 weeks of treatment with fluticasone propionate, 1000 micrograms bid. These improvements were maintained during subsequent fluticasone propionate treatment over a 1-year period.

A 12-week dose-ranging study of fluticasone propionate powder in the treatment of asthma.

Fluticasone propionate (FP) administered via metered-dose inhaler is a potent corticosteroid effective in the treatment of asthma. To evaluate the efficacy and safety of FP powder administered via a breath-activated inhaler (Diskhaler), a multicenter, double-blind, randomized, placebo-controlled, parallel-group study was conducted in adolescent and adult patients (n = 331) with mild-to-moderate asthma previously treated with beta 2-agonist therapy alone. Patients received FP powder 50, 100, or 250 micrograms or placebo twice daily for 12 weeks. FP-treated patients compared with placebo-treated patients had significantly (p < 0.001) greater improvements in morning predose forced expiratory volume in 1 sec (21-22% increase vs. 9%). Improvement in morning peak flow rate were also significantly (p < 0.001) greater with FP than with placebo (8-10% increase vs. 2% increase). There was also a significant overall treatment difference in the frequency of inhaled albuterol use (p < 0.001) and number of nighttime awakenings due to asthma (p = 0.005). There were no statistically significant difference among the FP treatment groups in any outcome measure. Physicians' global assessments also indicated significant (p < 0.001) differences in efficacy, with 67-74% of FP-treated patients rated as having "effective" or "very effective" treatment compared with 41% of placebo-treated patients. Significant beneficial effects of FP were observed in lung function and diary card parameters after just 1 week of treatment. Adverse events were similar across treatment groups and primarily related to local irritation. Effect on hypothalamic-pituitary-adrenal axis function was minimal. In summary, all three dosages of inhaled FP powder were well tolerated and improved various asthma-related variables. Improvements in pulmonary function, beyond those achieved with beta 2-agonist therapy alone, were maintained for the duration of the 12-week study.

Detection of active left ventricular thrombosis during acute myocardial infarction using indium-111 platelet scintigraphy.

Platelet scintigraphy with radioactive indium-111 may be used both to identify and to reflect the activity of thrombin in vivo in man. Forty-one patients with acute myocardial infarction were studied for active left ventricular thrombosis by platelet scintigraphy and followed until in-hospital death, discharge, or same-admission cardiac surgery for evidence of systemic embolization. A total of 4.7 +/- 2.4 X 10(9) platelets (mean +/- 1 SD) labelled with 381 mu Ci +/- 51 mu Ci of indium-111 was injected intravenously at 91 +/- 88 hours following the onset of chest pain. Patients were imaged in multiple views on the day of and three to four days after injection of the platelet suspension. Group 1 (n = 29) had transmural myocardial infarctions, of which 21 were anterior (peak total level of creatine phosphokinase [CPK], 2,272 +/- 2,026 IU; mean +/- 1 SD) and eight were inferior (CPK level, 1,673 +/- 589 IU). Group 2 (n = 12) had subendocardial myocardial infarctions (CPK level 799 +/- 751 IU). Those with subendocardial and transmural inferior myocardial infarctions had neither left ventricular thrombosis nor emboli. Ten (48 percent) of 21 with anterior transmural myocardial infarctions had left ventricular thrombosis by platelet scintigraphy. Three with and one without such thrombosis by scintigraphy had acute neurologic episodes. In the group with anterior myocardial infarctions, seven of ten patients with and four of 11 without left ventricular thrombosis received heparin subcutaneously (chi 2 = 1.22 [Yates correction]; p greater than 0.30). We conclude that platelet scintigraphy may be used to monitor antiplatelet and anticoagulant therapy in patients with anterior transmural myocardial infarctions who are at risk for left ventricular thrombosis and systemic embolization.