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Objective To evaluate the effects of treatment with fluticasone propionate vs placebo on bone, hypothalamic-pituitary-adrenal (HPA) axis function, and the eyes in patients with asthma. Patients and Methods This randomized, double-blind, placebo-controlled study of 160 patients with asthma who had minimal previous exposure to corticosteroids was conducted from July 1994 through June 1997. Patients received fluticasone at 88 µg twice daily, fluticasone at 440 µg twice daily, or placebo twice daily for 2 years. Bone mineral density (BMD) was evaluated every 6 months by lumbar spine, proximal femur, and total body scans. Measurements of HPA axis function and ophthalmic evaluations were conducted at similar intervals. Results Among the 3 groups, no significant differences were observed in BMD at week 104 (at any anatomical site). Mean percent change from baseline in the lumbar spine was less than 1% for all 3 groups. At all time points, HPA axis function was similar in the 88-µg fluticasone group compared with the placebo group. For mean change from baseline in corticotropin-stimulated peak cortisol ( P =.003 and P =.02 at weeks 24 and 52, respectively) and area under the stimulated plasma cortisol vs time curve ( P =.002 and P =.02 at weeks 24 and 52, respectively), statistically significant reductions from baseline were observed in the 440-µg fluticasone group compared with the placebo group. These reductions of 10% to 13% from baseline were not accompanied by other signs of systemic effect and did not persist with continued treatment (at weeks 76 and 104). No important ocular changes were observed. Conclusion Long-term treatment with 88 µg of fluticasone twice daily was comparable to placebo in all skeletal, ophthalmic, and HPA axis function assessments. Treatment with fluticasone at 440 µg twice daily resulted in no significant effects on BMD and a statistically significant but not clinically important temporary reduction in cortisol production.

Study objective: This dose-ranging study evaluated the clinical efficacy and safety of inhaled fluticasone propionate administered once daily via a multidose powder inhaler in patients with moderate asthma (FEV1, 45 to 75% predicted). Materials and methods: In this multicenter trial, 330 patients (> 12 years old) previously receiving inhaled corticosteroids or b2-agonists alone were randomized in a double-blind manner to receive fluticasone propionate at 100, 200, or 500 mg once daily or matching placebo for 12 weeks. Results: Once-daily treatment with fluticasone propionate resulted in an improvement in efficacy variables, such as FEV1, morning and evening peak expiratory flow (PEF), asthma symptom scores, nighttime awakenings, albuterol use, and duration of study participation. A dose-related trend was observed for improvements in morning and evening PEF and albuterol use. Statistical significance for pairwise comparisons was achieved for 200 mg and 500 mg fluticasone propionate vs placebo for all efficacy variables, and for 100 mg fluticasone propionate vs placebo for morning and evening PEF at most or all time points. Drug-related adverse events were few (< 5%) and mostly related to the topical effects of inhaled corticosteroids. No dose-response effect or clinically relevant differences were observed in morning plasma cortisol concentrations or after cosyntropin stimulation. Conclusion: Once-daily treatment with fluticasone propionate was well tolerated and demonstrated some dose-related trends in improvements in lung function and asthma control in patients with moderate asthma. (CHEST 2000; 118:296 ‐302)

Objective To evaluate the efficacy and safety of fluticasone propionate administered as a once-daily or twice-daily regimen over a period of 1 year to patients with moderate asthma. Design Double-blind, randomized, parallel group, and placebo-controlled phase (12 weeks) and an open-label phase (54 weeks). Setting Multicenter study in an outpatient setting. Participants Patients (n = 253; age,≥ 12 years) with a mean FEV 1 of 67% predicted normal were stratified according to baseline therapy of maintenance inhaled corticosteroids vs β 2 -agonists alone. Measurements and interventions Fluticasone propionate (250μ g bid or 500 μg qd) or placebo (bid) was administered via the Diskus multidose powder inhaler (Glaxo Wellcome; Research Triangle Park, NC) for 12 weeks. During open-label treatment, patients were re-randomized to once-daily or twice-daily fluticasone propionate. Results Compared to placebo, fluticasone propionate administered qd or bid significantly improved FEV 1 (p 1 , albuterol use, and withdrawal due to lack of efficacy. During 54 weeks of open-label treatment, FEV 1 and PEF continued to improve with both regimens, and improvements seen in the first 12 weeks were maintained in patients who switched from twice-daily to once-daily dosing. Fluticasone propionate treatment over a 54-week period was well tolerated, with few drug-related adverse events, which were primarily topical effects of inhaled corticosteroids. Conclusions Fluticasone propionate powder improved lung function when administered either qd or bid over a 1-year period to patients with moderate asthma, with twice-daily dosing demonstrating significantly greater improvement in some efficacy parameters than once-daily dosing over the first 12 weeks of treatment. Fluticasone propionate treatment was not associated with significant systemic effects.

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 μg, 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 (L 1 to L 4 ) bone density at week 104 was not significantly different between fluticasone propionate (–0.006 ± 0.008 g/cm 2 ) and placebo (–0.007 ± 0.010 g/cm 2 ). 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 μg 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. (J Allergy Clin Immunol 1999;103:1062-8.)

Background: Many patients with severe asthma are dependent on oral corticosteroids for maintenance control of their disease. Treatments that allow patients to be weaned off oral corticosteroids may help to minimize the risk of side effects associated with their chronic use. Objective : This study evaluated whether inhaled fluticasone propionate powder could maintain pulmonary function while reducing the dose of oral prednisone in patients with chronic, severe asthma. Methods : Oral prednisone–dependent (5 to 40 mg/day) adolescents and adults with asthma (n = 111; mean FEV 1 = 61% of predicted value) were randomized to placebo or twice daily fluticasone propionate 500 or 1000 μg administered by means of a multidose powder inhaler for 16 weeks in a double-blind, parallel-group study. Patients underwent controlled prednisone reduction on the basis of predetermined asthma stability criteria. Results : Oral prednisone was eliminated by 75% and 89% of patients in the twice daily 500 and 1000 μg fluticasone propionate groups, respectively, versus 9% of the placebo group ( P 1 , morning and evening peak expiratory flow, asthma symptoms, albuterol use, and nighttime awakenings improved with fluticasone propionate treatment, achieving statistical significance ( P ≤ .009) primarily in the 1000 μg twice daily group. Hypothalamic-pituitary-adrenal axis suppression observed at baseline improved when patients were weaned off oral prednisone to fluticasone propionate. Adverse events ascribed to drug treatment were primarily topical effects of inhaled corticosteroids or those associated with prednisone withdrawal. Patient quality of life assessed by means of the Asthma Quality of Life Questionnaire was clinically and significantly improved after fluticasone propionate treatment ( P ≤ .003). Conclusion : Fluticasone propionate powder (500 or 1000 μg twice daily) effectively improved lung function, adrenal function, and asthma-specific quality of life in patients with severe chronic asthma previously treated with oral prednisone while allowing most patients to be weaned off oral corticosteroid therapy. (J Allergy Clin Immunol 1999;103:267-75.)

The aim of these studies was to compare the pharmacokinetics of inhaled fluticasone propionate (FP) after repeated administration via the Diskus or Diskhaler dry powder inhalers (DPIs) to patients with mild-to-moderate asthma.Both studies evaluated the pharmacokinetics of inhaled administration of FP via a DPI to patients with mild-to-moderate asthma, according to a randomised, double-blind, placebo-controlled design. In the first study, FP 100 microg or 500 microg was administered twice daily via the Diskhaler for 6 weeks and, in the second, FP 500 microg was administered via the Diskus or Diskhaler for 12 weeks.In the first study, plasma FP concentrations could be detected consistently only with the higher dose; the lower dose produced concentrations close to or below the 0.025 microg/L quantification limit of the radioimmunoassay used. From detailed analysis of a subgroup of patients receiving the 500 microg dosage, steady-state plasma FP concentrations were attained within one week of commencing treatment. After 4 weeks, the maximum plasma FP concentration (Cmax) in this subgroup was 0.096 microg/L [95% confidence interval (CI) 0.066-0.141] and the area under the plasma FP concentration-time curve up to the last quantifiable concentration (AUClast) was 0.491 microg/L x h (95% CI: 0.256-0.940). The steady-state to single dose accumulation ratio for FP after twice-daily administration varied between patients: a ratio of approximately 1.7 was recorded after comparison of Cmax at week 4 and day 1. In the second study, the point estimate of the Diskus to Diskhaler ratio for Cmax in all patients was 0.91 (90% CI: 0.76-1.10) after 4 weeks' treatment. From a detailed analysis of a subgroup of patients, the corresponding ratio for AUClast at the same time point was 1.15 (90% CI: 0.69-1.94), indicating no significant difference in systemic exposure to FP between the 2 devices. Steady-state kinetics were achieved by week 1: the point estimate ratios of Cmax and AUClast at week 4 compared with week 1 were 0.88 (90% CI: 0.66-1.16) and 0.95 (90% CI: 0.66-1.36), respectively. Administration of FP via either DPI had no effect on plasma cortisol levels over the 12-hour postdose period.In patients with asthma receiving repeated inhaled doses of FP, the systemic exposure (AUC) after inhalation from the Diskus was similar to that from the Diskhaler, with no difference between the DPIs in the effects on cortisol suppression. The 2 DPIs therefore have very similar pharmacokinetic profiles.

Background Flovent Diskus is a powder formulation of the inhaled corticosteroid fluticasone propionate (FP) delivered via a breath-actuated, multidose inhaler. Objective To determine the efficacy and safety of dry powder FP administered once or twice daily (200 μg per day) to children with persistent asthma. Methods Twelve-week, randomized, double-blind, placebo-controlled, multicenter trial with a 52-week, open-label extension. Children aged 4 to 11 were required to have pulmonary function 50% to 85% of predicted values. The population was stratified for baseline therapy (inhaled corticosteroid/cromolyn or bronchodilators only). After a 2-week placebo run-in, 242 patients received dry powder FP 200 μg each morning, dry powder FP 100 μg BID, or placebo for 12 weeks; 192 were rerandomized to the QD or BID regimen for an additional 52 weeks of open-label treatment. Primary endpoints were mean changes in FEV 1 and morning PEF recorded at clinic visits. Results Both dry powder FP regimens significantly improved FEV 1 , evening PEF, and asthma symptoms at the double-blind phase endpoint ( P ≤ .017 compared with placebo). The BID regimen also significantly improved morning PEF and nighttime awakenings due to asthma ( P ≤ .005). Among patients previously treated with inhaled corticosteroids/cromolyn, improvements observed with the QD and BID regimens were similar. Patients switched from BID to open-label QD treatment showed additional improvements at week 52 generally comparable to patients who received the BID regimen during both phases. Fluticasone propionate was well tolerated for up to 64 weeks with few reports of drug-related adverse events or morning plasma cortisol abnormalities. Conclusions Once daily dosing of dry powder FP 200 μg is an effective and convenient alternative for children whose asthma is controlled with a more frequent dosing regimen of inhaled corticosteroids.

Background: There are limited published data regarding the efficacy of once- versus twice-daily administration of flutica-sone propionate. Objective: Our purpose was to evaluate the effectiveness of fluticasone propionate powder 200 μg/d administered as a once- or twice-daily dosage regimen in patients who were currently being treated with bronchodilators only (BD patients) and in patients who required inhaled corticosteroids for maintenance treatment of asthma (ICS patients). Methods: Five hundred seventy patients were randomly assigned to receive one of the following inhaled treatments through the Diskus device (Glaxo Wellcome, Research Triangle Park, NC) for 12 weeks: fluticasone propionate 100 μg twice daily (FP100BID) or 200 μg once daily (FP200QD) or placebo. Results: BD patients treated with FP100BID, FP200QD, and placebo had mean increases in FEV 1 from baseline to end point of 0.49 L, 0.37 L, and 0.21 L, respectively ( P P = .05, FP200QD vs placebo). ICS patients treated with FP100BID and FP200QD had mean increases in FEV 1 of 0.27 L and 0.11 L, respectively, compared with a decrease in FEV 1 of –0.08 L with placebo ( P P = .023, FP200QD vs placebo). BD patients treated with FP100BID and FP200QD had mean increases in morning peak expiratory flow from baseline to end point of 31 L/min and 27 L/min, respectively, compared with a 1 L/min increase in patients treated with placebo. ICS patients treated with FP100BID had a mean increase in morning peak expiratory flow (from baseline to end point) of 18 L/min compared with mean decreases of –3 L/min and –12 L/min in the FP200QD and placebo groups, respectively. More patients were withdrawn from placebo (26% and 48%, in BD and ICS patients, respectively) than from fluticasone propionate (7%-9% [BID-QD] and 18%-32% [BID-QD], in BD and ICS patients, respectively) because of failure to meet predetermined asthma stability criteria. Conclusion: The efficacies of FP100BID and FP200QD were comparable with regard to improvement in pulmonary function and asthma stability in BD patients. In ICS patients, asthma control was maintained with FP200QD, whereas FP100BID provided greater improvements in pulmonary function and asthma stability. (J Allergy Clin Immunol 2000;105:1153-61.)

In order to assess the bioequivalency of two USA commercially available brands of cephalothin sodium, neutral, USP, a double-blind, single-dose, human crossover study was conducted. Serum and urinary samples were tested by HPLC assay, and pharmacokinetic parameters were determined by computer analysis. The results revealed that both products are bioequivalent, and support a submission to the FDA for a claim of “aqueous bioequivalency” of the new Seffin™ (Glaxo) brand vs. the standard.Hospital cost-containment programs, such as the recent Diagnostic Related Group (DRG) legislation, necessitates that Pharmacy & Therapeutic Committees evaluate competitive brands of identical drugs in order to realize cost savings but without sacrificing quality. Where generic equivalents are concerned, the major basis of comparison rests on clinical pharmacokinetic studies.Cephalothin sodium for injection, USP (Neutral) has been available in the USA since 1975, but only as a single source product (Keflin®/ Lilly). An...

The pharmacokinetics of 10 of the newer, third-generation cephalosporins are reviewed. Important features are tabulated. Generalizations are made about structure-activity relationships, relationships between kinetic features, minimal inhibitory concentrations, dosage regimens, and tissue penetration. Tissue levels of ceftazidime are given as examples. These newer chemotherapeutic agents do not possess unique pharmacokinetic properties, but a combination of high antimicrobial activity, safety, and straightforward kinetics facilitates their use in a number of different clinical settings.