Biomedical subjects

Günther Hochhaus

Publications and source records attributed to Günther Hochhaus.

18 recordsLinked to original sources

PubMed2006

Contrary to adult, neonatal rats show pronounced brain uptake of corticosteroids.

Neurotoxic adverse effects after systemic corticosteroid administration are elevated in preterm infants. To test whether this might be related to an immature blood-brain barrier (BBB) that permits corticosteroids to enter the brain and induce neurotoxic effects, this study assessed the differences in brain permeability of triamcinolone acetonide after intratracheal administration to neonatal (10- to 11-day-old) and adult rats. Triamcinolone acetonide (or the phosphate prodrug in the case of neonatal rats) was administered intratracheally to neonatal rats at doses of 2.5, 25, or 50 microg/kg and to adult rats at 100 microg/kg. An ex vivo receptor binding assay was used to monitor the cumulative brain and liver glucocorticoid receptor occupancies over 6 h. Brain and liver receptor occupancies in neonates were similar for the 25 and 50 microg/kg triamcinolone acetonide phosphate (brain/liver receptor occupancy ratio, 1.10 +/- 0.14 and 0.87 +/- 0.13, respectively), whereas some reduction in the brain permeability was seen at the lower dose. After intratracheal administration of 100 microg/kg triamcinolone acetonide to adult rats, receptor occupancies in the brain were significantly lower (brain/liver ratio, 0.21 +/- 0.14; p < 0.001). The study demonstrated that glucocorticoids enter the brain of neonatal rats because of an immature BBB. The results of this study support the hypothesis that neurotoxic adverse effects in preterm infants after systemic corticosteroid administration might be related to an immature BBB.

Adrenal Cortex Hormones↗

PubMed2005

Comparative pharmacology, bioavailability, pharmacokinetics, and pharmacodynamics of inhaled glucocorticosteroids.

A comparison of the pharmacodynamics and pharmacokinetics of inhaled corticosteroids is necessary for their assessment. A good knowledge of these two aspects allows the optimization of efficacy and safety.The currently available inhaled corticosteroids already show some of the desired PK/PD parameters. The local adverse effects are decreased as soon as the inhaled corticosteroid is administered as an inactive prodrug or shows a bet-ter lung deposition. HFA-MDI beclomethasone dipropionate (BDP) and ciclesonide are two agents that illustrate this. Low oral bioavailability, rapid systemic clearance, and high plasma protein binding can minimize systemic adverse effects. Mometasone furoate, ciclesonide, and fluticasone propionate possess those characteristics. The pulmonary efficacy is maximized by high lung deposition and long pulmonary residence times. This effect can be achieved by slow dissolution in the lungs, as is the case for fluticasone propionate or lipid conjugation and has been shown for budesonide and ciclesonide. Furthermore, the lung deposition depends on the inhalation device, the particle size, and the inhalation technique. Therefore,improvement in the design of MDIs, DPIs, and nebulizers, and the development of more effective drug particles will lead to an optimized pulmonary targeting. Much progress has been made in the treatment of asthma. The available inhaled corticosteroids show a high safety profile and a good pulmonary selectivity. Development of newer compounds showed that improvement is possible as the result of a complete understanding of the PK/PD concepts. However,the introduction of further improved formulations with a better efficacy/safety profile will be difficult and protracted because the existing drugs are already highly efficient.

Administration, Inhalation↗

PubMed2005

Budesonide in previously untreated autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is a chronic liver disease that is effectively treated with immunosuppressive therapy. Predniso(lo)ne, often in combination with azathioprine, is the basic therapeutic option to induce remission. However, this regimen can cause numerous side effects. The aim of the present study was to evaluate budesonide as a treatment option in the induction of remission in patients with previously untreated AIH. METHODS: Between October 1998 and August 1999, 12 patients were treated with 3 mg budesonide thrice daily for 3 months in this open one-arm multicenter phase IIa study. Primary end point was induction of remission indicated by a drop of aspartate aminotransferase and alanine aminotransferase levels below two times the upper limit of normal. RESULTS: Seven of the 12 patients (58%) reached complete remission, three patients (25%) had a partial response. Thus, 10/12 individuals (83.3%) responded to therapy. Therapy was tolerated well in 10/12 cases (83.3%). CONCLUSIONS: Budesonide monotherapy was effective in the induction of remission and well tolerated in treatment naïve patients with AIH. It should be further evaluated in prospective controlled trials and should be compared to predniso(lo)ne both in monotherapy and in combination with azathioprine.

Adult↗

PubMed2005

Pharmacokinetic/pharmacodynamic evaluation of inhalation drugs: application to targeted pulmonary delivery systems.

Inhaled therapy with either glucocorticoids and/or beta(2)-adrenergic drugs remains the mainstay of asthma treatment. In the last few years, a number of new products have been introduced into the market with the goal of improving efficacy and safety. This review article summarises the pharmacokinetic and pharmacodynamic properties of inhaled drugs for topical delivery necessary to achieve this goal. Pharmacokinetic properties include a high pulmonary deposition, low oral bioavailability, optimised pulmonary residence time and a very high systemic clearance. Optimisation of pharmacodynamic properties, such as receptor selectivity, may also yield drugs with improved pulmonary selectivity. As existing drugs also provide high efficacy and safety profiles, future developments will represent only slight improvements and quantum leap improvements are unlikely to occur.

Administration, Inhalation↗

PubMed2004

Simultaneous quantification of beclomethasone dipropionate and its metabolite, beclomethasone 17-monopropionate in rat and human plasma and different rat tissues by liquid chromatography-positive electrospray ionization tandem mass spectrometry.

A sensitive, rapid and selective liquid chromatography-positive electrospray ionization tandem mass spectrometry (LC-(ESI+)-MS-MS) method has been developed and validated for the simultaneous quantification of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP) in rat plasma and different tissues using fluticasone propionate (FP) as the internal standard. The method was validated over a linear range from 0.05 to 5 ng/ml for both analytes. A solid-phase extraction procedure was used for plasma samples and a liquid-liquid extraction procedure for tissues samples (lung, liver and kidney). The between-day and within-day coefficients of variation for all compounds were </= 20% at the concentrations of lower limit of quantification (LLOQ) and </= 15% at other quality control concentrations. The same method was also partially validated for human plasma. The utility of this assay was demonstrated by monitoring BDP and 17-BMP plasma and tissue concentrations in an animal study designed for evaluation of pulmonary targeting after intratracheal administration of BDP dry powder.

Animals↗

PubMed2004

In vitro and in vivo anti-inflammatory activity of the new glucocorticoid ciclesonide.

The glucocorticoid ciclesonide is the 2'R-epimer of 2'-cyclohexyl-11beta-hydroxy-21-isobutyryloxy-16bH-dioxolo[5',4':16,17]pregna-1,4-diene-3,20-dione. The active metabolite desisobutyryl-ciclesonide (des-CIC) is derived from ciclesonide by esterase cleavage of isobutyrate at the C21 position. The relative binding affinities at the rat glucocorticoid receptor were dexamethasone, 100; ciclesonide, 12; des-CIC, 1212; and budesonide, 905. Des-CIC potently inhibited the activation of murine and human lymphocytes in a series of different in vitro systems. With the exception of concanavalin A-stimulated rat spleen cells, des-CIC was more potent than the parent compound. Des-CIC compared well with budesonide in all in vitro systems. Furthermore, the respective 2'S-epimers were always significantly less potent than the 2'R-epimers. In vivo, ciclesonide (intratracheal administration), des-CIC, and budesonide inhibited antigen-induced accumulation of eosinophils, protein, and tumor necrosis factor-alpha into the bronchoalveolar lavage fluid of ovalbumin-sensitized and -challenged Brown Norway rats with an ED(50) value ranging from 0.4 to 1.3 mg/kg, indicating similar potency, which suggests in vivo activation of the parent compound. Ciclesonide and budesonide inhibited the bradykinin-induced protein leakage into the rat trachea. In the rat cotton pellet model, ciclesonide inhibited granuloma formation (ED(50):= of 2 microg/pellet), whereas budesonide and des-CIC were 15- and 20-fold less active; thymus involution was induced with an ED(50) of 303, 279, and 154 microg/pellet, respectively. When applied orally to rats for 28 days, ciclesonide showed low potency in reducing weight of thymus and adrenals, suggesting low oral bioavailability. The in vivo data on ciclesonide highlight its effective local action and a reduced potential for side effects.

Administration, Oral↗

PubMed2004

Pharmacokinetic aspects of biotechnology products.

In recent years, biotechnologically derived peptide and protein-based drugs have developed into mainstream therapeutic agents. Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development in the global pharmaceutical industry. Pharmacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as protein nutrients. The first challenge frequently comes from a lack of sophistication in various analytical techniques for the quantification of peptide and protein drugs in biological matrices. However, advancements in bioassays and immunoassays--along with a newer generation of mass spectrometry-based techniques--can often provide capabilities for both efficient and reliable detection. Selection of the most appropriate route of administration for biotech drugs requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes. Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure to exert the intended pharmacological response. This poses a potential problem, especially for large protein drugs, with their typically limited distribution space. Binding phenomena and receptor-mediated cellular uptake may further complicate this issue. Elimination processes--a critical determinant for the drug's systemic exposure--may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Pharmacokinetic/pharmacodynamic (PK/PD) correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms. Extensive use of pharmacokinetic and exposure/response concepts in all phases of drug development has in the past been identified as a crucial factor for the success of a scientifically driven, evidence-based, and thus accelerated drug development process. Thus, PK/PD concepts are likely to continue and expand their role as a fundamental factor in the successful development of biotechnologically derived drug products in the future.

Animals↗

PubMed2004

Identification of stabilized dynorphin derivatives for suppressing tolerance in morphine-dependent rats.

PURPOSE: Modulatory actions on morphine-induced effects, such as tolerance and withdrawal, have been noted for dynorphin A(1-13) [Dyn A(1-13)] and similar peptides. These are currently of limited therapeutic potential due to extensive metabolism by human metabolic enzymes resulting in a half-life of less than 1 min in human plasma. The purpose of this study was to identify stabilized dynorphin A (Dyn A) derivatives, to determine their metabolic routes in human plasma, and to assess whether the pharmacodynamic activity is retained. METHODS: The stability of peptides in human plasma was tested using in vitro metabolism studies with and without enzyme inhibitors. Identification of the generated metabolites was performed by mass spectrometry after high performance liquid chromatography (HPLC) separation. The in vivo activity of a stabilized dynorphin was tested by tail-flick assay in morphine-tolerant rats. RESULTS: Though amidation of the Dyn A(1-13) was able to stop the majority of C-terminal degradation, metabolism of Dyn A(1-10) amide continued by captopril sensitive enzymes, suggesting that Dyn A(1-13) amide is a better candidate for additional stabilization. Two Dyn A(1-13) amide derivatives further stabilized at the N-terminal end, [D-Tyr1]-Dyn A(1-13) amide and [N-Met-Tyr1]-Dyn A(1-13) amide, showed half-lives in plasma of 70 and 130 min, respectively. The most stable derivative [N-Met-Tyr1]-Dyn A(1-13) amide was tested successfully for retention of the pharmacological activity in modulating antinociceptive activity. CONCLUSIONS: [N-Met-Tyr1]-Dyn A(1-13) amide showed significant stability and antinociceptive activity in the tail-flick test, thus pointing to the clinical potential of this derivative in the management of pain as well as its potential activity in suppressing opiate tolerance and withdrawal.

Aminopeptidases↗

PubMed2004

Intranasal loteprednol etabonate in healthy male subjects: pharmacokinetics and effects on endogenous cortisol.

Loteprednol etabonate (LE) is a glucocorticoid soft drug that is currently in development for intranasal use. The main objectives of this study were to examine the pharmacokinetics and potential effects on systemic cortisol of two intranasal suspension formulations of LE and to compare these findings with placebo and fluticasone propionate (FP, Flonase) control treatments. In this randomized, double-blind (except for FP), parallel-group study (n = 8/group), all subjects received for 14 days once daily in the morning two puffs of the following nasal spray formulations into each nostril: LE 0.1% (400 microg/day), LE 0.2% (800 microg/day), FP 0.05% (200 microg/day), and placebo. Drug trough levels were determined on days 1, 5, 12, 13, and 14, and a full pharmacokinetic profile was established on day 14, and 24-hour serum cortisol profiles were assessed prior to treatment (i.e., at baseline) and after the last dose. All subjects completed the protocol without treatment-emergent adverse findings. All formulations were rapidly absorbed (t(max) less than 1 h). The rather short mean terminal half-lives of 2.2 +/- 1.5 hours and 1.8 +/- 1.0 hours for LE 400 microg and LE 800 microg, respectively, and 4.2 +/- 1.8 hours for the 200-microg FP treatment explained the lack of any accumulation. Mean peak concentrations (C(max)) were 139 +/- 57 pg/mL with LE 400 microg and 164 +/- 54 pg/mL with LE 800 microg and thus fairly independent from dose. The 200-microg FP treatment resulted in a C(max) of only 15.5 +/- 5.9 pg/mL. Mean measured AUC(0-t) values (193 +/- 87 pg/h/mL(-1), 300 +/- 183 pg/h/mL(-1), and 40 +/- 34 pg/h/mL(-1) for LE 400 microg, LE 800 microg, and FP 200 microg, respectively) showed high variability and suggested nonlinear pharmacokinetics for the LE formulations, indicative of a less complete systemic uptake of LE from the 0.2% concentration. None of the treatments (LE 400 microg, LE 800 microg, and FP 200 microg) showed evidence for serum cortisol suppression when compared with placebo, respectively. The uptake and systemic exposure appears less complete from the 0.2% LE concentration, which principally favors this formulation for further clinical development.

Administration, Intranasal↗

PubMed2004

New developments in corticosteroids.

The goal of inhaled corticosteroid therapy is the targeted delivery of drug into the lung to achieve distinct pulmonary effects with reduced systemic side effects. Pharmacokinetic/pharmacodynamic assessment of pulmonary delivery suggests that an ideal inhaled corticosteroid and/or its delivery system should have the following characteristics: high pulmonary deposition efficiency, low oral bioavailability, high systemic clearance, optimized pulmonary residence time, and selective binding to the glucocorticoid receptor. Therefore, future developments will focus on improved delivery devices with higher pulmonary deposition; drugs or drug formulations providing prolonged pulmonary residence time (e.g., use of liposomes, microspheres, and nanothin coatings, or use of biological systems that achieve prolonged pulmonary residence time by ester formation and reactivation); drugs with efficient systemic clearance (e.g., soft drugs/hydrolyzable drugs); and/or improved pharmacodynamic selectivity.

Administration, Inhalation↗

PubMed2003

Validation of a simple liquid chromatography assay for creatine suitable for pharmacokinetic applications, determination of plasma protein binding and verification of percent labeled claim of various creatine products.

Creatine has been quantified in various tissues by a range of methodologies. This paper reports on the development and validation of a simplified HPLC assay to determine plasma creatine, plasma protein binding of creatine, creatine in microdialysate and creatine in over-the-counter products. An isocratic, reversed-phase (C(18)) HPLC assay, using potassium phosphate monobasic (pH 4) as a mobile phase, was validated in human plasma and microdialysis perfusion fluid (normal saline). The lower limit of quantification for the assay was 1 mg l(-1) in saline and 5 mg l(-1) in plasma. The RSD was below 6% and accuracy was below 12% in both matrices. Protein binding in human plasma was found to be negligible (<10%). Over-the-counter creatine monohydrate products tested contained 100% creatine monohydrate. This assay was found to be suitable for pharmacokinetic studies and the assessment of plasma creatine and skeletal muscle microdialysate.

Chromatography, High Pressure Liquid↗

PubMed2003

Performance of a corticosteroid inhaler with a spacer fashioned from a plastic cold-drink bottle: effects of changing bottle volume.

Some clinicians advocate using metered-dose inhaler (MDI) spacers prepared from common household bottles. We evaluated the in vitro aerosol characteristics of fluticasone from the MDI alone and through spacers fashioned from 237-, 500-, 1000-, and 1500-mL polyethylene terephlate plastic cold drink bottles using a cascade impactor. Ten 110-microg actuations of fluticasone were sampled into the impactor during each of five runs with each configuration. The primary outcomes were the respirable dose (i.e., quantity aerosol 1.1-4.7 microm in size) and the quantity trapped in the oropharynx. The mean fluticasone respirable dose from the MDI alone (46.2 microg/actuation) was no different (p > 0.05) compared with the same MDI mated to any of the bottle spacers, regardless of volume. The mean quantity of fluticasone trapped in the oropharynx from the MDI alone (39.2 microg/actuation) was greater (p < 0.001) than the same MDI mated with any bottle spacer (range 1.5-3.5 microg/actuation). These data suggest that any of the bottle spacers tested would be an acceptable method to decrease the quantity of fluticasone that would deposit onto the oropharynx and thereby diminish the risk of topical adverse effects. Among the range of volumes tested, there was no relationship between spacer volume and respirable dose of fluticasone.

Androstadienes↗

PubMed2003

Single- and multiple-dose pharmacokinetics of oral creatine.

Supplementation with exogenous creatine (Cr) has shown physiological benefits in humans, but little is known about the pharmacokinetics of Cr in humans. Six healthy males completed an open-label study consisting of a full pharmacokinetic analysis following a single oral dose of Cr monohydrate (71 mg kg-1) and at steady-state after 6 days of Cr administration (71 mg kg-1 qid). After the single oral dose, the clearance (CL/F) was 0.20 +/- 0.066 L h-1 kg-1, tmax was 1.9 +/- 0.88 hours, and Cmax = 102.1 +/- 11.2 mg h L-1. At steady-state, CL/F decreased to 0.12 +/- 0.016 L h-1 kg-1, tmax did not change, and Cmax increased to 162.2 +/- 30.0 mg L-1. Penetration (AUCMUSCLE/AUCPLASMA) of Cr into the interstitial muscle space, as determined by microdialysis, was 0.47 +/- 0.09 and 0.37 +/- 0.27 for the single dose and at steady-state, respectively. Plasma and muscle data were simultaneously fitted with a model incorporating a saturable absorption and first-order elimination process. In conclusion, repeated dosing of Cr caused a reduction in clearance that could result from saturation of the skeletal muscle pool of Cr.

Administration, Oral↗

PubMed2003

In vitro performance of two common valved holding chambers with a chlorofluorocarbon-free beclomethasone metered-dose inhaler.

STUDY OBJECTIVE: To compare in vitro aerosol deposition from a beclomethasone dipropionate metered-dose inhaler (MDI) containing hydrofluoroalkane propellant with that of the MDI in combination with two common valved holding chambers (VHCs) to evaluate how these VHCs affect the respirable dose of beclomethasone dipropionate. DESIGN: In vitro aerosol deposition study. SETTING: University research center. DEVICES: Beclomethasone dipropionate hydrofluoroalkane MDI alone, the MDI with OptiChamber VHC, and the MDI with AeroChamber-Plus VHC. INTERVENTION: The respirable dose (1-5-microm aerosol particles) of beclomethasone dipropionate was determined by sampling 10 80-microg actuations from five runs with each configuration (MDI alone, MDI with OptiChamber, and MDI with AeroChamber-Plus), using a well-established in vitro cascade impactor method. MEASUREMENTS AND MAIN RESULTS: Beclomethasone dipropionate aerosol was washed from the impactor with 50% methanol and quantified by means of high-performance liquid chromatography. Differences among outcomes were determined by using analysis of variance. Mean beclomethasone dipropionate respirable dose from AeroChamber-Plus (27.2 +/- 10.0 microg/actuation) was not significantly different (p>0.05) from that of the MDI alone (29.0 +/- 7.0 microg/actuation). OptiChamber respirable dose (12.8 +/- 6.0 microg/actuation) was less than half that produced by either the AeroChamber-Plus or the MDI alone (p=0.013). CONCLUSIONS: The OptiChamber and AeroChamber-Plus VHCs do not demonstrate equivalent in vitro performance when used with a beclomethasone dipropionate MDI that contains hydrofluoroalkane propellant. The respirable dose of beclomethasone dipropionate aerosol from the hydrofluoroalkane MDI was decreased by only 6% when the MDI was mated to an AeroChamber-Plus VHC and by 56% when used with an OptiChamber VHC.

Aerosol Propellants↗

PubMed2003

Pharmacokinetics of the dietary supplement creatine.

Creatine is a nonessential dietary component that, when supplemented in the diet, has shown physiological benefits in athletes, in animal-based models of disease and in patients with various muscle, neurological and neuromuscular disease. The clinical relevance of creatine supplementation is based primarily on its role in ATP generation, and cells may be able to better handle rapidly changing energy demands with supplementation. Although the pharmacological outcome measures of creatine have been investigated, the behaviour of creatine in the blood and muscle is still not fully understood. Creatine is most probably actively absorbed from the gastrointestinal tract in a similar way to amino acids and peptides. The distribution of creatine throughout the body is largely determined by the presence of creatine transporters. These transporters not only serve to distribute creatine but serve as a clearance mechanism because of creatine 'trapping' by skeletal muscle. Besides the pseudo-irreversible uptake by skeletal muscle, creatine clearance also depends on renal elimination and degradation to creatinine. Evidence suggests that creatine pharmacokinetics are nonlinear with respect to dose size and frequency. Skeletal muscle, the largest depot of creatine, has a finite capacity to store creatine. As such, when these stores are saturated, both volume of distribution and clearance can decrease, thus leading to complex pharmacokinetic situations. Additionally, other dietary components such as caffeine and carbohydrate can potentially affect pharmacokinetics by their influence on the creatine transporter. Disease and age may also affect the pharmacokinetics, but more information is needed. Overall, there are very limited pharmacokinetic data available for creatine, and further studies are needed to define absorption characteristics, clearance kinetics and the effect of multiple doses. Additionally, the relationship between plasma creatine and muscle creatine needs to be elucidated to optimise administration regimens.

Absorption↗

PubMed2002

A new solution-based intranasal triamcinolone acetonide formulation in patients with perennial allergic rhinitis: how does the pharmacokinetic/pharmacodynamic profile for cortisol suppression compare with an aqueous suspension-based formulation?

The present study was undertaken to describe the pharmacokinetics of a new solution-based intranasal triamcinolone acetonideformulation (Tri-Nasal) in patients with perennial allergic rhinitis and to use a pharmacokinetic/pharmacodynamic (PK/PD) simulation approach to compare the potential effects on plasma cortisol with that of an aqueous suspension-based nasal triamcinolone acetonide formulation (Nasacort AQ). Data from an open-label, randomized, three-way crossover study in patients with perennial allergic rhinitis receiving three doses (100, 200, and 400 microg) of a nasal solution-based triamcinolone acetonide formulation (Tri-Nasal) over 7 days were used to describe the pharmacokinetics of this formulation. Available literature data for a suspension-based aqueous triamcinolone acetonide formulation (Nasacort AQ) were used to describe its pharmacokinetic profile after similar single doses of 110, 220, and 440 microg. A PK/PD simulation approach was used to predict the anticipated cumulative cortisol suppression (CCS) of these two formulations. These simulations suggested a cortisol suppression of 8% to 16% for the single and steady-state doses of the solution-based product. Similar CCS estimates were predicted for equivalent doses of the aqueous suspension-based triamcinolone acetonide formulation with no difference between both formulations. Post hoc power analysis suggested that the predicted cortisol suppression is not likely to be significant for either preparation, including the clinically recommended doses of 200 and 220 microg of the solution-based and suspension-based formulations, respectively. In summary, based on the results of this PK/PD simulation, the plasma levels observed afternasal administration of the solution or the aqueous suspension are unlikely to induce a clinically relevant cortisol suppression, especially for the recommended dosing regimens of 200 and 220 microg/day.

Administration, Intranasal↗

PubMed2002

Differences in inhaled fluticasone bioavailability between holding chambers in children with asthma.

STUDY OBJECTIVE: To determine if differences between holding chambers in previous in vitro aerosol studies would agree with the bioavailability of inhaled fluticasone propionate between the same holding chambers in children with asthma. DESIGN: Double-blind, randomized, crossover study SETTING: University of Florida Clinical Research Center. PATIENTS: Eight children (aged 5-9 yrs) with stable asthma. INTERVENTION: Under observation, the children inhaled two 110-microg puffs of fluticasone twice/day through the InspirEase or E-Z Spacer holding chamber. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected at baseline and then at 0.5, 1, 1.5, 2, 4, and 6 hours after the last dose of fluticasone. Primary outcome measures were peak fluticasone steady-state plasma concentration (Cmax) and area under the fluticasone plasma concentration-time curve from 0-6 hours (AUC0-6). The fluticasone plasma concentrations were determined by high-performance liquid chromatography-mass spectrometric assay. Mean +/- SD Cmax from InspirEase (245 +/- 77 pg/ml) was 18% higher than that after E-Z Spacer (199 +/- 58 pg/ml, p < 0.05). Mean +/- SD AUC0-6 from InspirEase (1103 +/- 305 pg x hr(-1) x ml(-1) was 22% higher than that delivered from E-Z Spacer (863 +/- 258 pg x hr(-1) x ml(-1), p = 0.06). CONCLUSION: Differences in inhaled fluticasone bioavailability between these holding chambers in children with asthma corroborate differences reported in earlier in vitro aerosol studies.

Administration, Inhalation↗

PubMedDate not supplied

Simultaneous quantification of budesonide and its two metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone, in human plasma by liquid chromatography negative electrospray ionization tandem mass spectrometry.

A sensitive, rapid and selective liquid chromatography negative electrospray ionization tandem mass spectrometry [LC-(-)ESI-MS-MS] method has been developed and validated for the simultaneous quantification of budesonide (BUD) and its major metabolites, 6beta-hydroxybudesonide (OH-BUD) and 16alpha-hydroxyprednisolone (OH-PRED) in human plasma. The method was validated over a linear range from 0.1 to 10 ng/mL for all three analytes using a solid-phase extraction procedure with 9-fluoro-hydrocortisone as the internal standard. The between-day and within-day coefficients of variation for all compounds were < or =20% at the concentrations of lower limit of quantification and < or =15% at other quality control concentrations. The utility of this assay was demonstrated by monitoring BUD, OH-BUD and OH-PRED plasma concentrations in one healthy subject for 24 h following a 3 mg oral dose of budesonide, administered as a pH modified release capsule (Budenofalk) to healthy volunteers.

Budesonide↗