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Biomedical subjects

A Källén

Publications and source records attributed to A Källén.

15 recordsLinked to original sources
PubMed2001

Pharmacokinetics and systemic activity of fluticasone via Diskus and pMDI, and of budesonide via Turbuhaler.

AIMS: To determine the basal pharmacokinetics, lung uptake and plasma cortisol suppression for two commonly prescribed inhaled corticosteroids. METHODS: Twenty-one subjects (13 healthy and 8 mild asthmatic patients) received fluticasone propionate via a chlorofluorocarbon-propelled pressurized metered-dose inhaler (pMDI) (healthy subjects only) and Diskus and budesonide via Turbuhaler, 1000 microg twice daily for 7 days. Intravenous doses (200 microg) of both compounds were used as references. Plasma concentrations of fluticasone and budesonide were determined during 48 h by liquid chromatography plus tandem mass spectrometry (LC-MS-MS). Plasma concentrations of cortisol were determined by LC-MS every second hour for 24 h at baseline, and following each treatment. RESULTS: The volume of distribution was found to be larger and the elimination half-life and mean absorption time longer for fluticasone than for budesonide. The systemic availability of budesonide via Turbuhaler (39%) was significantly higher than that of fluticasone via Diskus (13%) (ratio 3.0 [2.5, 3.6] with 95% confidence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3, 2.3]). In addition, at steady state the systemic availability of fluticasone via pMDI was significantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The lung deposition of budesonide via Turbuhaler was 2.2-fold [1.7, 2.9] higher than that of fluticasone pMDI and 3.4-fold [2.8, 4.0] higher than that of fluticasone Diskus. In addition, the lung deposition of fluticasone via pMDI was 1.5-fold [1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h) was significantly reduced vs baseline for all three treatments. The cortisol concentration vs baseline was 12% for fluticasone pMDI, which was significantly lower (ratio 0.32 [0.24, 0.42]) than that for fluticasone Diskus (39%), and for budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol concentration did not differ significantly between treatments with fluticasone Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]). CONCLUSIONS: Budesonide and fluticasone differ in their pharmacokinetic properties in that although clearance is the same, the rate of uptake and elimination is slower for fluticasone. Despite a significantly higher pulmonary availability of budesonide via Turbuhaler, the plasma cortisol suppression is less than that of fluticasone via pMDI and similar to that of fluticasone via Diskus. There is no indication of any difference between healthy subjects and mild asthmatic patients in the pharmacokinetics and plasma cortisol suppression of fluticasone and budesonide.

Administration, Inhalation↗
PubMed2001

A randomized controlled assessment of the effects of different dosing regimens of budesonide on the HPA-axis in healthy subjects.

AIMS: To investigate the effect on the hypothalamo-pituitary-adrenal (HPA) axis of treatment with budesonide, 400 microg once daily, morning or evening, or 200 microg twice daily, and 800 microg twice daily via Turbuhaler in a randomized, placebo-controlled, double-blind, double-dummy crossover study. METHODS: Healthy men received budesonide, 400 microg in the morning (08.00-09.00 h) or evening (20.00-21.00 h), budesonide, 200 microg twice daily, 800 microg twice daily, and placebo twice daily, for 1 week each. Plasma and urine samples were obtained over 24 h on day 7 for cortisol determination. Twenty-five subjects completed all treatments, and 27 were included in the analysis. RESULTS: The 24 h plasma cortisol concentrations vs placebo (95% CI) were 98% (89, 108) for 400 microg in the morning, 92% (83, 100) for 400 microg in the evening, 95% (86, 104) for 200 microg twice daily, and 76% (70, 84) for 800 microg twice daily. CONCLUSIONS: Budesonide at a dose of 400 microg day-1 via Turbuhaler had no statistically significant effect on 24 h cortisol production, irrespective of whether treatment is given once or twice daily, whereas a dose of 800 microg twice daily resulted in a statistically significant suppression vs placebo. Neither could a significant difference be found between morning and evening dosing.

Adolescent↗
PubMed2000

A randomized controlled assessment of the systemic activity of budesonide when given once or twice daily via Turbuhaler.

OBJECTIVE: To compare the effects on the hypothalamo-pituitary-adrenal (HPA) axis of budesonide, delivered via Turbuhaler at doses of 800 microg once daily in the morning or evening or 400 microg twice daily. METHODS: Healthy men (n = 24) received four treatments in random order: budesonide, 800 Fg in the morning and placebo in the evening; budesonide, 800 microg in the evening and placebo in the morning; budesonide, 400 microg in the morning and evening; placebo in the morning and evening. Each treatment was given for 1 week, with a 2-week washout period between treatments. Blood samples for measurement of plasma cortisol were obtained before the evening dose on day 6 of each treatment period and over the following 22 h. RESULTS: All three budesonide regimens produced a statistically significant reduction (mean 16-19%) in the area under the curve of plasma cortisol concentration versus time over 22 h (AUC0-22h) compared with placebo. There were no statistically significant differences among the three regimens. These reductions in plasma cortisol concentrations were not considered to be clinically significant. Analysis of the fractional AUCs measured 0-10 h and 10-22 h after dosing showed that evening dosing had a greater effect on nocturnal cortisol than morning dosing; daytime cortisol was reduced by all treatments. CONCLUSION: There was no significant difference between the effects on plasma cortisol of budesonide 400 microg twice daily and 800 microg once daily in the morning or evening.

Adolescent↗
PubMed1999

Dose response studies: how do we make them conclusive?

In this paper we discuss how to make meaningful use of a dose response study. It is argued that concepts like the minimal effective dose are not clinically meaningful and that the purpose of a dose response study should be to identify the drug potency in relation to a known active control. We also discuss various ways of carrying out the analysis.

Dose-Response Relationship, Drug↗
PubMed1999

Dose-proportional pharmacokinetics of budesonide inhaled via Turbuhaler.

AIMS: The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 microg, 800 microg or 1600 microg administered twice daily by a dry-powder inhaler (Turbuhaler ) in adult patients with mild asthma. METHODS: A total of 38 patients received budesonide by inhalation, 13 received 400 microg twice daily, 12 received 800 microg twice daily and 13 received 1600 microg twice daily. Mean FEV1 at inclusion was 3.4, 4.0 and 3.9 l min-1 in the three groups, respectively. Blood samples were taken after a single dose, and after 3 weeks of daily treatment, for pharmacokinetic evaluation. Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry. RESULTS: Eleven evaluable patients remained in each dose group. Mean time to peak budesonide plasma concentration (tmax ) was short (0.28-0.40 h) and did not differ between treatment groups. Budesonide concentrations declined rapidly thereafter, indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. Cmax was 1. 4(2.0) nmol l-1 (single (repeated) doses), 2.6(3.6) nmol l-1 and 5. 4(6.4) nmol l-1 after 400, 800 and 1600 microg twice daily, respectively. The corresponding results for the area under the plasma concentration vs time curve (AUC) were 271(325), 490(628) and 915(1096) nmol l-1 min. Ninety percent confidence intervals for pairwise dose-normalized Cmax and AUC comparisons between groups were large but contained unity in all cases, thus indicating dose-proportional pharmacokinetics. Regression on analysis supported these findings. Mean AUC after repeated doses (AUC(0,12 h,RD)) was on average 23% higher than the mean AUC after single doses (AUC(0, infinity,SD)(P=0.04) with no significant differences between doses, indicating slight accumulation following bid dosing. CONCLUSIONS: In this relatively small study, budesonide inhaled via Turbuhaler appeared to have dose-proportional pharmacokinetics, both within and above the clinically recommended dose range for asthmatic patients.

Administration, Inhalation↗
PubMed1998

Effects of budesonide by means of the Turbuhaler on the hypothalmic-pituitary-adrenal axis in asthmatic subjects: a dose-response study.

BACKGROUND: As a general phenomenon, corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal (HPA) axis. The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects. OBJECTIVES: This clinical trial was performed to assess the effects of budesonide on the HPA axis (at 800, 1600, or 3200 microg/day, given as a twice daily regimen, administered by means of the Turbuhaler) in adult patients with mild, non-steroid-dependent asthma. METHODS: Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind, double-dummy, randomized, placebo-controlled, parallel-group, multicenter study. Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone (ACTH), cosyntropin. RESULTS: After 6 weeks of treatment, plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4% in the placebo group; by 13%, 11%, and 27% in the budesonide groups (800, 1600, and 3200 microg/day, respectively); and by 35% in the prednisone group. The decrease was significant only in the 3200 microg/day budesonide (p = 0.03) and prednisone (p = 0.005) groups. Over the same time period, decreases in basal plasma cortisol concentrations were 1% in the placebo group; 19%, 19%, and 34% in the three budesonide groups; and 37% in the prednisone group. Only in the prednisone group was the decrease significant (p = 0.03 vs placebo). CONCLUSIONS: In this study budesonide inhaled by means of the Turbuhaler, at doses recommended for clinical use (800 or 1600 microg/day), did not produce any statistically significant suppression of the HPA axis compared with placebo.

Administration, Inhalation↗
PubMed1998

Efficacy of cumulative doses of salbutamol administered via Turbuhaler or Diskhaler in patients with reversible airway obstruction.

The study aimed to estimate the relative dose potency of salbutamol inhaled via Turbuhaler and Diskhaler. The 24 adult patients participating had chronic reversible airway obstruction. The study was of a double-blind, double-dummy, crossover, randomized design. Five doses of salbutamol Turbuhaler, 50, 50, 100, 200, and 400 microg, were given on one study day at intervals of 30 min. On another study day, five doses of salbutamol Diskhaler, 200, 200, 400, 800, and 1600 microg, were given with the same interval. The treatment days were separated by a washout period of at least 24 h. The inhalation technique was standardized and supervised. Efficacy variables were recorded before and after each study dose. The primary efficacy variable was forced expiratory volume in 1 s (FEV1). When parallel and linear cumulative dose-response curves were statistically compared on a logarithmic scale, the dose potency of salbutamol Turbuhaler vs salbutamol Diskhaler was 1.99 (95% confidence interval 1.52-2.54). This study indicates that only half the dose of salbutamol is required via Turbuhaler as via Diskhaler for the same bronchodilating effect.

Administration, Inhalation↗
PubMed1997

Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects.

AIMS: The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation. METHODS: Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000 micrograms) of FP via Diskhaler and repeated inhalations (1000 micrograms twice daily) every 12 h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20 micrograms FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values. RESULTS: The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6-18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20-65]% and 95 [93-97]% for the single and repeated doses, respectivley. CONCLUSIONS: To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.

Administration, Inhalation↗
PubMed1997

Differences in bronchodilating potency of salbutamol in Turbuhaler as compared with a pressurized metered-dose inhaler formulation in patients with reversible airway obstruction.

Two studies are presented, with the aim of establishing the dose potency ratio for salbutamol given via Turbuhaler and via a pressurized metered-dose inhaler (pMDI). Both studies were of a double-blind, randomized design. Outpatients with mild-to-moderate chronic reversible airway obstruction were given single doses of salbutamol administered via Turbuhaler and via pMDI. Efficacy and safety variables were measured before and during 6 h after each dose. The first study was a four-way crossover study including 12 patients. The salbutamol doses given were: 50, 100 and 2x100 microg via Turbuhaler and 2x100 microg via pMDI (Ventolin). The study showed that 2x100 microg of salbutamol inhaled via Turbuhaler is more potent than 2x100 microg salbutamol inhaled via a pMDI, and that 100 microg salbutamol via Turbuhaler is at least as potent as 2x100 microg salbutamol inhaled via a pMDI. The second study including 50 patients was a placebo-controlled five-way crossover, study. Two doses of salbutamol via Turbuhaler, 50 and 2x100 microg, and via pMDI, 100 and 2x200 microg, were given. There was a dose-dependent response in forced expiratory volume in one second (FEV1) for both inhalers. Adjusted for differences in baseline FEV1 values, the estimated relative dose potency for Turbuhaler versus pMDI was 1.98:1 (95% confidence interval 12-3.2). These studies showed that the same bronchodilating effect can be achieved when half the dose of salbutamol given via a conventional pressurized metered-dose inhaler is given via Turbuhaler.

Administration, Inhalation↗
PubMed1995

Comparison of gamma scintigraphy and a pharmacokinetic technique for assessing pulmonary deposition of terbutaline sulphate delivered by pressurized metered dose inhaler.

A comparison has been made of pulmonary deposition of terbutaline sulphate from a pressurized metered dose inhaler (pMDI), measured in 8 healthy male subjects by gamma scintigraphy and by a pharmacokinetic (charcoal-block) method, involving drug recovery in urine. Measurements were carried out with a pMDI at slow (27 l/min) and fast (151 l/min) inhaled flows and with Nebuhaler large volume spacer device (average inhaled flow 17 l/min). Overall, the two methods did not differ significantly in their estimates of whole lung deposition, although values obtained by gamma scintigraphy exceeded those from the charcoal-block method for the pMDI with fast inhalation. The regional distribution of drug within the lungs and deposition in the oropharynx could be assessed by gamma scintigraphy, but not by the charcoal-block method. It is concluded that either method may be used to assess whole lung deposition of terbutaline sulphate from pMDIs, both with and without a spacer, although each method has its own inherent advantages and disadvantages.

Adult↗
PubMed1992

Comparison of BrdUrd and [3H]TdR incorporation to estimate cell proliferation, cell loss, and potential doubling time in tumor xenografts.

In this study, two different methods of estimating cell proliferation were compared: cell loss and potential growth rate of xenografted head and neck cancer grown in nude mice based on the detection of DNA incorporation of bromodeoxyuridine (BrdUrd) in one method, and [3H]thymidine ([3H]TdR) in the other. The 21-d-old xenografts were labelled in vivo, either with BrdUrd or [3H]TdR and excised at intervals during 65.5 h. In tumors containing BrdUrd, the percent labelling was measured in mid-S and mid-G1 phase windows of cytograms from bivariate DNA flow cytometry (FCM). In [3H]TdR-labelled tumors, the percent labelled mitoses (PLM) was determined by light microscopy evaluation of autoradiographs. With a computer program based on a theoretical model, the percent labelling versus time after injection was used to analyze cell cycle time, cell loss, tumor growth fraction, and potential doubling time. The values calculated from DNA incorporation with BrdUrd agreed well with those obtained from labelling with [3H]TdR, i.e., cell cycle time 2.3 vs. 2.4 d, and growth fraction 67 vs. 70%. The estimated potential doubling time was 3.1 d and cell loss factor 40% by both methods. Flow cytometry analysis of BrdUrd-labelling is considerably faster than the evaluation of [3H]TdR-labelling, and the present results provide further support for the BrdUrd labelling method as a promising alternative to the PLM method in cell cycle studies designed to evaluate the relevance of cell proliferative properties in relation to biological behavior in xenografted head and neck cancer.

Animals↗
PubMed1991

Bricanyl Turbuhaler in the treatment of asthma: a six week multi-centre study carried out in Sweden, the United Kingdom, Denmark, Norway and Finland.

Two hundred and fifty eight adult patients with bronchial asthma participated in an open, parallel group study of 8 wks duration. During a 2 wk run-in period the beta 2-agonist terbutaline (0.5 mg q.i.d) was delivered via a pressurized freon aerosol, Bricanyl metered dose inhaler (MDI). During the following 6 wks, one third of the patients continued with MDI and two thirds with the same dose of terbutaline in the form of dry powder, Bricanyl Turbuhaler. There were no statistically significant differences in the increases in peak expiratory flow rate (PEFR) after inhalation between the two treatment groups. The asthma symptom scores decreased in the Turbuhaler group during the study but remained the same in the MDI group. No difference in use of extra trial medication during the day was found. During the night, the difference was statistically significant in favour of Turbuhaler (p less than 0.05). Turbuhaler was well accepted and easy to use. As compared with the MDI used during run-in, 50% of the patients in the Turbuhaler group preferred to use Turbuhaler and 26% MDI, whilst 24% had no preference. In conclusion, Turbuhaler was at least as effective as MDI during the whole Turbuhaler life-span (6 wks).

Administration, Inhalation↗
PubMed1985

A simple model for the spatial spread and control of rabies.

A simple mathematical model for the spatial spread of rabies is presented. It models the dynamics of the front of an epizootic wave. We show how the model can be used to estimate the minimum width (in kilometers) of a break, that is, a region in which a control scheme is employed in order to stop the spatial progression of the rabies wave front. A simple expression is derived for the surviving fox population, after the passage of the epizootic, in terms of measurable parameters of the model.

Animals↗
PubMedDate not supplied

Cell cycle time, growth fraction and cell loss in xenografted head and neck cancer.

In a previous cell kinetic study with DNA flow cytometry (FCM) on xenografted human squamous cell carcinoma of the head and neck (HNSCC), there were significant variations in cell cycle phase distribution during early growth of the transplanted tumors. The object of the present study was to investigate further the cell kinetic mechanisms associated with variation in the growth rate of HNSCC. Xenografts from the same tumor line were examined on three different occasions: 12, 25 and 36 days following transplantation into nude mice. Cell cycle time "Tc", tumor growth fraction (GF) and cell loss factor were determined by computerized curve-fit analysis from percentage labelled mitoses curves. The mean growth curve of the tumors was logistic, with tumor doubling time (Td) ranging from 7.39 days to 8.86 days, and increasing as tumor volume increased. Although growth rate was higher in younger tumors, the cell cycle was longer with a median "Tc" of 69 hours on day 12 versus 34 hours on day 36. There were only minor variations in cell cycle phase distribution as measured by FCM. The growth fraction decreased slightly from 80% to 69% between day 12 and day 36, whereas cell loss factor increased markedly from 49% on day 12 to 78% on day 36. The results of the study emphasize the fact that cell loss is one of the most important cell kinetic determinants of tumor growth rate. This should be borne in mind when calculating proliferative cell kinetics in HNSCC.

Animals↗