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Biomedical subjects

L Thorsson

Publications and source records attributed to L Thorsson.

16 recordsLinked to original sources
PubMed2005

Idealhalers or realhalers? A comparison of Diskus and Turbuhaler.

Medication for the treatment of asthma and chronic obstructive pulmonary disease should be given locally by inhalation. There is, however, no such thing as an ideal inhaler, or 'Idealhaler', which has all desired properties with no drawbacks. In this short review, we have compared the relative merits of the two most commonly used dry powder inhalers -- Turbuhaler and Diskus. Clinical effect is related to the amount of inhaled drug that reaches the lungs, and this in turn depends on the amount of fine particles generated at inhalation. Turbuhaler is more than twice as effective as Diskus at generating fine particles, and the higher lung deposition with Turbuhaler is accompanied by a lower variability in lung deposition. Compared with Diskus, the lung deposition with Turbuhaler is affected less by factors such as humidity.

Administration, Inhalation↗
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↗
PubMed2000

Lung deposition of inhaled drugs increases with age.

Budesonide plasma concentrations after inhalation of a fixed dose of the drug from a pressurized metered dose inhaler (pMDI) with spacer (Nebuchamber) were compared in young children and adults: 26 patients with mild asthma comprising 8 children 2-3 yr, 8 children 4-6 yr, and 10 adults 20-41 yr. Budesonide 2 x 200 microg was given by pMDI via Nebuchamber with mouthpiece and noseclip. Children of 2-3 yr used a facemask. Plasma was collected regularly for 8 h after drug administration. Budesonide was measured by liquid chromatography plus tandem mass spectrometry. The dose to patient was estimated as the dose of budesonide delivered from the pMDI with adapter minus the amount of budesonide recovered from the spacer, facemask, or mouthpiece, mouth rinse, and facial skin. The systemic exposure was estimated from the plasma concentration and expressed as the area under the curve of plasma concentration versus time (AUC). Terminal half-life (T(1/2)) was evaluated. Dose to patient, AUC, and T(1/2) were similar in the three age groups (p > 0.35). Nebuchamber delivers the same dose of budesonide to young children and adults. Yet the plasma concentration of budesonide was similar in young children and adults. Therefore, lung dose is increased with age. This suggests that from a safety perspective, the prescribed dose of budesonide inhaled from a pMDI with Nebuchamber spacer need not be adjusted for age or use of facemask. Children and adults can use the same nominal dose of budesonide via Nebuchamber as adults without an increased risk of systemic exposure.

Administration, Inhalation↗
PubMed1999

Systemic availability of budesonide after nasal administration of three different formulations: pressurized aerosol, aqueous pump spray, and powder.

AIMS: The present study was undertaken to determine the absolute systemic availability of budesonide from three different devices for nasal administration: pressurized aerosol, aqueous pump spray, and powder. METHODS: Sixteen healthy, non-smoking, volunteers participated in this open, randomized, and crossover study. All subjects received budesonide as an intravenous dose of 400 microg, and as three, single-dose, intranasal administrations: pressurized aerosol 800 microg, aqueous pump spray 400 microg, and powder 800 microg. Blood was sampled for 10 h after each administration and budesonide was assayed in plasma by liquid chromatography plus mass spectrometry. RESULTS: The mean [95% CI] systemic availability of budesonide with reference to the metered dose was: 13 [10; 15]%, 29 [23; 37]%, and 20 [16; 23]%, and the maximum plasma concentration (Cmax) was attained at (tmax) 2.0, 0.7, and 0.4 h after administration for the pressurized aerosol, aqueous pump spray, and powder, respectively. CONCLUSIONS: The uptake of budesonide was more rapid and more complete, and the systemic availability of the drug was significantly higher from the aqueous pump spray and powder than from the pressurized aerosol.

Administration, Intranasal↗
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

Lung deposition of budesonide from a pressurized metered-dose inhaler attached to a spacer.

The absolute systemic availability and pulmonary deposition of budesonide inhaled from a pressurized metered-dose inhaler (pMDI) attached to a Nebuhaler spacer was determined in 15 healthy subjects. The study was of an open cross-over design. Each subject randomly received three single doses of budesonide on separate days: 0.5 mg given intravenously and 1.0 mg (0.2 mg x 5) by inhalation from a pMDI with a Nebuhaler, with or without concomitant oral charcoal intake to prevent gastrointestinal absorption. Charcoal intake did not significantly affect the systemic availability or deposition of budesonide. The systemic availability was 36+/-14% (metered dose, mean+/-SD) with charcoal and 35+/-10% without. The pulmonary deposition was 36+/-14% with charcoal and 34+/-11% without. Erroneous administration, in which the canister was shaken only before the first of the five actuations, halved the systemic availability. In conclusion, the pulmonary deposition of budesonide from a pressurized metered-dose inhaler with Nebuhaler is high under optimum conditions. The small discrepancy between the systemic availability and pulmonary deposition indicates that the contribution from deposition in the oropharynx and subsequent absorption from the gastrointestinal tract is negligible. The marked reduction in the systemic availability of budesonide with the unshaken canisters confirms that the performance of a pressurized metered-dose inhaler is very much dependent on proper handling.

Administration, Topical↗
PubMed1998

The effects of static charge in spacer devices on glucocorticosteroid aerosol deposition in asthmatic patients.

Electrostatic charge in plastic spacer devices has been shown in vitro to reduce delivery of asthma medications intended for inhalation, but the effect of static charge on in vivo drug deposition is unknown. A six-way randomized crossover study was conducted in 10 mild asthmatic patients. Two plastic spacers (Nebuhaler and Volumatic) and one metal spacer (Nebuchamber) were tested. The spacers were used either "primed" or "unprimed". Priming was performed by firing 20 doses of placebo aerosol into a new spacer, hence coating the inner surface with surfactant and minimizing static charge. Unprimed spacers were new and were not treated. Pressurized aerosol canisters delivering budesonide (200 microg Pulmicort) were radiolabelled with the radionuclide 99mTc and lung deposition was measured by gamma scintigraphy. The radiolabel was shown to be a valid marker for the drug substance prior to the clinical phase of the study. Priming significantly increased mean whole lung deposition following inhalation from plastic spacers (Nebuhaler primed 37.7% and unprimed 26.7%, p=0.01; Volumatic primed 32.0% and unprimed 22.1%, p=0.02). Priming had no effect on the mean whole lung deposition following inhalation from the Nebuchamber (primed 33.5% and unprimed 32.9%). Lung deposition in vivo from plastic spacer devices will vary according to the electrostatic charge on the spacer walls. Priming reduces retention of drug on plastic spacer devices and increases lung deposition. Metal spacers are not susceptible to static charge, which should result in more predictable lung deposition.

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↗
PubMed1995

Influence of inhaler systems on systemic availability, with focus on inhaled corticosteroids.

Local treatment of obstructive pulmonary diseases, such as asthma, is achieved by oral inhalation of the active substance. Drug deposited in the lung may then exert its effects locally before it is absorbed into the systemic circulation. The systemic availability of a drug is made up of the fraction deposited in the lung and the fraction deposited in the oropharynx, which is swallowed and absorbed from the gastrointestinal (GI) tract. For many drugs, the fraction absorbed from the GI-tract is subject to hepatic first-pass metabolism before reaching the systemic circulation, and for the corticosteroid budesonide, hepatic first-pass metabolism is substantial. Since metabolic inactivation of inhaled corticosteroids in the lung has not been demonstrated, the systemic absorption of the fraction deposited in the lower respiratory tract can be assumed to be proportional to lung deposition. The local versus total systemic availability (L/T-ratio) can be used to express the effectiveness of the inhaled formulation. For budesonide inhaled via a pMDI and the dry-powder inhaler, Turbuhaler, the L/T-ratio was 0.59 and 0.84, respectively. The ideal L/T-ratio is 1.0. Thus, for inhaled budesonide it is an advantage for patients to change from budesonide pMDI to budesonide Turbuhaler with respect to the balance between desired and undesired effects.

Administration, Inhalation↗
PubMed1994

Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI.

The pulmonary and systemic availability of budesonide after inhalation from a dry powder inhaler, Turbuhaler, and from a pressurized metered-dose inhaler (P-MDI) were compared in healthy volunteers. Two different methods were used to assess pulmonary availability: 1) calculated from the systemic availability corrected for an oral availability of 13% (n = 24); and 2) after blocking of gastrointestinal absorption by administration of a charcoal suspension (n = 13). An intravenous infusion of budesonide was used as a reference. The systemic availability of budesonide, calculated as a geometric mean and expressed as percentage of the metered dose, was 38% for Turbuhaler and 26% for P-MDI. The pulmonary availability, calculated using the first method, was 32% and 15% for Turbuhaler and P-MDI, respectively; and, using the second method, 32% and 18%, respectively. The results of the present study indicate that administration of budesonide via Turbuhaler gives rise to a lung deposition which is approximately twice that of a P-MDI, with less variability, but that systemic availability is only increased by approximately 50%. Thus, the present data suggest that by administrating budesonide via Turbuhaler, instead of a P-MDI, the same degree of asthma control can be achieved with a lower dose, which, in turn, reduces the risk of undesired systemic effects.

Administration, Oral↗
PubMed1993

Nasal distribution of budesonide inhaled via a powder inhaler.

The distribution pattern of budesonide in the nasal passages and lungs was investigated in 10 healthy subjects after nasal inhalation. The subjects inhaled drug powder, radiolabelled with 99mTc, at maximum flow rate (46.3 +/- 6.8 l/min) and at 29.9 +/- 2.5 l/min via Turbuhaler. At both flows, the majority of the dose was deposited in the anterior part of the nasal cavity on a single, rather localized area, but some particles also penetrated more posteriorly into the main nasal passages and to the lungs. At maximum flow rate the nasal deposition was 65.2% (range 39.5-84.1%) and the lung deposition 4.7% (range 1.4-9.3%) of the metered dose, and at 30 l/min, the nasal deposition was 67.6% (range 49.7-81.6%) and the lung deposition was 4.2% (range 1.7-7.9%). A large fraction of the metered dose was deposited in the nasal adaptor of the inhaler during the administration (mean values 29 and 28%, for the two inhalation flows). Of the dose actually reaching the subject, 91 and 93% (mean values) was deposited in the nose. There were no statistically significant differences in distribution pattern between the two inhalation flows.

Administration, Inhalation↗
PubMed1990

Residual proliferative capacity in F9 teratocarcinoma stem cell cultures treated with alpha-difluoromethylornithine, an inducer of parietal endoderm differentiation.

We have previously shown that inhibition of polyamine biosynthesis by treatment with 5 mM alpha-difluoromethylornithine (DFMO) causes growth arrest and induces differentiation of F9 teratocarcinoma stem cells. The resulting phenotype is similar to that of parietal endoderm, and these differentiated cells possess no apparent proliferative capacity. In the present study, however, it is demonstrated that some of the DFMO-treated cells are not terminally differentiated. Upon a change to DFMO-free growth medium these cells eventually start to proliferate. Using a colony forming efficiency assay, it is estimated that less than 1 out of 200,000 cells retains its proliferative capacity after 6-10 days of DFMO treatment. These cells exhibit no apparent resistance to DFMO, and their population doubling time is similar to that of untreated control F9 cells. Consequently, the possible existence of a small, quiescent, cell population possessing proliferative potential must be taken into account when designing therapeutic protocols for DFMO.

Cell Differentiation↗
PubMed1989

Feedback control of ornithine decarboxylase expression by polyamines. Analysis of ornithine decarboxylase mRNA distribution in polysome profiles and of translation of this mRNA in vitro.

Cell growth and differentiation require the presence of optimal concentrations of polyamines. Ornithine decarboxylase (ODC) catalyses the first and rate-controlling step in polyamine synthesis. In studies using cultures of Ehrlich ascites-tumour cells, we have shown that the expression of ODC is subject to feedback regulation by the polyamines. A decrease in the cellular polyamine concentration results in a compensatory increase in the synthesis of ODC, whereas an increase in polyamine concentration results in suppression of ODC synthesis. These changes in ODC synthesis were attributed to changes in the efficiency of ODC mRNA translation, because the steady-state amount of ODC mRNA remained constant. We now show that the number of ribosomes associated with ODC mRNA is low, and that the increase in ODC mRNA translation takes place without a shift in the distribution of ODC mRNA towards larger polysomes. This finding indicates that the polyamines regulate the efficiency of ODC mRNA translation by co-ordinately affecting the rates of initiation and elongation. By analysing ODC mRNA translation in vitro, using a rabbit reticulocyte lysate, polyadenylated RNA from a cell line with an amplified ODC gene, and a monospecific anti-ODC antibody, we also show that spermidine, but not putrescine, exerts a direct regulatory effect on ODC synthesis.

Animals↗