Search PubMed⌕ Search

Biomedical subjects

L I Harrison

Publications and source records attributed to L I Harrison.

At least 19 recordsLinked to original sources
PubMed2004

Direct measurement of BDP and 17-BMP in bronchial and peripheral lung tissue after inhalation of HFA- vs CFC-driven aerosols.

Indirect assessments have shown a superior lung deposition of HFA-BDP (Ventolair/Qvar) compared to CFC-BDP (Aerobec). The aim of this study was to assess the concentrations of BDP and its metabolite 17-BMP in airways and peripheral tissue from resected lung specimens after inhalation of these BDP formulations. Immediately prior to surgery for lung cancer, 10 patients inhaled 1000 microg of either CFC-BDP (n = 5) or HFA-BDP (n = 5) Mouthwash was collected after inhalation, and serum before, during, and after surgery. There was no significant difference between CFC and HFA in the concentration of 17-BMP in bronchi (median, 4365 vs 4121 pg/g tissue). After CFC, concentrations of 17-BMP were lower in peripheral tissue (1424 vs 2089 pg/g; ANCOVA, p = 0.001) and in serum taken immediately after inhalation (688 vs 1219 pg/ml, p < 0.01). Furthermore, the CFC group showed a higher concentration of BDP in the mouthwash (17,660 vs 1320 ng/ml, p < 0.05), but the concentration of 17-BMP was lower (452 vs 1028 ng/ml, n.s.). These findings indicate a predominantly peripheral deposition of HFA-BDP, in line with previous data. They also provide evidence for a faster uptake and metabolism of HFA-BDP, probably because BDP is dissolved in HFA and has a smaller particle size distribution than the CFC suspensions.

Administration, Inhalation↗
PubMed2003

Influence of particle size on lung deposition and pharmacokinetics of beclomethasone dipropionate in children.

We set out to evaluate lung deposition, systemic availability, and basic pharmacokinetic parameters of beclomethasone dipropionate (BDP) in children with chronic asthma. Plasma levels of BDP, 17 and 21 beclomethasone monopropionate (17-BMP and 21-BMP), and beclomethasone were measured after an intravenous infusion of 60 microg BDP and after inhalation of A) 100 microg HFA-BDP, B) 200 microg HFA-BDP, C) 200 microg HFA-BDP after ingestion of charcoal to block gastrointestinal (GI) absorption of drug, and D) 400 microg CFC-BDP. A breath-actuated pMDI (Autohaler) was used for HFA inhalations, and a pMDI with a large volume spacer (Volumatic) for CFC inhalations. Treatments A-D were given in a randomized, cross-over design. Fourteen patients aged 10-14 years completed all 5 study days. The mean systemic bioavailabilities in percent of dose leaving the canister valve (ex-valve) were 70% (100 HFA), 74% (200 HFA), 60% (200 HFA + charcoal), and 27% (400 microg CFC). After HFA treatment, 82% of the systemically available dose was absorbed through the lungs, and 18% from the gastrointestinal tract. The estimated bioavailability of BDP from the GI tract was 68%. BDP was metabolized to 17-BMP within minutes. Mean steady-state volume of distribution of 17-BMP was 84 L, and the mean terminal half-life (T((1/2))) after the four inhalations was 2.7 hr (range, 2.2-3.7 hr). Mean T((1/2)) and clearance after i.v. administration were 1.7 hr and 0.9 L/min, respectively. The HFA Autohaler delivers approximately three times as much BDP to the intrapulmonary airways as a CFC-pMDI with a large volume spacer.

Administration, Inhalation↗
PubMed2000

Tumour necrosis factor-alpha production in human alveolar macrophages: modulation by inhaled corticosteroid.

Using an ex vivo alveolar macrophage model, the hypothesis that inhaled preparations of corticosteroids might have important anti-inflammatory effects on cells of the peripheral airway was tested. The tumour necrosis factor (TNF)-alpha-inducing potential of three glycolipid preparations from nonpathogenic (arabinofuranasyl lipoarabinomannan (LAM (Ara-LAM)) and virulent (mannase LAM (ManLAM)) mycobacteria and Gram-negative bacteria (lipopolysaccharide (LPS)), in primary alveolar macrophage preparations was investigated. A novel inhaled chlorofluorocarbon (CFC)-free preparation of beclomethasone dipropionate (hydrofluoroalkane 134a (HFA)-BDP) with increased peripheral lung deposition was investigated for its ability to modulate glycolipidinduced TNF-alpha production by human alveolar macrophages, in comparison with a CFC-containing preparation and placebo. Compared to the basal TNF-alpha bioactivity of 0.72 ng x mL-1 (geometric mean), the TNF-alpha bioactivity in the macrophage preparation increased following incubation with LPS (138 ng x mL-1, p<0.001), AraLAM (12.6 ng-mL-1, p<0.001) and ManLAM (1.42 ng x mL-1, p=0.02). HFA-BDP, administered in vivo, significantly reduced LPS- and ManLAM-induced TNF-alpha production by alveolar macrophages cultured ex vivo. No change in glycolipid-induced TNF-alpha production was observed following in vivo administration of CFC-BDP or HFA-placebo. This is the first demonstration of an immunomodulatory effect on alveolar cells of corticosteroid delivered via metered dose inhaler. The present findings suggest that alveolar deposition of beclomethasone dipropionate is capable of modulating the inflammatory potential of the alveolar macrophage population.

Administration, Inhalation↗
PubMed2000

Commentary on the FDA draft guidance for bioequivalence studies for nasal aerosols and nasal sprays for local action: an industry view.

In June 1999, the Food and Drug Administration issued draft guidance for bioequivalence studies for nasal aerosols and nasal sprays for local action. The purpose of this opinion paper is to highlight the need for a balanced scientific debate before this guidance is used by underscoring the areas in the document that are in opposition to prevailing scientific understanding.

Absorption↗
PubMed1999

Adrenal effects and pharmacokinetics of CFC-free beclomethasone dipropionate: a 14-day dose-response study.

Since equivalent efficacy is achieved with lower doses of the reformulated beclomethasone dipropionate in the chlorofluorocarbon (CFC)-free propellant HFA-134a (HFA) than with the original CFC-beclomethasone dipropionate formulation, it is possible the HFA-beclomethasone dipropionate may have less safety concerns than the CFC formulation. Despite its chronic use, the steady-state pharmacokinetics of beclomethasone dipropionate has never been studied before. This double-blind study examined adrenal effects and pharmacokinetics after 14 days of dosing with HFA-beclomethasone dipropionate. Forty-three steroid-naïve asthmatic patients were randomised into 5 parallel groups and dosed every 12 h for 14 days with: HFA-placebo; 200, 400 or 800 microg day(-1) HFA-beclomethasone dipropionate; or 800 microg day(-1) CFC-beclomethasone dipropionate. After two weeks of dosing, the 24-h urinary free cortisol of all but one patient remained within the normal range, showing that all doses were well tolerated from a systemic safety perspective. The active HFA-beclomethasone dipropionate treatment groups showed a dose-related fall in 24-h urinary free cortisol. Total-beclomethasone (beclomethasone dipropionate and metabolites) pharmacokinetics after either the first dose of HFA-beclomethasone dipropionate or CFC-beclomethasone dipropionate were not substantially affected by subsequent doses. The extent of drug absorption from 800 microg day(-1) HFA-beclomethasone dipropionate and CFC-beclomethasone dipropionate was in the ratio of 1.7 : 1. A non-linear correlation between 24-h urinary free cortisol and the pharmacokinetic parameters was observed, reflecting smaller changes in 24-h urinary free cortisol than in pharmacokinetics as the dose was increased. No clinically meaningful change in the pharmacokinetics of beclomethasone dipropionate plus metabolites was seen on multiple dosing. The greater systemic availability of HFA-beclomethasone dipropionate was still associated with adrenal effects comparable with that of the CFC formulation at the same dose.

Administration, Inhalation↗
PubMed1999

Pharmacokinetic differences between chlorofluorocarbon and chlorofluorocarbon-free metered dose inhalers of beclomethasone dipropionate in adult asthmatics.

We have compared the serum pharmacokinetics of the metabolites of beclomethasone dipropionate after inhalation from chlorofluorocarbon (CFC) and hydrofluoroalkane HFA-134a (HFA) formulations in asthmatic patients. Twenty-three patients completed this open-label, randomized, single-dose, three-period crossover study. Each patient received in separate periods 200 microg or 400 microg HFA-beclomethasone dipropionate, or 400 microg CFC-beclomethasone dipropionate. Venous blood samples were collected over 24 h for the determination of beclomethasone esters and beclomethasone in the serum. Significant differences in pharmacokinetics following HFA- and CFC-beclomethasone dipropionate were observed. Following a 400 microg beclomethasone dipropionate dose, the HFA formulation gave mean maximum concentrations (Cmax) and area under the curve (AUC) values of beclomethasone esters of 1153 pg mL(-1) and 4328 pg h mL(-1), respectively, and beclomethasone Cmax and AUC values of 69 pg mL(-1) and 682 pg h mL(-1), respectively. These values were approximately 2-3-fold those seen with the CFC formulation (beclomethasone esters Cmax and AUC of 380 pg mL(-1) and 1764 pg h mL(-1), respectively; beclomethasone Cmax and AUC of 41 pg ml(-1) and 366 pg h mL(-1), respectively). Beclomethasone esters, the major component of beclomethasone dipropionate in the serum, peaked significantly earlier for the HFA formulation (0.8 h) than for the CFC formulation (2 h). Tests for dose proportionality of beclomethasone esters pharmacokinetics following HFA-beclomethasone dipropionate showed that the two hydrofluoroalkane strengths were proportional. The more rapid and greater efficiency of systemic drug delivery of the HFA formulation compared with the CFC formulation can be explained if most of each inhalation from CFC-beclomethasone dipropionate is swallowed and absorbed orally, whereas most of each inhalation from HFA-beclomethasone dipropionate is absorbed through the lungs. There is a need for comprehensive dose-response efficacy trials, with the use of the steep portion of the dose-response relationship, to evaluate the significance of these pharmacokinetic differences.

Adult↗
PubMed1998

Beclomethasone relative availability of oral versus inhaled beclomethasone dipropionate from an HFA-134A metered dose inhaler.

3M has formulated a new chlorofluorocarbon-free (CFC-free) beclomethasone dipropionate (BDP) metered-dose inhaler (MDI) with the use of the propellant HFA-134a (HFA). Lung deposition studies demonstrated that the HFA BDP MDI delivers to the lungs approximately 56% of the BDP dose (ex-adaptor), a substantially higher percentage than the 5-30% delivered by conventional CFC BDP MDIs. As new sensitive bioanalytical methods are becoming available to quantitate systemic levels of inhaled corticosteroids, pharmacokinetic evaluations are emerging as sensitive and reproducible methods that can be used as a complement to the data obtained from lung deposition studies to assess and compare the performance of MDIs. The present study was designed to determine the beclomethasone (BOH) availability of oral BDP relative to inhaled HFA BDP as a first step to alloy MDI product comparisons in the future. Forty mild asthmatic patients completed this open-label, randomized, single-dose, two-period crossover study. Each patient received an oral dose of BDP (0.2, 0.5, 1, 2 or 5 mg) in one period and an inhaled dose of BDP (0.2 or 0.8 mg) in the other period, with four patients allocated to each of ten different treatment sequences. The BOH availability of orally administered BDP was approximately 40% relative to inhaled HFA BDP. In addition, the fraction of an oral dose that reaches the systemic circulation was estimated from the 40% relative availability and previous lung deposition data to be 0.26. These estimated pharmacokinetic parameters will be used in the future to further characterize the pharmacokinetics of inhaled BDP and to compare the performance of different MDI products.

Administration, Inhalation↗
PubMed1998

Effect of changing the fine particle mass of inhaled beclomethasone dipropionate on intrapulmonary deposition and pharmacokinetics.

Reformulation of beclomethasone dipropionate (BDP) in the chlorofluorocarbon (CFC)-free propellant hydrofluoroalkane-134a (HFA) gave the opportunity to produce a solution formulation that provides a greater total mass of fine drug particles than the current CFC suspension metered dose inhaler (MDI). The HFA-BDP MDI was studied in three pharmacokinetic trials in asthmatic patients. Serum levels of BDP plus metabolites [total beclomethasone (total BOH) assay] were used to test whether the increased fine particle mass of HFA-BDP would result in improved intrapulmonary deposition and subsequent differences in serum profiles. Serum levels, maximum serum concentrations and area under the serum concentration-time curves of total BOH following both single and multiple doses of HFA-BDP were similar to those obtained with approximately twice the dose of CFC-BDP. The observed lower bioavailability of CFC-BDP compared with HFA-BDP could be explained if most of each inhaled dose from the CFC-BDP MDI was swallowed and absorbed from the gastrointestinal tract, while most of each inhaled dose from the HFA-BDP MDI was absorbed from the lungs. Deposition studies have confirmed this explanation. These results suggest that asthmatic patients can be treated with lower total daily doses of drug from HFA-BDP extrafine aerosol than from CFC-BDP.

Administration, Inhalation↗
PubMed1997

Pharmacokinetics and dose proportionality of beclomethasone from three strengths of a CFC-free beclomethasone dipropionate metered-dose inhaler.

As part of a development program to offer alternatives to chlorofluorocarbon (CFC) containing metered-dose inhalers, beclomethasone dipropionate has been formulated in a CFC-free system at three strengths: 50, 100, and 200 micrograms/actuation ex valve. To measure serum levels and dose proportionality of the beclomethasone derived from beclomethasone dipropionate, 13 mild to moderate asthmatic patients received a single dose of eight inhalations from each strength according to a double-blind crossover design. Seven patients were studied over 4 h and six patients over 12 h. For the total doses of 400, 800, and 1600 micrograms studied over 12 h, Cmax and AUC increased in a ratio of 1:1.8:3.1. A good correlation was seen between the fine-particle mass delivered and the in vivo performance of the three strengths. From a clinical point of view, the predictable increases in serum levels with an increase in dose will permit the clinician to effectively titrate a patient with this product.

Administration, Inhalation↗
PubMed1997

Comparative serum estradiol profiles from a new once-a-week transdermal estradiol patch and a twice-a-week transdermal estradiol patch.

Two identical open-label, randomized crossover studies were conducted to compare serum estradiol profiles from the new 12.5- and 25-cm2 once-a-week adhesive patches with those from the 10- and 20-cm2 commercially available twice-a-week Estraderm patches when applied as directed during a 1-week patch-wear period. Both studies were conducted in healthy postmenopausal women; serum estradiol levels were determined by gas chromatography/mass spectroscopy (GC/MS). Although both sizes of both patch treatments produced mean serum estradiol levels in the therapeutic range, the once-a-week patch provided more constant mean levels, avoiding large peak-to-trough fluctuations. As expected, the differences in mean serum estradiol concentrations between the two patch treatments occurred during the second application of the twice-a-week patch. Based on these results, the once-a-week drug in adhesive patch appears to be an acceptable means of hormone replacement therapy.

Administration, Cutaneous↗
PubMed1996

Systemic concentrations of salbutamol and HFA-134a after inhalation of salbutamol sulfate in a chlorofluorocarbon-free system.

The objective of this study was to determine if salbutamol was absorbed from a new salbutamol sulfate chlorofluorocarbon (CFC)-free metered-dose inhaler (MDI). Measurement of HFA-134a, the CFC-free propellant, was included to provide proof of delivery of this MDI. Eight healthy men received two inhalations (90 micrograms salbutamol base equivalents per inhalation ex adapter) from the CFC-free inhaler (MDI A) in period 1 and from a reference CFC inhaler (MDI V) in period 2. Eight postdose samples were collected for the determination of salbutamol serum levels over a 4-h period. Salbutamol levels were not quantifiable in most samples. Four subjects given MDI A and two given MDI V had a few transient salbutamol levels, which occurred in the first hour after dosing, within a narrow range of 1-2 ng/ml and close to the lower limit of detection (1 ng/ml). No pharmacokinetic analyses were possible. Blood samples were also collected after MDI A for propellant quantitation. HFA-134a levels were seen in all subjects, verifying absorption. We conclude that the transient salbutamol serum levels can be attributed to the two-inhalation dose and not to either propellant system.

Administration, Inhalation↗
PubMed1996

Twenty-eight-day double-blind safety study of an HFA-134a inhalation aerosol system in healthy subjects.

A 28-day double-blind parallel group study has been conducted to compare the safety and tolerability of HFA-134a, a chlorofluorocarbon-free propellant in a pressurized metered-dose inhaler (MDI A), with a chlorofluorocarbon propellant (MDI C). Sixteen subjects were randomly assigned to receive one of the two MDIs, either four inhalations four times per day for 14 days or eight inhalations four times a day for 14 days, and were then crossed over to the alternative exposure regime with the same propellant for the next 14-day period. No clinically significant changes occurred in blood pressure, heart rate, electrocardiograms, pulmonary function (FEV1, FVC, FEF25-75%), haematology or serum chemistry. One subject in the MDI A group had elevated eosinophil counts throughout the study; there were no other remarkable clinical laboratory data. Fifty six adverse events were related to the study propellants; 34 of these occurred in the MDI C group and 22 in the MDI A group. For each adverse event no statistically significant differences were detected between propellant systems or between exposure levels. The most frequent adverse event was headache, which was reported by four subjects with each propellant system. Blood samples for HFA-134a in the MDI A group were collected on day 28 to measure systemic absorption. Blood levels of HFA-134a were detected in all subjects given this propellant within 1 min post-exposure, and these levels decreased to one-tenth of the original value by 18 min after the start of exposure. The safety and tolerability of an HFA-134a chlorofluorocarbon-free system was demonstrated over 28 days of exposure in healthy subjects. These negative results are clinically important because they indicate it will be safe to proceed with the study of this chlorofluorocarbon-free system in asthmatic patients.

Adolescent↗
PubMed1995

Determination of the chlorofluorocarbon substitute 1,1,1,2-tetrafluoroethane (HFA-134a) in human and animal blood using gas chromatography with headspace analysis.

A gas chromatographic procedure with headspace analysis and flame-ionization detection is described for the determination of the chlorofluorocarbon substitute 1,1,1,2-tetrafluoroethane (HFA-134a). A 0.5-2 ml sample of heparinized whole blood from a laboratory animal or human is added directly into a presealed headspace vial from which an equivalent volume of air has been removed. The internal standard 1,1,2,2-tetrafluoroethane is added and the sample frozen until analysis. Chromatographic separation is achieved using a PoraPlot Q porous-layer capillary column. The analytical range is 5.8-3298 ng/ml when 2-ml human blood samples are used. The concentration range of the calibration curve can be easily adapted to accommodate the concentrations expected in either pharmacokinetic or toxicokinetic studies. Automation of the assay permits the maximum number of samples to be processed in a day.

Adult↗
PubMed1995

Dynamic monitoring of total-body absorption by 19F NMR spectroscopy: one hour ventilation of HFA-134a in male and female rats.

Six male and six female Sprague-Dawley rats were ventilated head-only for 1 h on a 15% atmosphere of 1,1,1,2-tetrafluoroethane (HFA-134a) in air in a magnetic resonance imaging spectrometer. Results from these dynamic 19F NMR studies suggest that a steady-state in vivo concentration of HFA-134a was approached at approximately 25 min into the exposure. Quantitative integration analysis using an external standard estimated this plateau to be 58.3 +/- 11.9 mg of absorbed HFA-134a per rat. The HFA-134a 19F NMR signal disappeared rapidly following removal of the test atmosphere, with an elimination half-life of 4.6 +/- 0.6 min in the male rats and 4.9 +/- 1.5 min in the female rats. The data suggest that there was no statistical difference between the sexes in amount absorbed or in elimination half-lives.

Absorption↗
PubMed1995

Acute safety of the CFC-free propellant HFA-134a from a pressurized metered dose inhaler.

The acute safety of the alternative chlorofluorocarbon-free (CFC-free) propellant HFA-134a from a pressurized metered-dose inhaler (MDI) was assessed in 12 healthy male subjects according to a double-blind, randomized, crossover design. On each of three consecutive days, cumulative doses of 1,2,4,8 and 16 inhalations were administered 30 min apart from one of three MDIs. The three MDIs contained either the HFA-134a CFC-free system without drug (HFA-Placebo), the CFC-free system with salbutamol sulphate (HFA-Salbutamol), or a conventional CFC propellant mixture without drug (CFC-Placebo). Pulmonary function (FEV1, FEF25-75%), cardiovascular performance (heart rate and blood pressure), objective tremor measurements and serum potassium were measured after each incremental dose. Similar responses for pulmonary function, cardiovascular performance, tremor and serum potassium were observed between the HFA-Placebo and CFC-Placebo groups. No statistically significant difference was seen in change from baseline of any parameter between the two propellant systems. The administration of HFA-Salbutamol produced statistically significant dose-related increases in heart rate, systolic blood pressure and tremor and a significant dose-related decrease in serum potassium; these responses were expected based on cumulative doses of active drug. Blood samples for HFA-134a analysis were collected to measure systemic absorption of this propellant. Levels of HFA-134a between 200 and 700 ng.ml-1 were detected in all subjects given the CFC-free system. This study shows that acute inhalation of HFA-134a in a CFC-free system is as safe as a CFC propellant system. Salbutamol sulphate in the CFC-free system can be delivered in a dose-linear fashion, without any noticeable change in the safety profile of active drug.

Adolescent↗
PubMed1994

Comparative pharmacokinetics of morning and evening doses of once-a-day theophylline capsules.

The objective of this study was to determine if the theophylline diurnal variation that has been observed primarily between morning and evening doses of twice-a-day products could be overcome by a once-a-day formulation. Eighteen healthy, nonsmoking, adult male subjects were given 900-mg theophylline doses as three 300-mg once-a-day theophylline capsules in the morning or evening for 5 days in a single-blind fashion. Matching placebo capsules were administered midway between each dose of active drug. Predose theophylline serum levels on day 3-6 were statistically equivalent within each treatment, indicating that approximate steady-state conditions were achieved by day 3. Mean serum level profiles over the 24-h interval following the active dose on day 5 were almost superimposable for the morning and evening treatments. All pharmacokinetic parameters were equivalent between the treatments, except for the time to peak serum level (Tmax), which was significantly shorter for the morning dose. Given the flatness of the serum level curves for both treatments, the Tmax difference was judged to be clinically unimportant. A small peak-trough level fluctuation of about 50% was seen with each treatment. We conclude that by designing a dose form in which drug release was the rate-limiting step in drug absorption, the diurnal variation commonly associated with theophylline formulations may be eliminated.

Adolescent↗
PubMed1993

Kinetics of absorption of a new once-a-day formulation of theophylline in the presence and absence of food.

Two three-way crossover studies were done to characterize the drug release characteristics of Monospan (3M Pharmaceuticals, St. Paul, MN) capsules, a new once-a-day theophylline formulation. In the first study, 22 healthy males received single 450-mg doses of Monospan in the presence and absence of a high-fat breakfast; the same dose of Somophyllin (Fisons, Rochester, NY) immediate-release liquid was given to fasted subjects as a reference. The second study involved 29 healthy males given a single dose of 900 mg of Monospan in the presence and absence of the same high-fat meal; Theo-24 (G. D. Searle and Co., Skokie, IL) capsules were given to fasted subjects as a reference. The results of both studies showed that food did not affect the absorption of theophylline from Monospan; peak concentration, to and area under the serum concentration-time curve were all unchanged. The absorption rates were similar with both strengths and dietary conditions and showed that theophylline was absorbed slowly from Monospan at a constant rate (approximately 3.2%/h) over 24 h. Absorption continued past 24 h, and the extent of absorption from Monospan compared with that from each reference averaged 88% or higher. A good correlation (r > 0.980) was observed for Monospan between the amount absorbed in vivo and the amount released in the in vitro dissolution test, a result that demonstrates the precise rate control of Monospan. We conclude that Monospan is a suitable once-a-day formulation that can be taken without regard to food.

Absorption↗