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Biomedical subjects

D J Clark

Publications and source records attributed to D J Clark.

At least 55 records · Page 3Linked to original sources
PubMed1996

Evaluation of plasma and urinary salbutamol levels in COPD.

OBJECTIVE: To evaluate the use of trough plasma salbutamol and overnight urinary salbutamol excretion in the assessment of nebulised salbutamol delivery in patients with chronic obstructive pulmonary disease (COPD). METHODS: Twenty in-patients with COPD receiving nebulised salbutamol, age 69.7 years, FEV1 38.1% predicted, were studied on two consecutive days, receiving four 2.5 mg doses of nebulised salbutamol on day 1 and four 5 mg doses of nebulised salbutamol on day 2, the first dose at 8.00 h the last dose at 22.00 h. Salbutamol delivery was assessed after the last dose by trough plasma salbutamol 8.00 h and overnight urinary excretion of salbutamol (22.00-8.00 h). RESULTS: Levels of urinary salbutamol were detectable in all 20 patients at both doses, whereas for plasma salbutamol detectable levels were only found in 16/20 cases at the 2.5 mg dose and in all cases at the 5 mg dose. For overnight urinary salbutamol (microgram x 10 h-1 n = 20) the results were 141 for 2.5 mg and 249 for 5 mg. The dose ratio for urinary salbutamol between 2.5 mg and 5 mg doses was 1.83. Results for plasma salbutamol (ng/ml, n = 16) were 1.58 at 2.5 mg and 2.43 at 5 mg: dose ratio (geometric mean) 1.49. CONCLUSION: Overnight urinary salbutamol provides a simple and effective measure of nebulised salbutamol delivery in patients with COPD, which would be suitable for studying nebuliser performance and compliance.

Administration, Inhalation↗
PubMed1996

Lung bioavailability of chlorofluorocarbon free, dry powder and chlorofluorocarbon containing formulations of salbutamol.

With the future advent of a world wide ban on chlorofluorocarbon containing aerosols, a study was designed to compare the in vivo lung bioavailability of salbutamol via chlorofluorocarbon-containing metered-dose inhaler (CFC), chlorofluorocarbon-free metered-dose inhaler (CFC-free), and dry powder inhaler (DPI). Twelve healthy male subjects were given 1200 micrograms salbutamol and measurements made of plasma and urinary salbutamol. CFC-free produced significantly higher plasma salbutamol levels (ng ml-1; mean and 95% CI for difference) than either CFC or DPI: Cmax, CFC-free 4.18 vs CFC 3.29 (95% CI 0.10-1.68), vs DPI 3.42 (95% CI -0.03-1.56). The ratio for the difference in Cmax between CFC and CFC-free formulations was 1.32 (95% CI 1.02-1.61). There were no significant differences between CFC and DPI formulations. Urinary salbutamol results did not reveal any significant differences between the three inhalers (micrograms 30 min-1): CFC-free 42.4, CFC 43.8, DPI 45.3. Thus, the lung bioavailability of CFC-free was greater than that of CFC or DPI formulations of salbutamol.

Adult↗
PubMed1996

Effect of multiple actuations, delayed inhalation and antistatic treatment on the lung bioavailability of salbutamol via a spacer device.

BACKGROUND: The aim of this study was to extend previous in vitro observations regarding the effects of multiple actuations of aerosols into spacer devices, delayed inhalation, and antistatic treatment of spacer devices on the amount of drug delivered for inhalation. An in vivo study of lung bioavailability of salbutamol from a large volume (Volumatic) spacer was conducted. METHODS: Ten healthy volunteers of mean age 20.5 years with a mean forced expiratory volume in one second of 112.1% predicted were studied in a randomised single blind (investigator blind) crossover study. 1200 micrograms of salbutamol was given with mouth rinsing (100 micrograms/puff) on four study days: single puffs via spacer, multiple puffs via spacer (3 x 4 puffs), single puffs with 20 second delay before inhalation via spacer, and single puffs via an antistatic treated spacer. All spacers, including those treated with antistatic, were prewashed prior to each study day. Measurements of lung bioavailability were made at five, 10, and 20 minutes after inhalation to determine peak (Cmax) and average (Cav) plasma salbutamol levels. Systemic beta 2 responses including finger tremor, heart rate, and plasma potassium levels were also evaluated. RESULTS: Single puffs from the spacer produced higher plasma salbutamol levels and greater systemic beta 2 responses than either multiple puffs or single puffs with delayed inhalation for a 1200 micrograms dose. For Cmax this amounted to a 1.93-fold (95% CI 1.68 to 2.19) greater lung bioavailability for single puffs than for multiple puffs and a 1.80-fold (95% CI 1.59 to 2.00) greater lung bioavailability for single puffs than for single puffs with a 20 second delay. Comparison of the normal and antistatic treated spacers (both prewashed) revealed differences for Cmax with levels 1.23-fold (95% CI 1.04 to 1.41) greater for the normal spacer. CONCLUSIONS: Delayed inhalation from a Volumatic spacer and the use of multiple puffs results in a considerable decrease in the delivery of salbutamol to the lungs with an approximate twofold reduction in lung bioavailability. Washing a Volumatic spacer is as effective as an antistatic lining in reducing the effects of static charge on salbutamol delivery in vivo.

Adult↗
PubMed1996

Comparative adrenal suppression with inhaled budesonide and fluticasone propionate in adult asthmatic patients.

BACKGROUND: A study was performed to compare the adrenal suppression caused by inhaled fluticasone propionate and budesonide on a microgram equivalent basis, each given by metered dose inhaler to asthmatic patients. METHODS: Twelve asthmatic patients of mean age 29.9 years, with a forced expiratory volume in one second (FEV1) 92.9% predicted and forced expiratory flow 25-75% (FEF25-75) 69.5% predicted, on less than or equal to 400 micrograms/day inhaled corticosteroid, were studied in a double blind placebo controlled crossover design comparing single doses of inhaled budesonide 400, 1000, 1600, 2000 micrograms and fluticasone propionate 500, 1000, 1500, 2000 micrograms. Doses were administered at 22.00 hours by metered dose inhaler with mouth rinsing and measurements were made in the laboratory 10 hours later. RESULTS: Serum cortisol levels compared with placebo (mean 325.2 nmol/l) were suppressed by fluticasone at doses of 1500 micrograms (211.6 nmol/l) and 2000 micrograms (112.3 nmol/l) and by budesonide at 2000 micrograms (243.4 nmol/l). Fluticasone propionate 2000 micrograms produced lower absolute serum cortisol levels than budesonide 2000 micrograms (95% CI for difference 42.9 to 219.2). The dose ratio (geometric mean) for the relative potency was 2.89 fold (95% CI 1.19 to 7.07). In terms of percentage suppression versus placebo, fluticasone propionate also produced greater effects (means and 95% CI for difference): budesonide 1600 micrograms (16.0) versus fluticasone propionate 1500 micrograms (40.9) (95% CI -0.6 to 50.6), budesonide 2000 micrograms (26.0) versus fluticasone 2000 micrograms (65.2) (95% CI 10.5 to 67.8). Individual serum cortisol levels at the two highest doses showed 15 of 24 patients below the normal limit of the reference range (150 nmol/l) for fluticasone and five of 24 for budesonide. Fluticasone propionate also caused greater ACTH suppression than budesonide (as % versus placebo): budesonide 1600 micrograms (12.0) versus fluticasone propionate 1500 micrograms (31.9) (95% CI 7.6 to 32.1), budesonide 2000 micrograms (13.5) versus fluticasone propionate 2000 micrograms (44.4) (95% CI 13.2 to 48.7). For overnight 10 hour urinary cortisol (nmol/10 hours) there was a difference between the lowest doses of the two drugs: budesonide 400 micrograms (37.2) versus fluticasone propionate 500 micrograms (19.9) (95% CI 6.9 to 27.8). CONCLUSIONS: Like budesonide the systemic bioactivity of fluticasone propionate is mainly due to lung vascular absorption. Fluticasone propionate exhibited at least twofold greater adrenal suppression than budesonide on a microgram equivalent basis in asthmatic patients.

Administration, Topical↗
PubMed1996

Lung bioavailability of generic and innovator salbutamol metered dose inhalers.

BACKGROUND: The aim of this study was to determine whether significant differences exist in lung bioavailability between generic (Salamol, Salbulin) and innovator (Ventolin) formulations of inhaled salbutamol given by metered dose inhalers. METHODS: Ten healthy volunteers of mean age 20.5 years with a forced expiratory volume in one second (FEV1) of 112.1% predicted were studied in a randomised double blind single dosing crossover study. Salbutamol, 1200 micrograms, was given with mouth rinsing and lung bioavailability was assessed by measuring plasma salbutamol levels and urine excretion of salbutamol. RESULTS: No differences were seen between innovator and generic salbutamol metered dose inhalers in plasma salbutamol levels, urinary salbutamol excretion, or extrapulmonary beta 2 activity. The maximum plasma salbutamol concentration (mean Cmax) and time to maximum concentration (median Tmax) were: Ventolin (2.93 ng/ml, 10 minutes), Salbulin (3.01 ng/ml, 10 minutes), Salamol (3.33 ng/ml, 10 minutes). The geometric mean ratio and 95% confidence interval for Cmax were: Salbulin/Ventolin 1.02 (0.69 to 1.41) and Salamol/Ventolin 1.13 (0.94 to 1.35). CONCLUSIONS: No differences are apparent between the two generic and innovator formulations of salbutamol metered dose inhaler in terms of lung bioavailability.

Adult↗
PubMed1996

Adrenal suppression with inhaled budesonide and fluticasone propionate given by large volume spacer to asthmatic children.

BACKGROUND: The aim of this study was to compare the systemic bioactivity of inhaled budesonide (B) and fluticasone propionate (F), each given by large volume spacer, on a microgram equivalent basis in asthmatic children. METHODS: Ten stable asthmatic children of mean age 11 years and forced expiratory volume in one second (FEV1) 81.6% predicted, who were receiving treatment with < or = 400 micrograms/day of inhaled corticosteroid, were studied in a placebo controlled single blind (investigator blind) randomised crossover design comparing single doses of inhaled budesonide and fluticasone propionate 400 micrograms, 800 micrograms, and 1250 micrograms. Doses were given at 20.00 hours with mouth rinsing and an overnight 12 hour urine sample was collected for estimation of free cortisol and creatinine excretion. RESULTS: The results of overnight 12 hour urinary cortisol output (nmol/12 hours) showed suppression with all doses of fluticasone propionate (as geometric means): F400 micrograms (11.99), F800 micrograms (6.49), F1250 micrograms (7.00) compared with placebo (24.43), whereas budesonide caused no suppression at any dose. A comparison of the drugs showed that there were differences at 800 micrograms and 1250 micrograms levels for urinary cortisol: B800 micrograms versus F800 micrograms (2.65-fold, 95% CI 1.26 to 5.58), B1250 micrograms versus F1250 micrograms (2.94-fold, 95% CI 1.67 to 5.15). The results for the cortisol/creatinine ratio were similar to that of urinary cortisol, with fluticasone causing suppression at all doses and with differences between the drugs at 800 micrograms and 1250 micrograms. CONCLUSIONS: Single doses of inhaled fluticasone produce greater systemic bioactivity than budesonide when given by large volume spacer on a microgram equivalent basis in asthmatic children. The systemic bioactivity of fluticasone, like budesonide, is due mainly to lung bioavailability.

Administration, Inhalation↗
PubMed1996

Decreased body-core temperature during acute hypoxemia in guinea pigs during postnatal maturation: a regulated thermoregulatory response.

In newborn mammals, hypoxemia produces a decrease in body-core temperature (Tbc), the mechanism of which is unknown. Experiments were therefore carried out to determine whether this decrease results from a regulated or a forced thermoregulatory response. Seven Hartley strain guinea pigs were studied on postnatal days 2, 5, 10, 15, and 26 following implantation of a biotelemetry transmitter into the peritoneal cavity on day 1 to measure Tbc. During each experiment, Tbc and selected ambient temperature were determined in a thermocline (15-40 degrees C gradient) during a control period of normoxemia, an experimental period of hypoxemia (produced by decreasing the fraction of inspired oxygen from 0.21 to 0.10), and a recovery period of normoxemia. We reasoned that no change or a decrease in selected ambient temperature while Tbc decreased during hypoxemia would indicate a regulated thermoregulatory response, whereas an increase in selected ambient temperature while Tbc decreased during hypoxemia would indicate a forced thermoregulatory response. Tbc decreased during hypoxemia at all ages; the response was accentuated on days 15 and 26 compared with day 2. Selected ambient temperature decreased during hypoxemia in the youngest animals but remained the same in the older animals. Our data provide evidence that postnatal maturation influences the thermoregulatory response to hypoxemia in guinea pigs and support the hypothesis that the decrease in Tbc during hypoxemia results from a regulated thermoregulatory response.

Acute Disease↗
PubMed1995

Overcoming a nucleosomal barrier to transcription.

We have studied the kinetics of transcription through a nucleosome core. RNA polymerase transcribes the first approximately 25 bp of nucleosomal DNA rapidly, but then hits a barrier and continues slowly to the nucleosomal dyad region. Here, the barrier disappears and the transcript is completed at a rapid rate, as if on free DNA, indicating that histone octamer transfer is completed as polymerase reaches the dyad. If DNA behind the polymerase is removed during transcription, the barrier does not appear until the polymerase has penetrated up to 15 bp farther into the nucleosome. On a longer template, the barrier is almost eliminated. We have shown previously that the octamer is transferred around the transcribing polymerase via an intermediate containing an intranucleosomal DNA loop. Our results exclude the possibility that polymerase has difficulty breaking histone-DNA contacts and suggest instead that polymerase pauses because it has difficulty transcribing DNA in the loop.

Base Sequence↗
PubMed1994

A histone octamer can step around a transcribing polymerase without leaving the template.

The mechanism by which nucleosome cores are displaced and re-formed during transcription in vitro has been investigated. A nucleosome core was assembled on a short linear DNA template (227 bp) containing an SP6 RNA polymerase promoter and a nucleosome-positioning sequence. Transcription induced the translocation of the nucleosome core over 75 or 80 bp to two positions at the other end of the template, blocking the promoter. At low rNTP concentrations, transfer occurred only on the same template molecule, even in the presence of large excesses of competitor DNA. On a longer template (262 bp), nucleosome core position after transcription depended on its position before transcription. The data suggest that the octamer transfers without dissociation from DNA and provide strong evidence for a translocation mechanism in which DNA ahead of the polymerase uncoils from the octamer as the DNA behind coils around it. In this way, the octamer steps around the transcribing polymerase.

Base Sequence↗
PubMed1994

Body-core temperature decreases during hypoxic hypoxia in Long-Evans and Brattleboro rats.

In newborn mammals, hypoxic hypoxia produces a regulated decrease in body-core temperature, the mechanism of which is unknown. Since plasma and cerebrospinal fluid levels of arginine vasopressin increase during hypoxemia and intracerebroventricular administration of arginine vasopressin decreases body-core temperature, it has been hypothesized that an increase in central arginine vasopressin may mediate this response. Experiments were therefore carried out to test the hypothesis that the body-core temperature response to hypoxic hypoxia would be different in Brattleboro rats (which lack arginine vasopressin containing cells in the central nervous system) compared with that observed in Long-Evans rats (which have arginine vasopressin containing cells in the central nervous system). Both mild (15% oxygen) and severe (10% oxygen) hypoxic hypoxia decreased body-core temperature in both strains of rats, the decrease actually being accentuated in the Brattleboro rats. Thus, our data do not support the hypothesis that an increase in central arginine vasopressin mediates the regulated decrease in body-core temperature during hypoxic hypoxia in rats.

Animals↗
PubMed1994

The costs of treating febrile neutropenia in patients with malignant blood disorders.

Retrospective data were collected over a 1-year period from the medical records of patients admitted to a district general hospital, either with febrile neutropenia or who developed this complication whilst receiving inpatient chemotherapy. Costs were calculated for inpatient stay, drug treatment and diagnostic tests. The median total costs for 46 episodes of febrile neutropenia were 2068.35 pounds and the median total cost per day was 139.41 pounds. Inpatient bed-days accounted for 57.8% of total costs, followed by drug treatment at 25.8% and diagnostic tests at 16.4%. The costs of blood products were excluded since they are frequently administered irrespective of the neutropenia. This study serves as a useful pointer to the expenditure in measurable antibiotic costs and investigations in patients with malignant blood disorders who develop febrile neutropenia.

Adult↗
PubMed1993

Effect of positive supercoiling on DNA compaction by nucleosome cores.

We have used the analytical ultracentrifuge to measure the ability of histone octamers to compact DNA as a function of DNA supercoiling. Plasmid DNA (3.25 kb) was prepared at various linking numbers (delta Lk), ranging from -35 to +8. Relaxed plasmid (delta Lk = 0) was the least compact. We reconstituted a fixed number of nucleosome cores (either 11 or 13) on these DNAs. The dependence of the frictional coefficient of delta Lk showed that the reconstitute with an initial number of negative supercoils equal to the number of nucleosome cores was the least compact, as expected if each nucleosome core formed requires the constraint of one negative supercoil, resulting in relaxed linker DNA. With DNAs containing an initial number of negative supercoils unequal to the number of nucleosome cores, reconstitutes contained either negative or positive unconstrained supercoils. Reconstitutes with the same number of unconstrained supercoils, whether positive or negative, have similar frictional coefficients and are, therefore, compacted to similar degrees. We conclude that nucleosome cores compact positively and negatively supercoiled DNA equally well. Thus, nucleosome cores formed on positively supercoiled DNA with a superhelical density as high as +0.07 are not significantly unfolded.

Animals↗
PubMed1993

Simple mixing technique for the preparation of blood samples of known oxygen saturation.

A mixing technique for the preparation of whole blood samples of known oxygen saturation is described. The technique, which uses basic equipment and a very simple procedure, is capable of accuracies better than +/- 2% across the full range of saturation and is extendable to use with other applications with only slight reductions in accuracy.

Anaerobiosis↗
PubMed1993

Novel monochromatic optical density meter.

A novel monochromatic optical density meter is described for use with radiographic films. The principles of the instrument are outlined together with a brief description of the construction of a prototype model. The calibration of the meter shows high accuracy (r = 0.9999) in the optical density range 0-1.5 OD when compared to standard neutral density filters.

Optics and Photonics↗
PubMed1993

Effects of pH and temperature on the scanning Soret oximeter.

A new optical measurement technique based on spectral scanning (the scanning Soret oximeter) has previously been described. The technique has now been tested under extremes of physiological pH and temperature, the effects of which are shown to be negligible.

Calibration↗
PubMed1992

Two related genes encoding extremely hydrophobic proteins suppress a lethal mutation in the yeast mitochondrial processing enhancing protein.

The processing enhancing protein of mitochondria (PEP) is an essential component that has been shown to participate in proteolytic removal of NH2-terminal signal peptides from precursor proteins imported into the mitochondrial matrix. Using a yeast strain bearing a PEP mutation that renders it temperature-sensitive, an approach of genetic suppression was taken in order to identify additional components that could be involved with protein import: high copy plasmids comprising a yeast genomic library were tested for ability to suppress the 37 degrees C growth defect. Two plasmids were isolated, pSMF1 and pSMF2, which suppressed the growth defect nearly as well as the cloned PEP gene itself. Sequence analysis of the rescuing genes predicted extremely hydrophobic proteins with sizes of 63 and 60 kDa, respectively. Remarkably, the predicted SMF1 and SMF2 products are 49% identical to each other overall. To test the requirement for SMF1 and SMF2, the chromosomal genes were disrupted. Individual disruption was without effect, but cells in which both genes were disrupted grew poorly. When mitochondria were prepared from the double disruption strain grown in a nonfermentable carbon source, they were morphologically normal but defective for translocation of radiolabeled precursor proteins. SMF1 protein was provisionally localized to the mitochondrial membranes using epitope tagging. We suggest that SMF1 and SMF2 are mitochondrial membrane proteins that influence PEP-dependent protein import, possibly at the step of protein translocation.

Amino Acid Sequence↗