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Biomedical subjects

D Webber

Publications and source records attributed to D Webber.

At least 19 recordsLinked to original sources
PubMed2002

Cilomilast (Ariflo) does not potentiate the cardiovascular effects of inhaled salbutamol.

We investigated the safety and potential pharmacodynamic interactions arising from the co-administration of inhaled beta(2)-agonist salbutamol and cilomilast (Ariflo), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease and asthma. This was a randomised, double-blind, placebo-controlled, multiple-dose, three-period crossover study involving non-smoking volunteers between the ages of 18 and 50 years. Volunteers were randomly assigned to receive cilomilast plus nebulised salbutamol, cilomilast plus nebulised placebo or placebo plus nebulised salbutamol. Each volunteer received cilomilast (10 mg twice daily) or placebo for 5 days. On day 5, the morning dose of cilomilast or placebo was followed 1 h later with a single dose of nebulised salbutamol (2.5 mg) or placebo. Primary variables were average change from pre- to 1.5 h post-salbutamol or placebo inhalation in blood pressure, pulse rate, 12-lead ECG and total number of heartbeats measured by 4-h Holter ECG. Thirteen volunteers completed the study. There was no evidence of a clinically important pharmacodynamic interaction between cilomilast and salbutamol in healthy volunteers. Both agents were well tolerated. In conclusion, the pharmacodynamic effects associated with salbutamol inhalation were unaffected by co-administration of cilomilast.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Perspectives on stimulating industrial research and development for neglected infectious diseases.

This paper summarizes recent thinking on stimulating industrial research and development (R&D) for neglected infectious diseases and argues that it is critical to enlarge the value of the market for medicines and vaccines through, for example, global purchase funds. The most important economic barriers to R&D are that the commercial markets are small and that individual purchasing power is severely limited, even though the number of patients may be very large. Since R&D costs for all diseases are high, this means that returns will not cover investments. Various mechanisms have been proposed to address this economic imbalance (accepting that other barriers will also need to be considered). Economic devices which reduce the costs of R&D--push factors--are useful, but our review suggests that high costs do not explain the shortfall in R&D. Economic devices which address the lack of viable markets have been termed pull factors and are designed to create or secure a market, thereby improving the likelihood of a return on investments. One pull mechanism is the commitment in advance to purchase a product that meets specified criteria, if invented. The purchase-precommitment approach has a number of attractive features. For example, it only rewards successful outputs rather than supporting research that may not succeed. Pull programmes effectively mimic the market and lead companies to favour lines of attack that they believe will lead to marketable products. Overall, a combination of push and pull mechanisms is likely to represent an attractive approach. This could combine, for example, increased funding for public laboratories, public-private partnerships in R&D, purchases of underutilized existing products, and a precommitment to purchase new drugs and vaccines when developed.

Communicable Diseases↗
PubMed2001

Enhancing recall of information from a patient education booklet: a trial using cardiomyopathy patients.

A quasi-experimental trial was conducted to compare the effect on information recall of: (a) the use of adjunct questions (AQ) in printed materials; and (b) a procedure (the 5Rs) for integrating printed patient education materials into face-to-face teaching. A total of 51 patients with severe left ventricular failure (cardiomyopathy) was assigned to one of three groups (n=17). Each group worked with a purpose-prepared booklet, the first in association with the 5Rs procedure; the second group with a version of the booklet containing adjunct questions; and the third with a text only version of the booklet. Recall of information from the booklet was measured using a checklist scored on the basis of responses secured in a standardised interview. Improved recall was associated with both the adjunct questions and the 5Rs procedure, with the latter achieving a substantially superior outcome. The practical implications of these findings are presented and directions for further research indicated.

Analysis of Variance↗
PubMed2001

Easy-to-implement Bayesian methods for dose-escalation studies in healthy volunteers.

In phase I clinical trials, experimental drugs are administered to healthy volunteers in order to establish their safety and to explore the relationship between the dose taken and the concentration found in plasma. Each volunteer receives a series of increasing single doses. In this paper a Bayesian decision procedure is developed for choosing the doses to give in the next round of the study, taking into account both prior information and the responses observed so far. The procedure seeks the optimal doses for learning about the dose-concentration relationship, subject to a constraint which reduces the risk of administering dangerously high doses. Individual volunteers receive more than one dose, and the pharmacokinetic responses observed are, after logarithmic transformation, treated as approximately normally distributed. Thus data analysis can be achieved by fitting linear mixed models. By expressing prior information as 'pseudo-data', and by maximizing over posterior distributions rather than taking expectations, a procedure which can be implemented using standard mixed model software is derived. Comparisons are made with existing approaches to the conduct of these studies, and the new method is illustrated using real and simulated data.To whom correspondence should be addressed.

Journal Article↗
PubMed2001

Bioavailability of the oral selective phosphodiesterase 4 inhibitor cilomilast.

STUDY OBJECTIVE: To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers. SETTING: Clinical pharmacology unit. DESIGN: Five prospective pharmacokinetic studies: one single-blind, dose-escalating, placebo-controlled trial; four open-label, randomized studies. SUBJECTS: Ninety-six healthy adult volunteers who were nonsmokers. INTERVENTION: In the first study, four subjects received intravenous cilomilast 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomilast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a total of 76 subjects were given single oral 15-mg doses; one study compared its effects in fed versus fasted subjects, one looked for differences of morning versus evening dosing, and one examined coadministration with aluminum hydroxide-magnesium hydroxide. MEASUREMENTS AND MAIN RESULTS: After intravenous administration of cilomilast, plasma concentrations increased in an approximately dose-proportional manner; the half-life, approximately 6.5 hours, was dose independent. Cilomilast clearance and volume of distribution were small. After oral dosing, the absolute bioavailability was consistently close to 100%. Absorption was slower in fed subjects than in fasted (median 2-hr delay in time to reach maximum plasma concentration, average 39% reduction in maximum plasma concentration), but the area under the concentration-time curve from time zero to infinity (systemic availability) was unaffected. Pharmacokinetic parameters were not influenced by time of dosing or coadministration of antacid. CONCLUSION: The absolute bioavailability of oral cilomilast was 100%; it was not adversely affected by time of dosing or coadministration with food or antacid.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Surgical confirmation of ProstaScint abnormalities in two patients with high risk prostate cancer.

We describe our initial experience using ProstaScint scanning in addition to conventional imaging modalities for staging of high risk prostate cancer. Using our protocol, ProstaScint images detected abnormalities in pelvic lymph nodes not seen on CT scan or magnetic resonance imaging (MRI) in two patients. Subsequent surgical pelvic lymphadenectomy confirmed these abnormalities. Further patients will be accrued on this study to estimate the sensitivity and specificity of ProstaScint scanning.

Aged↗
PubMed2000

Pilot study of the tolerability and toxicity of intravesical valrubicin immediately after transurethral resection of superficial bladder cancer.

OBJECTIVES: To assess in a pilot study the safety, tolerability, and technical feasibility of administering intravesical valrubicin immediately after transurethral resection of bladder tumors (TURBT) in patients with superficial bladder cancer and to evaluate the optimal dose of valrubicin and its systemic absorption. METHODS: Twenty-two patients with recurrent or newly diagnosed Stage Ta or T1 transitional cell tumors received a single dose of 400 mg, 600 mg, or 800 mg of intravesical valrubicin immediately after TURBT. Four patients thought to be at high risk of recurrence were followed up with five additional doses of 800 mg valrubicin, given weekly. RESULTS: The use of valrubicin after TURBT was generally well tolerated. Little evidence was found to suggest a direct relationship among the dose of valrubicin, the time between the end of TURBT and drug instillation, and the occurrence of most bladder symptoms. The most commonly reported adverse events included dysuria (77%), hematuria (59%), and urgency/frequency (23%). Pharmacokinetic analyses revealed that the mean systemic exposure to valrubicin and its metabolites depended on the extent of the TURBT and the damage to the bladder wall. CONCLUSIONS: The results of this study indicated that administration of valrubicin immediately after TURBT is feasible.

Administration, Intravesical↗
PubMed1999

A novel Bayesian decision procedure for early-phase dose-finding studies.

Phase I first-in-man studies in normal, healthy volunteers are performed to define a maximum safe dose and to identify a range of acceptable doses for later drug development studies in patients. Analysis of pharmacokinetic and pharmacodynamic data using mixed-effects modeling can be used to fit an overall dose-response relationship. By expressing prior information as pseudodata, the same methodology can be used to perform a Bayesian analysis and to determine posterior modal estimates for the model parameters. Decision theory can then be applied to maximize a chosen gain function, utilizing real-time data capture for choosing safe doses in a way that will provide more informative responses, thus accelerating study completion. The methodology is introduced elsewhere (1). The purpose of this paper is to describe software currently in development and to illustrate the method using an example from a recent study.

Area Under Curve↗
PubMed1998

A double blind placebo controlled study to determine the effects of intermittent cyclical etidronate on bone mineral density in patients on long-term oral corticosteroid treatment.

BACKGROUND: A double blind, placebo controlled study was undertaken to determine the effects of 104 weeks of intermittent cyclical etidronate therapy on bone mineral density (BMD) in patients undergoing long-term oral corticosteroid therapy. METHODS: Forty nine patients of mean age 59 years on long-term (> 6 months) corticosteroid treatment were randomised to receive either 400 mg/day etidronate or placebo for 14 days followed in both groups by calcium (equivalent to 97 mg elemental Ca/day) with vitamin D (400 IU) for 76 days. The cycle was repeated a total of eight times over a period of two years. Dual energy x ray absorptiometry (DEXA) measurements of the lumbar spine and hip BMD and biochemical bone marker analyses were performed at baseline and every six months. RESULTS: Twenty six patients (10 men) received cyclical etidronate and 23 (nine men) received placebo. The mean (SD) dose of corticosteroid (prednisone or equivalent) at baseline in the etidronate group was 8 (4) mg/day and in the placebo group was 7 (4) mg/day. Most of the patients (43%) suffered from asthma. Forty one patients completed the study (22 in the etidronate group and 19 in the placebo group). All had a low BMD at entry and with treatment a significant difference was observed between groups in the mean (SE) percentage change from baseline in lumbar spine BMD at week 104 of 4.5 (1.65)% (p = 0.007) with a 95% confidence interval (CI) of 1.12 to 7.87%. No clinically or statistically significant treatment differences were observed at the hip or with bone markers. The incidence of adverse events was similar in the two groups. CONCLUSIONS: The results show that intermittent cyclical etidronate therapy with calcium and vitamin D supplementation significantly increases lumbar spine BMD in patients with osteoporosis resulting from long-term treatment with corticosteroids.

Aged↗
PubMed1995

Osteoclast 121F antigen expression during osteoblast conditioned medium induction of osteoclast-like cells in vitro: relationship to calcitonin responsiveness, tartrate resistant acid phosphatase levels, and bone resorptive activity.

Osteoclast differentiation from hematopoietic precursors into multinucleated cells uniquely capable of removing the organic and inorganic components of bone matrix occurs in multistep process, during which osteoclasts acquire the specialized characteristics necessary for bone resorptive activity and physiological regulation. Among those traits is a novel plasma membrane glycoprotein, reactive with the anti-osteoclast monoclonal antibody 121F, which is expressed during the course of osteoclast differentiation, shares structural and functional homologies with Mn2+/Fe2+ superoxide dismutase, and has been hypothesized to protect the osteoclast from the damaging effects of superoxide radicals generated during active bone resorption. We have reported previously that the expression of this membrane antigen is induced on multinucleated giant cells when the prefusion marrow mononuclear cells are cultured in conditioned medium from avian calvaria. The studies reported here were designed to investigate the relationship between expression of the 121F antibody-reactive osteoclast membrane antigen and tartrate resistant acid phosphatase levels, bone resorptive activity, calcitonin responsiveness, and ultrastructural features of avian bone marrow-derived multinucleated giant cells formed either in the presence or absence of diffusible osteoblast secreted factors. Parallel analyses of in vivo formed osteoclasts isolated from the same animals were performed for direct comparisons. In this report we demonstrate: (1) that the 121F monoclonal antibody-reactive osteoclast membrane antigen is stably induced in giant cells by soluble osteoblast-derived factors in a species nonrestricted but concentration- and temporal-dependent manner; (2) that osteoblast-mediated antigen induction is reflected in both increased numbers of cells and elevated expression of individual cells that are reactive with the 121F antibody, as determined by ELISA and histomorphometry; (3) that osteoblast conditioned medium, in addition to inducing this antigen in bone marrow cells, also elevates other defining osteoclast characteristics in these avian giant cells including their TRAP activity, cell retraction from the bone surface in response to calcitonin, bone resorptive function, and expression of a series of additional osteoclast antigenic markers; and (4) that secreted osteoblast products alone do not raise the levels of these traits for in vitro formed marrow giant cells to the extent associated with in vivo formed osteoclasts. Therefore, osteoblast soluble factors alone appear unable to promote the full differentiation of bone marrow cells in vitro into mature bone-resorbing osteoclasts.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid Phosphatase↗
PubMed1995

Physiology and behaviour of free-swimming Atlantic cod (Gadus morhua) facing fluctuating temperature conditions

Atlantic cod (Gadus morhua L.), acclimated to 5 °C, were equipped with ultrasonic transmitters which allowed the continuous monitoring of their vertical movements and heart rate. Fish were then placed in a 125 m3 tower tank in which the various thermal conditions they encounter in their natural environment were reproduced. Physiological and behavioural responses of cod were followed in parallel to the induced environmental changes. The experimental conditions studied in the tower tank were also reproduced in a swimming respirometer, where oxygen consumption and heart rate could be monitored within the activity range of a free-swimming animal. In a homogeneous water column, a rise in temperature induced marked increases in fish swimming activity, heart rate and heart beat-to-beat variability. In a thermally stratified environment, voluntary activity also increased when the thermal structure of the water column was altered, though no temperature-dependent changes in heart rate were observed. In this case, fish avoided the new temperature conditions, exhibiting distinct thermoregulatory behaviour. Stratification of the water column also prompted daily cyclic changes in fish distribution, animals tending to be in deeper and colder water layers during the day and in shallower and warmer layers at night. Respirometry experiments revealed that the thermoregulatory behaviour observed in free-ranging fish was probably driven by the energetic expedient of maintaining the physiological status quo ­ i.e. avoiding bioenergically costly reacclimation processes. Indeed, acute temperature increases or decreases of 2.5 °C led to marked differences in oxygen consumption, with metabolic rate changes of 15 and 30 %, respectively. The persistent linear relationship between heart rate and oxygen consumption allowed us to estimate, from the heart rate recorded in free-swimming fish, the entire range of metabolic responses that cod underwent voluntarily while experiencing a thermally stratified water column. The most profound metabolic effect, however, was observed with feeding, when oxygen consumption increased by as much as 80 %, resulting in an estimated 90 % reduction in their subsequent scope for activity.

Journal Article↗
PubMed1995

Physiology and behaviour of free-swimming Atlantic cod (Gadus morhua) facing fluctuating salinity and oxygenation conditions

1. Atlantic cod (Gadus morhua L.) acclimated to a temperature of 5 &deg;C and 30 salinity were equipped with ultrasonic transmitters which allowed continuous monitoring of their heart rate and their position in the water column. Fish were placed in a 125 m3 tower tank which permitted various environmentally relevant modifications of the salinity and oxygenation conditions. Cod physiological and behavioural responses were followed in parallel to the environmental manipulations. Some of the experimental conditions studied in the tower tank were also reproduced in a swimming respirometer where fish oxygen consumption and heart rate were monitored at various levels of activity. 2. Lowering salinity from 30 to 26 did not change resting oxygen consumption, but increased active oxygen consumption. 3. Lowering salinity from 30 to 26 increased heart rate over the whole range of swimming speeds except at maximum speed. 4. Lowering oxygen tension to 9 kPa decreased oxygen consumption over the whole range of swimming speeds and decreased resting heart rate. 5. Low salinity did not significantly affect the relationship between heart rate and oxygen consumption. 6. Low oxygen levels decreased the oxygen transported per heart beat. 7. In the tower tank, bursts of activity were associated with tachycardias. 8. In uniform conditions, fish swam more deeply during the day than at night. 9. After an exploratory period of approximately 6 h, fish chose to remain in a low-salinity upper layer of the tank. Thereafter, high salinities were avoided. Fish tended to select low salinities if a choice was provided. 10. Fish generally avoided zones of low oxygen (<9 kPa) but continued voluntarily to enter regions with values as low as 3.0 kPa for short excursions or if food was offered.

Journal Article↗
PubMed1994

The effect of varying type and volume of sedimenting agents on leukocyte harvesting and labelling in sickle cell patients.

Leukocyte labelling in patients with sickle cell anaemia has been reported as difficult if not impossible due to the slow erythrocyte sedimentation rate (ESR) in these patients. This study investigated standard sedimentation methods in patients with sickle cell disease (n = 16) and compared the results obtained with those following changes in the amount and type of sedimenting agent used. Labelling with either 111In-oxine or 99Tcm-exametazime was attempted in only five patients. Replacement of the commonly used 6% Hetastarch (Hespan) with Dextran or Haemaccel did not improve leukocyte harvesting, even when the proportions used of these agents were increased. In most cases where standard procedures for leukocyte collection did not lead to harvesting of viable samples, it was possible to obtain adequate leukocyte labelling in the majority of sickle cell patients using a minor modification of standard techniques. In this group of patients a ratio of 8 ml of Hespan to 16 ml of blood should be used for cell separation. If this fails then donor cells, anti-granulocyte antibody labelling or HIG should be considered.

Anemia, Sickle Cell↗
PubMed1994

The farmers' market coupon program for low-income elders.

The Massachusetts Farmers' Market Coupon Program provides coupons to low-income elders redeemable for fresh produce at farmers' markets. The program was conceived to create new direct marketing opportunities for small farmers, while at the same time introducing people at nutritional risk to farmers' markets. This article reports on the results of an evaluation of the program by participating elders and draws conclusions regarding program successes based on the data.

Aged↗