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Biomedical subjects

C G Wilson

Publications and source records attributed to C G Wilson.

At least 19 recordsLinked to original sources
PubMed2002

Effect of chitosan on a periodontal pathogen Porphyromonas gingivalis.

Local delivery systems of antimicrobial agents for treatment of the periodontal diseases received considerable attention during the past decade due to the disadvantages of the systemic administration. An ideal formulation should exhibit ease of delivery, a good retention at the application site, and a controlled release of the drug. The application of bioadhesive gels provides a long stay in the oral cavity, adequate drug penetration, high efficacy and acceptability. In dentistry and oral medicine, various applications of chitosan, which is a bioadhesive polymer have been proposed due to its favorable properties such as biocompatibility and biodegradability. The aim of this study was to determine the antimicrobial activity of chitosan formulations either in gel or film form against a periodontal pathogen, Porphyromonas gingivalis. The viscosity, bioadhesive properties and antimicrobial activity of chitosans at different molecular weight and deacetylation degree were evaluated in the absence or presence of chlorhexidine gluconate (Chx), incorporated into the formulations at 0.1 and 0.2% concentrations. The flow property of the gels were found to be suitable for topical application on the oral mucosa and to syringe into the periodontal pocket. Bioadhesion of the gels and films examined ex-vivo using fresh porcine buccal mucosa showed that both the film and gel formulations exert bioadhesive properties and was not affected by incorporation of Chx. Chitosan is shown to have an antimicrobial activity against P. gingivalis and this was higher with high molecular weight chitosan. The combination of chitosan with Chx showed a higher activity when compared to that of Chx alone, which would provide Chx application at lower concentrations thus avoiding its unwanted side effects. Chitosan films and gels seem to be promising delivery systems for local therapy of periodontal diseases with its bioadhesive property and antimicrobial activity.

Anti-Bacterial Agents↗
PubMed2001

Transport of rare earth element-tagged soil particles in response to thunderstorm runoff.

The downslope transport of rare earth element-tagged soil particles remobilized during a spring thunderstorm was studied on both a natural prairie and an agricultural field in southwestern Iowa (U.S.A.). A technique was developed for tagging natural soils with the rare earth elements Eu, Tb, and Ho to approximately 1,000 ppm via coprecipitation with MnO2. Tagged material was replaced in target locations; surficial soil samples were collected following precipitation and runoff; and rare earth element concentrations were determined by inductively coupled plasma mass spectrometry. Diffusion and exponential models were applied to the concentration-distance data to determine particle transport distances. The results indicate that the concentration-distance data are well described by the diffusion model, butthe exponential model does not simulate the rapid drop-off in concentrations near the tagged source. Using the diffusion model, calculated particle transport distances at all hillside locations and at both the cultivated and natural prairie sites were short, ranging from 3 to 73 cm during this single runoff event. This study successfully demonstrates a new tool for studying soil erosion.

Agriculture↗
PubMed2001

The use of scintigraphy to demonstrate the rapid esophageal transit of the oval film-coated placebo risedronate tablet compared to a round uncoated placebo tablet when administered with minimal volumes of water.

As our population ages, and the consumption of pharmaceutical products rises, the incidence of solid oral dosage forms lodging in the esophagus is likely to increase and may be formulation dependent. The aim of this study was to compare the esophageal transit of the commercial film-coated risedronate tablet and a round uncoated tablet resembling the alendronate 10 mg tablet which is reported to cause esophagitis if ingested with little to no water. Water volumes of 30 ml and 50 ml were selected as these volumes can detect formulations prone to esophageal adhesion and a habits and practice study showed that these volumes are within the range preferred by women (7-385 ml). A total of 28 healthy postmenopausal women completed the four-way crossover scintigraphy study. For both volumes of water, the film-coated placebo risedronate tablet had a statistically significant faster esophageal transit time than the uncoated placebo tablet (P=0.002 for 30 ml water and P<0.001 for 50 ml water). Among those taking the round, flat, uncoated tablet, five subjects had esophageal stasis (transit >20 s) and in three subjects the tablet remained in the esophagus at the end of the 10-min imaging period. No stasis was observed for the oval film-coated placebo risedronate tablet. This study demonstrates that tablet size, shape and coating are pharmaceutical parameters which can be controlled to minimize esophageal contact of a dosage form with esophageal tissue.

Calcium Channel Blockers↗
PubMed2001

Direct perfusion measurements of cancellous bone anisotropic permeability.

More extensive characterization of trabecular connectivity and intertrabecular space will be instrumental in understanding disease states and designing engineered bone. This project presents an experimental protocol to define the directional dependence of transport properties as measured from healthy cancellous bone when considered as a biologic, porous medium. In the initial design phases, mature bovine bone was harvested from the femoral neck (n=6 cylinders) and distal condyle (n=4 cubes) regions and used for "proof of concept" experimentation. A power study on those results led to the presented work on 20 cubic samples (mean volume=4.09cm(3)) harvested from a single bovine distal femur. Anisotropic intrinsic permeabilities (k(i)) were quantified along the orthogonal anatomic axes (i=medial-lateral, anterior-posterior, and superior-inferior) from each individual cubic bone sample. Using direct perfusion measurements, permeability was calculated based upon Darcy's Law describing flow through porous media. The maximum mean value was associated with the superior-inferior orientation (4.65x10(-10)m(2)) in comparison with the mean anterior-posterior (4.52x10(-10)m(2)) and medial-lateral (2.33x10(-10)m(2)) direction values. The results demonstrate the anisotropic (p=0.0143) and heterogeneous (p=0.0002) nature of the tissue and encourage the ongoing quantification of parameters within the established poroelastic models.

Animals↗
PubMed2001

Oesophageal transit, disintegration and gastric emptying of a film-coated risedronate placebo tablet in gastro-oesophageal reflux disease and normal control subjects.

BACKGROUND: Risedronate sodium is a pyridinyl bisphosphonate, proven effective for the treatment and prevention of postmenopausal osteoporosis and glucocorticoid-induced osteoporosis and Paget's disease of the bone. AIM: To compare the oesophageal transit, disintegration and gastric emptying of the commercial film-coated risedronate tablet in subjects with gastro-oesophageal reflux disease (GERD) and normal control subjects. METHODS: A total of 30 subjects, 15 patients with GERD and 15 age- and sex-matched, normal control subjects, participated in a single-centre, open-label, comparative gamma scintigraphy study. The GERD subjects had active erosive oesophagitis within 4 weeks prior to dosing. RESULTS: The mean oesophageal transit (GERD, 4.4 s; controls, 3.1 s), mean disintegration (GERD, 21.8 min; controls, 19.2 min) and mean gastric emptying (GERD, 15.9 min; controls, 15.0 min) were similar in the two subject groups. The oesophageal transit is rapid and given the rapid disintegration and gastric emptying, oesophageal contact occurring via reflux of risedronate was unlikely since most, if not all, of the dosage form exited from the stomach within 30 min. CONCLUSIONS: The oval shape and film-coating on the commercial risedronate tablet promotes rapid oesophageal transit and minimizes oesophageal contact, even in the high-risk GERD population.

Aged↗
PubMed2001

A methodology for achieving high-speed rates for artificial conductance injection in electrically excitable biological cells.

We present a novel approach to implementing the dynamic-clamp protocol (Sharp et al., 1993), commonly used in neurophysiology and cardiac electrophysiology experiments. Our approach is based on real-time extensions to the Linux operating system. Conventional PC-based approaches have typically utilized single-cycle computational rates of 10 kHz or slower. In thispaper, we demonstrate reliable cycle-to-cycle rates as fast as 50 kHz. Our system, which we call model reference current injection (MRCI); pronounced merci is also capable of episodic logging of internal state variables and interactive manipulation of model parameters. The limiting factor in achieving high speeds was not processor speed or model complexity, but cycle jitter inherent in the CPU/motherboard performance. We demonstrate these high speeds and flexibility with two examples: 1) adding action-potential ionic currents to a mammalian neuron under whole-cell patch-clamp and 2) altering a cell's intrinsic dynamics via MRCI while simultaneously coupling it via artificial synapses to an internal computational model cell. These higher rates greatly extend the applicability of this technique to the study of fast electrophysiological currents such fast a currents and fast excitatory/inhibitory synapses.

Animals↗
PubMed2000

Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker-network model.

We review a new unified model of respiratory rhythm generation - the hybrid pacemaker-network model. This model represents a comprehensive synthesis of cellular and network mechanisms that can theoretically account for rhythm generation in different functional states, from the most reduced states in the neonatal nervous system in vitro to the intact adult system in vivo. The model incorporates a critical neuronal kernel consisting of a network of excitatory neurons with state-dependent, oscillatory bursting or pacemaker properties. This kernel, located in the pre-Bötzinger complex of the ventrolateral medulla, provides a rudimentary pacemaker network mechanism for generating an inspiratory rhythm, revealed predominately in functionally reduced states in vitro. In vivo the kernel is embedded in a larger network that interacts with the kernel via inhibitory synaptic connections that provide the dynamic control required for the evolution of the complete pattern of inspiratory and expiratory network activity. The resulting hybrid of cellular pacemaker and network properties functionally endows the system with multiple mechanisms of rhythm generation. New biophysically realistic mathematical models of the hybrid pacemaker-network have been developed that illustrate these concepts and provide a computational framework for investigating interactions of cellular and network processes that must be analyzed to understand rhythm generation.

Animals↗
PubMed2000

Limited exposure of the healthy distal colon to orally-dosed formulation is further exaggerated in active left-sided ulcerative colitis.

BACKGROUND: Active distal ulcerative colitis is often resistant to topically acting oral formulations. We speculated that the left side of the colon is underexposed to orally-dosed topical agents in patients with active distal colitis. METHODS: Twenty-two healthy volunteers (12 males, aged 22-47 years), and 10 patients (6 males, aged 33-73 years) with active left-sided ulcerative colitis ingested a Eudragit-coated gelatine capsule containing 111In-labelled amberlite resin on four successive days. Regional colonic distribution, transit times and percentage of daily dose resident were calculated from the average of four serial gamma camera images on the 4th day. RESULTS: (mean [95% CI]). When compared to controls, patients with colitis had significantly faster total colon transit (24.3 h [9.5-39.1] vs. 51.7 h [41.1-62.3]) as well as faster proximal colon transit (18.7 h [9.1-28.3] vs. 36.7 [28.5-44.9]), and distal colon transit (3.1 h [-0.5 to 6.8] vs. 15.0 h [10.5-19.5]), respectively (all P < 0.01). Material was asymmetrically distributed in health (proximal colon 69% [63-76] vs. distal colon 31% [24-37]). This asymmetry was more extreme in colitis, with corresponding values of 91% [85-96] vs. 9% [4-15]. As a result colitics had less material in the left-sided colon (9% [4-15] vs. 31% [24-37]), P < 0. 001. Colitics had a significantly lower percentage of the daily dose resident within the left side of the colon compared to controls (13% [-2 to 28] vs. 63% [44-81]), P < 0.01. CONCLUSIONS: Delayed release oral formulation is asymmetrically distributed within the colon in health. This asymmetry is exaggerated in active left-sided ulcerative colitis and, together with faster colonic transit, results in reduced exposure of the distal colon to orally-dosed topical agents.

Administration, Oral↗
PubMed1999

Dry powder dosing in liquid vehicles: ocular tolerance and scintigraphic evaluation of a perfluorocarbon suspension.

The ocular tolerance and precorneal disposition of 99mTc-labelled sterile carbon-perfluorodecalin (PFD) and carbon-aqueous suspensions were examined in a cohort of healthy volunteers. Formulations were prepared in PFD or saline using charcoal particles, radiolabelled with [99mTc]diethylenetriaminepentaacetic acid (DTPA) under GMP conditions. Colloidal silicon dioxide was used as a suspending agent. Ocular tolerance was examined following the instillation of each formulation to the eyes of 12 volunteers. The precorneal distribution of both formulations in man was monitored using gamma scintigraphy. Dynamic and static data acquisitions were taken over a period of 150 min after dosing. Carbon particulates suspended in PFD did not show any irritation to the eye. Administration of PFD formulation in man produced a significant increase in ocular retention over a saline formulation (mean residence time (MRT)=157+/-42 and 0.29+/-0.08 min, respectively, P=0.0001). Distribution of the carbon in man followed the same pattern as in a previous reported study in animals. The carbon deposited uniformly along the lid margin in the case of the PFD vehicle, whereas it agglomerated following dosing in the saline vehicle and was ejected from the eye. The novel non-aqueous vehicle system is able to significantly improve the ocular retention of charcoal particles in man and provides a unique distribution of the particles in the eye, which suggests a potential for the PFD system for the treatment of periocular diseases.

Adult↗
PubMed1999

Esophageal transit of risedronate cellulose-coated tablet and gelatin capsule formulations.

Risedronate sodium is an orally active antiresorptive agent and a member of the pyridinyl class of bisphosphonates. It has been approved for the treatment of Paget's disease of the bone and is under development as a chronic therapy for the treatment and prevention of osteoporosis. A novel cellulose film-coated tablet formulation was developed to optimize esophageal transit of this bisphosphonate. The aim of the present study was to compare the esophageal transit of the film-coated tablet formulation of risedronate with its original gelatin capsule dose form. A total of 25 elderly, healthy volunteers (mean 66 years), who were dysphagia-free, participated in this randomized cross-over study. On separate occasions, volunteers swallowed radiolabeled placebo formulations with 50 ml water. Dynamic images with participants in a sitting position were recorded for 10 min using a gamma camera. Scintigraphic imaging showed a delay in esophageal transit (greater than 15 s) in 28% of patients in the capsule group but in none of the tablet group (P<0.05). The mean transit times of the capsules and tablets were 23.8 and 3.3 s, respectively. Esophageal transit of film-coated tablets was faster than gelatin capsules, suggesting that film-coated tablets would be the appropriate formulation for all pivotal trials with risedronate and for subsequent commercialization.

Aged↗
PubMed1999

Temporal dependence of ectopeptidase expression in alveolar epithelial cell culture: implications for study of peptide absorption.

There is little data available regarding the extent of peptide metabolism encountered following inhalation to the lung. We have studied the activity of five ectopeptidases in primary rat alveolar epithelial cells, A549 cells and pulmonary macrophages. Peptidase activity was assayed in the plasma membrane fractions (PMF) of primary type II alveolar epithelial cells (ATII cells) after 2 days in culture and after 7 days in culture when they had formed monolayers of type I-like cells (ATI-like cells). Dipeptidyl peptidase IV (DPP) activity fell from 36.65 mU/mg protein to 16.29 mU/mg protein between day 2 and day 7 in culture, aminopeptidase N (AMN) activity increased from 16.16 mU/mg protein to 23.99 mU/mg protein, angiotensin-converting enzyme (ACE) activity was lost (4.29 mU/mg protein at day 2, not detected at day 7), and carboxypeptidase M (CPM) activity was acquired (not detected at day 2, 5.20 mU/mg protein at day 7). The profile of exopeptidase expression in A549 cells was similar to that of primary rat alveolar cells at day 7 in culture (DPP 24.24 mU/mg protein, AMN 47.74 mU/mg protein, CPM 4.28 mU/mg protein, ACE not detected). Macrophages expressed high levels of aminopeptidases (DPP 46.85 mU/mg protein, AMN 28.28 mU/mg protein) but carboxypeptidase activity was not detected. Low neutral endopeptidase 24.11 (NEP) activity was found in all cell types studied (0.96-2.41 mU/mg protein). The qualitative and quantitative changes in the peptidase activity of primary cultured rat alveolar cells between day 2 and day 7 in culture has implications for the use of alveolar cell monolayers as drug absorption models to investigate peptide absorption from the lung. Ectopeptidase activity in cultured alveolar cells can be used to infer the peptide-metabolising capacity of the surface of the alveolar epithelium. The aminopeptidase activity in particular, if representative of enzyme activity in vivo, would offer a significant metabolic barrier to systemic delivery of peptides via the lung.

Absorption↗
PubMed1999

Stool water content and colonic drug absorption: contrasting effects of lactulose and codeine.

PURPOSE: By varying stool water content using lactulose and codeine, we investigated the influence of luminal water content on the absorption of quinine, a transcellular probe, and 51Cr-EDTA, a paracellular probe, from the distal gut. METHODS: Sixteen volunteers entered a three-way cross-over trial in which absorption of probe markers from a timed-release delivery system was determined following treatment with lactulose 20 mls tds (increasing water content), or codeine 30 gms qds (decreasing water content), and compared with control untreated values. Stool water content was assessed by freeze drying stool samples. Site of release was determined by gamma scintigraphy, and absorption was measured by plasma levels and urinary recovery of the marker probes. RESULTS: Lactulose accelerated ascending colon transit (3.7 +/- 0.8 vs 4.5 +/- 1.4 hrs, p < 0.05), increased stool water content (75 +/- 2 vs 71 +/- 2%, p < 0.01), caused greater dispersion of released material (dispersion score 3.4 +/- 0.3 vs 1.8 +/- 0.2, p < 0.01), and enhanced absorption of the transcellular probe quinine (4.66 +/- 0.78 vs 3.02 +/- 0.63%, p < 0.05) compared to control. Conversely codeine slowed ascending colon transit (8.9 +/- 1.8 hrs), reduced stool water content (61 +/- 2 vs 71.2%, p < 0.05), and tended to diminish absorption (2.60 +/- 0.77 vs 3.02 +/- 0.63%, p = 0.20). Within the ascending colon specifically, there was a significant trend for treatments increasing luminal water content to enhance quinine absorption (medians: codeine = 1.2%, [n = 81 < control = 2.3%, [n = 5] < lactulose = 3.2%, [n = 71, p < 0.01). Delivery site also had an important influence on absorption, with more distal release resulting in less absorption in the control arm (medians: small intestine = 4.4% [n = 5] > ascending colon = 2.3% [n = 5] > transverse colon = 1.5% [n = 6], p < 0.005). CONCLUSIONS: Lactulose accelerates transit, increases stool water content, and enhances drug absorption from the distal gut whilst codeine slows transit, decreases stool water content, and tends to diminish absorption, compared to controls. We conclude that water content may be an important determinant in colonic drug absorption.

Adult↗
PubMed1999

Regional differences in quinine absorption from the undisturbed human colon assessed using a timed release delivery system.

PURPOSE: To investigate the regional absorption characteristics of the distal gut using two markers of permeability, quinine (a transcellular probe) and 51CrEDTA (a paracellular probe). METHODS: The permeability markers were delivered to the undisturbed gastrointestinal tract in 39 healthy volunteers using an oral timed-release delivery vehicle which allowed pulsed release within a particular site of the gut. Site of release was identified using gamma scintigraphy. Absorption of quinine and 51CrEDTA was assessed by measuring the percent excretion in the urine using HPLC and gamma counting respectively. Serial plasma samples allowed time-concentration curves for quinine to be plotted. RESULTS: There was a significant trend for diminished absorption with more distal delivery of the transcellular probe, quinine, which was: 6.26 +/- 0.87% (small intestine, n = 10); 4.65 +/- 0.93% (ascending colon, n = 16); and 2.59 +/- 0.52% (transverse colon, n = 10) of the ingested dose excreted respectively (p < 0.001). No such gradient was seen with the paracellular marker, 51CrEDTA. CONCLUSIONS: These results suggest that delayed release formulations should aim for release in the distal small bowel and proximal colon if absorption is to be maximised. Absorption by the transcellular route diminishes in the more distal colon, a fact which has implications for delayed or sustained release formulations.

Adult↗
PubMed1999

Night-time quiescence and morning activation in the human colon: effect on transit of dispersed and large single unit formulations.

OBJECTIVES: Controlling the delivery of drugs to different regions of the colon remains an elusive goal. The aim of this study was to define the diurnal variation in colonic transit and show how this influences the colonic distribution and residence time of different formulations given either in the morning or evening. METHODS: Colonic transit of small particulates and a large capsule was measured during nocturnal sleep and daytime wakefulness. Eighteen healthy volunteers participated in a randomised crossover study. 111In-labelled resin (150-300 microm) and a large 99mTc-labelled non-disintegrating capsule (22 x 8 mm) were swallowed at either 0800h or 1700h. MAIN OUTCOME MEASURES: The geometric centre of isotope (range 1-9) was calculated from serial scintiscans allowing comparison of overnight and daytime transit. RESULTS: Transit of resin was delayed in the overnight compared to daytime 8 h periods (change in geometric centres (GCs), mean +/- SEM, 0.59 +/- 0.14 vs 1.46 +/- 0.39 respectively, P < 0.02). Maximal resin movement occurred immediately after awakening, prior to breakfast, in 9/18 studies (P < 0.05). The capsule was more distal than the resin at the end of the study 15 h after dosing (P < 0.001). There was marked inter-individual variability in distribution of both resin and capsule at 15 h, the range of GCs being 2.8-9 and 2.2-9, respectively. CONCLUSION: Sleep delays colonic transit and large capsules travel faster than dispersed small particles. However, substantial inter-individual variability in transit makes targeting specific regions of the human colon unreliable with either dispersed or single unit formulations.

Administration, Rectal↗
PubMed1998

Mebeverine decreases mass movements and stool frequency in lactulose-induced diarrhoea.

BACKGROUND: In spite of its frequent use in the treatment of irritable bowel disease little is known about mebeverine's mode of action in man. AIM: To examine mebeverine's effect on transit though the gut during lactulose-induced diarrhoea. METHODS: Nine healthy volunteers undertook a two-way randomized crossover study. Diarrhoea was induced using lactulose pre-treatment (20 m t.d.s., 4 days) and subjects received either mebeverine (135 mg t.d.s.) or no treatment. Transit of two enteric-coated capsules containing radiolabelled 8.4 mm tablets and 180-250 microM ion exchange resin were followed using gamma scintigraphy. Stool frequency and symptoms were assessed by diary cards. RESULTS: Mebeverine reduced mean daily stool frequency associated with lactulose ingestion from a median of 2.25 (interquartile range (IQR) 1.75-2.75) to 1.5 (IQR 1.25-2.25) movements. Mebeverine significantly reduced the number of mass movements observed in the colon during the 11 h of the study from 2 (2-2) to 1 (1-2), and the number of retrograde movements from 1 (0-2) to 0 (0-0) (P < 0.05). Mebeverine did not significantly alter the gastric emptying rate of the intact capsule (2.9 (1.9-3.2) to 2.8 (2.6-4.0) h) however it induced a small but significant acceleration in small intestinal transit of the capsule (1.6 (0.8-2.0) h to 1.0 (0.52-1.32) h, P=0.02). CONCLUSION: Mebeverine reduces the diarrhoeal effect of lactulose by decreasing the mass movements induced in the ascending colon. This effect may contribute to its clinical effect in irritable bowel syndrome.

Adolescent↗