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Biomedical subjects

C Washington

Publications and source records attributed to C Washington.

At least 19 recordsLinked to original sources
PubMed2004

Partition of antimicrobial additives in an intravenous emulsion and their effect on emulsion physical stability.

A number of antimicrobial agents are potentially applicable to the preservation of small-volume parenteral emulsions. However, the physical stability of these emulsions is of paramount importance in ensuring their safety, and it is possible that antimicrobial additives could reduce the emulsion stability by a number of mechanisms. We have studied the effects of several antimicrobial agents on the physical stability of Diprivan, an intravenous anaesthetic emulsion. A particular problem is that many antimicrobial additives require an acidic pH in order to be effective (e.g. sodium benzoate, sodium metabisulphite) and the emulsion surface potential is insufficient to stabilize the emulsion to coalescence under these conditions. In addition several antimicrobial agents (e.g. methyl paraben and benzoic acid) partition into the oil phase of the emulsion, requiring the use of increased concentrations to remain effective. We describe an assay technique to quantify the oil partition, liposomal partition, and droplet surface adsorption of the additives. This illustrates that significantly more additive is partitioned out of the water phase than might be predicted from simple oil/water partition experiments.

Anti-Infective Agents↗
PubMed2001

Physical properties and stability of two emulsion formulations of propofol.

We have compared the physical properties of two commercial emulsion formulations of the intravenous anaesthetic propofol, (Diprivan, AstraZeneca, and Propofol Intravenous Emulsion, Gensia Sicor Pharmaceuticals) which appear to differ primarily in the additive content and formulation pH. Diprivan contains disodium edetate and has a pH of 7-8.5, while the Gensia product contains sodium metabisulphite and is formulated to a pH of 4.5-6.4. The average zeta potential of Diprivan at pH 8 was -50 mV while that of the Gensia product at pH 4-5 was -40 mV. This information suggests that the physical stability of Propofol Intravenous Emulsion should be lower than that of Diprivan. Three random batches of both products were subjected to a range of stability tests, including shaking, thermal cycling, and freeze-thaw cycling, and the emulsion droplet size distribution was then assessed by dynamic light scattering, light diffraction, and electrical and optical zone sensing. Both emulsions initially showed narrow submicrometre particle size distributions. An increased level of droplets larger than 5 microm could be detected in Propofol Intravenous Emulsion after as little as 4 h shaking (300 strokes/min at room temperature) and visible free oil could be detected after 8-12 h shaking. In contrast, Diprivan showed no increase in the large droplet count after shaking for times up to 16 h. A similar difference in the emulsions was found after one freeze-thaw cycle, with Propofol Intravenous Emulsion exhibiting extensive coalescence, while that of Diprivan was at the limits of detection. We conclude that these two products have different physical stability characteristics, and that this may in part be due to the reduced zeta potential in Propofol Intravenous Emulsion compared to that of Diprivan.

Anesthetics, Intravenous↗
PubMed2001

High-resolution chromosome 3p allelotyping of breast carcinomas and precursor lesions demonstrates frequent loss of heterozygosity and a discontinuous pattern of allele loss.

We performed high-resolution allelotyping for loss of heterozygosity (LOH) analysis on microdissected samples from 45 primary breast cancers, 47 mammary preneoplastic epithelial foci, and 18 breast cancer cell lines, using a panel of 27 polymorphic chromosome 3p markers. Allele loss in some regions of chromosome 3p was detected in 39 of 45 (87%) primary breast tumors. The 3p21.3 region had the highest frequency of LOH (69%), followed by 3p22-24 (61%), 3p21.2-21.3 (58%), 3p25 (48%), 3p14.2 (45%), 3p14.3 (41%), and 3p12 (35%). Analysis of all of the data revealed at least nine discrete intervals showing frequent allele loss: D3S1511-D3S1284 (U2020/DUTT1 region centered on D3S1274 with a homozygous deletion), D3S1300-D3S1234 [fragile histidine triad (FHIT)/FRA3B region centered on D3S1300 with a homozygous deletion], D3S1076-D3S1573, D3S4624/Luca2.1-D3S4597/P1.5, D3S1478-D3S1029, D3S1029 (with a homozygous deletion), D3S1612-D3S1537, D3S1293-D3S1597, and D3S1597-telomere; it is more than likely that additional localized regions of LOH not examined in this study also exist on chromosome 3p. In multiple cases, there was discontinuous allele loss at several 3p sites in the same tumor. Twenty-one of 47 (45%) preneoplastic lesions demonstrated 3p LOH, including 12 of 13 (92%) ductal carcinoma in situ, 2 of 7 (29%) apocrine metaplasia, and 7 of 25 (28%) usual epithelial hyperplasia. The 3p21.3 region had the highest frequency of LOH in preneoplastic breast epithelium (36%), followed by 3p21.2-21.3 (20%), 3p14.2/FHIT region (11%), 3p25 (10%), and 3p22-24 (5%). In 39 3p loci showing LOH in both the tumor and accompanying preneoplasia, 34 (87%) showed loss of the same parental allele (P = 1.2 x 10(-6), cumulative binomial test). In addition, when 21 preneoplastic samples showing LOH were compared to their accompanying cancers, 67% were clonally related, 20% were potentially clonally related but were divergent, and 13% were clonally unrelated. Overall this demonstrated the high likelihood of clonal relatedness of the preneoplastic foci to the tumors. We conclude that: chromosome 3p allele loss is a common event in breast carcinoma pathogenesis; involves multiple, localized sites that often show discontinuous LOH with intervening markers retaining heterozygosity; and is seen in early preneoplastic stages, which demonstrate clonal relatedness to the invasive cancer.

Adult↗
PubMed2000

An investigation into the efficacy of the pectin based anti-reflux formulation-Aflurax.

The properties of the new pectin-based anti-reflux agent Aflurax (Ferrosan) were studied in vitro and in vivo. Aflurax had a significantly higher in vitro raft strength than the placebo which was matched to the active except for the pectin (4.66+/-2.10 and 0. 22+/-0.04 g, respectively). In the modified Rossett and Rice test, the pectin raft remained above pH 3 for 130 min, whereas the pH in the acid phase remained unchanged. A modification to the stirring speed of the Rossett and Rice test was required to obtain a neutralisation profile for the placebo. The neutralisation profiles for the Aflurax and placebo were the same since both contained 5 mEq of base per tablet. In the in vivo study, subjects were randomly assigned to two groups, which either received radiolabelled food and unlabelled formulation, or unlabelled food and radiolabelled formulations. A pH probe was passed naso-gastrically and placed 5 cm from the cardia, and a small gamma detector was placed on the chest wall, coincident with the pH probe. The subjects received the test meal after an overnight fast. The pectin formulation or placebo was administered 30 min later. Each part of the study was performed as a single-blind two-way cross over with the active versus placebo. The reflux of radiolabel and acid was monitored for three hours postprandially. Aflurax reduced the H(+) concentration (total refluxed hydrogen ion index for Aflurax=3.5 x 10(3)+/-2.1 x 10(3), placebo=29 x 10(3)+/-16 x 10(3)) and amount of radiolabelled food reaching the oesophagus (total refluxed count index of food in counts x 1000 min(-1) Aflurax=19.2+/-2.3, placebo=525+/-423). The mean time for which the oesophageal pH fell below pH 4 was 2.58+/-1. 0 and 0.86+/-0.4 minutes for the placebo and Aflurax groups, respectively. The total amount of radiolabelled formulation which reached the oesophagus was 1000+/-660 for the placebo and 621+/-580 for the Aflurax.

Adolescent↗
PubMed2000

Controlled release of macromolecules from PLA microspheres: using porous structure topology.

Release of hydrophilic macromolecules (FITC-dextran, M(w)=71 and 2000 kDa) from porous poly (D,L-lactic acid), PLA, microspheres was studied by applying percolation theory. Microspheres were prepared by the double emulsion method using high molecular weight PLA. The microspheres showed a percolation threshold, rho(C), at porosity 0. 34. From this parameter, the effective diffusion coefficients, D(eff), and the accessible porosity (total releasable active ingredient), rho(A), of the microspheres were calculated using the Bethe lattice model with coordination number 4. Decreasing porosity of the microspheres decreased the release rate of the active ingredients and a long-term release was observed for the microspheres with porosity close to rho(C). The calculated rho(A) agreed with the experimental data and also the calculated D(eff) for the microspheres with larger porosity (>0.4) was a good estimation to predict the experimentally determined release profiles by applying the continuum structure model (CSM). For microspheres with porosity larger than 0.4 which contained FITC-dextran M(w)=71 kDa, a lag time was observed, which was attributed to delayed saturation of the microspheres with release medium. For microspheres with porosity close to rho(C), the limited number of exit holes on the exterior surface changed the mechanism of release and controlled the release rate rather than the tortuosity of the porous structure of the microspheres.

Algorithms↗
PubMed2000

First order release rate from porous PLA microspheres with limited exit holes on the exterior surface.

We applied the finite element method (FEM) to calculate release profiles from computer simulated slabs, one with a limited number of exit holes on the exterior surface, and the other with uniform structure. The former slab showed a first order release rate, and a nearly uniform drug concentration distribution within the device during the release process. It was concluded that circulation of the drug molecules within the slab resulted in the uniform concentration and consequently first order release rate. This theoretical work was used to explain the first order release rate of an active ingredient (flourescin-4-isothiocyanate-dextran, M(W)=71000 Da) from porous PLA (poly(D,L)-lactic acid) microspheres, which by canning electron microscopy (SEM) examination showed only a few exit holes on their exterior surface. Calculations indicated that the internal surface adsorption of the active ingredient, or the pore size distribution of the microspheres, could not influence the mechanism for the first order release rate, and the small number of exit holes on the exterior surface was likely to be the rate-determining factor. The exit holes could be observed by SEM and their size and number is consistent with our interpretations.

Computer Simulation↗
PubMed2000

Loss of heterozygosity in fibrocystic change of the breast: genetic relationship between benign proliferative lesions and associated carcinomas.

Loss of heterozygosity (LOH), a genetic change frequently detected in cancer, can also occur in benign epithelial foci in the breast. To characterize LOH in benign breast tissue, 32 cases containing the various components of fibrocystic change in the absence of malignancy were studied. Microdissected foci of ductal hyperplasia, apocrine metaplasia, sclerosing adenosis, and morphologically normal terminal duct lobular units (TDLUs) were analyzed for LOH at 14 polymorphic loci representing seven chromosomal arms. LOH was detected in 22% of normal TDLUs (6/27), 17% of adenosis (4/23), 19% of hyperplasia (4/21), and 53% of apocrine metaplasia (10/19) specimens. Because of the high percentage of LOH in apocrine metaplasia in nonneoplastic specimens, the genetic relationship between apocrine metaplasia and cancer was studied in a panel of breast cancer cases. Of 14 examples of apocrine metaplasia adjacent to a carcinoma, seven were found to have LOH with at least one marker. In all seven cases, the tumor and apocrine metaplasia shared LOH at one or more markers. The results demonstrate that LOH occurs frequently in the components of fibrocystic change as well as in normal TDLUs and suggest that foci of apocrine metaplasia can share a genetically altered precursor cell with an associated carcinoma.

Adult↗
PubMed2000

Genetic heterogeneity in ductal carcinoma of the breast.

Genetic heterogeneity in breast cancer has been observed both by cytogenetic and loss of heterozygosity (LOH) analyses; however, the frequency with which genetically heterogeneous clones arise is unknown. In this study, a panel of 115 breast carcinomas was analyzed to determine the extent of clonal divergence in tumor foci at progressive stages of tumor evolution. Intraductal, infiltrating, and metastatic tumor components were microdissected from each tumor and tested for LOH at 20 microsatellite markers on seven chromosomal arms. Of these cases, 24 (21%) demonstrated genetically divergent clones during tumor progression. Clonal divergence, inferred from discordant LOH patterns, was observed most commonly between intraductal and infiltrating tumor (18 cases), but was also demonstrated between infiltrating and metastatic tumor (11 cases). Discordant LOH was observed with markers on one chromosomal arm in 16 cases, on two in 7 cases, and on four in 1 case, and was observed most commonly with markers on 17p, 17q, and 16q. More detailed microdissection of four cases provided evidence for a specific chronology of genetic alterations occurring during the progression of each tumor. The results indicate that the different tumor components observed microscopically in breast cancer specimens often represent genetically divergent clones.

Breast Neoplasms↗
PubMed2000

Mucoepidermoid carcinoma of an accessory lacrimal gland with orbital invasion.

PURPOSE: To report a case of mucoepidermoid carcinoma of an accessory lacrimal gland with orbital invasion. METHODS: The clinical history and pathologic findings of a patient with a left upper eyelid lesion were reviewed. RESULTS: The patient was evaluated and found to have an epithelial tumor arising in an accessory lacrimal gland. Special stains showed mucin production by individual tumor cells. The tumor was classified as mucoepidermoid carcinoma. CONCLUSIONS: Mucoepidermoid carcinoma may arise in accessory lacrimal glands and invade the orbit.

Biopsy↗
PubMed1999

Solution and adsorption behaviour of lecithin surfactants in CFC suspensions: a light scattering study in aerosol propellants.

The behaviour of the lecithin Epikuron 200 was studied in solution in a chlorofluorocarbon (CFC) aerosol propellant (P113) using light scattering to determine the micellar structure as a function of temperature. At room temperature Epikuron 200 formed micelles with a radius of approximately 25 nm. The radius increased with decreasing temperature until a phase boundary was reached at 15-16 degrees C, below which the micellar radius increased rapidly to 150-250 nm. This was accompanied by a large increase in the viscosity and turbidity of the solution. We consider that this behaviour is due to the formation of large wormlike micelles similar to those reported for lecithin in cyclohexane. The adsorption of Epikuron 200 on salbutamol sulphate was measured over this temperature range. The adsorbed amount of Epikuron 200 increased with decreasing temperature, and the hemimicelle concentration decreased rapidly at a temperature corresponding to the threshold for the formation of wormlike micelles. It is likely that these structures do form in CFC-MDI systems (particularly during cold-fill formulation), and that the structure of the adsorbed surfactant layer changes at low temperature. This may have implications for the formulation of stable aerosol suspensions.

Adsorption↗
PubMed1999

Determination of the internal morphology of poly (D,L-lactide) microspheres using stereological methods.

The morphological characteristics of the internal structure of poly (D,L-lactide) microspheres have been determined by stereological methods in two different formulations of microspheres, with different internal structures, prepared by using a double emulsion method. In one formulation the internal emulsion was produced by homogenisation at 3000 rpm, whilst the other was prepared at 11000 rpm. As expected the formulation prepared at the lower speed contained larger and more broadly distributed pores than that prepared at the higher speed. The porosity, pore size distribution and total internal surface area of the microspheres were obtained by stereological methods from electron microscopic measurements of the sectioned microspheres. It was found that whilst the porosity of the microspheres was 0.6 in both formulations, the preparation method gave rise to large differences in their pore size distribution characteristics. The pore size distribution was simulated by computer modelling to validate and compare alternative stereological algorithms. It was found that the Saltykov unfolding method predicts the measured pore size distribution more accurately than the Cruz-Orive unfolding method (at significance level alpha=0.1). This finding was attributed to the violation of one of the basic assumptions of the Cruz-Orive unfolding method.

Algorithms↗
PubMed1999

Dual pH probe monitoring versus single pH probe monitoring in infants on milk feeds: the impact on diagnosis.

OBJECTIVES: Oesophageal pH monitoring is the gold standard technique for the detection of gastro-oesophageal reflux in adults and children. A standard parameter used to define "abnormal" reflux is the percentage of recording time for which the gastric pH is < 4. This study investigated the relevance of this measure in infants on regular milk feeds whose gastric contents and refluxate will be neutral for most of the recording time. METHODS: Simultaneous oesophageal and gastric pH monitoring was carried out on all infants who were milk fed exclusively and admitted to hospital for suspected gastro-oesophageal reflux. In vitro studies were performed to establish the buffering capacities of the fruit juice, Dioralyte (a glucose electrolyte solution), breast milk, and milk formula feeds available on the paediatric wards. RESULTS: Complete sets of data were obtained from 30 babies with a mean age of 4 months. Gastric pH was </= 4 for a mean (SEM) of 42.4 (4.9)% of the recording time. The mean (SEM) percentage time that oesophageal pH was < 4 for the total recording period was 6.89 (0.92)%. Recalculation of the percentage of time that the gastric pH was > 4 increased this value to 17.81 (2. 46)%. Using a cut off point of 10%, 11 of the 30 babies would have been diagnosed positive for reflux using the conventional method; however, recalculation by ignoring the time for which gastric pH was high doubled this to 22 positive for reflux. CONCLUSION: Combined oesophageal and gastric pH monitoring greatly increases the number of positive results from tests in infants on regular milk feeds.

Animals↗
PubMed1998

Patterns of food and acid reflux in patients with low-grade oesophagitis--the role of an anti-reflux agent.

BACKGROUND: Food and acid have been shown to be refluxed independently of each other in healthy volunteers, and anti-reflux agents decrease the reflux of both parameters. Until now this phenomenon had not been studied in patients with low-grade oesophagitis, who are the group most likely to use anti-reflux medication. AIM: To assess patterns of gastro-oesophageal reflux of acid and food in 12 ambulant patients with endoscopically proven oesophagitis of between grades I and II, but who were otherwise healthy. Also to assess the effectiveness of a single dose of an alginate-containing anti-reflux agent in controlling food and acid reflux in this patient group. METHODS: Oesophageal pH monitoring and external ambulatory gamma detection were used to study food and acid reflux. A pH electrode was positioned 5 cm above the cardia and the gamma detector was positioned externally over the pH electrode. The patients then received a technetium-99m labelled meal designed to provoke reflux. Thirty minutes later the patients were given a 20 ml dose of alginate (Liquid Gaviscon), or 20 ml of tap water. Incidence of reflux was monitored for approximately 4 h from the end of the meal. Allocation to treatment group was randomized, with patients receiving the alternative treatment on the second study day after approximately a 7-day washout period. RESULTS: The mean percentage time oesophageal pH remained below 4 was 16.3 min for the control group and 5.4 min for the treatment group (P = 0.03). Food reflux was detected 23.7% of the time in the control group compared to 12% of the time in the treatment group (P = 0.02). The anti-reflux agent was also successful in decreasing the number of events, but the duration of the reflux events was not significantly different. CONCLUSIONS: Patients with grades I and II oesophagitis reflux food and acid independently, and are predominantly either food refluxers or acid refluxers, but not both. Liquid alginate decreases the number of both food and acid reflux events, but does not change their duration.

Adult↗
PubMed1997

An investigation of lower oesophageal redox potentials in gastro-oesophageal reflux patients and healthy volunteers.

Oesophageal electrical properties are thought to be important in the development of gastro-esophageal reflux. This study simultaneously monitored the intraoesophageal pH and redox potentials in 18 patients with gastro-oesophageal reflux symptoms and 15 asymptomatic controls, for a 24 h period. The pH and redox electrodes were positioned 5 cm proximal to the lower oesophageal sphincter, the position of which had been determined by manometry. Since significantly different behaviour was observed during the day and night, the data were divided into periods of waking and sleeping. Data were analysed for acid reflux (pH < 4) and transients in the redox potential-time curve. Both patients and normal subjects showed negative redox transients which were more frequent and pronounced at night than during the day, and which were uncorrelated with acid reflux. The only parameter which was significantly different between normal and refluxing groups was the amount of nocturnal redox activity, which was lower in refluxing subjects than in normals. Some possible hypotheses for these observations, and the origin of the redox species, are discussed.

Adult↗
PubMed1996

Evidence for the formation of amphotericin B-phospholipid complexes in Langmuir monolayers.

PURPOSE: To study the interaction of the polyene antifungal amphotericin B with phospholipid Langmuir monolayers and to correlate with stability of phospholipid-stabilized drug emulsions. METHODS: Pressure-area isotherms of mixed monolayers of amphotericin B (0-20 mol%) and different phospholipid types were recorded using conventional Langmuir trough methods. Emulsion stability of amphotericin B-containing lipid emulsions was measured using dynamic light scattering. RESULTS: Incorporation of amphotericin B into monolayers composed of saturated phospholipids (Lipoid E80-3) had a profound effect on the shape of the isotherm. This effect was directly related to the concentration of amphotericin B in the monolayer. At high drug concentrations, the shape of the isotherms became progressively similar to that of pure DPPC, thus exhibiting regions attributable to phospholipid in different phase states. This effect on isotherm shape was not observed following incorporation of the drug into monolayers composed of the equivalent unsaturated lecithin (Lipoid E80). CONCLUSIONS: These results are interpreted as indicating the formation of an amphotericin B-phospholipid complex, resulting in phase separation within the monolayer. The extent and nature of this phase separation was dependent on both the concentration of drug in the system, and the saturation state of the phospholipid component. The relevance of these observations to the stability of amphotericin B drug emulsions stabilised by saturated and unsaturated phospholipid emulsifiers is discussed. These observations may also be relevant to the toxicity of these, and other novel amphotericin B formulations.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1996

Characterization of surfactant effect on aggregates in model aerosol propellent suspensions.

A novel technique of rheometry combined with image analysis to study model aerosol suspensions used in inhalation technology has been used. The role of surfactants in the stability and aggregation of such suspensions was also investigated. Addition of increasing concentrations of sorbitan monooleate (Span 80) to suspensions of micronized polar solids in model CFC suspensions caused marked changes in aggregate morphology and suspension stability. The aggregate behaviour was characterized in a modified constant stress rheometer by use of image analysis techniques, allowing the measurement of particle size, elongation and fractal dimension as a function of shear stress. This method was used to study the effect of Span 80 on suspensions of lactose and salbutamol sulphate in P113. Lactose suspensions showed a gradual reduction in aggregate size, and more spherical structure, with increasing surfactant concentration. Salbutamol sulphate suspensions displayed a more prominent transition from an aggregated state to a weakly aggregated state at 0.02% w/w surfactant. Both suspensions were disaggregated by shear, the resulting fractal properties of the aggregates in shear demonstrating the increased particle mobility caused by the surfactant.

Adrenergic beta-Agonists↗
PubMed1996

The effect of surfactant and solid phase concentration on drug aggregates in model aerosol propellent suspensions.

The effect of increasing solid phase concentration on the morphology and flocculation rate of model aerosol suspensions has been investigated. Suspensions of micronized salbutamol sulphate and lactose in trichlorotrifluoroethane (P113) were studied under conditions of increasing shear stress. By use of image analysis techniques, measurement of aggregate size, fractal dimension and rate of aggregation was performed. The effect of the surfactant sorbitan monooleate on morphology and flocculation rate was also studied. Increased solid phase concentration caused an increase in the rate of aggregation and average aggregate size at a given value of shear stress. Surfactant addition retarded the aggregation rate, and caused a shift from a diffusion-limited cluster aggregation to a reaction-limited cluster aggregation mechanism. The aggregate profiles showed a corresponding change from rugged and crenellated without surfactant, to increasingly smooth and Euclidian with increasing surfactant concentration. The morphological changes were characterized by a decrease in the average boundary fractal dimension which also correlated well with the corresponding reduction in aggregation rate.

Adrenergic beta-Agonists↗