Development of biodegradable microcapsules as carrier for oral controlled delivery of amifostine.

The primary objective of this project was to develop a biodegradable, orally active controlled-release formulation of amifostine. Development of such a formulation will mark an important advancement in the areas of chemoprotection and radioprotection. Biodegradable microcapsules of amifostine were prepared using poly(lactide/glycolide) (PLGA 50:50). The microcapsules were prepared by solvent evaporation technique. Amifostine-loaded microcapsules were evaluated for particle size, surface morphology, thermal characteristics, and drug release. Particle size and surface morphology were determined using scanning electron microscopy (SEM). Thermal characterization was conducted using differential scanning calorimetry (DSC). In vitro release study was performed at 37 degrees C using phosphate buffer (pH 7.4). Amifostine release was calculated by measuring the amount of drug remaining within the microcapsules at a specific sampling time. The amount of amifostine in the samples was determined by high-performance liquid chromatography (HPLC) using an electrochemical detector. The yield of microcapsules was 75%. Scanning electron microscopy pictures revealed that the particles were nearly spherical and smooth with an average size of 54 microm. Differential scanning calorimetry thermograms showed that microcapsules loaded with amifostine have a glass transition at 39.4 degrees C, and the melting endotherm of amifostine was absent. The absence of a melting endotherm for amifostine was an indication that amifostine was not in the crystalline state in the microcapsules, but rather in the form of a solid solution in PLGA. Approximately 50% amifostine was released during the first 6 hr of the in vitro release study. The drug, however, continued to release over the observed period of 12 hr during which 92% amifostine was released.

Upper gastroduodenal ulceration in arthritis patients treated with celecoxib.

OBJECTIVE: To evaluate the comparative incidence of endoscopic gastroduodenal ulcers in patients with rheumatoid arthritis or osteoarthritis treated with celecoxib. DESIGN: Quantitative systematic review of randomized controlled trials. SUBJECTS: Patients (n = 4632) with rheumatoid arthritis or osteoarthritis reported in five trials. MAIN OUTCOME MEASURES: Rate ratios, rate differences, and the number needed to harm were calculated for the incidence of endoscopically documented gastroduodenal ulcers. RESULTS: Pooled rate ratios (RRs) relative to placebo for endoscopic ulcers at 12 weeks were 1.96 (95% CI 0.85 to 4.55) for celecoxib 100 mg twice daily and 2.35 (95% CI 1.02 to 5.38) for celecoxib 200 mg twice daily. There was no significant difference in gastroduodenal ulcers at 12 weeks between celecoxib 200 mg twice daily and celecoxib 100 mg twice daily; the corresponding pooled RR was 1.21 (95% CI 0.62 to 2.38). In contrast, celecoxib 200 mg twice daily was associated with a significantly lower rate of gastroduodenal ulcers than was naproxen 500 mg twice daily at 12 weeks (RR 0.24; 95% CI 0.17 to 0.33). On average, for every seven patients treated with naproxen, one more had an endoscopic ulcer than if they were treated with celecoxib. Celecoxib 200 mg twice daily also had a significantly lower risk of endoscopic ulcers than did either modified-release diclofenac 75 mg twice daily at 24 weeks (RR 0.24; 95% CI 0.11 to 0.52) or ibuprofen 800 mg three times daily at 12 weeks (RR 0.30; 95% CI 0.20 to 0.46). CONCLUSIONS: Endoscopic studies have shown that celecoxib, at a wide range of doses, is associated with a lower incidence of gastroduodenal ulcers than are diclofenac, ibuprofen, or naproxen. The incidence rates of gastroduodenal ulcers associated with celecoxib were similar, although not equivalent, to placebo. Head-to-head comparisons suggest that, at the wide range of doses studied (100-800 mg/d), there are no dose-related increases in endoscopic gastroduodenal ulcers with celecoxib. The results of longer term comparative trials of celecoxib based on clinical outcomes are needed to determine celecoxib's ultimate risk-benefit profile.

Porous biodegradable microparticles for delivery of pentamidine.

The primary objective of this study was to develop a method for the preparation of porous biodegradable controlled release formulation of poly(lactide/glycolide) (PLGA). The model drug used for this study was pentamidine. Scanning electron microscopy pictures showed that these microparticles are highly porous and spherical in shape. A comparison of particle size reveals a similar median particle size (54-68 microm) in all six batches. The particles are all smaller than 90 microm. Differential scanning calorimetry thermograms revealed that pentamidine was mostly present in the crystalline form in the microparticles and did not dissolve in PLGA. The efficiency of encapsulation of pentamidine was higher than 58% in all six batches. The amount of drug released from these microparticles was at least 12% within the first 60 min. At least 50% of the total drug was released within the first 4 h. Drug release from these microparticles continued for up to 12 h. This faster drug dissolution was due to the highly porous surface. This highly porous surface will allow large molecules to release at a much faster rate than the regular microcapsules/microspheres.

Why are patients prescribed proton pump inhibitors? Retrospective analysis of link between morbidity and prescribing in the General Practice Research Database.

OBJECTIVES: To establish the relation between new prescriptions for proton pump inhibitors and recorded upper gastrointestinal morbidity within a large computerised general practitioner database. DESIGN: Retrospective survey of morbidity and prescribing data linked to new prescriptions for proton pump inhibitors and comparison with licensed indications between 1991 and 1995. SETTING: General Practice Research Database and prescribing analysis and cost (PACT) data for the former West Midlands region. SUBJECTS: Information for 612 700 patients in the General Practice Research Database. Anonymous PACT data for all general practitioners in West Midlands region. MAIN OUTCOME MEASURES: Diagnostic codes linked to the first prescriptions issued for proton pump inhibitors; relation between new prescriptions and licensed indications; yearly change in ratio of new to repeat prescriptions and prescribing volumes measured as defined daily doses. RESULTS: Oesophagitis was the commonest recorded indication in 1991, accounting for 31% of new prescriptions, but was third in 1995 (14%). During the study new prescriptions increased substantially, especially for duodenal disease (780%) and non-ulcer dyspepsia (690%). In 1995 non-specific morbidity accounted for 46% of new prescriptions. The total volume of prescribing rose 10-fold between 1991 and 1995, when repeat prescribing accounted for 77% of the total. CONCLUSIONS: Changes in recorded morbidity associated with new prescriptions of proton pump inhibitors did not necessarily reflect changes in licensed indications. Although general practitioners seemed to respond to changes in licensing, particularly for duodenal and gastric disease, prescribing for unlicensed indications non-ulcer dyspepsia and non-specific abdominal pain increased.

Buccaling under the pressure: influence of secondary care establishments on the prescribing of glyceryl trinitrate buccal tablets in primary care.

OBJECTIVE: To determine which characteristics were the best predictors of high rates of prescribing of glyceryl trinitrate buccal tablets. DESIGN: Practice and patient characteristics from 197 practices were examined, and a multiple regression analysis was performed to examine which variables were important in predicting this prescribing. SETTING: Former family health services authority (197 practices). MAIN OUTCOME MEASURE: Volume of prescribing of glyceryl trinitrate buccal tablets. RESULTS: Four variables contributed significantly to a multiple regression model: the catchment area of the secondary care establishment; the number of partners in a practice; the level of practice deprivation; and whether the practice served an urban or a rural area. The model suggests that the most important variable was the catchment area of the secondary care establishment in which the practice was located. CONCLUSION: Although only the prescribing of short acting glyceryl trinitrate buccal tablets was studied, an impact of this size on primary care prescribing may have extensive implications for all drug expenditure in primary care.

Characterization of the sphericity of particles by the one plane critical stability.

A method has been developed to characterize the roundness of particles in terms of the angle necessary to tilt a plane such that the particles would roll, the 'one plane critical stability'. The method is based on determination of the centre of gravity of the particle from a digitized image of the coordinates of its outline and computing the angle necessary to incline a plane such that the centre of gravity moves outside the boundary of the particle. The method is particularly applicable to differentiate between the various shapes formed during the production of spherical granules by extrusion/spheronization.

The vibratory consolidation of particle size fractions of powders.

The use of controlled sinusoidal vibration as a means of consolidating packings of lactose within small containers has been examined. Vertical vibration was found significantly more effective and reproducible than horizontal vibration in terms of the degree of consolidation achieved. An optimum frequency range was identified within which the densification was greatest, and this range was largely independent of particle size for particle size fractions of mean volume diameters ranging from 15.6 to 155 micrometers. The consolidation increased with increasing vibration acceleration up to a level beyond which no further decrease in porosity resulted. Typical effective vibration conditions were characterized by amplitudes of an order of magnitude similar to the particle sizes studied. For particle size fractions of mean diameters 17.8, 37.5 and 80.8 micrometers, there is evidence that an optimum particle size range exists, within which energy requirements for consolidation are at a minimum.

Campylobacter enteritis in Johannesburg.

In order to establish a reasonable protocol for a diagnostic laboratory we conducted a survey during which we confined the routine culture of stool samples for Campylobacter fetus to two groups--all infants under 2 years of age, and older children and adults with obviously diarrhoeic stools. Camp. fetus was isolated from 100 of 2323 stool specimens (4,3%). This is within the 3 - 8% isolation rates previously reported from surveys in which all specimens were cultured. Camp. fetus isolates represented 16,9% of all bacterial pathogens isolated, and Black infants showed a significantly greater isolation rate than White infants. We feel that culture for Camp. fetus is an essential part of any routine bacteriological investigation of diarrhoea. A partially selective culture policy for Camp. fetus will result in a recovery rate at least equal to that of Salmonella and enteropathogenic Escherichia coli.