Use of Stable Isotopes for Evaluation of Drug Delivery Systems: Comparison of Ibuprofen Release in Vivo and in Vitro from Two Biphasic Release Formulations Utilizing Different Rate-Controlling Polymers

Certain delivery systems are intended to release the active ingredient in different phases to obtain the desired therapeutic effect. For these formulations, such as a bilayer tablet, it is desirable to distinguish and measure the release of drug from the different phases simultaneously. Mass spectrometric methods were developed to measure three ibuprofen isotopomers in serum and two in dissolution fluid. The analytical methods were linear (r 0.992) over the concentration range of interest and recovery was greater than 99.2% for all isotopomers. Coadministration of [²H₀]ibuprofen, [²H₄]ibuprofen, and [²H₇]ibuprofen to male beagles demonstrated that the isotopomers were bioequivalent and verified the absence of any kinetic isotope effect due to deuterium incorporation (p = 0.286). These methods were then used to evaluate a bilayer tablet formulation composed of an immediate release layer of 100 mg [²H₄]ibuprofen and a sustained release layer with a drug load of 300 mg [²H₀]ibuprofen. Two different rate-controlling polymer matrices that provided similar in vitro dissolution profiles were compared in the sustained release phase, while the immediate release formulation remained the same. In male beagles, the HPMC matrix delivered a significantly greater amount of ibuprofen (p < 0.05). The AUC was threefold greater for HPMC (1067 ± 437 nmole * h/ml) versus EUDRAGIT^® (320 ± 51), and C_max was nearly four times greater (145 ± 62.1 nmole/ml for HPMC versus 37.9 ± 14.4 for EUDRAGIT^®). Although T_max for HPMC (3.4 ± 1.9 h) lagged behind EUDRAGIT^® (2.0 ± 0.82 h), the difference was not significant (p > 0.05). The immediate release layer was absorbed to the same extent as an oral solution (containing [²H₇]ibuprofen) that was administered concomitantly with the bilayer tablet. Using the stable isotope markers also demonstrated that the release rates of the two layers were independent of each other, both in vivo and in vitro. Stable isotope techniques are a useful tool in the development of biphasic release formulations since they can be used to determine proper drug load of each phase as well as the appropriate rate of release.     

EMG Biofeedback as a Tool for Simulating the Effects of Specific Leg Muscle Weakness on a Lifting Task

This study investigated the use of EMG biofeedback to simulate weakened rectus femorii and gastrocnemii muscles during the performance of a lifting task. Eight healthy women performed 15 kg free-style lifts from floor level. Three conditions were tested: unconstrained lifting, lifting with rectus femorii activity volitionally limited bilaterally through EMG biofeedback to less than 45% of maximal EMG activity, and lifting with the gastrocnemii limited to a similar level. Limiting leg muscle activity through biofeedback led to an alteration of lifting strategy, with resulting performance variables (joint angles and torques, angular velocities, center of pressure excursion, and segment coordination) comparing favorably with those from lifting trials performed by six women with moderate leg muscle weaknesses. The data indicate that EMG biofeedback can be used to simulate the effects of leg muscle weakness during these lifts, providing a new tool to study the biomechanics of muscle weakness.     

Achieving population health goals: perspectives on measurement and implementation from Australia

Health goals and targets have been widely used to indicate strategic direction and priority for health improvement on a population basis. This paper provides an overview of Australia's experience in using health targets and considers the relevance of this experience for Canada. It gives special attention to the challenge of developing a broadly based set of targets that reflect the social, economic and environmental determinants of health alongside more traditional measures of health status. It examines how the technical challenge of measurement, the bureaucratic barriers between government departments, and the political conservatism inherent in federal systems of government present formidable barriers to effective action on comprehensive national health targets. The paper concludes with a reminder of the need for inter-sectorial action to address the determinants of health. Based on the Australian experience, it suggests for Canada an ideal combination of a national population health framework to guide direction and priority, to be implemented through action at a more local level, through well-defined partnerships.     

Computed radiography versus screen-film radiography: detection of pulmonary edema in a rabbit model that simulates neonatal pulmonary infiltrates.

PURPOSE: To determine if computed radiography is equivalent to screen-film radiography in depicting pulmonary edema and to determine if radiation exposure can be reduced with computed radiography while maintaining equivalent diagnostic accuracy for pulmonary edema. MATERIALS AND METHODS: Oleic acid was intravenously injected into three rabbits at each of four doses: 0, 0.02, 0.04, and 0.06 mL/kg. Two hours later, chest computed radiographs and screen-film radiographs were obtained at 60 kVp and 1.1 mAs. Additional computed radiographs were obtained after reducing milliampere seconds or by reducing milliampere seconds and increasing the kilovolt peak, which reduced bone marrow exposure by up to 20%. The presence of pulmonary opacities, "truth," was established by the wet-dry weight ratio and by chest computed tomography (CT). The radiographs were masked and randomized. Four observers rated the images for the presence of parenchymal opacities with a dichotomous score and judged the quality of the radiographs on a scale from 1 (worst) to 6 (best). Cochran Q tests and McNemar tests were used to analyze the differences in paired comparisons. Image quality was evaluated with logistic regression analysis. RESULTS: There was no significant difference between truth and observer ability to detect opacity for either modality or for any exposure (P > .05). There was no significant difference between computed radiography and screen-film radiography for image quality (P > .05). CONCLUSION: Computed radiography is equivalent to screen-film radiography in the detection of pulmonary edema. Radiation exposure reduction of 20% can be achieved without affecting pulmonary edema detection or image quality.     

The application of Ion chromatographic method for bioavailability and stability test of iron preparations

Postabsorptive serum iron level was determined after oral administration of the compounds to human. In serum and whole blood, Fe3+ was measured by ion chromatography (IC) using a pyridine-2,6-dicarboxylic acid (PDCA) as an eluent. The serum sample solutions were pretreated with I N HCI and 50% TCA. The whole blood sample solutions were treated with 3 N HCI for 30 min at 125 degrees C. The limit of detection (LOD) of the IC technique is 0.2 microM for Fe2- and 0.1 microM for Fe3+. The area under concentration (AUC) can be obtained by the above analytical condition. In addition, to compare the stability of Fe2+ to that of Fe3+ in pharmaceutical preparations, accelerated stability test was carried out. After storing the samples under 40 degrees C, 75%RH in light-resistant container for various time intervals, the contents of iron of different valencies were determined separately by the IC technique and the change and/or the interchange of among those iron species in preparations was investigated. Iron raw materials are stable, but Fe2+ in Fe3+ source materials was slightly converted to Fe3+ by oxidation. Fe2+ in Fe3+ source raw materials and Fe3+ in Fe2+ raw materials are determined as impurities. Therefore, IC technique is found to be an appropriate method for comparative evaluation of dissimilar bioavailability of Fe2+ and Fe3+, stability of Fe2+ and Fe3+ raw materials and preparations.     

Flexible fiberoptic sigmoidoscopy—The monroe clinic experience

Analysis of 5000 consecutive flexible fiberoptic sigmoidoscopies form the basis of this report. It is concluded that this method of examination of the distal large bowel is not only safe and comfortable for the patient but is a more appropriate examination than the rigid proctosigmoidoscopy because of the significant increase in pathologic material found. This examination has proven practical and acceptable in a multispecialty clinic setting and has completely replaced rigid proctosigmoidoscopy. Flexible sigmoidoscopy is now the standard "routine" examination of the rectum and distal colon. The rationale for this conclusion is presented in this timely report.     

An analysis of the effects of implementing the teaching-family model in two community-based group homes

The effects of implementing the Teaching-Family Model in two community-based group homes were assessed through a series of pre-post measures. Data analysis indicates substantial positive change in youth social skills, program quality, youth and staff satisfaction levels, social climate, and staff accountability for care of the children.Requests for reprints, samples of the Staff Accountability Scale, and other forms or the questionnaires in this study should be addressed to Kurt Scheider at The Maryville Academy, 1150 North River Road, Des Plaines, IL 60016     

Staged TRAM Breast Reconstruction: Combining the Advantages of Tissue Expansion with Surgical Delay

The TRAM flap has become the gold standard in breast reconstruction but suffers from the disadvantages of poor color match, different texture, and impaired sensation compared to the normal breast. This study reports on a two-stage procedure to address these problems. The first stage consists of insertion of a tissue expander and surgical delay of the TRAM flap. The second stage consists of removal of the tissue expander and transposition of a deepithelized TRAM flap into the tissue expanded cavity. (The capsule is excised.) Four cases of breast reconstruction are reported. The advantage of this procedure is that it offers the benefits of tissue expansion, viz., normal color match, texture, and sensation, and in addition, reconstruction is achieved with autologous tissue by a pedicled TRAM flap. The vascularity of the TRAM is enhanced by a surgical delay procedure.     

Association of SULT1A1 phenotype and genotype with prostate cancer risk in African-Americans and Caucasians.

Exposure to heterocyclic amines may increase prostate cancer risk. Human sulfotransferase 1A1 (SULT1A1) is involved in the bioactivation of some dietary procarcinogens, including the N-hydroxy metabolite of the food-borne heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine. This study compares a polymorphism in the SULT1A1 gene, SULT1A1 enzyme activity, meat consumption, and the risk of prostate cancer in a population based case-control study. Prostate cancer patients (n = 464) and control individuals (n = 459), frequency matched on age and ethnicity, provided informed consent, answered a survey, and provided a blood sample. Platelets were isolated for phenotype analysis, and DNA was isolated from lymphocytes for genotype determination. Meat consumption was assessed using a dietary questionnaire. Caucasians homozygous for the SULT1A1*1 high activity allele were at increased risk for prostate cancer [odds ratio (OR), 1.68; 95% confidence interval (CI), 1.05-2.68] compared with individuals homozygous for the low-activity allele. The association between SULT1A1 genotype and prostate cancer risk in African-Americans did not reach significance (OR, 1.60; 95% CI, 0.46-5.62). When SULT1A1 activity was considered, there was a strong association between increased SULT1A1 activity and prostate cancer risk in Caucasians (OR, 3.04; 95% CI, 1.8-5.1 and OR, 4.96; 95% CI, 3.0-8.3, for the second and third tertiles of SULT1A1 activity, respectively) compared with individuals in the low enzyme activity tertile. A similar association was also found in African-American patients, with ORs of 6.7 and 9.6 for the second and third tertiles of SULT1A1 activity (95% CI, 2.1-21.3 and 2.9-31.3, respectively). When consumption of well-done meat was considered, there was increased risk of prostate cancer (OR, 1.42; 95% CI, 1.01-1.99 and OR, 1.68; 95% CI, 1.20-2.36 for the second and third tertiles, respectively). When SULT1A1 activity was stratified by tertiles of meat consumption, there was greater risk of prostate cancer in the highest tertile of meat consumption. These results indicate that variations in SULT1A1 activity contributes to prostate cancer risk and the magnitude of the association may differ by ethnicity and be modified by meat consumption.