Control of gentamicin release from a calcium phosphate cement by admixed poly(acrylic acid)

The aim of this work was to develop a calcium phosphate cement (CPC) providing controlled release of the antibiotic gentamicin sulfate (GS) over at least 1 week. The CPC was made of beta-tricalcium phosphate [beta-TCP; beta-Ca(3)(PO(4))(2)], monocalcium phosphate monohydrate [MCPM; Ca(H(2)PO(4))(2). H(2)O] and water. Release of GS was controlled by admixture of poly(acrylic acid) (PAA). The effects on the GS release kinetics of the molecular weight of PAA, of the amount of admixed PAA, and of the pH of the release medium were investigated. A typical cement sample weighed 3.6 g and contained 100 mg of GS and between 0 and 150 mg of PAA. In the following, PAA content is expressed as the weight ratio, lambda, with respect to GS. At a low PAA content in the CPC (lambda < 0.7), GS was released over 1-2 days according to a square-root-of-time kinetics, but not all GS was released. The unreleased GS fraction increased from 0 to 58% with an increase of PAA content (up to lambda = 0.7). At high PAA content (lambda > 0.7), GS was released over a period of up to 8 days according to a combination of a square-root-of-time and a zero-order kinetics. The total GS fraction released increased again from 58 to 100% with an increase of the amount of PAA (up to lambda = 1.5). These observations were explained by molecular interaction between PAA and GS resulting in gel formation. The maximum fraction of GS released from the cement was indeed a function of the solubility of the PAA-GS (coacervate) complex in the release medium. Thus, GS release was controlled by two mechanisms: (1) diffusion of free GS molecules through the porous cement (square-root-of-time kinetics); and (2) dissociation of GS from the PAA-GS complex (zero-order kinetics). The first mechanism was predominant at low lambda, whereas the second mechanism became important at high lambda and later release times. As the solubility of the PAA-GS complex decreased with an increase in PAA molecular weight, the higher molecular weight PAA yielded more prolonged release periods of up to 8 days. Interestingly, the use of 450 kDa PAA at lambda = 1.00 provided an almost constant release profile over a period of 7 days. Gel formation between PAA and GS was explained in terms of hydrogen bonding of PAA carboxyl groups with GS amino groups. The molar ratio between carboxyl groups and amino groups in the gel was estimated to be approximately 1.9. In conclusion, admixture of PAA into calcium phosphate cement appeared to be a very elegant tool to control the release of the antibiotic over a period of 7 to 8 days.     

Degradation mechanism and stability of 5-aminolevulinic acid

The physiological substance and precursor of the heme synthesis 5-aminolevulinic acid (ALA) is a promising prodrug for photodiagnosis and photodynamic therapy of epithelial tumors, particularly in urological and gynecological tissues. For the clinical use of this substance, a chemically stable and sterile drug formulation is required. In the present study, degradation mechanism of ALA in aqueous solution and possibilities to improve its stability were examined. A capillary electrophoretic method was developed that was suitable for the quantification of ALA and of two degradation products. The intermediate degradation product was 2, 5-dicarboxyethyl-3,6-dihydropyrazine, which was further oxidized to 2,5-dicarboxyethylpyrazine. The structures of the degradation products were proven by (1)H and (13)C nuclear magnetic resonance spectroscopy. ALA degradation was very efficiently inhibited by adjusting the pH of the aqueous solution to a value <5 and by purging with nitrogen. Additives such as antioxidants did not improve the ALA stability. These results demonstrated that low pH ALA aqueous solution may be one possible dosage form to be considered for market introduction.     

Chemotherapie beim metastasierten Mammakarzinom

Ohne Zusammenfassung     

Cancer of the large intestine--a sequela of ureterosigmoidostomy

Carcinoma or polyps of the colon as a late complication of ureterosigmoidostomia (USS) have been reported with increasing frequency. Three patients are presented, two of them developed a signet-ring cell carcinoma after USS; one patient showed, 6 years after rediversion of the ureter, a carcinoma at the anastomotic site. Changes in the secretion patterns of sialo- and sulphomucines of the tumor and mucosa are histochemically demonstrated and, together with an appraisal of etiologic factors, discussed. We suggest a careful follow-up of patients with USS, particularly of those performed many years ago.     

Percutaneous drainage access: a simplified coaxial technique

We describe an access technique that we have used in 150 nephrostomy and biliary drainage procedures and for access to some abscesses and viscera. The system provides safe coaxial access with a 22-gauge removable hub needle, which then acts as a guide wire and is replaced by an 18-gauge cannula. A major advantage is that only one guide wire is used (0.038-inch) for the entire drainage procedure. No significant complications have occurred to date with this method.     

Compromised integrity of excised porcine intestinal epithelium obtained from the abattoir affects the outcome of in vitro particle uptake studies.

Excised porcine intestinal tissue obtained from the local abattoir was studied for its suitability to examine the uptake and transport of poly(lactic-co-glycolic acid) (PLGA) nanoparticles in Peyer's (PP) and non-Peyer's patch (NPP) tissue in vitro. Incubation of such tissue with fluorescent PLGA and polystyrene particles revealed negligible uptake into the intercellular space with no noticeable difference between PP and NPP tissue. Similarly, yeast cells, which were used as a positive control for selective uptake into PP tissue, were found in the subepithelial area of both PP and NPP tissue. Therefore we examined the morphological integrity of the tissue for the duration of the experiments. For this purpose, excised intestinal tissue from the abattoir transported to the laboratory was examined for morphological changes by light microscopy and compared to intestinal tissue from freshly slaughtered piglets. Already after 25 min postmortem, we observed lysis and defoliation of the epithelial cell layer followed by a complete loss of villus architecture and, consequently, resulting in a complete loss of the integrity of the intestinal tissue. This may explain the limited and non-selective particle uptake when using excised intestinal tissue from the abattoir. It is suggested to avoid small intestine obtained from the abattoir and to use tissue from freshly sacrificed animals within a few minutes postmortem. Experiments should then be performed under adequate oxygenation of the excised intestinal tissue.     

Measles-mumps vaccination in the FRG: an empirical analysis after 14 years of use. II. Tolerability and analysis of spontaneously reported side effects

Four hundred and thirty-three reports of suspected side effects following measles-mumps vaccination had been received at Behringwerke by the end of December 1989. The analysis of the data shows that no new risks of the vaccination could be identified and that the frequency of side effects is in good agreement with the findings of other authors. It therefore can be assumed that the relative risks of the vaccination continue to be distinctly outweighed by the benefits. The findings clearly demonstrate once more that it is necessary to carry out a thorough differential diagnosis before one can assume that the symptoms observed are causally related to the vaccination. In addition the analysis shows the importance of the epidemiological approach to the assessment of rare side effects.     

Survival of operated bronchus carcinoma patients: a prospective study

Maximum diameter, tumour volume, and inflammatory response of host tissue in 282 surgical specimens with primary carcinoma of the bronchus were measured. Cell type, pT- and pN-stage, maximum diameter and volume of the primaries, and inflammatory response of host tissue were analyzed in respect to survival of the patients. Date of death was evaluated by quarterly communications with the house physicians. Survival rates were computed by use of Kaplan-Meier estimation. Mean survival of all patients was calculated at 480 days. Lymph node involvement and tumour volume were found to have a major influence on survival. In accordance with the weak contribution of maximum diameter of the tumour to survival, no major differences in survival between pT1- and pT2-stage were found. If severe inflammatory response at the tumour boundary was noted, patients showed slightly increased survival in all tumour stages. Cell type and tumour grading were found to be of minor influence in respect to survival.