Microcrystalline Cellulose as a Sponge as an Alternative Concept to the Crystallite-Gel Model for Extrusion and Spheronization

Pharmaceutical Research -     

Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: Outcome related to measured tumor size and mean absorbed dose.

The purpose of this work was to (a) investigate the efficacy of radioimmunotherapy using 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2 (nonspecific antibody) against differently advanced ovarian cancer in mice; (b) image the tumor growth on the peritoneum; and (c) calculate the specific energy and mean absorbed dose to tumors and critical organs. METHODS: Two experiments with 5-wk-old nude mice (n = 100 + 93), intraperitoneally inoculated with approximately 1 x 10(7) NIH:OVCAR-3 cells, were done. At either 1, 3, 4, 5, or 7 wk after inoculation animals were intraperitoneally treated with approximately 400 kBq 211At-MX35 F(ab')2 (n = 50 + 45), approximately 400 kBq 211At-Rituximab F(ab')2 (n = 25 + 24), or unlabeled Rituximab F(ab')2 (n = 25 + 24). At the time of treatment 29 animals were sacrificed and biopsies were taken for determination of tumor sizes using scanning electron microscopy (SEM). Eight weeks after each treatment the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined. The specific energy and mean absorbed dose to tumors were calculated. The activity concentration was measured in critical organs and abdominal fluid. RESULTS: When given treatment 1, 3, 4, 5, or 7 wk after cell inoculation the tumor-free fraction (TFF) was 95%, 68%, 58%, 47%, 26%, and 100%, 80%, 20%, 20%, and 0% when treated with 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2, respectively. The SEM images revealed maximum tumor radius of approximately 30 mum 1 wk after cell inoculation, increasing to approximately 340 mum at 7 wk. Specific energy to cell nuclei varied between 0 and approximately 540 Gy, depending on assumptions regarding activity distribution and tumor size. The mean absorbed dose to thyroid, kidneys, and bone marrow was approximately 35, approximately 4, and approximately 0.3 Gy, respectively. CONCLUSION: Treatment with 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2 resulted in a TFF of 95%-100% when the tumor radius was < or =30 microm. The TFF was decreased (TFF < or = 20%) for 211At-Rituximab F(ab')2 when the tumor radius exceeded the range of the alpha-particles. The specific antibody gave for these tumor sizes a significantly better TFF, explained by a high mean absorbed dose (>22 Gy) from the activity bound to the tumor surface and probably some contribution from penetrating activity.     

Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: A randomized,multicenter study of pre-operative radiotherapy and chemotherapy. The second scandinavian trial in esophageal cancer

In a prospective multicenter study, 186 patients with squamous cell esophageal carcinoma, who after evaluation were considered suitable for surgery, were randomized to 4 treatment groups: Group 1, surgery alone; Group 2, pre-operative chemotherapy (cisplatin and bleomycin) and surgery; Group 3, pre-operative irradiation (35 Gy) and surgery; Group 4, pre-operative chemotherapy, radiotherapy, and surgery. Three-year survival was significantly higher in the pooled groups receiving radiotherapy as compared with the pooled groups not receiving radiotherapy. Comparison of the groups having pre-operative chemotherapy with those not having chemotherapy showed no significant difference in survival. Female patients had a significantly better survival than males. The results indicate that pre-operative irradiation had a beneficial effect on intermediate term survival, whereas the chemotherapy regime used did not influence survival.

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Resumen En un estudio prospectivo multicéntrico sobre 186 pacientes con carcinoma escamocelular del esófago candidatos para cirugía, se constituyeron cuatro grupos para randomización: Grupo 1, cirugía solamente; Grupo 2, quimioterapia preoperatoria (cisplatino y bleomicina) y cirugía; Grupo 3, irradiación preoperatoria (35 Gy) y cirugía; Grupo 4, quimioterapia preoperatoria, radioterapia y cirugía. La comparación entre el grupo que recibió quimioterapia y el que no la recibió no demostró diferencia significativa en cuanto a supervivencia. Las pacientes femeninas exhibieron una mejor supervivencia que los pacientes masculinos. Los resultados indican que la irradiación preoperatoria tuvo un efecto benéfico sobre la sobrevida a término medio, en tanto que la quimioterapia, en el regimen utilizado, no tuvo influencia sobre la supervivencia.

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Résumé Dans une étude prospective, multicentrique, 186 patients ayant un cancer épidermoïde de l'oesophage ont été randomisée dans quatre groupes: le groupe 1 a eu la chirurgie seule; le groupe 2, une chimiothérapie préopératoire (cis-platine et bléomycine); le groupe 3, une radiothérapie préopératoire suivie de chirurgie; et le groupe 4, une chimiothérapie et une radiothérapie préopératoires suivies de chirurgie. La survie à trois ans a été supérieure chez l'ensemble des patients ayant reçu la radiothérapie préopératoire par rapport à ceux qui n'en ont pas eu. Aucune différence de survie n'a pu être mise en évidence dans les groupes ayant eu ou pas de chimiothérapie. La survie des femmes a été significativement supérieure à celle des hommes. Ces résultats indiquent que la radiothérapie préopératoire apporte un plus en ce qui concerne la survie à moyen terme, alors que la chimiothérapie n'influence pas la survie.

     

The impact of the cox-2 inhibitor issue on perceptions of the pharmaceutical industry: content analysis and communication implications

The field of risk communication has its roots in the environmental, chemical, space, and nuclear arenas. As a number of these sectors have now vastly improved their communication strategies, attention is being placed on sectors that have been more problematic as of late. Examples of such sectors, include the food industries and the pharmaceutical/health sector. This article focuses on how large, multinational pharmaceutical companies can better communicate risks by analysis of one specific case, namely, that of the Cox-2 controversy.(1) For purposes of this article, risk communication is best described as "the flow of information and risk evaluations back and forth between academic experts, regulatory practitioners, interest groups and the general public," and "big pharma" refers to the more traditional R & D-based, innovative pharmaceutical companies.     

The seasonal interrelationship between melatonin, vasopressin, and serum osmolality in elderly subjects

Abstract: Plasma concentration of arginine vasopressin (AVP) and melatonin and serum osmolality were measured at noon and at midnight in individuals living in the northern hemisphere on March 22–23, June 13–14, September 26–27, and December 12–13 in 35 healthy volunteers (15 men and 20 women) aged 60–74 years. The nocturnal increase in melatonin was highest in the autumn and lowest in the winter in both sexes. The midnight serum osmolality level was lower in the autumn than in any other time of the year. In both the men and the women the AVP level was higher in winter than in any other season ( P < 0.01 and P < 0.0001, respectively). In men, the AVP level was higher at noon than at midnight in 49% of the investigated 24 hr periods, at the same level in 15% and lower in 36% (NS). The corresponding figures for women were 55%, 25%, and 20%, respectively ( P < 0.05). This study suggests a possible relationship between melatonin and serum osmolality.     

Detection of intestinal metaplasia in distal esophagus and esophagogastric junction by enhanced-magnification endoscopy

BACKGROUND: Standard videoendoscopy identifies columnar-lined esophagus but cannot distinguish intestinal metaplasia from other types of epithelium. Enhanced-magnification endoscopy identifies different mucosal pit patterns. A preliminary study suggested that a type 3 pattern is associated with the presence of intestinal metaplasia. This study assesses the value of enhanced-magnification endoscopy for the detection of intestinal metaplasia in the distal esophagus and esophagogastric junction in patients undergoing diagnostic EGD. METHODS: Patients undergoing diagnostic endoscopy for upper-GI symptoms underwent enhanced-magnification endoscopy after instillation of 1.5% acetic acid. The enhanced-magnification endoscopy mucosal pattern was classified into 3 types: 1, normal pits; 2, slit-reticular pattern; and 3, gyrus-villous pattern. Preliminary studies indicated that the type 3 pattern was related to intestinal metaplasia. One to 6 biopsies were targeted to areas having a type 3 pattern in columnar-appearing mucosa in the distal esophagus or esophagogastric junction. In the absence of type 3 pattern, one to 8 biopsies were targeted to areas with a type 2 pattern in columnar-appearing mucosa in the distal esophagus or esophagogastric junction. RESULTS: The overall frequency of intestinal metaplasia in the esophagus and esophagogastric junction was 38.8% (26/67 patients). There was a good correlation between the type 3 pattern and intestinal metaplasia in targeted biopsy specimens (sensitivity 88.5%, specificity 90.2%, positive predictive value 85.2%, negative predictive value 92.5%, overall accuracy 90.0%). CONCLUSIONS: Enhanced-magnification endoscopy is useful for detection of intestinal metaplasia in distal esophagus and esophagogastric junction.     

Development and Evaluation of a Semi-automated Segmentation Tool and a Modified Ellipsoid Formula for Volumetric Analysis of the Kidney in Non-contrast T2-Weighted MR Images

Volumetric analysis of the kidney parenchyma provides additional information for the detection and monitoring of various renal diseases. Therefore the purposes of the study were to develop and evaluate a semi-automated segmentation tool and a modified ellipsoid formula for volumetric analysis of the kidney in non-contrast T2-weighted magnetic resonance (MR)-images. Three readers performed semi-automated segmentation of the total kidney volume (TKV) in axial, non-contrast-enhanced T2-weighted MR-images of 24 healthy volunteers (48 kidneys) twice. A semi-automated threshold-based segmentation tool was developed to segment the kidney parenchyma. Furthermore, the three readers measured renal dimensions (length, width, depth) and applied different formulas to calculate the TKV. Manual segmentation served as a reference volume. Volumes of the different methods were compared and time required was recorded. There was no significant difference between the semi-automatically and manually segmented TKV (p = 0.31). The difference in mean volumes was 0.3 ml (95% confidence interval (CI), ?10.1 to 10.7 ml). Semi-automated segmentation was significantly faster than manual segmentation, with a mean difference = 188 s (220 vs. 408 s); p < 0.05. Volumes did not differ significantly comparing the results of different readers. Calculation of TKV with a modified ellipsoid formula (ellipsoid volume × 0.85) did not differ significantly from the reference volume; however, the mean error was three times higher (difference of mean volumes ?0.1 ml; CI ?31.1 to 30.9 ml; p = 0.95). Applying the modified ellipsoid formula was the fastest way to get an estimation of the renal volume (41 s). Semi-automated segmentation and volumetric analysis of the kidney in native T2-weighted MR data delivers accurate and reproducible results and was significantly faster than manual segmentation. Applying a modified ellipsoid formula quickly provides an accurate kidney volume.     

Nocturnal giddiness in relation to nocturia and other symptoms and to medication in the elderly

The aim of this study was to evaluate the relation of nocturia, somatic diseases, symptoms, and medication to nocturnal giddiness in a group of elderly men and women. A questionnaire survey was undertaken among 10,216 elderly subjects. The mean (+/-S.D.) ages of the men and women were 73.0 +/- 6.0 and 72.6 +/- 6.7 years, respectively. Nocturnal giddiness was reported by 14.1% of the men and 9.1% of the women. Poor health was reported by 44.4% (P < 0.0001) of the men with nocturnal giddiness and by 14.0% of the men without, and among the women these figures were 45.5% and 20.0% (P < 0.0001), respectively. In a multiple logistic regression analysis significant independent correlates of nocturnal giddiness were: nocturnal micturition episodes >or=3 versus nocturia or=80 years versus <70 years (2.5; 1.7-3.6); eyesight, poor versus good (1.8; 1.4-2.4); hearing, poor versus good (1.4; 1.1-1.9); pain in the cervical spine (2.1; 1.5-2.8); spasmodic chest pain (1.5; 1.1-2.0); diabetes (1.6; 1.0-2.4); analgesics (1.8; 1.3-2.4); and diuretics (1.4; 1.1-21.8). Sex, irregular heartbeats, and sleep medication were deleted by the logistic model.     

Comparison of therapeutic efficacy and biodistribution of 213Bi- and 211At-labeled monoclonal antibody MX35 in an ovarian cancer model

IntroductionThe purpose of this study was to compare the therapeutic efficacy and biodistribution of the monoclonal antibody MX35 labeled with either ²¹³Bi or ²¹¹At, both α-emitters, in an ovarian cancer model.MethodsOne hundred female nude BALB/c (nu/nu) mice were inoculated intraperitoneally with human ovarian cancer cells (OVCAR-3). Two weeks later, 40 of these mice were injected intraperitoneally with ～2.7 MBq of ²¹³Bi-MX35 (n=20) or ～0.44 MBq of ²¹¹At-MX35 (n=20). Four weeks after inoculation, 40 new OVCAR-3-inoculated mice were injected with the same activities of ²¹³Bi-MX35 (n=20) or ²¹¹At-MX35 (n=20). Presence of tumors and ascites was investigated 8 weeks after therapy. Biodistributions of intraperitoneally injected ²¹³Bi-MX35 and ²¹¹At-MX35 were studied in tumor-free nude BALB/c (nu/nu) mice (n=16).ResultsThe animals injected with ²¹³Bi-MX35 or ²¹¹At-MX35 2 weeks after cell inoculation had tumor-free fractions (TFFs) of 0.60 and 0.90, respectively. The untreated reference group had a TFF of 0.20. The groups treated with ²¹³Bi-MX35 or ²¹¹At-MX35 4 weeks after inoculation both had TFFs of 0.25, and the reference animals all exhibited evidence of disease. The biodistributions of ²¹³Bi-MX35 and ²¹¹At-MX35 were very similar to each other and displayed no alarming activity levels in the investigated organs.ConclusionsMicrometastatic growth of an ovarian cancer cell line was reduced in nude mice after treatment with ²¹³Bi-MX35or ²¹¹At-MX35. Treatment with ²¹¹At-MX35 provided a non-significantly better result for the chosen activity levels. The radiolabeled MX35 did not accumulate to a high extent in the investigated organs. No considerable signs of toxicity were observed.     

Physical activity promotion in schools: which strategies do schools (not) implement and which socioecological factors are associated with implementation?

We studied the implementation and associated factors of strategies (e.g. sports after school and during lunch break, active schoolyards, active school commuting) and organizational principles (e.g. safe bike racks, pupil involvement) that facilitate the physical activity (PA)-promoting role of schools. Key representatives of 111 elementary and 125 secondary schools filled out an online survey. Less than half of the elementary schools organized sports during lunch-break or after school. In secondary schools the least implemented strategies were the promotion of active school commuting and after-school sports. In general pupil, parental and community involvement scored low. Better knowledge of community schools and having attended in-service training were associated with higher implementation scores in elementary and secondary schools. Better implementation of the strategies was found in larger schools. Participation in activities from the School Sports Association and more perceived interest from parents and the school board were also associated with higher implementation scores. In conclusion, knowledge of community schools and in-service training next to sufficient human resources are potential key factors to promote PA. Efforts are needed to convince and help schools to increase parental and pupil involvement and to build a policy on school-community partnerships.