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41.
Marcel B. Bally Dana Masin Rajiv Nayar Pieter R. Cullis Lawrence D. Mayer 《Cancer chemotherapy and pharmacology》1994,34(2):137-146
Summary Previously we have demonstrated that the L1210 antitumor activity of liposomal doxorubicin increased significantly as the size of the liposomal carrier was reduced from 1.0 to 0.1 m. It is demonstrated herein that empty and drug-loaded small (0.1-m diameter) liposomes accumulate efficiently into the peritoneal cavity of normal and ascitic L1210 tumor-bearing animals following i.v. administration. In normal mice injected with 100 nm DSPC/chol liposomal doxorubicin (drug-to-lipid ratio of 0.2; wt/wt) approximately 2.8 g drug could be recovered from the peritoneal cavity following peritoneal lavage at 24 h. Although this represents only 0.7% of the injected doxorubicin dose, this level of drug is 2 orders of magnitude greater than that achieved following administration of an equivalent dose of free drug (20 mg/kg). The drug levels achieved within the peritoneal cavity are dependent on the physical characteristics (size, drug-to-lipid ratio and lipid composition) of the liposomes employed. Optimal delivery is obtained employing 100 nm DSPC/chol liposomal doxorubicin, a vesicle system that is known to retain entrapped drug following i.v. administration and exhibits extended circulation lifetimes. Analysis of drug and liposome distribution within the peritoneal cavity of normal mice indicates that as much as 50% of the measured doxorubicin and liposomal lipid is cell-associated. Flow cytometric analysis of the peritoneal cells demonstrated that cell-associated doxorubicin resides almost exclusively within resident peritoneal macrophages. The increased delivery of doxorubicin to the peritoneal cavity of normal mice following i.v. administration of small (0.1-m) liposomal doxorubicin is correlated with a pronounced (>90%) and prolonged (>14-day) suppression of resident peritoneal cells. Liposomal drug accumulation increased dramatically in animals with an established L1210 ascitic tumor. More than 5% of the injected dose was found in the peritoneal cavity of these animals 24 h after treatment with DSPC/chol liposomal doxorubicin as compared with a value of 0.03% of the injected dose achieved with free drug. It is proposed that accumulation of liposomes into the peritoneal cavity of normal and tumor-bearing mice may serve as a useful model for characterizing factors mediating the transfer of liposomes from the vascular compartment to extravascular sites. 相似文献
42.
Keijser LC Schreuder HW Buma P Weinans H Veth RP 《Archives of orthopaedic and trauma surgery》1999,119(7-8):440-444
Cryosurgery is an established adjuvant treatment of bone tumors which reduces the local recurrence rate. In this study, cryosurgical experiments were carried out in rabbits to study the temperature field, the extent of necrosis, and the revitalization process in order to optimize treatment. Intramedullary freezing of long bones with a closed liquid nitrogen cryoprobe and three consecutive sessions induces osteonecrosis down to the -10 degrees C isotherm without compromising the soft tissues. The application of a tourniquet does not influence the thermodynamics. The revitalization process is distinguished into an osteogenic and a remodelling phase. In rabbits, there is an obvious periosteal osteogenesis starting from 1 week after operation and overlapping the remodelling phase, which starts between 3 and 5 weeks after operation. Two out of eight rabbits sustained a pathologic fracture within 3 weeks of cryosurgery. No pathologic fractures were encountered during the remodelling phase, probably because of the profuse periosteal bone apposition that added mechanical strength. In clinical practice, no profound periosteal bone apposition and a high risk for pathologic fractures during the remodelling phase were noted. Future research should focus on bone strength during the remodelling phase of cryosurgically treated long bones, to decide on the role of preventive osteosynthesis or postoperative restrictions. This animal model is not advised for these biomechanical experiments because of its profuse periosteal bone apposition. 相似文献
43.
Pieter H. Van der Graaf Nigel P. Shankley James W. Black 《Naunyn-Schmiedeberg's archives of pharmacology》1996,354(3):389-392
We have studied the effects of idazoxan in rat aorta and small mesenteric artery. In the aorta, idazoxan behaved as a partial agonist (pKA=6.30). Prazosin produced rightward shift (pA2=9.88) and steepening of the idazoxan curve. In contrast, idazoxan had no effect of basal tension in the mesenteric artery, but shifted the noradrenaline curve to the right in a parallel manner (pA2=6.12). The selective al-adrenoceptor agonist, indanidine, also behaved as a partial agonist in the aorta and produced no significant contractions of the small mesenteric artery. Since idazoxan and indanidine have been reported to raise blood pressure in the pithed rat via an action at vascular 1-adrenoceptors, these results call into question the reliability of the small mesenteric artery assay as a predictor for 1-adrenoceptor-mediated pressor activity in vivo. 相似文献
44.
Pramod R. Saxena Carlos M. Villalón K. Mohan Dhasmana Pieter D. Verdouw 《Naunyn-Schmiedeberg's archives of pharmacology》1992,346(6):629-636
Summary Although 5-hydroxytryptamine (5-HT) increases porcine atrial force and rate via 5-HT4 receptors, its effect on left ventricular contractility is not known. Therefore, using the maximum rate of rise of left ventricular pressure (LVdP/dtmax) as an index of cardiac contractility, we have attempted to analyze the possible role of ventricular 5-HT4 receptors in the anaesthetized pig. The full agonists at 5-HT4 receptors, 5-HT and 5-methoxytryptamine (each 3, 10 and 30 g · kg–1), and the -adrenoceptor agonist, isoprenaline (0.01, 0.03 and 0.1 g · kg–1), increased heart rate, LVdP/dtmax and cardiac output. For a given degree of tachycardia, the increase in LVdP/dtmax by isoprenaline was substantially more than that observed with either 5-HT or 5-methoxytryptamine. The 5-HT4 receptor partial agonist, renzapride (3, 10, 30, 100 and 300 g · kg–1), also increased heart rate and LVdP/dtmax dose-dependently. When the heart was paced at 150 beats · min–1, increases in LVdP/dtmax as well as cardiac output (except with the highest doses) by 5-HT, 5-methoxytryptamine and isoprenaline were clearly attenuated. However, the magnitude of attenuation of LVdP/dtmax responses by cardiac pacing was more marked in the case of 5-HT and 5-methoxytryptamine than with isoprenaline.The effects of renzapride (300 g · kg–1) and tropisetron (0.3 and 3 mg · kg–1) on increases in heart rate and LVdP/dtmax by 5-HT, 5-methoxytryptamine and isoprenaline were also studied. In the absence of atrial pacing, both renzapride and tropisetron (3 mg · kg–1) effectively antagonized the responses to 5-HT and 5-methoxytryptamine; except for some decrease in the LVdP/dtmax response by tropisetron, the effect of isoprenaline remained essentially unchanged after the antagonists. During atrial pacing, renzapride significantly antagonized the responses to the first two doses of 5-HT, but the responses to the highest 5-HT dose and to 5-methoxytryptamine remained unaffected. Though, particularly after its higher dose, tropisetron reduced the responses to 5-HT and 5-methoxytryptamine, isoprenaline responses were also affected.The above results show that a significant part of the increase in LVdP/dtmax by 5-HT receptor agonists in the anaesthetized pig is a consequence of tachycardia elicited by these compounds via 5-HT4 receptors. Since the increase in LVdP/dtmax, compared to tachycardia, was much less with 5-HT and 5-methoxytryptamine than with isoprenaline, and since the antagonism by renzapride and tropisetron against 5-HT and 5-methoxytryptamine during atrial pacing was relatively weaker and/or unspecific, it appears unlikely that the increase in LVdP/dtmax, during atria] pacing is mediated by ventricular 5-HT4 receptors. This view is substantiated by our recent in vitro experiments where 5-HT (0.01 to 100 mol/l) failed to significantly increase contractions of porcine left ventricular trabeculae.Correspondence to P. R. Saxena at the above address 相似文献
45.
Ate van der Gaast Pieter Sonneveld Dennis R. A. Mans Ted A. W. Splinter 《Cancer chemotherapy and pharmacology》1992,29(4):335-337
Summary Two patients presenting with malignant meningitis resulting from small-cell carcinoma of the lung and with lymphoblastic leukemia, respectively, were treated by intrathecal administration of etoposide. In both cases, this treatment was well tolerated and produced relief of the central nervous system symptoms. Pharmacokinetic data showed that cerebrospinal fluid drug levels of up to 5.2 g/ml were achieved, which were considerably higher than those obtained after i.v. administration of high-dose etoposide. 相似文献
46.
Carla M van Herpen Maaike Looman Marijke Zonneveld Nicole Scharenborg Peter C de Wilde Louis van de Locht Matthias A W Merkx Gosse J Adema Pieter H de Mulder 《Clinical cancer research》2004,10(8):2626-2635
The objective of this Phase II study was to evaluate the pharmacodynamic and immune effects of intratumorally administered recombinant human interleukin-12 (IL-12) on regional lymph nodes, primary tumor, and peripheral blood. Ten previously untreated patients with head and neck squamous cell carcinoma were injected in the primary tumor two to three times, once/week, at two dose levels of 100 or 300 ng/kg, before surgery. We compared these patients with 20 control (non-IL-12-treated) patients. Toxicity was high, with unexpected dose-limiting toxicities at the 300 ng/kg dose level. Dose-dependent plasma IFN-gamma and IL-10 increments were detected. These cytokine levels were higher after the first injection than after the subsequent injections. A rapid, transient reduction in lymphocytes, monocytes, and all lymphocyte subsets, especially natural killer cells, was observed, due to a redistribution to the lymph nodes. In the enlarged lymph nodes of the IL-12-treated patients, a higher percentage of natural killer cells and a lower percentage of T-helper cells were found compared with control patients. The same pattern was detected in the infiltrate in the primary tumor. Real-time semiquantitative PCR analysis of peripheral blood mononuclear cells in the peripheral blood showed a transient decrease of T-bet mRNA. Interestingly, the peripheral blood mononuclear cells in the lymph nodes showed a 128-fold (mean) increase of IFN-gamma mRNA. A switch from the Th2 to a Th1 profile in the lymph nodes compared with the peripheral blood occurred in the IL-12-treated patients. In conclusion, in previously untreated head and neck squamous cell carcinoma patients, recombinant human IL-12 intratumorally showed dose-limiting toxicities at the dose level of 300 ng/kg and resulted in measurable immunological responses locoregionally at both dose levels. 相似文献
47.
Arvid Kropveld Pieter J. Slootweg Marinus A. Blankenstein Chris H. J. Terhaard Gerrit J. Hordijk 《The Laryngoscope》1998,108(10):1548-1552
Objective: To study the relationship between the proliferative capacity, represented by the immunohistochemical labeling index (LI) of proliferation marker Ki-67, and the p53 status, as in theory an intact p53 cell cycle checkpoint system should result in a lower proliferative capacity. Study Design: From a group of 128 patients with a T2 laryngeal carcinoma, presented from 1989 to 1993 at the University Hospital Utrecht, 20 patients with recurrent disease and 16 patients without recurrent disease were randomly selected. All patients received primary irradiation. Methods: Denaturing gradient gel electrophoresis and immunohistochemistry determined the p53 status. MIB-1 staining was used to determine the Ki-67 LI. Results: In 36% of specimens we found a p53 mutation with overexpression (LI, 31%). In 8% a p53 mutation without p53 overexpression was found (LI, 18%). Forty-two percent showed no mutation but, nevertheless, overexpression (LI, 35%). Neither mutation nor overexpression was found in 14% (LI, 38%). No correlation exists between p53 status and proliferative capacity of tumors (analysis of variance [ANOVA]; P = .104). The proliferation rate as established with Ki-67 LI positively correlates with response to radiotherapy (P = .006). Conclusions: 1. Overexpression of wild-type p53 protein does not result in cell cycle arrest measurable by a lower Ki-67 LI in comparison with cases overexpressing mutant type p53 protein. 2. A high Ki-67 LI correlates with a favorable response to radiotherapy. Laryngoscope, 108:1548–1552, 1998 相似文献
48.
Influence of matching for exposure time on estimates of attributable mortality caused by nosocomial bacteremia in critically ill patients. 总被引:2,自引:0,他引:2
Stijn Blot Dirk De Bacquer Eric Hoste Pieter Depuydt Koenraad Vandewoude Jan De Waele Dominique Benoit Johan De Schuijmer Francis Colardyn Dirk Vogelaers 《Infection control and hospital epidemiology》2005,26(4):352-356
OBJECTIVE: To evaluate the influence of matching on exposure time on estimates of attributable mortality of nosocomial bacteremia as assessed by matched cohort studies. DESIGN: Two retrospective, pairwise-matched (1:2) cohort studies. SETTING: A 54-bed intensive care unit (ICU) in a university hospital. PATIENTS: Patients with nosocomial Escherichia coli bacteremia (n = 68) and control-patients without nosocomial bacteremia (n = 136 for each matched cohort study). INTERVENTION: In both matched cohort studies, the same set of bacteremic patients was matched with control-patients using the APACHE II system. In the first study, control-patients were required to have an ICU stay at least as long as the respective bacteremic patient prior to onset of bacteremia (matching on exposure time). In the second study, control-patients were required to have an ICU stay shorter than the stay prior to the development of bacteremia in the respective bacteremic patient (no matching on exposure time). RESULTS: For bacteremic patients, the mean ICU stay before onset of the bacteremia was 9 days (median, 6 days). In the first matched cohort study, hospital mortality was not different between bacteremic patients and control-patients (44.1% vs 43.4%; P = .999). In the second study, mortality of bacteremic patients and control-patients was also not different (44.1% vs 47.8%; P = .657). Mortality rates between control groups were not different (43.4% vs 47.8%; P = .543). CONCLUSION: Matching or not matching on exposure time did not alter the estimate of attributable mortality for ICU patients with E. coli bacteremia. 相似文献
49.
50.
Assessment of drug interactions in hepatobiliary transport using rhodamine 123 in sandwich-cultured rat hepatocytes. 总被引:8,自引:0,他引:8
The purpose of the present study was to explore the utility of sandwich-cultured rat hepatocytes as an in vitro tool to examine drug interactions at the hepatic transport level. Rhodamine 123 was used as a model substrate for P-glycoprotein-mediated biliary excretion. Effects of various types of P-glycoprotein modulation on the biliary excretion index (BEI; a relative measure of the extent of biliary excretion) and the in vitro biliary clearance (CL(bile)) were determined. Significant reductions in rhodamine 123 BEI and CL(bile) were noted in the presence of the P-glycoprotein inhibitors verapamil (30-100 microM) and progesterone (100 microM). The P-glycoprotein activator quercetin (10-100 microM) enhanced rhodamine 123 CL(bile) by approximately 4-fold, with only a minor effect on BEI, suggesting that quercetin had a more pronounced effect on uptake at the basolateral membrane rather than excretion across the canalicular membrane. Treatment of hepatocytes for 48 h with dexamethasone (10 microM) resulted in significant enhancement of CL(bile), whereas rifampin (5-50 microM) increased both BEI and CL(bile), indicating that the inducing effects of dexamethasone and rifampin were occurring at the basolateral and canalicular membranes, respectively. Total rhodamine 123 uptake in sandwich-cultured rat hepatocytes was partly saturable and was affected by the presence of typical Oatp1a4 substrates (digoxin, quinine, d-verapamil, 17beta-estradiol-d-17beta-glucuronide). In summary, sandwich-cultured rat hepatocytes are a useful tool to study mechanisms of hepatobiliary drug disposition and to predict the potential for drug interactions in hepatic transport. 相似文献