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1.

001-es BibID:BIBFORM029731
Első szerző:Ali, M. J.
Cím:Isolation of drug delivery from drug effect : problems of optimizing drug delivery parameters / Ali M. J., Navalitloha Y., Vavra M. W., Kang E. W., Itskovich A. C., Molnar P., Levy R. M., Groothuis D. R.
Dátum:2006
ISSN:1522-8517
Megjegyzések:A recurring question in the treatment of malignant brain tumors has been whether treatment failure is due to inadequate delivery or ineffective drugs. To isolate these issues, we tested a paradigm in which the "therapeutic" agent was a toxin about which there could be no question of efficacy, provided it was delivered in adequate amounts; we used 10% formalin. We infused 10% formalin into 5- to 8-mm subcutaneous RG-2 and D54-MG gliomas at increasing rates until we achieved 100% tumor cell kill. In RG-2 gliomas, infusions of 10 microl/h x 7 days, and 2, 4, 6, and 8 microl/min x 2 h failed to kill tumors, although growth was delayed, while infusion rates of 12 microl/min x 60 min and 48 microl/min x 15 min produced 100% tumor kill. In D54-MG tumors, infusions of 4, 8, and 24 microl/min produced 100% tumor kill. 14C-Formalin autoradiographs showed a heterogeneous distribution after infusions of 2 microl/min x 2 h, whereas infusions of 48 microl/min x 15 min showed a homogeneous distribution within the tumor, but more than 95% of tissue radioactivity was found in tissue surrounding tumor. Drug delivery remains a major issue in brain tumor treatment: Distribution inhomogeneity, rapid efflux, and consequent treatment failures are likely due to high interstitial fluid pressure. Because the infusion rates being used in the treatment of human brain tumors are low and the tumors are larger, treatment failures can be expected on the basis of inadequate drug delivery alone, regardless of the effectiveness of the drug.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Neuro-Oncology. - 8 : 2 (2006), p. 109-118. -
További szerzők:Navalitloha, Y. Vavra, M. W. Kang, E. W. Itskovich, A. C. Molnár Péter Pál (1951-) (pathológus) Levy, R. M. Groothuis, Dennis
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2.

001-es BibID:BIBFORM055551
Első szerző:Blasberg, Ronald
Cím:A review of hyperosmotic blood-brain barrier disruption in seven experimental brain tumor models / Ronald G. Blasberg, Dennis Groothuis, Peter Molnár
Dátum:1990
ISBN:0-444-81120-6
Tárgyszavak:Orvostudományok Klinikai orvostudományok könyvfejezet
Megjelenés:Pathophysiology of the blood-brain barrier : long term consequences of barrier dysfunction for the brain / eds. Barbro B. Johansson, Christer Owman, Hakan Widner. - p. 197-220. -
További szerzők:Groothuis, Dennis Molnár Péter Pál (1951-) (pathológus)
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3.

001-es BibID:BIBFORM029757
Első szerző:Blasberg, Ronald
Cím:Drug delivery to brain tumors : physiological and pharmacokinetic aspects of chemotherapy / Blasberg R. G., Groothuis D. R., Wright D. C., Molnár P.
Dátum:1986
Tárgyszavak:Orvostudományok Klinikai orvostudományok könyvfejezet
Megjelenés:Biology of Brain Tumor / eds. Walker, M. D., Thomas D. G. T. - p. 211-220
További szerzők:Groothuis, Dennis Wright, D. C. Molnár Péter Pál (1951-) (pathológus)
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4.

001-es BibID:BIBFORM029712
Első szerző:Blasberg, Ronald
Cím:Concurrent measurements of blood flow and transcapillary transport in avian sarcoma virus-induced experimental brain tumors : implications for chemotherapy / Blasberg R., Molnar P., Groothuis D., Patlak C., Owens E., Fenstermacher J.
Dátum:1984
ISSN:0022-3565
Megjegyzések:A blood-to-tissue transfer constant, K, and tissue blood flow, F, were measured concurrently in seven rats with a total of 19 separate brain tumors induced by intracerebral inoculation of avian sarcoma virus. Regional and local measurements of K and F were obtained using double-label quantitative autoradiography with alpha-[14C]aminoisobutyric acid and [131I]iodoantipyrine, computerized microdensitometry and image analysis. Apparent tissue extraction fractions and capillary permeability-surface area products were calculated for different tumor regions, brain adjacent to tumor and tumor-free brain. The following observations were made: five histological categories of the tumors were found; significant local and regional variations of both K and F were typical in each group, resulting in marked regional variability of permeability-surface area products but more uniform values of apparent extraction fraction; the values of F, K, permeability-surface area products and apparent extraction fraction correlated poorly with morphological features of the tumors (necrosis, cellularity, cytology, location and size); the extraction fraction of alpha-aminoisobutyric acid was usually highest in tumor centers and then decreased in a gradient from tumor periphery through adjacent brain; and regardless of classification or histological features, capillary permeability and surface area, and not tissue perfusion or blood flow, seem to determine the blood-to-tissue transport processes (delivery of bloodborne materials) in most regions of these experimental brain tumors. An operational pharmacokinetic model of drug concentration in tumor tissue is developed and the results of our analysis indicate that increases in capillary permeability such as measured in these studies would not be sufficient to deliver adequate amounts of water-soluble drugs with short plasma half-lives to tumor tissue.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal Of Pharmacology And Experimental Therapeutics. - 231 : 3 (1984), p. 724-735. -
További szerzők:Molnár Péter Pál (1951-) (pathológus) Groothuis, Dennis Patlak, Clifford S. Owens, E. Fenstermacher, Joseph D.
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5.

001-es BibID:BIBFORM029711
Első szerző:Blasberg, Ronald
Cím:Application of quantitative autoradiographic measurements in experimental brain tumor models / Blasberg R. G., Groothuis D. R., Molnar P.
Dátum:1981
ISSN:0271-8235
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Seminars In Neurology. - 1 : 3 (1981), p. 203-221. -
További szerzők:Groothuis, Dennis Molnár Péter Pál (1951-) (pathológus)
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6.

001-es BibID:BIBFORM029710
Első szerző:Blasberg, Ronald
Cím:Regional blood flow in ethylnitrosourea-induced brain tumors / Blasberg Ronald G., Kobayashi Tomowo, Horowitz Marc, Rice J. M., Groothuis Dennis, Molnar Peter, Fenstermacher Joseph D.
Dátum:1983
ISSN:0364-5134
Megjegyzések:Regional blood flow was measured in experimental brain tumors using iodoantipyrine labeled with carbon 14 and quantitative autoradiography. A total of fifteen oligodendrogliomas, sixteen mixed gliomas, one astrocytoma, one ependymoma, and three malignant schwannomas were studied in 9 rats. The mean tumor blood flows for all glioma classifications were similar, averaging 45 +/- 3 (standard error of the mean) ml . hg-1 . min-1. Flow was fairly uniform within individual oligodendrogliomas and there was no apparent correlation between blood flow and tumor size or location. The mixed gliomas were larger than the oligodendrogliomas and had a wider range of blood flow. Small focal areas of necrosis were observed in 7 mixed gliomas, and low flows were usually measured in these regions; these flows were not always the lowest regional values measured within the mixed gliomas or total group of tumors, however. Small tumor regions with increased vascularity, frequently with endothelial cell proliferation, were observed in oligodendrogliomas and to a greater extent in mixed gliomas; these regions were correlated with small elevations in blood flow (10 to 15 ml . hg-1 . min-1) in comparison with surrounding tumor tissue. Brain adjacent to tumor usually had higher blood flows than that in tumor periphery. Hemispheric differences in blood flow related to the site of primary tumor growth were not observed.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Annals Of Neurology. - 14 : 2 (1983), p. 189-201. -
További szerzők:Kobayashi, Tomowo Horowitz, Marc Rice, Jerry M. Groothuis, Dennis Molnár Péter Pál (1951-) (pathológus) Fenstermacher, Joseph D.
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7.

001-es BibID:BIBFORM029709
Első szerző:Blasberg, Ronald
Cím:Regional blood-to-tissue transport in ethylnitrosourea-induced brain tumors / Blasberg R. G., Kobayashi T., Horowitz M., Rice J. M., Groothuis D., Molnar P., Fenstermacher J. D.
Dátum:1983
ISSN:0364-5134
Megjegyzések:Regional blood-to-tissue transport, expressed as a unidirectional transfer rate constant (K), was measured in experimental brain tumors using alpha-aminoisobutyric acid (AIB) labeled with carbon 14 and quantitative autoradiography. A total of sixteen oligodendrogliomas, four mixed gliomas, three astrocytomas, two diffuse gliomatosis, one anaplastic astrocytoma, one ependymoma and four malignant schwannomas were studied in 9 rats. The mean Ks for all glioma classifications were similar, averaging 2.6 +/- 0.4 (standard error of the mean) ml . kg-1 . min-1, and were only slightly higher than those for nontumorous parietal cortex (2.1 ml . kg-1 . min-1), corpus callosum (0.9 ml . kg-1 . min-1), and a comparable region of brain tissue in the contralateral hemisphere (1.3 ml . kg-1 . min-1). Values of K varied minimally in the intracerebral gliomas and were marginally correlated with tumor cell morphology in only two tumors. In some (but not all) of the larger gliomas, increased vascularity, with or without endothelial proliferation, was associated with a 3- to 15-fold increase in K. Regional K values in malignant schwannomas were highly variable (4 to 207 ml . kg-1 . min-1) and generally were not correlated with specific histological features of the tumor, except in some regions with increased vascularity. Estimates of the average fractional extraction of AIB by the intracranial gliomas and malignant schwannomas were 0.01 and 0.2, respectively; average fractional extractions for nontumorous brain were approximately 0.003.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Annals Of Neurology. - 14 : 2 (1983), p. 202-215. -
További szerzők:Kobayashi, Tomowo Horowitz, Marc Rice, Jerry M. Groothuis, Dennis Molnár Péter Pál (1951-) (pathológus) Fenstermacher, Joseph D.
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8.

001-es BibID:BIBFORM029746
Első szerző:Groothuis, Dennis
Cím:Hyperosmotic Blood-Brain Barrier Disruption : reply / Dennis Groothuis, Gregory Lapin, Peter Warnke, Peter Molnar
Dátum:1990
ISSN:0022-3085
Tárgyszavak:Orvostudományok Klinikai orvostudományok levél
Megjelenés:Journal Of Neurosurgery. - 73 : 5 (1990), p. 806-807. -
További szerzők:Lapin, Gregory D. Warnke, Peter C. Molnár Péter Pál (1951-) (pathológus)
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9.

001-es BibID:BIBFORM029745
Első szerző:Groothuis, Dennis
Cím:Blood-brain barrier disruption in brain-tumor therapy / Dennis R. Groothuis, Peter C. Warnke, Peter Molnar, Gregory D. Lapin, Michael A. Mikhael.
Dátum:1990
Tárgyszavak:Orvostudományok Klinikai orvostudományok levél
Megjelenés:Journal of Neurosurgery. - 73 : 3 (1990), p. 476-477. -
További szerzők:Warnke, Peter C. Molnár Péter Pál (1951-) (pathológus) Lapin, Gregory D. Mikhael, Michael A.
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10.

001-es BibID:BIBFORM029733
Első szerző:Groothuis, Dennis
Cím:Effect of hyperosmotic blood-brain barrier disruption on transcapillary transport in canine brain tumors / Groothuis Dennis R., Warnke Peter C., Molnar Peter, Lapin Gregory D., Mikhael Michael A.
Dátum:1990
ISSN:0022-3085
Megjegyzések:Whether hyperosmotic blood-brain barrier (BBB) disruption is a technique that can be used to increase permeability of brain-tumor capillaries and thereby transiently increase drug delivery to the brain tumor is controversial. Nine virally induced brain tumors were studied in seven dogs, before and after hyperosmotic BBB disruption with 1.4 osmolar mannitol. Each dog was studied with computerized tomography (CT) after administration of the water-soluble tracer meglumine iothalamate. Each study lasted 30 minutes. A baseline CT scan and 35 to 40 additional CT scans were obtained to provide a time-related measurement of the amount of meglumine iothalamate in tissue (Am(t], and 30 plasma samples were collected to provide the time-related measurement of meglumine iothalamate in plasma (Cp(t]. The data were analyzed by three different methods: 1) a two-compartment model and nonlinear curve fitting were used to calculate K1 (blood-to-tissue or influx constant), k2 (tissue-to-blood or efflux constant), and Vp (plasma vascular space); 2) K1 values were calculated with a two-compartment model, assuming no efflux, at the time point for each CT scan; and 3) a "tissue advantage ratio" was calculated that expressed the ratio of tissue uptake of meglumine iothalamate at each time point, comparing values before and after BBB disruption. Regardless of which method of data analysis was used, there was a marked and significant increase in transcapillary transport of meglumine iothalamate to tumor-free brain regions, while there was only a small, transient, and insignificant increase to the brain tumors. Although there were often marked increases in delivery to cortex in the same hemisphere as the tumors, there was no significant increase to brain immediately surrounding the tumors, perhaps due to altered circulatory dynamics in this region. These data raise serious questions as to the wisdom of using this technique to increase drug delivery to brain tumors in patients and strongly support the continued study of this technique in experimental brain tumors before it is used in patients.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Journal Of Neurosurgery. - 72 : 3 (1990), p. 441-449. -
További szerzők:Warnke, Peter C. Molnár Péter Pál (1951-) (pathológus) Lapin, Gregory D. Mikhael, Michael A.
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11.

001-es BibID:BIBFORM029725
Első szerző:Groothuis, Dennis
Cím:The effect of an amino acid-lowering diet on the rate of melphalan entry into brain and xenotransplanted glioma / Groothuis D. R., Lippitz B. E., Fekete I., Schlageter K. E., Molnar P., Colvin O. M., Roe C. R., Bigner D. D., Friedman H. S.
Dátum:1992
ISSN:0008-5472
Megjegyzések:Melphalan (L-phenylalanine mustard, L-PAM, alkeran; molecular weight, 305,000) is transported across tumor cell membranes and the blood-brain barrier by the large neutral amino acid (LNAA) transport system. Normally, plasma LNAA levels are high enough and the affinity low enough that this system does not transport much melphalan into the brain. However, plasma amino acids can be reduced by fasting and protein-free diet. We used this method to reduce competition and to increase melphalan transport into brain tumors. In nude mice fasted for 12 h and then fed a protein-free diet for 2 and 6 h, mean plasma LNAA levels were 46% and 42% of control values. Nude mice with xenotransplanted D-54MG human gliomas were used to study tissue distribution and uptake kinetics of [3H]melphalan in a control group and a diet group (after a 12-h fast and 2 h of a 0% protein diet). The K1 (blood-to-tissue transfer constant) of melphalan, determined by graphical analysis and by nonlinear fitting to a 2-compartment model, was higher in the diet group in all tumor regions except the necrotic center of subcutaneous tumors; the increase was significant in the tumor periphery of brain and s.c. tumors. The ratio of K1s (diet to control) varied from 1.2 to 1.3 in brain tumors, 1.9 to 2.1 in subcutaneous tumors, and 1.8 to 3.1 in tumor-free brain. The apparent [3H]melphalan distribution space was significantly higher in the tumor periphery of both brain and subcutaneous tumors of the 15- and 30-min diet group. We also measured blood-brain barrier transport of [alpha-14C]aminoisobutyric acid and blood flow (with [131I]iodoantipyrine): the K1 of [alpha-14C]aminoisobutyric acid was 28.1 +/- 6.6 (SE) in brain tumors and 24.3 +/- 8.9 microliters/g/min in subcutaneous tumors. Blood flow was 58.2 --> 3.9 in brain tumors and 5.2 +/- 0.4 ml/100 g/min in subcutaneous tumors. Fasting, when combined with a protein-free diet, reduces plasma amino acid levels and thereby reduces competition between melphalan and LNAAs. This may increase the amount of melphalan that can enter a brain tumor without increasing the administered drug dose and suggests a therapeutic manipulation that can be used to increase the delivery of melphalan.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Cancer Research. - 52 : 20 (1992), p. 5590-5596. -
További szerzők:Lippitz, Bodo E. Fekete István (1951-) (neurológus, pszichiáter) Schlageter, Kurt E. Molnár Péter Pál (1951-) (pathológus) Colvin, Michael O. Roe, Charles R. Bigner, Darell Friedman, Henry S.
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12.

001-es BibID:BIBFORM029685
Első szerző:Groothuis, Dennis
Cím:Regional blood flow in avian sarcoma virus (ASV)-induced brain tumors / Groothuis D., Blasberg R. G., Molnár P., Bigner D., Fenstermacher J. D.
Dátum:1983
ISSN:0340-5354
Megjegyzések:Regional blood flow (F) was measured in avian sarcoma virus (ASV)-induced brain tumors in rats. Blood flow was variable in individual as well as different tumors; tumor F did not correlate with histologic classification, tumor size, central versus peripheral tumor regions, intraparenchymal location, cell density, or specific cytologic characteristics. Low values of F did correlate with tumor necrosis and hydrocephalus; high values of F correlated with tumorous invasion or association with choroid plexus. Mean tumor F was not significantly different from that of the same anatomic, tumor-free brain region of the contralateral hemisphere, but F in brain tissue adjacent to the tumor was depressed significantly. Depression of F was observed in tumor-free cortex and corpus callosum, especially in the hemisphere ipsilateral to the main tumor mass and in those animals with hydrocephalus.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Neurology. - 33 : 6 (1983), p. 686-696. -
További szerzők:Blasberg, Ronald Molnár Péter Pál (1951-) (pathológus) Bigner, Darell Fenstermacher, Joseph D.
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