Evaluation of hepatic artery infusion chemotherapy with a procedure they term arterial angiocomputed tomography.
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Antineoplastic Agents↗
Biomedical subjects
R J Lutz
Publications and source records attributed to R J Lutz.
Isoprenoid modification of rab proteins terminating in CC or CXC motifs.
Mevalonate starvation of hamster fibroblasts resulted in a shift of rab1b from the membrane to the cytosolic fraction, suggesting that rab1b depends upon an isoprenoid modification for its membrane localization. rab1b and rab3a proteins expressed in insect cells incorporated a product of [3H]mevalonate, and gas chromatography analysis of material released by Raney nickel cleavage demonstrated that rab1b and rab3a are modified by geranylgeranyl groups. Additionally, in vitro prenylation analysis demonstrated farnesyl modification of H-ras but geranylgeranyl modification of five rab proteins (1a, 1b, 2, 3a, and 6). Together, these results suggest that the carboxyl-terminal CC/CXC motifs (X = any amino acid) specifically signal for addition of geranylgeranyl, but not farnesyl, groups. A rab1b mutant protein lacking the two carboxyl-terminal cysteine residues was not prenylated in vitro. However, since a mutant H-ras protein that terminates with tandem cysteine residues was also not modified, the CC motif may be essential, but not sufficient, to signal prenylation of rab1b. Finally, rab1b and rab3a proteins were not efficient substrates for either farnesyl- or geranylgeranyltransferase activities that modify CAAX-containing proteins (A = any aliphatic amino acid). Therefore, rab proteins may be modified by a prenyltransferase(s) distinct from the prenyltransferases that modify carboxyl-terminal CAAX proteins.
Amino Acid Sequence↗
In vitro study of simultaneous infusion of incompatible drugs in multilumen catheters.
Multilumen catheters are commonly used to simultaneously administer incompatible drugs to critically ill patients. Though there are no known documented reports that this practice has been responsible for harmful events in patients, likewise there are no published data to verify the safety and efficacy of this practice. This study utilized an in vitro model flow system to examine the physicochemical phenomena that occur when two incompatible drugs (phenytoin and total parenteral nutrition) are simultaneously administered through multilumen catheters. Flow conditions and drug infusions in the venous model were designed to mimic the in vivo clinical situation to evaluate two central venous catheter types, a double- and a triple-lumen catheter. Video recordings were made of drug interactions, and assays of phenytoin concentration were performed on samples of the circulating fluid. White clouds of phenytoin precipitation were observed near the tip of the double-lumen catheter but not the triple-lumen catheter. Infusion through the double-lumen catheter resulted in an average of 6% loss of phenytoin to precipitate, which, on microscopic examination, appeared as spindle-shaped crystals 25 to 50 microns in length and 5 to 10 microns wide. In some cases, millimeter-size fragments of phenytoin precipitate were seen to dislodge from the tip of the double-lumen catheter. The adjacent orifices at the tip of the end hole of the double-lumen catheter appeared to permit interaction of the two effusing streams of the incompatible drugs, whereas the staggered orifices of the triple-lumen catheter reduce this interaction.(ABSTRACT TRUNCATED AT 250 WORDS)
Catheterization, Central Venous↗
Defective elongation of fatty acids in a recessive 25-hydroxycholesterol-resistant mutant cell line.
The Chinese hamster ovary recessive mutant, crB, has been selected for its resistance to the cytotoxic effects of 25-hydroxycholesterol in sterol-free media (Sinensky, M., Logel, J., and Torget, R. (1982) J. Cell. Physiol. 113, 314-319). Growth of crB in a chemically defined lipid-poor medium is very slow and is enhanced by a mixture of saturated and unsaturated fatty acids. Incorporation of [3H]acetate into total fatty acids is 4-fold lower in crB compared to that in parental Chinese hamster ovary K1 and in contrast to the wild-type cells, crB cells are unable to synthesize either stearate or oleate. In addition, crB cells can not elongate exogenous palmitate, while they are capable of desaturating exogenous stearate. The mutant cells are also pleiotropically defective in the regulation of mRNA levels for the enzymes of cholesterol biosynthesis. 25-Hydroxycholesterol is a poor regulator of the synthesis and degradation of the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-coenzyme A reductase in crB in comparison to the wild-type Chinese hamster ovary K1 cells. The defect in the elongation of fatty acids is reversed in revertants of crB selected for their ability to grow in lipid-poor medium. Such revertants exhibit normal regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity by 25-hydroxycholesterol. Regulation of reductase activity in crB cells can also be restored by supplementing the culture medium with a mixture of fatty acids that restores normal growth rate. The defective regulation of reductase in crB does not appear to be due to nonspecific adverse effects of fatty acid starvation nor is it due to any gross change in the fatty acid composition of cellular phospholipids. These results strongly suggest a direct relationship between the fatty acid auxotrophy of crB and defective regulation of the enzymes of cholesterol biosynthesis.
Acetates↗
Hepatic artery model for evaluating the distribution of intraarterial chemotherapy infusion: nonpulsed versus pulsed infusions.
The effect of a commercially available pulsatile slow-infusion system on the degree of infusate mixing and distribution was assessed in a life-size glass model of the hepatic arterial system. The authors determined, both visually and quantitatively, the mixing homogeneity of a low-flow infusion (1.4 mL/min) of red dye through a side-hole catheter (2.5 F outer diameter) into pulsatile flow (300 mL/min) of a fluid with the same viscosity as blood. When comparing nonpulsed versus pulsed infusion techniques, the authors found that the pulsatile infusion system did not significantly improve the inhomogeneity of dye distribution in the 16 hepatic arterial branches. The results of this in vitro study suggest that a pulsatile infusion system that uses low pulse velocities without regard for cardiac cycle is less than optimal and does not significantly improve drug mixing at the standard slow infusion rates. Moreover, as potential new intraarterial delivery systems are developed to improve drug mixing, in vitro models may be the most useful means of initially evaluating their efficacy.
Hepatic Artery↗
Purification of a phospholipase C from rat liver cytosol that acts on phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-phosphate.
A soluble phospholipase C from rat liver was purified to homogeneity using phosphatidylinositol 4,5-bisphosphate (PIP2) as substrate. After ammonium sulfate fractionation, the purification involved chromatography on phosphocellulose, DEAE-Sepharose CL-6B, hydroxylapatite, Reactive Blue 2 dye-linked agarose, and Mono S cation exchanger. Under the conditions of the assay, the pure enzyme had a specific activity of 407 mumol/mg protein/min. It migrated as a single band with a molecular mass of 87 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The water-soluble product formed during the hydrolysis of PIP2 by the purified enzyme was inositol 1,4,5-trisphosphate. The enzyme shows one-half of maximum velocity at 2 microM Ca2+ with PIP2 as substrate. Between 0 and 100 microM Ca2+, the enzyme shows approximately the same activity with phosphatidylinositol 4-phosphate (PIP) as it does with PIP2, and very low activity with phosphatidylinositol. The enzyme is activated by low concentrations of basic proteins; for example, with PIP2 as substrate, 1 microgram/ml histone activates the enzyme 3.6-fold. The enzyme shows an almost absolute requirement for monovalent salts which can be met by different alkali metal halides. A second, minor peak of PIP2-hydrolyzing phospholipase C activity was resolved during chromatography of the enzyme on hydroxylapatite. The substrate specificity suggests that PIP and PIP2 are normal substrates of this enzyme. Under physiological conditions of activation, the enzyme may therefore generate inositol 1,4-bisphosphate and inositol 1,4,5-trisphosphate in amounts determined by the ratio of PIP and PIP2 present in the cellular membranes.
Animals↗
Mixing studies during hepatic artery infusion in an in vitro model.
A glass model of the hepatic artery network was used to study the effect of infusion rate on the degree of mixing from an end hole catheter placed in the gastroduodenal artery. Red dye solutions were infused at rates ranging from 1 ml/hour to 20 ml/minute. Effluent samples from each of 16 branch arteries were collected and dye concentrations were analyzed by means of a spectrophotometer. Low infusion rates, e.g., up to 5 ml/minute, showed streaming of the dye solutions and a nonhomogeneous dye distribution in the distal branches. At 20 ml/minute, dye distribution was much more uniform. These experiments are designed to simulate intrahepatic infusion of chemotherapeutic drug solutions. Theoretical considerations suggesting a pharmacokinetic advantage of intraarterial delivery implicitly assume uniform distribution of drug solutions to all perfused tissue. The in vitro data in this study suggests that this assumption may not be operative under certain infusion conditions. Slow infusion can lead to streaming and nonuniform distribution of infused drug solutions, which may in part explain the variability in tumor response in different tissue regions and also some observed toxicities, such as bile duct stricturing and fibrosis after intrahepatic infusions.
Antineoplastic Agents↗
Mixing problems of low flow hepatic artery infusion. Improvement with small caliber double lumen balloon catheters.
The problem of inhomogeneous mixing encountered during hepatic artery (HA) chemotherapy infusion was assessed and a practical solution examined. A glass model of the human HA distribution was used to determine mixing homogeneity of low flow (1.4 mL/minute) dye infusion into pulsatile flow (280-300 mL/minute) of a fluid isoviscous to blood. Dye concentration in each of 16 HA branches was determined by photospectrometry. Dye infusion was carried out through 2-2.5F double lumen end hole or proximal side hole balloon catheters without balloon inflation, with balloon inflation maintaining full HA flow, and with the balloon inflated so that HA flow was reduced by 50%. The measurements taken without balloon inflation showed gross inhomogeneity of dye concentration in various branches. The inhomogeneity was not improved during balloon inflation as long as full HA flow was maintained. After balloon inflation reduced HA flow by 50%, dye mixing was improved significantly, with infusion through side hole catheters (alpha = .002) but not significantly (alpha = .2) with infusion through end hold catheters. This investigation suggests that the proposed technique might be useful for clinical application and deserves further evaluation in an in vivo system.
Antineoplastic Agents↗
Implications of pharmacokinetic modeling in risk assessment analysis.
Physiologic pharmacokinetic models are a useful interface between exposure models and risk assessment models by providing a means to estimate tissue concentrations of reactive chemical species at the site of action. The models utilize numerous parameters that can be characterized as anatomical, such as body size or tissue volume; physiological, such as tissue blood perfusion rates, clearances, and metabolism; thermodynamic, such as partition coefficients; and transport, such as membrane permeabilities. The models provide a format to investigate how these parameters can influence the disposition of chemicals throughout the body, which is an important consideration in interpreting toxicity studies. Physiologic models can take into account nonlinear effects related to clearance, metabolism, or transport. They allow for extrapolation of tissue concentration from high dose to low dose experiments and from species to species and can account for temporal variations in dose.
Animals↗
A flow system for the study of shear forces upon cultured endothelial cells.
A parallel plate chamber in a flow system has been designed to study the effects of fluid shear stresses on cells. The system was applied to the study of cultured endothelial cells grown on cover slips which were accommodated in recessed wells in the base plate. Dye injection studies in the chamber indicated laminar flow over the cells. Shear rates measured over the cover slips by an electrochemical technique were found to be linear with flow rate. Laser doppler anemometry showed parabolic profiles between the plates. Endothelial cells subjected to flow showed a correlation between the time required for orientation and the magnitude of the shear stress.
Biomechanical Phenomena↗
Glioblastoma: catheter techniques for isolated chemotherapy perfusion.
Techniques have been developed for isolated perfusion of chemotherapeutic agents in patients with glioblastoma. Three catheters that facilitate crossing the carotid siphon have been developed; two are based on an everting or toposcopic principle, and one uses microjets for deflectability and improved mixing. Blood from the ipsilateral jugular vein is aspirated at high volumes (300 ml/min) for extracorporeal circulation through an adsorption column (for recovery of carmustine) or dialysers (for recovery of cisplatin). Preliminary experience in 10 patients suggests that high doses of chemotherapeutic agent can be administered using these catheters, with reduced retinal and systemic toxicity.
Brain Neoplasms↗
Mixing studies during intracarotid artery infusions in an in vitro model.
Sporadic instances of retinal damage and of focal brain toxicity have been observed following intracarotid artery infusions of chemotherapeutic agents (such as BCNU and cis-platinum) for the treatment of glioblastomas. The episodic nature of these toxicities is consistent with the possibility that the drug solutions were streaming from the catheter tip and, therefore, were not well mixed or not uniformly distributed in all branches distal to the catheter tip location. To test this hypothesis, an in vitro system was fabricated which included a transparent model of the human carotid artery and its major branches. These were furnished with pulsatile flow of a blood simulant. Dye solutions infused at several infusion rates through various types of catheters in both supraophthalmic and infraophthalmic positions were monitored and recorded on videotape and photographic film. The effluent streams from distal branches of the model were collected, and the relative concentrations of dye in each branch were determined spectrophotometrically. The results indicate that infusate streaming occurs at low infusion rates. In some cases, the concentration in a given branch can be at least five times the expected concentration. Similar occurrences of streaming in vivo could cause focal toxicity. Methods to improve mixing should be used during intra-arterial administration of drugs; these include increasing the infusion rates and improving catheter tip design.
Antineoplastic Agents↗
Drug streaming during intra-arterial chemotherapy.
Treatment of brain tumors by intra-arterial (IA) chemotherapy is occasionally complicated by sites of focal toxicity in the brain and retina. A possible cause of focal toxicity is non-uniform drug delivery due to intravascular drug streaming. To investigate this phenomenon in vivo, the authors examined the distribution of drug delivery after internal carotid artery (ICA) infusion in rhesus monkeys. Carbon-14 (14C)-labeled iodoantipyrine was delivered into the ICA of eight monkeys at slow infusion rates (1% to 2% of ICA flow) or at fast infusion rates (20% of ICA flow) combined with additional techniques to promote mixing with ICA blood. Two monkeys received intravenous (IV) 14C-antipyrine. Uniformity of delivery was assessed by comparing high-to-low ratios of isotope concentration in four brain regions evaluated by quantitative autoradiography. There was striking non-uniformity of drug delivery in the slow IA infusion group, with as much as 13-fold differences in drug concentration in anatomically contiguous areas. The values of high-to-low concentration ratios (mean +/- standard deviation) in individual autoradiographic planes were: 1) frontoparietal cortex: slow IA infusion 4.54 +/- 2.07, fast IA infusion 1.71 +/- 0.31, IV infusion 1.30 +/- 0.174; 2) frontoparietal white matter: slow IA infusion 2.94 +/- 1.45, fast IA infusion 1.59 +/- 0.41, IV infusion 1.34 +/- 0.21; 3) temporal cortex: slow IA infusion 5.43 +/- 3.57, fast IA infusion 1.69 +/- 0.24, IV infusion 1.67 +/- 0.25; 4) basal ganglia: slow IA infusion 3.6 +/- 2.9, fast IA infusion 1.18 +/- 0.10, IV infusion 1.09 +/- 0.04. Differences between concentration ratios after slow IA and fast IA infusion are significant (p less than 0.01); those between fast IA and IV infusion are not significant. Intra-arterial drug administration at infusion rates analogous to those currently used clinically results in drug streaming with markedly heterogeneous drug deposition in the perfused hemisphere. This may cause suboptimal drug levels in the tumor, and toxic levels at sites within the perfused hemisphere. This effect can be abrogated by techniques that eliminate drug streaming.
Animals↗
Comparison of steady and pulsatile flow in a double branching arterial model.
Data are presented to compare fluid flow parameters for steady flow with those for time-varying flow in a simplified two branch model which simulates the region of the abdominal aorta near the celiac and superior mesenteric branches of the dog. Measurements in the model included laser doppler anemometry velocity profiles during steady flow, sinusoidal flow with a superimposed mean flow (referred to as simple oscillatory flow) and arterial pulsatile flow. Shear rate measurements were made by an electrochemical technique during steady flow. Flow visualization studies were done during steady and pulsatile flow. Fluid flow effects in the simplified model during steady flow showed many similarities to the results from previous steady flow studies in a canine aortic cast. Shear rates in the region of the proximal (first, or celiac) branch were independent of flow rates in the distal (second, or mesenteric) branch, but the shear pattern within the proximal branch changed significantly as flow in the proximal branch increased. Shear rates on the proximal flow divider (leading edge into the distal branch) depended primarily on the flow rate to the proximal branch, but not on flow to the distal branch. At certain daughter branch flow ratios (approximately 2:1, proximal to distal), flow separation was promoted at the outer wall of the second branch, but flow separation did not occur in the first branch. In contrast to the canine aortic case results, flow separation was never detected on the distal (mesenteric) flow divider of the simplified model. This observation reflects the subtle effects of geometry on flow since the mesenteric flow divider in the canine cast protrudes into the main flow whereas the distal flow divider in the simplified model does not. There were distinct differences in the flow phenomena between steady, simple oscillatory and arterial pulsatile flow. Peak shear rates during pulsatile flow were as much as 10--100 times greater than steady flow shear rates at comparable mean flow rates. Particularly noteworthy for the pulsatile flow with a Womersley parameter of sixteen were very blunt velocity profiles throughout systole, and the absence of flow separation or reversal in those regions of the model that exhibited flow separation during steady flow. The shape of the waveform influences the nature of the flow during time-varying flows. Future studies of fluid dynamics in model systems must consider the pulsatile nature of the flow if a true interpretation of arterial flow phenomena is to be made.
Aorta, Abdominal↗
Physiological pharmacokinetics: an in vivo approach to membrane transport.
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Animals↗
In vivo methotrexate transport in murine Lewis lung tumor.
Methotrexate uptake by murine Lewis lung tumor was measured in vivo over a wide dose range. The data were analyzed according to a model previously developed for tissues in which methotrexate uptake is rate limited by transport across the cell membrane. Methotrexate transport in this tumor followed Michaelis-Menten kinetics with a rate constant for permeability (k/K) of 0.012 min-1. The methotrexate binding capacity of dihydrofolate reductase in the tumor was not exceeded at any dose studied. A low membrane permeability in conjunction with a high dihydrofolate reductase level explains the resistance of this tumor to methotrexate.
Animals↗
Pharmacokinetic study of cis-dichlorodiammineplatinum(II) (DDP) in the beagle dog: thermodynamic and kinetic behavior of DDP in a biologic millieu.
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Animals↗
The construction of a pharmacokinetic model for the disposition of polychlorinated biphenyls in the rat.
The construction of a preliminary pharmacokinetic model for the distribution, long-term storage sites, excretion, and metabolism of selected polychlorinated biphenyls (PCBs) in the rat is described. Following intravenous administration of radioactive PCBs, several metaboiltes of each PCB isomer were detected in urine or feces, excreted primarily as glucuronide conjugates. The relative and absolute amount of metabolites excreted depended upon the degree of chlorination and the position of the chlorine on the biphenyl molecule. Concerning long-term storage sties, an unanticipated finding was accumulation in skin, as revealed by the particularly long half-life of the 6-CB isomer in skin. A flow diagram of the model is presented, as are the differential equations, solved by computer for a given dose schedule, for the individual mass balances on parent and metabolite in each of the compartments that represent the organs or regions in which the concentration is assumed to be uniform. Low-level, long-term doses of PCBs produce a variety of toxicologic symptoms which appear only after long-time exposure. Such models should be useful in explaining and predicting the toxicities induced by exposure to PCBs and similar contaminants and the time required to reach a steady-state tissue concentration for given long-term doses.
Animals↗