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C S Patlak

Publications and source records attributed to C S Patlak.

At least 73 records · Page 4Linked to original sources
PubMed1985

Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations.

The method of graphical analysis for the evaluation of sequential data (e.g., tissue and blood concentrations over time) in which the test substance is irreversibly trapped in the system has been expanded. A simpler derivation of the original analysis is presented. General equations are derived that can be used to analyze tissue uptake data when the blood-plasma concentration of the test substance cannot be easily measured. In addition, general equations are derived for situations when trapping of the test substance is incomplete and for a combination of these two conditions. These derivations are independent of the actual configuration of the compartmental system being analyzed and show what information can be obtained for the period when the reversible compartments are in effective steady state with the blood. This approach is also shown to result in equations with at least one less nonlinear term than those derived from direct compartmental analysis. Specific applications of these equations are illustrated for a compartmental system with one reversible region (with or without reversible binding) and one irreversible region.

Animals↗
PubMed1984

Local blood flow in Walker 256 metastatic brain tumors.

Local blood flow (F) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid artery injection of WL-256 tumor cells in rats was measured using 14C-iodoantipyrine and quantitative autoradiography. Blood flow was variable in the tumors; the overall range was 2 to 222 ml hg-1 min-1 and the maximum range in an individual tumor extended over 150 ml hg-1 min-1. Small tumors had mean blood flows similar to surrounding brain. Medium to large tumors had significantly lower flows; the lowest values were usually measured in necrotic or cystic regions, although low values (less than 20 ml hg-1) were also measured in some viable-appearing tumor regions. Blood flow was significantly reduced in brain adjacent to medium and large but not small tumors. A global depression of brain and tumor blood flow was measured in two animals with hydrocephalus and the largest tumor burden. The blood flow patterns of the WL-256 metastatic tumor model are not uniquely different from other brain tumor models although some individual differences exist.

Animals↗
PubMed1984

Local blood-to-tissue transport in Walker 256 metastatic brain tumors.

Local blood-to-tissue transfer constants (K) in metastatic Walker 256 (WL-256) brain tumors produced by the intracarotid artery injection of WL-256 tumor cells in rats were measured using 14C-alpha-aminoisobutyric acid and quantitative autoradiography. Small compact and diffuse infiltrative intraparenchymal tumors had values of K similar to that of contralateral nontumorous brain tissue. Medium and large tumors, meningeal metastases and intraventricular tumors had higher K values (5 to 30 fold) than contralateral nontumorous brain tissue indicating that intraparenchymal tumor size and location in meningeal and choroidal tissue influence the permeability of tumor capillaries. The local intratumor values of K varied considerably in these tumors and this variability of K correlated to only a few specific histopathologic features of the tumors. The value of K abruptly decreased at the tumor-brain interface when this interface was sharply defined, indicating that the metastatic tumors have only a small effect on the permeability of adjacent brain capillaries. Low blood-to-tumor transport of water soluble drugs will significantly affect drug concentrations in the tumor and the tumor-drug exposure.

Aminoisobutyric Acids↗
PubMed1984

An evaluation of errors in the determination of blood flow by the indicator fractionation and tissue equilibration (Kety) methods.

In this report, the effects of various errors and plasma time courses of indicator concentration on the accurate determination of cerebral blood flow (F) are theoretically analyzed for the tissue equilibration and the indicator fractionation techniques. For the indicator fractionation technique, the impact of sample timing and tissue assaying errors and of indicator backflux were examined; for the tissue equilibration method, errors in the value of the partition coefficient (lambda), sample timing, and tissue assaying were considered. The recommended ways to decrease the effects of errors in the indicator fractionation technique are to administer the indicator by an intravenous bolus and to sample the tissue about 10 s thereafter. Possible errors in the assessment of F by the tissue equilibration technique are diminished by using an indicator infusion schedule which yields a continuous rise in arterial concentration and by selecting a 30-s experiment duration. Surprisingly, the impact of sample timing errors is greater on the determination of F with the tissue equilibration method than with the indicator fractionation technique. For the chosen plasma time courses, there is always a backflux error in an indicator fractionation estimation of F, and this error increases as the flow rate increases. Thus, provided the sample timing and tissue assay errors are small and the value of lambda is known, the tissue equilibration method is the more accurate of the two. If lambda is unknown, then the indicator fractionation technique should be used. In many cases, the indicator fractionation method will provide as accurate an estimate of F as will the tissue equilibration method.

Animals↗
PubMed1984

Local cerebral glucose utilization in fetal and neonatal sheep.

The newborn mammalian brain of several species has been shown to have a lower average rate of energy metabolism and a narrower range of rates in its various components than is found in maturity. In a further study of cerebral energy metabolism during development, we have employed the [14C]deoxyglucose method for measuring local cerebral glucose utilization in fetal and neonatal sheep. After establishing the lumped constant to be 0.40 and finding the rate constants for the kinetic behavior of deoxyglucose in plasma and brain to be close to those in other species, we measured the rates of glucose utilization in 44 regions of the brain. The rates were low and homogeneous in midgestation, except for those of brain stem nuclei of the auditory and vestibular systems and those of the hippocampus which were relatively high. In the last 7 wk, local rates rose approximately threefold. After birth there was a further average increase of 50% above full-term levels. The study shows that cerebral energy metabolism rises in most structures during prenatal maturation, a time when sensory stimulation is at a relatively low level and behavioral responses are minimal.

Animals↗
PubMed1984

Drainage of interstitial fluid from different regions of rat brain.

Studies were carried out in anesthetized rats comparing dynamics and pathways of interstitial fluid (ISF) drainage from different regions of brain. Rates of drainage from brain and flow into cerebrospinal fluid (CSF) were estimated from the efflux from brain and influx into CSF of radioiodinated albumin (RISA) following microinjection into caudate nucleus, internal capsule, or midbrain: pathways of flow through the subarachnoid space and into lymph were traced from the distribution of horseradish peroxidase and/or Evans blue-labeled albumin after injection into brain. ISF drainage rates (mul X g brain-1 X min-1) estimated for the three injection sites were 0.18, 0.19, and 0.29, respectively. Flow of ISF into bulk CSF sampled from the cisterna magna accounted for 60-75% of efflux from midbrain but only 10-15% of efflux from caudate nucleus or internal capsule. RISA was concentrated in the subarachnoid space, relative to bulk CSF, in sleeves of adventitial tissue surrounding pericerebral arteries, possibly accounting for the low recovery of isotope from bulk CSF. From the subarachnoid space, some fluid drained via olfactory nerve sheaths to retropharyngeal lymph nodes.

Animals↗
PubMed1983

Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data.

A theoretical model of blood-brain exchange is developed and a procedure is derived that can be used for graphing multiple-time tissue uptake data and determining whether a unidirectional transfer process was dominant during part or all of the experimental period. If the graph indicates unidirectionality of uptake, then an influx constant (Ki) can be calculated. The model is general, assumes linear transfer kinetics, and consists of a blood-plasma compartment, a reversible tissue region with an arbitrary number of compartments, and one or more irreversible tissue regions. The solution of the equations for this model shows that a graph of the ratio of the total tissue solute concentration at the times of sampling to the plasma concentration at the respective times (Cp) versus the ratio of the arterial plasma concentration-time integral to Cp should be drawn. If the data are consistent with this model, then this graph will yield a curve that eventually becomes linear, with a slope of Ki and an ordinate intercept less than or equal to the vascular plus steady-state space of the reversible tissue region.

Blood-Brain Barrier↗
PubMed1983

Transport of alpha-aminoisobutyric acid across brain capillary and cellular membranes.

The transport of alpha-aminoisobutyric acid (AIB), N-methyl-AIB (MeAIB), and diethylenetriaminepentaacetic acid (DTPA) from blood to brain was measured over different experimental periods in eight regions of the rat brain. Unidirectional transfer rate constants were determined from multiple-time/graphical and single-time analysis of the experimental data; values of 0.0018, 0.00057, and 0.000021 ml g-1 min-1, respectively, were obtained for the thalamus by graphical analysis. The initial distribution volume of AIB and MeAIB in brain tissue was several-fold greater than that of DTPA and the tissue plasma volume, and this difference was not accounted for by red blood cell uptake. This discrepancy could be due to rapid transport of AIB and MeAIB into brain endothelial cells in addition to the relatively rapid uptake by choroidal, meningeal, and ependymal associated tissues that was demonstrated by autoradiography. Thus, it may be misleading and erroneous to consider the blood-brain barrier (BBB) to be a simple, single-membrane structure when analyzing the blood-brain transfer data of solutes such as amino acids. The data from the ventriculocisternal perfusion experiments and previously published AIB uptake data in mouse brain slices were used to estimate the transfer rate constants across brain cell membranes. These studies indicated that the transport of AIB into brain cells was approximately 110 to 265 times greater than that across normal brain capillaries per unit mass of brain tissue, and that the BBB limits blood-to-brain cell transport of this amino acid. These observations (low rate of transport across normal brain capillaries and rapid concentrative uptake by brain cells) indicate that AIB is a good marker for measuring moderate to large increases in BBB permeability by experiments that require unidirectional flux of the tracer.

Aminoisobutyric Acids↗
PubMed1983

Selection of experimental conditions for the accurate determination of blood--brain transfer constants from single-time experiments: a theoretical analysis.

Reliable blood-brain transfer constants can be determined from data obtained in single-time experiments (i.e., a single experimental time for tissue sampling). The accuracy of such measurements depends on factors such as the test molecule used and the experimental time chosen; therefore, the selection of optimal experimental conditions is important. In this presentation, a model of transport across the blood--brain barrier (BBB) was developed and used to determine appropriate experimental protocols for single-time experiments. Transfer numbers derived from published data with alpha-aminoisobutyric acid (AIB; a compound of low BBB permeability that is readily taken up by brain cells) and diethylenetriaminepentaacetic acid (DTPA; a compound of very low BBB permeability that is not taken up by brain cells) were inserted into the model and apparent blood-to-brain transfer constants (K1) were obtained. In addition, the two basic sets of transfer numbers were altered to mimic various experimental and pathological changes in blood--brain transport. The results of this analysis indicate that moderate to large transfer rates across the BBB (0.01-1.0 ml g-1 min-1) are more easily and reliably measured by AIB-like compounds. In contrast, compounds like DTPA are better test-molecules for measuring small changes in the BBB transfer rate (0.0001-0.001 ml g-1 min-1), provided an appropriate experimental time is chosen.

Aminoisobutyric Acids↗
PubMed1983

Increased blood-brain transfer in a rabbit model of acute liver failure.

The blood-to-brain transfer of [14C]alpha-aminoisobutyric acid was investigated by quantitative autoradiography in normal rabbits and rabbits with acute liver failure induced by the selective hepatotoxin galactosamine. The blood-to-brain transfer of alpha-aminoisobutyric acid was similar in control animals and animals 2 and 7 h after galactosamine injections, but was increased five- to tenfold in certain gray-matter areas of the brain in animals 11 and 18 h after galactosamine treatment. No detectable differences in white-matter uptake of [14C]alpha-aminoisobutyric acid were found between the control and treated groups. The increase in alpha-aminoisobutyric acid transfer within the gray-matter areas suggested that a general or nonspecific increase in brain capillary permeability occurred in these areas. No clinical signs of early hepatic encephalopathy were observed in the treated rabbits, except for 1 animal from the 18-h postgalactosamine group. Thus, enhanced blood-brain transfer of alpha-aminoisobutyric acid preceded the development of overt hepatic encephalopathy. The distribution of radioactivity after the intravenous administration of [14C]galactosamine showed that virtually none of the hepatotoxin localized in the brain, suggesting that the drug itself does not have a direct effect upon the blood-brain barrier or the brain. The increased uptake of alpha-aminoisobutyric acid at 11 and 18 h implies that the transfer of other solutes would also be enhanced, that central nervous system homeostasis would be compromised, and that the resulting changes in brain fluid composition could contribute to or cause hepatic encephalopathy.

Aminoisobutyric Acids↗
PubMed1981

Efflux of radiolabeled polyethylene glycols and albumin from rat brain.

Experiments were carried out to evaluate the role of convection in the removal of large molecules from brain interstitial fluid. Radiolabeled test compounds were injected into the caudate nucleus of anesthetized rats through a guide cannula implanted 1 wk previously and the concentrations of isotope in brain and cerebrospinal fluid (CSF) determined at various times after injection. Control studies with 22Na indicate that the permeability of the blood-brain barrier is normal in tissue surrounding the intracerebral injection cannula. For 69,000 dalton serum albumin, 4,000 dalton polyethylene glycol, and 900 dalton polyethylene glycol, clearance from brain approximates a single exponential decay with half times of disappearance of 12.2, 12.6, and 14.4 h, respectively. Similarly in efflux rate, despite a fivefold difference in diffusion coefficient, is consistent with convective losses from brain, and the maximal rate of interstitial fluid removal estimated on the basis of these data is 0.11 microliter.g brain-1.min-1. Only 10-20% of total efflux is into bulk CSF withdrawn from the cisterna magna.

Animals↗
PubMed1981

Regional blood flow, capillary permeability, and glucose utilization in two brain tumor models: preliminary observations and pharmacokinetic implications.

Regional quantitative autoradiographic measurements of blood flow, capillary permeability, and glucose utilization were made in rats harboring an intracerebral Walker 256 metastatic tumor or a well-differentiated oligodendroglioma. Distinct differences were observed between the two brain tumor models; regional differences within the metastatic tumor appeared to be partly related to tumor size. The pharmacokinetic implications of these physiological measurements with respect to drug delivery to tumor tissue are discussed. The interrelationship of commonly used parameters to quantitate transport across the blood-brain barrier--permeability coefficient, permeability-surface area product, transfer constant, extraction fraction, equilibrium half-time, and blood flow--and their relevance to effective brain tumor chemotherapy are demonstrated.

Animals↗
PubMed1980

Heuristic modeling of drug delivery to malignant brain tumors.

It is apparent that chemotherapy against malignant brain tumors is generally ineffective. While some agents are more effective than others, none appreciably alters the clinical course of and the poor prognosis for patients with brain tumors. Even though new and more effective agents are being or will be developed, chemotherapy depends as much on the delivery of drug as it does on the drug used. Therefore, we have defined factors that we believe are of primary importance in drug delivery to brain tumors, and, using computer simulation, we have modeled the effects of these factors. In this article we discuss (a) the extent of the "breakdown" in the blood-brain barrier (BBB) that accompanies the development of malignant tumors in the brain, (b) factors that influence drug transport from tumor capillaries to tumor cells at varying distances from the capillaries, (c) the problems inherent in drug delivery from a well-vascularized tumor outward to normal brain tissue that might harbor malignant cells but that does not have leaky vessels (i.e., normal BBB), and (d) the difficulties in drug delivery from a well-perfused, highly permeable outer tumor shell to a central, poorly perfused tumor core.

Animals↗