Biomedical subjects
Publications and source records attributed to C S Patlak.
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Drug delivery to tumours and the accessibility of tumour cells to drugs remains a problem of foremost importance and is affected by many factors. We will discuss models we have developed for drug delivery from tumour capillaries to tumour cells, and drug delivery from well perfused, well oxygenated tumour regions to less well perfused hypoxic regions in terms of computer simulation of drug delivery for the anticancer agent BCNU and the hypoxic cell radiosensitizer misonidazole.
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We evaluated the hydraulic conductivity (Pf, micron s-1) of superficial proximal straight tubules isolated from rabbit kidney. Tubules were perfused with hypotonic (270 mosmol/kg H2O) and bathed with isotonic (290 mosmol/kg H2O) NaCl buffers at 25 degrees C. Due to the tendency of transepithelial osmosis plus solute entry to produce osmotic equilibrium along the perfused length, we observed that the total net volume absorption ('JV, nl min-1) increased from 0.64 to 2.21 when the perfusion rate (VO, nl min-1) was increased from 11 to 45 in a group of tubules with an average length of 0.86 mm. From a 'JV of 2.21 nl min-1 at VO = 45 nl min-1 we computed a minimum Pf of 2,200 micron s-1. And extrapolation of the data to VO leads to infinity gave a Pf value of 5,200-7,600 micron s-1. The same perfusion rate dependence of 'JV in a group of tubules with an average length of 3.29 mm gave quantitatively similar results. A theoretical analysis of radial osmosis occurring simultaneously with axial osmotic equilibration showed that Pf values in the range of 3,000-4,000 micron s-1 accurately predicted the observed relations between VO, 'JV, and tubule length.
Renal tubules reabsorb solutes from the glomerular filtrate. The relationship between "filtered load" and reabsorption has been previously discussed and analyzed in detail. One aspect which has not been emphasized, however, is that, when reabsorption of a solute causes its concentration (or activity) in the tubule lumen to decrease below the level in the blood, solute may enter the tubule down this concentration gradient adding a "leaked load" to the filtered load. The leaked load should be taken into account when quantifying tubular transport. In the present study we derived equations for estimating the leaked load and its contribution to transport. The importance of the leaked load of glucose in the rabbit proximal convoluted tubules is evaluated with parameters derived from in vitro perfusion and by solving the equations numerically. It is shown that, depending on the conditions, the leaked load of glucose may account for a substantial part of the glucose present in the tubule lumen and reabsorbed from the tubule. Also, the leaked load could conceivably be an important factor in the transport of other solutes such as lactase and bicarbonate in proximal tubules.
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1. Distributions of dense bodies per platelet were evaluated in unstimulated human platelets and in platelets stimulated to secrete by the addition of varying amounts of thrombin or the ionophore A23187. Since distributions were not Gaussian, they were compared by non-parametric methods. 2. Most distribution obtained following varying levels of dense-body release differed significantly from the control (unstimulated) distribution. In general, distribution from points widely separated in terms of per cent release of total dense-body content also differed significantly. Distributions obtained at points where the total number of dense bodies lost was approximately the same did not differ significantly, regardless of the drug and incubation conditions used to produce the dense-body loss. 3. Dense bodies were lose from platelets during the secretory process (measured as the release of either calcium or ATP), and the number of dense bodies lost correlated at a significant level with the amounts of both substances secreted. 4. Following maximal secretion produced by either thrombin or A23187, a population of dense bodies (refractory dense bodies) remained in platelets. The refractory dense bodies could not have been distributed uniformly among the control populations of either platelets or dense bodies. The distribution of refractory dense bodies could, however, be described by a model in which platelets containing large numbers of dense bodies had a greater proportion of their dense-body complement refractory than did platelets containing fewer dense bodies.
The distribution of 10 radioactively labeled materials from blood to CSF, extradural fluid (EDF), telencephalon (cerebrum), medulla, and spinal cord was studied in the dogfish shark. Plasma volumes, blood flows, and blood-to-tissue or fluid-transfer half-times (t1/2) were calculated from these distribution data. Blood-EDF exchange occurred at slow but similar rates for all tracers. Urea uptake by the CSF was very rapid compared to that of the other compounds and may be facilitated by a special mechanism. The tissue plasma spaces of all three CNS regions were small (1.1-1.5%). The calculated rates of tissue blood flow (in ml/g-min) were 0.11 for telencephalon and medulla and 0.055 for spinal cord. Choroid plexus blood flow was estimated to be 2.3 ml/g-min, a surprisingly high rate. Transport between blood and tissue was most rapid for water ethylene glycol and slowest for inulin. The tissue t1/2's of urea indicated that a significant portion of this compound's net uptake by periventricaul brain tissue occurred via the CSF.
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The transport of [14C]5-hydroxy-3-indoleacetic acid (5-HIAA) by the spinal cord was investigated with spinal subarachnoid perfusions of 20 rhesus monkeys. For spinal white matter, [14C]5-HIAA was found to distribute in a tissue space of 50-55% and to exchange readily between tissue and blood across parenchymal capillaries. The data were analyzed with a model of the spinal cord as a cylinder and a mean capillary transfer half-time of 20 min determined. The spinal cord cleared [14C]5-HIAA from 19 mul/min of CSF. Administration of probenecid yielded a somewhat lower mean tracer clearance rate (14 mul/min) but did not alter the capillary exchange half-time or the distribution volume of [14C]5-HIAA in the spinal cord. The data suggest that capillaries within spinal white matter transport 5-HIAA by a mechanism which is insensitive to inhibition by probenecid and that lumbar CSF concentrations reflect only a small portion of total 5-HIAA production by the central nervous system.
Spinal subarachnoid perfusions of rhesus monkeys were performed to study the transport of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) by the spinal cord. The perfusate contained [3H]MHPG and a reference extracellular space marker ([14C]sucrose of [14C]ethylenediaminetetraacetic acid-calcium complex). The mean (+/- S.D.) clearance of MHPG by the monkey spinal cord was 33 (+/- 4) mul/min. Analysis of serial sections of spinal tissue after each perfusion facilitated determination of several basic parameters of MHPG transport. MHPG has a spinal tissue distribution space of 70-80%. MHPG enters capillaries within spinal tissue throughout the entire spinal cord. The mean capillary exchange half-time was 8.2 min +/- 1.9 min. MHPG crosses cell membranes easily and diffuses through cells rapidly. The apparent tissue diffusion coefficient approximated the diffusion coefficient in water (8.5 x 10(-6) sq.cm/sec). The data suggests that CSF levels of MHPG are an uncertain indicator of norepinephrine metabolism and that lumbar CSF levels of MHPG reflect in large part spinal cord rather than brain metabolism.
It is sometimes desirable to obtain a specified blood level which obeys a prescribed mathematical form. Following an approach based on impulse analysis via Laplace Transform techniques, a general method for an input injection schedule which will achieve this goal is derived. Specific infusion schedules are given which attain blood levels that are constant, increase linearly, decay exponentially, and increase exponentially. Further, simpler approximate infusion schedules are also derived whose outputs achieve the desired function after a short time. Two illustrative experimental examples-one for [14C]EDTA-Ca in anesthetized rhesus monkeys and the other for 2-deoxy-D-[1-14C]glucose in the conscious rat-are presented in detail. The assumptions are discussed and an error analysis is performed.
Spinal subarachnoid perfusions of rhesus monkeys were performed to study spinal transport of homovanillic acid in control and probenecid-treated animals. Homovanillic acid enters capillaries within spinal tissue throughout the spinal cord. The mean capillary exchange half-time for homovanillic acid was 19.2+/-2.8 minutes; probenecid did not affect this value significantly. Despite its polar nature, homovanillic acid crosses cell boundaries easily and equilibrates in a distribution volume (55 percent) approaching the total water space. The spinal cord clears homovanillic acid from 21+/-4 mul per minute of cerebrospinal fluid. The rate of clearance after probenecid administration was not significantly different. The apparent diffusion coefficient in tissue of homovanillic acid approximated the diffusion coefficient in water (8.0 X 10(-6) cm2 per second). The data show that homovanillic acid is transported by capillaries throughout spinal tissue by a mechanism largely insensitive to inhibition by probenecid. Lumbar cerebrospinal fluid concentrations of homovanillic acid even after probenecid administration therefore reflect only part of the total dopamine metabolism.
We studied salt and water absorption in isolated rabbit superficial proximal straight tubules perfused and bathed with solutions providing oppositely directed transepithelial anion gradients similar to those which might obtain in vivo. The perfusing solution contained 138.6 mM Cl- 3.8 mM HCO-3 (pH 6.6) while the bathing solution contained 113.6 mM Cl- and 25 mM HCO-3 (pH 7.4); the system was bubbled with 95% O2-5% CO2. At 37 degrees C, net volume absorption (Jv nl min-1 mm-1) was 0.32 +/- 0.03 (SEM); Ve, the transepithelial voltage (millivolts; lumen to bath), was +3.1 +/- 0.2. At 21 degrees C, Ve rose to +3.7 +/- 0.1 and Jv fell to 0.13 +/- 0.01 (significantly different from zero at P less than 0.001); in the presence of 10(-4)M ouabain at 37 degrees C, Ve rose to +3.8 +/- 0.1 and Jv fell to 0.16 +/- 0.01 (P less than 0.001 with respect to zero). In paired experiments, the ouabain- and temperature-insensitive moieties of Jv and Ve became zero when transepithelial anion concentration gradients were abolished. Titrametric determinations net chloride flux at 21 degrees C or at 37 degrees C with 10(-4) M ouabain showed that chloride was the sole anion in an isotonic absorbate. And, combined electrical and tracer flux data indicated that the tubular epithelium was approximately 18 times more permeable to Cl- than to HCO-3. We interpret these results to indicate that, in these tubules, NaCl absorption depends in part on transepithelial anion concentration gradients similar to those generated in vivo and in vitro by active Na+ absorption associated with absorption to anions other than chloride. A quantitative analysis of passive solute and solvent flows in lateral intercellular spaces indicated that fluid absorption occurred across junctional complexes when the osmolality of the lateral intercellular spaces was equal to or slightly less than that of the perfusing and bathing solutions; the driving force for volume flow under these conditions depended on the fact that sigmaHCO3 exceeded sigmaCl.
Influence of capillary permeability on local cerebral blood flow (LCBF) estimated by the autoradiograhpic diffusible-indicator method was analyzed by computer simulation. Its influence increases with increasing flow. With normal perfusion rates in gray matter, capillary permeability coefficient x surface area (PS value) must exceed 0.12 cm3-s(-1)-g(-1) for estimated LCBF to attain 95% of true values in all structures. In white matter, with its lower perfusion rates, the PS value must exceed 0.035 cm3-s(-1)-g(-1) for equivalent accuracy. [14C]antipyrine, widely used in the LCBF technique, has a PS value below these values and leads to undersestimation of LCBF. Experimental studies in cats in which LCBF was measured with either [14C]antipyrine or the freely diffusible, radioactive gas, [131I]trifluoroiodomethane, demonstrated consistently lower estimates of LCBF with [14C]antipyrine than with the gas; the deviations in the various cerebral structures approximated those predicted by the theoretical analyses. These results suggest that the uptake of [14C]antipyrine by cerebral tissues is diffusion limited as well as flow limited, and it therefore is not an ideal tracer for the autoradiographic LCBF technique.
The amount of radioactivity in brain was estimated at different times after intracarotid injection in the pentobarbital-anesthetized rat. Fifteen seconds after injection, six radiolabeled solutes minimally metabolized by brain, 3H2O , isopropanol, nicotine, antipyrine, 3-O-methyglucose, and codeine, left the brain according to first-order kinetics. Two solutes metabolized by brain, lactic acid, and heroin, behaved in a more complex fashion. The behavior of the six nonmetabolized solutes was interpreted satisfactorily by a simple model in which the brain is treated as a single compartment. From the model, uptake at 15 s as a percentage of the dose is linearly related to the permeability when the uptake is low, i.e., 30% or less. In higher uptakes blood flow becomes increasingly important. The efflux rate is similarly related to permeability and blood flow, but additionally it depends inversely on brain space. The exchanges of 3H2O, isopropanol, and nicotine were determined almost solely by blood flow and brain space. Movements of codeine and 3-O-methylglucose depended primarily on permeability and those of antipyrine on both factors.
Ventriculocisternal perfusions of mongrel dogs were performed for 1-6 h with solutions containing isotopically labeled compounds. At the conclusion of the perfusion period, serial brain samples were taken from the caudate nucleus and analyzed for radioactivity. Tissue concentration profiles were constructed from the data, and apparent tissue diffusion and capillary exchange coefficients were determined. The tissue diffusion constant of sucrose was 3 X 10(-6) cm2/s, which is approximately 45% of its free-water value. The permeability of the brain capillary complex to creatinine, sodium, and mannitol was so low that it could not be accurately measured by this technique. Capillary transfer coefficients, expressed as half-times, were determined for water, urea, and ethylene glycol; the t1/2 values were 1.5, 15, and 17 min, respectively. These numbers were converted to PS products and compared to other published values. This work suggests that the exchange of these compounds between blood and brain is partially (water) or nearly completely (urea and ethylene glycol) limited to membrane permeability.