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Biomedical subjects

J F Gross

Publications and source records attributed to J F Gross.

At least 19 recordsLinked to original sources
PubMed1992

Perivascular oxygen tensions in a transplantable mammary tumor growing in a dorsal flap window chamber.

Fischer 344 rats with R3230 Ac mammary carcinomas implanted in dorsal flap window chambers served as a model to obtain measurements of perivascular and stromal oxygen tension in normal and tumor tissues using Whalen recessed-tip microelectrodes (3- to 6-microns tip). Perivascular measurements were made adjacent to vessels with continuous blood flow. Thus the measurements and models provided are reflective of conditions leading to chronic hypoxia. Perivascular oxygen tensions averaged 72 +/- 13 mmHg in normal tissue vessels adjacent to tumor, 26 +/- 5 mmHg in tumor periphery, and 12 +/- 3 mmHg in tumor central vessels. There was a significant trend toward lower perivascular oxygen tensions in the tumor center (Kruskal-Wallis test, P = 0.002). A similar tendency was seen with a limited number of stromal measurements. Krogh cylinder models, which incorporate these data for perivascular oxygen tension, along with morphometric data obtained from the same tumor model suggest that hypoxic regions will exist between tumor vessels in the tumor center unless O2 consumption rates are well below 0.6 ml/100 g/min. The low perivascular measurements observed near the tumor center combined with the theoretical considerations suggest, for this model at least, that tissue oxygenation may best be improved by increasing red cell velocity and input pO2 and reducing oxygen consumption. The low perivascular oxygen tensions observed near the center also suggest that conditions conducive to increased red cell rigidity exist, that drugs which can decrease red cell rigidity could improve tumor blood flow and oxygenation, and that the endothelium of those vessels may be susceptible to hypoxia-reoxygenation injury.

Animals↗
PubMed1992

Effects of bradykinin on the hemodynamics of tumor and granulating normal tissue microvasculature.

Bradykinin (BK) is an important endogenous mediator of microvascular flow modulation. Since the structure of the microcirculation is very different in tumor tissues than in normal tissues, bradykinin may elicit different responses in tumors. This study was designed to test the hypothesis that local administration of bradykinin increases blood flow preferentially in normal tissue relative to adjacent tumor tissue, resulting in a "vascular steal" phenomenon. Microvessel diameters (D), velocities (Vc), length densities, shear rates, and intermittent flow frequencies were measured every 10 min before, during, and after 40 min exposure to BK in rats with dorsal flap window chambers 9 days after tumor implantation. Separate studies were made of normal vessels outside the tumor margin, the hypervascular tumor periphery, and the tumor center. Bradykinin was administered with a suffusion medium flowing over the tissue at 1-2 ml/min with a BK concentration of 1.6 x 10(7) M. Administration of BK created five distinct changes in normal and tumor vessel function that varied over time, but coincidentally reached a maximum effect after 20 min exposure to BK. In normal vessels, increased Vc and D led to increased flow, which reached a peak 20 min after onset of suffusion with BK. In contrast, in centrally located tumor vessels, decreased D and Vc were observed in most vessels during the initial 10-20 min of suffusion. In addition, there was a significant increase in intermittent flow frequency in tumor central vessels, which peaked after 20 min of suffusion with BK. These five separate observations that coincided at 20 min of suffusion are consistent with a "vascular steal" phenomenon. The increase in normal microvessel D and Vc at 20 min suggests that BK causes vasodilation in arterioles. The coincident decrease in tumor microvessel D and Vc suggests that tumor feeding vessels are less able to respond to BK by vasodilating. The concomitant increase in intermittent flow frequency in tumor vessels suggests that a reduction in pressure drop occurred after 20 min exposure to BK, which is also consistent with "vascular steal." Since BK is also known to increase vascular permeability, it is possible that increases in interstitial fluid pressure brought on by exposure to BK contributed to the observed reduction in tumor blood flow. In normal vessels, reduced D and Vc, relative to peak values, were noted after 40 min suffusion with BK. Adherence of leukocytes to the vessel walls was prominent and microthrombi were also observed during this period. No evidence of such adhesion was seen in tumor vessels, although microthrombi were observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1979

Kinetics of intravenous melphalan.

We have studied the disposition and elimination of melphalan after intravenous administration in 9 patients with cancer. High-pressure liquid chromatography and 14C-melphalan were used to assay drug concentration in plasma and urine. Composite plasma t1/2alpha was 7.7 +/- 3.3 and t1/2beta was 108 +/- 20.8 min for 8 of the patients. The mean 24-hr urinary excretion of melphalan was 13.0 +/- 5.4% of the administered dose. In 2 patients, 80% to 100% of the measured 14C counts in plasma and urine samples at each study interval, up to 24 hr after drug administration, could be accounted for by the sum of parent compound, monohydroxy and dihydroxy products, and methanol nonextractable radioactivity (i.e., protein-bound activity). These data and evidence of rapid disappearance from plasma at 37 degrees in vitro suggest that spontaneous degradation, and not enzymatic metabolism, is the major determinant of the t1/2 of melphalan in vivo.

Adult↗
PubMed1979

Pharmacokinetics of drugs subject to enterohepatic circulation.

The influence of the changes in biliary excretion and reabsorption rates on the pharmacokinetics of drugs subject to enterohepatic circulation was examined analytically. A recently proposed two-compartment model with drug elimination occurring in each compartment was adapted to represent the body and the GI tract. Enhanced reabsorption was equivalent to biliary excretion rate reduction, except that the latter always decreased alpha and prolonged the alpha-phase half-life while the former always increased alpha and shortened the half-life. However, depending on the relative values of the two elimination rate constants, biliary excretion reduction (or reabsorption enhancement) could either increase or decrease the terminal drug half-life (beta-phase). Whether the terminal drug half-life was prolonged or shortened, a biliary excretion reduction always increased the area under the plasma decay curve for intravenous and oral doses and also raised the steady-state drug level in the body for constant-rate intravenous infusion. As a consequence, the lethality, toxicity, or effectiveness of the drug will be increased for patients with impaired bile flow or enhanced drug reabsorption; therefore, the clinical dosage may have to be reduced.

Enterohepatic Circulation↗
PubMed1979

Clearance constants in physiologically based pharmacokinetic models.

The intrinsic clearance of an organ is usually approximated by the apparent clearance from that organ in the development of a physiologically based pharmacokinetic model. In this study, the exact relationship between the two clearances was derived and analyzed. When the extraction ratio of the drug was small (less than 0.05), the approximation was reasonable. However, when the extraction ratio was high (greater than 0.2), serious errors could be made by using the approximation. These errors could be as much as 50% reduction in the estimated extraction ratio and as much as an order-of-magnitude difference in the intrinsic clearance.

Kinetics↗
PubMed1979

Physiologically based pharmacokinetic models for anticancer drugs.

The rationale and history of the development of physiologically based pharmacokinetic models are briefly reviewed in this paper. The methods of model construction and the previous application of this type of model to anticancer drugs are discussed. Future research should be focused on the following areas: (1) interspecies scaling, (2) the effects of disease states on the pharmacokinetics of anticancer drugs, and (3) the applications of pharmocokinetics to the studies of growth behavior of cancer cells. The ultimate goal will be to utilize this basic information to design an optimal dosage regimen and treatment schedule for the safe and effective cancer chemotherapy of each individual patient.

Ancitabine↗
PubMed1979

Estimation of tissue-to-plasma partition coefficients used in physiological pharmacokinetic models.

An important parameter in the development of pharmacokinetic models is the ratio of tissue drug concentration to the concentration of the drug in the arterial plasma or the effluent plasma. The relationship between these two tissue/plasma ratios is derived analytically for different routes of drug administration. The two are equal only in compartments with no elimination when the drug is infused at constant rate. For other routes of administration, the two ratios are identical in all compartments only when there is no elimination process. The tissue/plasma concentration ratios for infusion equilibrium are not equal to the corresponding values for the postdistribution phase after an intravenous bolus injection. When the plasma concentration for infusion and injection are the same, more drug will appear in the lung during infusion steady state than during the postdistribution equilibrium. The reverse is true for the other organs. The importance of properly defining the tissue/plasma ratio and its implication for pharmacokinetic modeling are discussed. The results may have important therapeutic implications for the availability of drugs using different routes of administration.

Absorption↗
PubMed1979

Analysis of oxygen diffusion from arteriolar networks.

A mathematical model of oxygen transport in the precapillary microcirculation is presented. The theory is then used to simulate oxygen distribution in the arteriolar network of the hamster cheek pouch. Theoretical prediction of transmural and longitudinal oxygen tension (PO2) gradients is in qualitative agreement with available experimental data. The effect of the variation of inlet network PO2, blood flow rate, blood hematocrit, and other parameters on the transport characteristics is studied. The calculations predict that the luminal PO2 in small arterioles is practically independent of the inlet network PO2 leve if the latter is sufficiently high; when this inlet PO2 level is low, then the longitudinal gradients of luminal PO2 vanish. It is further shown that retardation of blood flow may cause a significant increase in precapillary oxygen losses.

Animals↗
PubMed1979

Tissue perfusion inhomogeneity during early tumor growth in rats.

Tissue perfusion in BA 1112 sarcomas of WAG inbred Rijswijk rats was determined from in vivo measurements of capillary density, length, and erythrocyte velocity in modified Algire chamber preparations. Studies were done with the use of television techniques in situ during a period of 26 days, both in control chambers and after implantation of a 0.1-mm3 piece of tumor tissue. Perfusion in control areas void of tumor tissue. Perfusion in control areas void of tumor was approximately 8-10 ml/minute/100 g of tissue. Flow in active tumor growth regions on the outward side of the tumor edge was through undifferentiated channels and had characteristics of flow through a porous medium. Despite enhanced arterial supply, the stabilized tumor microcirculation at the inward side of the growing tumor retained its perfusion rate constant (15-18 ml/min/100 g). Perfusion in central portions of the tumor was about 2-4 ml/minute/100 g during 12 days, whereas the tumor doubled in diameter. Our findings support the concept of temporal and functional blood flow inhomogeneity in the microcirculation of spreading tumors.

Animals↗
PubMed1978

Prediction of adriamycin disposition in cancer patients using a physiologic, pharmacokinetic model.

A ten-compartment flow-limited pharmacokinetic model scaled from rabbit tissue distribution data was used to predict plasma adriamycin concentrations in 23 patients and adriamycin tissue uptake in nine surgery patients following iv bolus doses of 10--60 mg/m2. The predicted concentrations were compared to experimentally determined adriamycin using a specific thin-layer chromatographic fluorescence scanning procedure. The predicted plasma time course for 11 of 16 patients with relatively normal liver and kidney function agreed closely with the observed plasma time course. Deviations in the other five patients were ascribed to possible changes in the profile of metabolite formation and/or fluctuations in biliary clearance. All four patients with elevated serum bilirubin demonstrated significantly higher and more prolonged plasma levels than predicted. The results of two patients with impaired kidney function and one patient with both hepatic and renal involvement were inconclusive. The comparison between predicted and observed tissue concentrations in biopsy samples was varied; however, all were within an order of magnitude. It is concluded that the model depicts adriamycin uptake and distribution reasonably well; however, more needs to be known concerning individual variation in metabolic and biliary excretion rates for this to become more patient-specific. Also, a tumor compartment appears to be an important addition in modifying the model to allow for clinical utility.

Animals↗
PubMed1977

Mathematical model for cyclocytidine pharmacokinetics.

The pharmacokinetics of the drug cyclocytidine in humans were modeled by using a physiological and anatomical approach. Each pertinent tissue is represented by a single compartment, and these compartments are linked together by the circulatory system. Each compartment is then represented by an ordinary differential equation that represents the rate of change in drug concentration as function of convecting transport, metabolism, and urinary clearance. The models for cyclocytidine and cytarabine are linked together by a hydrolysis term in each equation set. The resulting equation sets are then solved numerically to predict the concentration of both drug species in situ. The models use physiological blood flows, tissue volumes, and clearance parameters. The results of the model show that cyclocytidine can act as a reservoir for cytarabine in vivo over the time studied. This effect is confined to relatively long times and relatively low plasma concentrations.

Ancitabine↗