Vojtech Ličko

Behavioral pharmacokinetics of marijuana

Male volunteer subjects smoked one marijuana cigarette containing 100, 200, or 250 μg/kg Δ-9-tetrahydrocannabinol (THC) and were tested on three perceptual-motor performance measures related to driving. Performance was measured and blood samples were collected for 24 h after smoking. The covariation between phamacodynamics of performance and pharmacokinetics of THC in plasma was investigated for decrement in performance as the response to smoking a single marijuana cigarette. A significant linear correlation was found between tracking errors under divided attention and THC plasma levels over 5–25 ng/ml for approximately 2 h after smoking. A sigmoid relation was found between critical tracking breakpoint and log THC plasma levels over 2–25 ng/ml for approximately 7 h after smoking.

The nature of passive flows through tightly folded membranes. The influence of microstructure.

SummaryMembrane processes such as microvilli and folded structures greatly increase the area for passive transport. A mathematical analysis of flows through folded membrane structures demonstrates that the increase in flows is not proportional to the increase in area. Furthermore, the flows of salt and water do not increase in the same ratio: that of water can be several times the increase in area and that of salt a fraction of the increase in area. A preferential passive flow of water is created by the structure. It is only in the neighborhood of the isotonic state that the effect is significant, but in that region, the effect can be dramatic.A parameter study shows that the effect is most sensitive to the relative dimensions of the folded membrane structure and to the salt permeability. The effect of stirring within the folds is also studied. In the general case, the system of two-dimensional diffusion equations is integrated numerically; an analytical solution is presented for the special case of negligible convection coupling. The calculations show that salt-concentration profiles within the folds establish a distribution of thermodynamic driving forces across the membrane barrier which differs significantly from that found across a plane membrane separating the same bathing solutions. The overall behavior of the flows through folded membrane structures is thus nonlinear.

Threshold secretory mechanism: A model of derivative element in biological control

A secretory system can be considered a collection of packets of a stored substance, each pecket characterized by a threshold to a stimulatory releasing agent. In terms of macroscopic release of the substance, the rate equation contains explicitly and naturally the time derivative of the stimulus intensity. Elaboration of this general model for threshold secretory mechanisms was motivated by insulin secretion data discussed here. Experimental data on the same type of secretory system (pancreas), the hormone secretion as well as electrical characteristics of the secretory cells, lead to a conjecture that the packets might be identified with the whole secretory cells, rather than the granules or vessicles of the stored hormone.

Pituitary corticotropin-inhibiting peptide: Properties and use in study of corticotropin action

Abstract The biological properties of the naturally occurring pituitary peptide αh7–38-adrenocorticotropin (ACTH) have been investigated. αh7–38-ACTH is devoid of steroidogenic activity but inhibits competitively ACTH-induced steroidogenesis in vitro as well as in vivo. The long-term actions of ACTH on normal and tumor adrenal cells in culture are also antagonized by αh7–38-ACTH. The apparent Ki for the inhibition of cyclic AMP production by αh7–38-ACTH (301 ± 62 n m ) was significantly higher than the apparent Ki for the inhibition of corticosterone synthesis (21.6 ± 6.8 n m ). Analysis of the inhibition of ACTH-induced steroidogenesis and cyclic AMP production in normal rat adrenocortical cells indicates that two separate receptors may be involved in mediating these responses.

Open-loop glucose-insulin control with threshold secretory mechanism: Analysis of intravenous glucose tolerance tests in man

Abstract The shape of the plasma insulin curve during a glucose tolerance test in man suggests that the threshold secretory process, as demonstrated in rat pancreatic perfusions, must be included in a model of insulin secretion, distribution, and removal for analysis of the data. A mathematical model was developed and subsequently applied to the intravenous tolerance test (IVGTT) obtained in human subjects. An important feature of the model is that the IVGTT is essentially a perturbation to an open-loop control system. A nonlinear regression analysis of the IVGTT in 23 normal subjects indicated that the model can account for the variety of insulin response curves found experimentally and provided the parameters of the system.

Kinetic studies of 18O exchange of inorganic phosphate using mass spectral measurements on the tris-(trimethylsilyl) derivative

Abstract The kinetics of 16 O exchange into 18 O-enriched inorganic phosphate catalyzed by Escherichia coli alkaline phosphatase have been followed by generating the tris-(trimethylsilyl) derivative of the phosphate samples and subjecting this volatile derivative to mass spectral analysis. The series of sequential reactions involved in the 18 O exchange have been analyzed mathematically, and theoretical plots of the time courses of the exchange processes have been generated assuming various fractional initial 18 O distributions. Using this mathematical model, a rate constant was obtained which gives the best fit to the experimental kinetic data. This approach is much less time-consuming than the traditional method of thermal conversion of the 18 O-enriched phosphate samples to carbon dioxide using vacuum line techniques. Morcover, the data analysis, alboit more complex than that using the traditional method, enables five independent determinations of the exchange rate to be made from each phosphate sample. Although this new approach requires much more highly 18 O-enriched water than does the traditional method, such highly enriched water is now readily available at reasonable cost.

Sex differences in sulfobromophthalein-glutathione transport by perfused rat liver

Sex differences have been described in the hepatic transport of many organic anions. Proposed mechanisms include differences in the rate of metabolism, in the degree of binding to cytoplasmic proteins, and in the rate of membrane transport. To better define these factors, we used the perfused rat liver to study the hepatic transport of the glutathione conjugate of sulfobromophthalein (BSP-GSP), a model compound that does not require metabolism for excretion. Hepatic transport of BSP-GSH was saturable for both sexes. Clearance of BSP-GSH from 1% albumin solutions at steady-state was 35-52% greater in female livers than in male livers, and reflected a 47% larger apparent Vmax with no change in the apparent Km. Analysis of the rate of disappearance of BSP-GSH from recirculating perfusate and its appearance in bile using a simple two-compartment model indicated that the ratio of influx to efflux was greater in female livers. These findings are compatible with sex-related differences in the electrochemical driving forces for BSP-GSH uptake.

Effects of marijuana on testosterone in male subjects

Clinical studies have given contradictory reports on the effect of smoking marijuana on the plasma levels of testosterone in males. A reanalysis of existing data established that testosterone levels are depressed both after smoking one marijuana cigarette and after intravenous infusion of delta-9-tetrahydrocannabinol, a pharmacologically active component of marijuana. Simulation of the marijuana interaction, under the assumption that delta-9-tetrahydrocannabinol inhibits testosterone production or secretion, suggests a minimum of 24 hours are required for testosterone to return to pre-smoking levels. A series of clinical studies are specified to clarify the nature of the interaction.

Transport across epithelia: A kinetic evaluation

Compartmental analysis of three models for solute transport across epithelial tissue is presented. The simplest model describes only one tissue compartment, the second incorporates the notion of a pore as a parallel pathway and the third model introduces a serial compartment corresponding to non-epithelial portions of the tissue. Experimental data were obtained, using a modified Ussing and Zerahn technique ((1951 Acta Physiol. Scand. 23, 110-127), for salicylate transport across rat jejunum in vitro and analyzed in terms of these three models. The conclusions based solely on the mathematical analysis of this rather simple experiment are: the tissue is not a homogeneous penetration barrier as often considered. Transport is not limited by unstirred layers either at the tissue surfaces or within the tissue itself. Salicylate is not passively transported. Parallel transport pathways do exist.

The Hepatocellular Transport of Sulfobromophthalein-Glutathione by Clofibrate Treated, Perfused Rat Liver

The hypolipidemic drug clofibrate is known to affect the hepatic transport of various organic anions including bilirubin, fatty acids and sulfobromophthalein. Changes in the rate of metabolism and/or intracellular transport have been claimed responsible for the effect. To evaluate these possibilities, the transport of sulfobromophthalein-glutathione, a model compound that does not require metabolism for biliary excretion, was studied in perfused livers isolated from clofibrate-treated and control rats. Cytosolic fatty acid binding protein and glutathione S-transferase activity were also measured. Clofibrate treatment significantly increased liver weight; as a result glutathione S-transferase activity (toward 1-chloro-2,4-dinitrobenzene) fell if expressed per gram of liver (4560±420 (SE) vs 7010±260 nmoles/min for clofibrate treated and controls respectively, p<0.002), but was unchanged when expressed per total liver (60.8±6.5 vs 64.6±3.5 μmoles/min for clofibrate and controls p>0.5). Irrespective of how it was expressed fatty acid binding protein was significantly increased by the drug treatment. Steady state sulfobromophthalein-glutathione removal velocity was saturble with increasing concentrations of sulfobromophthalein-glutathione in both control and clofibrate-treated livers. Steady state extraction ratio, as well as Vmax and Km for removal, did not differ between the two groups. In keeping with other observations, these data collectively indicate that the hepatic steady state removal of nonmetabolized compounds is not affected by clofibrate. Because the concomitant decrease in glutathione S-transferase activity only reflects an opposite change in liver weight, it remains to be determined whether clofibrate alters the hepatic transport of sulfobromophthalein and other compounds that are conjugated with glutathione solely by changing their rate of metabolism.