James E. McNamee

Cigarette Smoking Pharmacokinetics and its Relationship to Smoking Behaviour

SummaryThe yield of a cigarette is determined by the tobacco blend, the length of the cigarette, the cigarette paper, the filter and air dilution. Cigarette yield has been defined by tradition and by law to be the yield of nicotine, tar and carbon monoxide obtained from a 35ml puff volume of 2-second duration taken every minute during the burning time of the cigarette.Normally smokers draw a puff into their mouth and then inhale. Mouth delivery is largely determined by personal smoking behaviour. The puff volume, number of puffs taken per cigarette, and number of cigarettes smoked per day determine both the volume and the mass of daily mouth delivery. There are marked differences in smoking behaviour, and the delivery is substantially altered from the yield values obtained with the standardised test procedure. Body uptake of smoke ingredients is determined by smoke chemical parameters, smoker inhalation behaviour, lung morphology, and physiological parameters. The physiological parameters include tidal volume, vital capacity, rate of breathing, and rate of clearance for the lung.Given these behavioural and physiological differences in individual delivery and uptake it is not surprising that differences in measured parameters occur within smokers of cigarettes with a particular yield. Biological differences among individuals, such as metabolic and size differences, cause additional variations in these values. Therefore, the estimates of nicotine and tar delivery can vary widely in studies of individual uptake when the estimates are based upon sample population data.The variables in both smoking behaviour and in chemical and physiological factors which alter uptake make it essential to have a crossover design for any study. The large standard error for the plasma concentration of cotinine (a major metabolite of nicotine) within a sample population, and the log linear nature of the plasma cotinine concentration curve, requires a very large sample size for any study of cigarette delivery or uptake. When comparisons of brands are made, average values are misleading in that the skew to the high values obscures frequency differences among the lower values within the samples. It is important to remember that smoker compliance with study design is very essential. It would be impossible to know that individual smokers failed to remain on the prescribed regimen during a study that attempted to have smokers of higher yield brands switch to lower yield brands.Epidemiology studies consistently find a higher incidence of both lung cancer and cardiovascular disease among smokers compared with non-smokers. There is evidence that the reduction in sales-weighted average tar yield of 30mg to 15mg has been accompanied by a decrease in the incidence of those diseases reported to be increased in the smoking population over non-smokers. Several studies have shown a dose-response relationship for the number of cigarettes smoked and lung cancer. The dose-response relationship for cardiovascular disease is less clear. A major part of the reduction in these disease states could be related to reduced numbers of smokers per 100,000 population. As cigarette yields decrease to tar values near 1rng, measurements of tar and nicotine uptake must be improved.

Endothelin-1 induces endothelial barrier failure in the cat hindlimb

Our purpose was to see whether endothelin- (ET) 1 could produce a change in the endothelial membrane barrier to protein in skeletal muscle. Previous studies in other tissues have suggested that ET-1 affects this barrier, but the measurement methods used could not exclude vascular protein extravasation due to microvascular pressure changes or the effects of changes in perfused capillary surface area. We measured the protein sieving coefficient, a specific measure of the permeability of the membrane to protein, in the isolated, perfused cat hindlimb preparation. The integral-mass balance method determined this coefficient from the changes in hematocrit and plasma protein concentration induced by a period of transvascular fluid filtration. The data clearly indicate that ET-1 produces a dose (1-20 nM) dependent increase in permeability indicative of barrier dysfunction. Hence, elevated ET levels may contribute to the perivascular edema, hemoconcentration, and impaired tissue perfusion found in systemic inflammatory response syndromes and related diseases.

Interaction of Endothelin-1 and Nitric Oxide in Endothelial Barrier Failure in the Cat Hindlimb

Objective: To determine the interactions of endothelin‐1 (ET‐1) and nitric oxide (NO) in the regulation of endothelial barrier function in skeletal muscle.

Fractal character of pulmonary microvascular permeability

The pulmonary microvasculature offers a heterogeneous barrier to the motion of large solutes as they pass between blood and lymph. While this barrier has been approximated by a few discrete pathways or by statistical ensembles of many pathways, these descriptions only partly capture the structural and functional properties of the pulmonary microcirculation. The concept that this barrier may be a fractal object is explored. Endothelial cleft geometry displays scaling in junctional path length and self-similarity in its spatial organization. It is shown that a fractal cleft produces heterogeneous spaces capable of transporting water and macromolecules. Cleft location, size, and depth are characterized, in part, by a fractal dimension of approximately 0.8. The consequences for transport through a fractal barrier are then determined. Predicted sieving of macromolecules by a fractal barrier is found to be consistent with lung microvascular transport data. Nonlinear transport phenomena are one consequence of a barrier having a fractional dimension.

Distribution of transvascular pathway sizes through the pulmonary microvascular barrier.

Mathematical models of solute and water exchange in the lung have been helpful in understanding factors governing the volume flow rate and composition of pulmonary lymph. As experimental data and models become more encompassing, parameter identification becomes more difficult. Pore sizes in these models should approach and eventually become equivalent to actual physiological pathway sizes as more complex and accurate models are tried. However, pore sizes and numbers vary from model to model as new pathway sizes are added. This apparent inconsistency of pore sizes can be explained if it is assumed that the pulmonary blood-lymph barrier is widely heteroporous, for example, being composed of a continuous distribution of pathway sizes. The sieving characteristics of the pulmonary barrier are reporduced by a log normal distribution of pathway sizes (log mean=−0.20, log s.d.=1.05). A log normal distribution of pathways in the microvascular barrier is shown to follow from a rather general assumption about the nature of the pulmonary endothelial junction.

Prediction of Permeability-Surface Area Product Data by Continuous-Distribution Pore Models

Objective: To investigate the ability of continuous‐distribution pore models to accurately predict permeability‐surface area product (PS) experimental data in skeletal muscle.

Introduction to fractals in biomedical research

Man-made objects are easily identified. They are formed through centuries of practice by the straight edges and smooth curves of Euclidean geometry. More recently, technological systems designed by man have exploited algebraic and linear systems theory. Deterministic models of mans creations are accurately portrayed, therefore, by the same mathematical equations from which those creations took shape. In contrast, naturally occurring objects and living systems have been difficult to describe with Euclidean shapes or analytical equations. This may be due to the fact that mathematics is a creation of mans mind rather than natures hand. The simplicity of mathematics may also be at odds with the innate complexity and the many levels of detail found in natural and living things. The description of living systems and our interactions with them benefits from a language capable of recognizing and expressing many layers of organization. Fractal mathematics is such a language. From their inception in the early 1970s, fractals have shown a remarkable capability to mimic naturally occurring shapes: the outline of a fern frond, the texture of an weathered mountain, the coagulation of proteins in solution. Objects in nature are often formed by the repeated breaking or fracturing (from which the word fractal was coined) of a larger object or by the result of accretion or layering of smaller objects to create a larger structure. The ability of fractal mathematics to replicate these events comes from the recursive manner in which fractals are defined. Students of the human body are quick to observe that form and function are intimately related. The ability of fractals to approximate familiar biological shapes also endows them with the potential to provide functional descriptions of living processes as well. Both static and dynamic relationships can be expressed in the language of fractal mathematics. The papers collected in this volume arose primarily from a symposium sponsored by the Biomedical Engineering Society held during May 1989 in New Orleans at the Federation of American Societies for Experimental Biology meeting. They illustrate the diversity of nature and the richness of fractal mathematics to describe it. King et al. introduce the fractal, address the subject of scaling, and explore its meaning and methods of dealing with it in the context of determining the spatial uniformity of myocardial blood flow. In the next paper, McNamee considers the structure and function of the pulmonary blood-lymph barrier. Thought to be a collection of heterogeneous pathways, the endothelial junction seems to possess characteristics of fractal shape and corresponding transport functions. The fractal qualities of the lungs mass transport systems not only give rise to interesting forms and functions but they confer

Fractal analysis of lung fluid flow

The human lung brings a continuous flow of blood into close proximity with a cyclic flow of air so that respiratory gases can readily diffuse between these two fluids. Nature has created an intricate arrangement of spaces to accomplish this task. A 3-dimensional cylinder of venous blood leaving the right ventricle is transformed into a nearly 2-dimensional film of blood by the time it arrives at the alveolus. At the same time, a bolus of inhaled air is divided into smaller streams and pockets until its surface area approaches 100 m2. Both processes distribute a fluid through a repeatedly bifurcating network. The configuration of these networks as well as their relative sizes have been difficult to summarize using the conventional language of Euclidean geometry [7].