CLOSED LOOP DRUG DELIVERY

The field of pharmacokinetics concerns the analysis of fac­tors that affect absorption, distribution, and elimination of drugs in the body. In contrast, pharmacodynamics refers to interactions at the receptor site. Drugs may primarily act locally (the so-called topical type such as eye drops or inhaled aerosols) or they may more or less simultaneously (intentionally or not) influence many organs in the whole body (i. e., systemic type). Obviously, temporal as well as spatial considerations are relevant in pharmacokinetics. The route of administration mainly determines where a pharmacological substance exerts its primary action. Be­cause of the frequently occurring side effects of almost all drugs, it is also important to gather information about the distribution and uptake of a drug at a site that is not the primary target. Apart from the site of administration, it is important to have some estimate about the optimal speed of delivery at the desired location. Injection into the blood­stream is fast and potentially transient, while application on the skin (transdermal route) is slow but has the advan­tage ofbeing long-acting and rather constant. In particular, in iontophoresis a drug is delivered transdermally by using an electric field to enhance the transport of small, poorly absorbed ionic drugs across the skin surface with the ad­vantage that only a low dosage of the drug is required (16). All these considerations make clear that it is useful to de­velop models that incorporate the various (anatomical and physiological) compartments that are spatial and chemical in nature in order to predict the concentration and time pattern at a target site dependent on the location of in­troduction of the substance, as well as the particular time sequence (e. g., bolus versus repeated doses) of administra­tion.

VISION RESEARCH AND EYE MOVEMENT

Various aspects of eye movement have been extensively described in PHYSIOLOGICAL MODELS, DEVELOPMENT by T. Bahill. Therefore, we focus here on our main theme, namely fluctuations, instability, and variability as observed in the oculomotor control system. Basic concepts of the neuro­muscular system controlling movement of hands and limbs also apply to eye tracking. The task of permanently center­ing a moving image on the fovea is realized by a multilevel system involving reflex loops, volitional control, and pre­dictors. Saccades are rapid successions of conjugate steps of eye rotation that permit the positioning of a target image onto the fovea. The eyes voluntarily move from one fixation point to another, as can be observed during reading. They are preceded by a reaction time of about 0.20 s and follow a typical course of rapid acceleration and subsequent de­celeration with occasionally a small overshoot. Accommo­dation (focusing) is driven by a blur of the target image on the retina. Smooth pursuit involves a slow but continuous following movement needed to perform a smooth tracking task. Disjunctive movements of both eyes permit vergence (binocular fixation system resulting in convergent or diver­gent movement). Accommodation and vergence form an in­teractive dual-feedback system. Physiological nystagmus (min eye movements) are repetitive fast and slow move­ments that adds to the visual acuity by preventive bleach­ing while shifting to different receptors. Acceleration ofthe body requires the vestibulo-ocular reflex to become oper­ational. It is believed that (white) noise enhances stabil­ity (as in HRV), while fluctuations affect accommodation. Hung described a nonlinear static model, containing the depth of field (as a dead-space operator for accommoda­tion) as well as Panum’s (17) fusional area (as a dead-space operator for vergence), and found that these operators are able to account for the discrepancy between results using the phoria and fixation disparity methods (18).

RESPIRATORY CONTROL

During inspiration, air enters the lungs from the nasal pas­sages (conchae) or the mouth via a branching system of tubes ending in numerous small but highly elastic hollow structures (alveoli). These elastic elements are in contact with small blood vessels and are therefore the sites of gas

Figure 5. There is increased local obstruction at point C in case of asthma, whereas in emphysema the trajectory between C and the alveoli shows a permanent decrease of diameter.

exchange. Expiration implies transport in the opposite di­rection, from the lungs towards the final tube (the wind­pipe or trachea). Expansion of the lungs is normally real­ized by muscular activity of both the diaphragm and the intercostal muscles (19).

The dynamics of respiration are commonly described in terms of a pressure-volume relationship (to study restric­tive diseases such as interstitial fibrosis and pulmonary edema) and derived quantities such as flow ( Q, to study obstructive diseases such as lung emphysema) and com­pliance (the ratio of volume changes resulting from varia­tions in pressure). In contrast to emphysema, asthma is a reversible obstructive airway disease, because it is caused by an increase in smooth muscle tone in the large bronchi. Figure 5 illustrates the nature of these abnormalities in a lumped parameter model, consisting of the thoracic wall ( T), an overall spherical elastic element with alveolar pres­sure ( Palv) inside, atmospheric pressure ( Patm), pleural pressure ( Ppl), total airway resistance ( Raw), and C is the usual point of collapse of the airways acting as a Starling resistor (i. e., a collapsible tube affected by the pressure of its surroundings). It can be derived that

Q (inspiration) = (Pstm — Palv >/tfSw = —Q(expiration)

The stimulus to breathing is controlled by a particular area in the brain stem called the respiratory center. The rhythmical contraction of the diaphragm and intercostal muscles determine the inspiration sequences, that is, the brain generates alternating cycles of firing and quiescence in the responsible motor neurons.

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