A.H. Hashish

Drug delivery by inhalation of charged particles

Abstract All solid and liquid particles produced naturally or by energetic industrial processes are electrically charged. Although the natural levels of charge are normally insufficient to influence the deposition of inhaled particles in the lung it is possible to increase charge levels so that a significant increase in lung deposition is caused. By careful control of breathing, particle size and charge it is possible to target specific regions of the lung. Predictions of targeted deposition using the Southampton lung model are presented and a brief description of complementary clinical studies is given.

Evaluation of the accuracy and precision of lung aerosol deposition measurements from planar radionuclide imaging using simulation

Planar images of known, theoretical distributions of radioaerosol in the lung have been simulated using lung models derived from magnetic resonance studies on human subjects. Total lung activity was evaluated from the simulated images together with the absolute penetration index (PI) and a relative value expressed as a fraction of that in a simulated ventilation image. The accuracy and precision of these measurements were calculated by comparison with the true values used in the simulation. Total activity was assessed with systematic errors within 5% and precision within 6.5%. Measured PIs varied only slowly with true PI and inter-model variation masked changes between measurements on the different distributions. The relative PI reduced inter-model variation and provided significant differences between all the distributions. PI was significantly affected by misalignment of the lung region of interest. The conducting airways deposition fraction (CADF) used in the simulation correlated linearly with the fractional activity in a central lung region, allowing CADF to be estimated with a precision of 21%.

LUNG DEPOSITION OF PARTICLES BY AIRWAY GENERATION IN HEALTHY SUBJECTS: THREE-DIMENSIONAL RADIONUCLIDE IMAGING AND NUMERICAL MODEL PREDICTION

Multi- modality medical imaging enables measurement of the three-dimensional spatial distribution of inhaled, radiolabelled aerosol within the human lung. Using a conceptual model of spatial lung morphology, this data may be transformed to provide information on deposition by airway generation in the conducting airways. This methodology has been used to study intrapul- monary deposition patterns in control subjects for two polydisperse aerosols produced by jet-type nebulisers of mass median aerodynamic diameter (MMAD) 1. 8 and 6.8 pm. Comparison between derived experimental results and those from computer modelling shows reasonable agreement for total body, oropharynx and lung deposition and also for the difference in deposition pattern between the two aerosols. However, experiment suggests significantly less deposition in the central airways than is predicted by modelling. The new methodology has considerable potential in the fields of inhalation therapy and deposition modelling though more detailed validation is still required. 0 1998 Elsevier Science Ltd. All rights reserved

On modelling the immune system as a complex system

We argued that immune system is an adaptive complex system. It is shown that it has emergent properties. Its network structure is of the small world network type. The network is of the threshold type, which helps in avoiding autoimmunity. It has the property that every antigen (e.g. virus or bacteria) is typically attacked by more than one effector. This stabilizes the equilibrium state. Modelling complex systems is discussed. Cellular automata (CA)-type models are successful, but there are much less analytic results about CA than about other less successful models e.g. partial differential equations (PDE). A compromise is proposed.

Modelling the effect of charge on selective deposition of particles in a diseased lung using aerosol boli.

The technique of using a charged bolus of aerosol to deliver a drug or other agent is advantageous since sites of interest within the lung can be selectively targeted. Ideally, the volume of the bolus should match that of the targeted region allowing the aerosol bolus particles to be confined to the selected area during the pause period after inhalation. Our existing computer model for predicting the deposition of charged aerosol particles has been developed to encompass aerosol boli, some diseased lung morphologies and drug dose administered per breathing cycle. Aerosol deposition in the targeted region is found to be enhanced by increasing particle charge, pause period and particle size. For particles in the size range 1-2.5 microm, aerosol deposition in the region affected by bronchoconstriction does not alter significantly with flow rate variation (range 250-1000 ml s(-1)) for a targeted charged bolus of matched volume. The technique may enable the optimal delivery of therapeutic or other agents to diseased or normal lungs.

On modelling of immune memory mechanisms

In human body, the acquired protection against illness is a biological property known as immunological memory. Different mechanisms for immunological memory are proposed and modeled. The first mechanism is the persisting antigen (Ag) where parts of the Ag are anticipated to persist on some Ag presenting cells. A novel application of the Hsu et al.’s model allows stable low Ag density equilibrium state. This state will correspond to the persisting Ag mechanism for the immune memory. The second is idiotypic and extremal mechanisms where mathematical models showed that a memory state could arise in this case. Finally, a simple model is given which shows that competition between effectors may contribute to the memory state.

A design method for the electrostatic atomization of liquid aerosols

Abstract A design method based on analysing and matching the physical time constants of the electrostatic atomization process in the cone jet mode is presented. An algorithm is developed whereby the liquid properties are used as a basis for recommending a capillary diameter and a liquid flow rate such that a stable spray will result once appropriate electric field conditions are established. The algorithm also predicts the droplet diameter about which the aerosol is distributed. Experimental results are presented which confirm the design methodology.

Selective deposition of pulsed aerosols in the human lung

Abstract A mathematical model, for predicting the deposition of aerosol particles in the human lung, has been extended to deal with the case of pulsed aerosols. A pulsed aerosol is one which is administered subsequent to the start of inhalation and which terminates before the end of inhalation. The pulse technique can be used to assist in the “targeting” of therapeutic or other agents on to different sites within the lung. Mathematical prediction of inhaled particle deposition patterns, obtained using the model, can assist in the planning of medical procedures. Efficient and controlled delivery of therapeutic agents to the tracheobronchial and alveolar regions can be achieved by optimizing: pulse duration and pulse delay time, flowrate, pause period, particle size and particle charge.

On managing complex adaptive systems motivated by biosystems application to infections

Many attempts to control Complex adaptive systems (CAS) have failed. Here we try to learn from biosystems to derive some principles for CAS management. An application to managing infections is given.

Towards understanding the immune system

It is proposed that using both self–non–self and danger theories give a better understanding of how the immune system works. It is proposed that comparing the immune system to the police force is useful in this case since the police respond both to danger or damage signals and foreign or suspicious behavior even if no danger signals existed. We also propose that due to low zone tolerance, immunotherapy needs to be combined with another treatment method for cancer, e.g., chemotherapy or/and radiotherapy, to get sufficient eradication of tumors. Finally, we propose that fractional order differential equations are more suitable than the familiar integer order differential equations. A fractional order example of two immune effectors attacking an antigen is given.