1 I n t r o d u c t i o n THE DOSE OF an anticancer drug is critical because of the fine line which divides the killing of the tumour and normal tissue. Although patients are counselled on the importance of regularly taking their medication there has always been considerable doubt (RICHARDSON et al., 1988) over the outcome. One reason for this is that these drugs often cause severe side-effects, such as nausea and vomit- ing, and as a consequence the patient may not fully comply with the prescribed dose regimen.

To assess the degree of compliance of patients a tablet container has been developed which internally records the times at which the lid is removed. At the end of the period of treatment (2-4 weeks typically) the recorded times of opening may be examined. Although other devices have been described which accomplish this (MouLDING et al., 1970; YEE et al., 1974; DICKINS et al., 1986), none resem- bled the type of tablet bottle in common usage. The device

described here was designed so that the patient would receive no clue that monitoring was taking place, as this may well have influenced the compliance behaviour.

2 D e s c r i p t i o n o f t h e d e v i c e The device is in the form of a bottle with a lightproof

inner container and lid. The inner container (Fig. l) is of transparent plastic whose outer surface has a white coating covered in turn by a lightproof layer (black PVC insulat- ing tape). This arrangement acts sufficiently as a light pipe that, even with the container full of tablets, light finds its way to the cadmium sulphide photoconductive cell in the base. Even in subdued room lighting it is possible to detect the removal of the lid by the change in photocell resist- ance. For the geometry and photocell (ORP12) used, a resistance fall below 1 MQ gave reliable indication of the removal of the lid. The translucent layer in the base of the inner container is to disguise the presence of the photocell and has negligible effect on its operation. The outer con- tainer (Fig. 2) is a standard blow-moulded polyethylene bottle with outer dimensions 100 x 50 x 50mm of a type often found in pharmacies. The outer surface of the lid was sprayed with black lacquer.

photocell

Fig. 1 Construction of the inner container

First received 9th November 1990 and in final form 16th January 1991

�9 IFMBE: 1991

Medical & Biological Engineering & Computing

Fig. 2 View of the device and the component parts

November 1991 607

The circuit (Fig. 3) uses a 1024 x 4 bit static RAM, although only one data bit is used, and the hourly signals advance the counter and hence the address (0 to 1023) of the memory. Thus the maximum period of data gathering is 42 days. Before use all memory locations are initialised to contain '0' in the data bit. Removal of the bottle lid causes the - 4 divider to reset and in turn to produce a chip-enable signal to the memory. The data line of the memory is normally held high by a pull-up resistor, and so any chip-enable signal will write '1' to the current address.

1MQ

2..

1per min ~ l p,.er h

I~F

Fig. 3 Block diagram of the circuit

monostable

t counter

memory

The function of the :--4 divider is to provide 3-4 min delay before a further chip-enable signal to the memory can be produced. This is in effect a 'contact debounce' device which is necessary when bottle opening occurs near the turn of the hour and which may otherwise result in writing '1' to two adjoining memory locations.

Read-out of data stored in the memory is achieved by connecting to a reader device which asserts control over the signal lines of the clock, the RAM chip-enable, the RAM read/write, the RAM data and the reset line for the - 6 0 divider and counter. After asserting the reset signal, the externally supplied clock pulses cause the memory address to be incremented and allow the stored data to be read out. Initialisation of all the memory contents to '0', in readiness for the next period of data gathering, is achieved by stepping the counter, but with "0' asserted on the data input of the RAM. Full circuit details are available from the author.

The circuit was realised with five CMOS integrated cir- cuits which could operate on a supply voltage down to 3 V. Power was supplied by three 60 mA h NiCd button cells (3.6 V), which resulted in a current drain of ,,~ 10/LA, and the cells provide ample capacity for the 42-day data- gathering period. The cells can be recharged without removal. The electronic components are concealed in the space between the inner and outer containers (see Fig. 2) and before assembly were sprayed with a silicone-based lacquer to obviate any condensation problems. The base of the bottle carries a self-adhesive label which conceals a small electrical socket to enable connection to be made to the reading device or battery charger. The label is made of smooth metal foil and its condition reveals any at tempt at

s tar t openings

77 o ? o ? ? ,~ ? i l : ~ i i i i :

Fig. 4 Part of a data record displayed in graphic form

removal by the patient. Fig. 4 shows a sample of the readout data presented in graphical form.

3 T e s t i n g a n d u s e o f t h e d e v i c e Initial trials with the device established that the lid

opening was recorded even when the level of ambient lighting was below that which most people would regard as tolerable for removing tablets from the container. At the other extreme, even in bright sunlight with the lid not fully screwed home, the circuit recorded it as closed. The effect of electromagnetic interference was tested by the use of a car ignition coil and spark gap placed a few centimetres away. The circuit was rendered immune to this source of interference by the inclusion of several decoupling capa- citors. For some drugs it was necessary for the patient to store the bottle in a refrigerator; removal to a warm room may cause water condensation on the circuit board. However, repeated trials failed to uncover any malfunction due to this.

The device has been in use wi th patients for approx- imately two years. Because the device was used with cyto- toxic drugs and could not be made with a childproof lid some caution in its use was necessary and patients were carefully counselled. Patients were also told that the bottle has a special light-tight construction and should be returned at the next clinic visit. Out of approximately 100 courses of treatment to date no patient has failed to return the device. Where treatment was started using the device patients accepted it without apparent suspicion. However, it was notable that where a patient had had an earlier course of treatment with the same drug in a different con- tainer there was some suspicion over the change in con- tainer. Only one patient persisted in his enquiries to the point that it was felt that the nature of the device should be revealed to him.

Clearly, the fact that the device indicates an opening of the container does not guarantee ingestion of the medica- tion by the patient. However this is less of a problem than it might seem. In essence the use of the device is to identify patients who fail to ingest their medication and this will nearly always be accompanied by the absence of an opening. Thus when a regular pattern of opening is seen, it would almost certainly indicate regular ingestion. One undesirable possibility would be where the patient trans- fers tablets from the device to another container. To reduce the risk of this the patient was told the tablets should be always be kept in it because of its special light- tight properties.

The device was designed for laboratory construction in limited numbers; however, with some modification, e.g. the substitution of a custom-designed circuit chip, the design would form the basis for manufacture in larger numbers.

Acknowledgments--I would like to thank Mr B. J. Smith of Stuart Pharmaceuticals Ltd., Wilmslow, Cheshire, for the gener- ous supply of the bottles which form the outer container of the device.

References DICKINS, J., CROSS, G., TERRY, V. G., NICHOLSON, P. W., SULLENS,

C. M., CHEUNG, R., DENHAM, M. J. and DOBBS, S. M. 0986) Measurement of compliance with drug therapy in the elderly: a new approach. Br. J. Clin. Pharmacol., 22, 246P.

MOULDING, Z., ONSTAD, G. O. and SBARBARO, J. A. (1970) Super- vision of outpatient drug therapy with medication monitor. Ann. Int. Med., 73, 559 564.

RICHARDSON, J. L, MARKS, G., and LEVINE, A. (1988) The influ- ence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J. Clin. Oncol., 6, 1746-1752.

YEE, R. D., HAHN, P. M. and CHRISTENSEN, R. E. (1974) Medica- tion monitor for opthalmology. Am. J. Opthal., 78, 774-778.

608 Medical & Biological Engineering & Computing November 1991