Pharmaceutical blend infusion thereof and Parkinson's disease monitoring system

Abstract

The invention relates to a system for administering drug to a Parkinson's disease patient comprising (a) a drug; (b) a storing bag for the drug; (c) a pump for administering the drug; (d) a pump controller for controlling the pump activity, the pump controller having access to a correlation of a first parameter t.sub.x and a second parameter A.sub.t, and to the current first parameter t.sub.x, wherein the first parameter t.sub.x is correlated with a certain activity of the patient and the second parameter A.sub.t is correlated with a dosage of the drug and the pump controller controls the pump activity in dependence of the first parameter t.sub.x and the correlation, and/or wherein the system comprises (e) a storing hag the drug suitable for pre-filling and long-term oxidations-free storage having a multi layer wall with the internal layer made of EVA or cyclic polyolefines and at least one further layer made of EVOH.

Claims

1. A system for administering a drug to a Parkinson's disease patient comprising (a) a drug, (b) a storing bag for the drug, (c) a pump for administering the drug, and (d) a pump controller for controlling the pump activity, the pump controller having access to a correlation of a first parameter t.sub.x and a second parameter A.sub.t, to a current first parameter t.sub.x, and to a mobility calendar indicating start and finish times for particular values of the first parameter t.sub.x, wherein the first parameter t.sub.x is correlated with an activity level of the patient and the second parameter A.sub.t is correlated with a dosage of the drug and the pump controller controls a flow rate of the drug based on changes of the first parameter t.sub.x scheduled in the mobility calendar of the first parameter t.sub.x and the correlation of the first parameter t.sub.x and the second parameter A.sub.t; and wherein the controller further has access to a parameter b, wherein the controller controls the pump activity in case of a change of the first parameter by a multiplication of parameter b with the difference between an adjusted second parameter A.sub.t+z that is correlated with an adjusted first parameter t+z after the change and the second parameter A.sub.t that is correlated with the first parameter t.sub.x before the change to amend the dosage z minutes prior to the change by adding the result of the multiplication b*(A.sub.t+zA.sub.t) to the dosage according to the second parameter A.sub.t, wherein z is the time delay of the drug action being constant for each different drug and infusion path.

2. The system according to claim 1, wherein the storing bag for the drug comprises internal micro-striation texture.

3. The system according to claim 1, wherein the system comprises (f) at least one sensor for therapy feedback measurement and report and/or (g) recording and monitoring infusion, and/or (h) at least one sensor for remote therapy regiment adjustment.

4. The system according to claim 1, wherein the controller further has access to a parameter a for a master volume control, wherein the controller controls the pump activity by a multiplication of the parameter a with the second parameter A.sub.t that is correlated with the first parameter t.sub.x.

5. The system according to claim 1, wherein the controller further has access to a parameter a for a master volume control, wherein the controller controls the pump activity by a multiplication of the parameter a with the second parameter A.sub.t that is correlated with the first parameter t.sub.x; wherein the system is arranged in a way that the first parameter t.sub.x can be amended by the patient while parameters a, b and A.sub.t can be amended by an attending physician and/or by a control system that is in contact with the system.

6. The system according to claim 1, wherein the system further comprises an interface for submitting data to a remote control system and/or a remote data storage unit and/or an attending physician and/or wherein the system further comprises an interface for receiving data from a remote control system and/or a remote data storage unit and/or the attending physician.

7. The system according to claim 1, wherein the system further comprises at least one sensor for measurement of the status of the patient.

8. The system according to claim 7, wherein the at least one sensor for measurement of the status of the patient are selected from the group consisting of a 3D accelerometer, a gyroscope, an electromyogram, and a bed foil with sensing of movement, heart rate and/or respiration during sleep capability.

9. The system according to claim 8, having a sensor for movement measurement which is done in vicinity of a proximity sensor that is activated when two wrists come close together or a button is pressed on a wrist band.

10. The system according to claim 7, wherein the at least one sensor for measurement of the status of the patient are selected from the group consisting of a 3D accelerometer, a gyroscope, and an electromyogram.

11. The system according to claim 1, wherein the system comprises a patient's feedback function which comprises an input interface for a response of the patient to questions asked by the patient's feedback function.

12. The system according to claim 1, comprising a sensor for detecting malfunction of the system.

13. The system according to claim 1, wherein the system is arranged in a way that in case of negative feedback by the patient, critical status of the patient and/or malfunction of the system the respective information is automatically submitted to a remote control system and/or a remote data storage unit and/or an attending physician.

14. The system according to claim 1, wherein the drug comprises Levodopa and/or Carbidopa and/or benserazide suspended in a viscous liquid having a viscosity of 30030 mPa-s measured at a moderate shear rate.

15. The system according to claim 1, wherein the drug is apomorphine.

16. The system according to claim 1, further comprising a catheter for delivering the drug to the digestive tract or the nasal cavity.

17. The system according to claim 1, wherein the storing bag for the drug is suitable for pre-filling and long-term oxidations-free storage has a multi layer wall with the internal layer made of ethylene vinyl acetate (EVA) or cyclic polyolefines and at least one further layer made of ethylene vinyl alcohol (EVOH).

18. The system according to claim 1, wherein, starting z minutes prior to the start time of a new activity, (i) when the activity level of the new activity is higher than the initial activity level, the flow rate of the drug is increased above a maintenance flow rate of the drug for the new activity, (ii) when the activity level of the new activity is lower than the initial activity level, the flow rate of the drug is decreased below a maintenance flow rate of the drug for the new activity, or (iii) both option (i) and option (ii), wherein z is the time delay of the drug action being constant for each different drug and infusion path.

19. The system according to claim 1, wherein the user is the patient or an assistant.

20. The system according to claim 1, wherein the drug comprises Levodopa and/or Carbidopa and/or benserazide in the form of microscopic particles.

21. The system according to claim 1, wherein the system is adapted to allow a user to schedule and/or update the particular values of the first parameter t.sub.x in the mobility calendar.

Description

FIGURE LEGENDS

(1) FIG. 1 Shows the potential stratifications of a multi layered flexible plastic bag.

(2) FIG. 2 Shows a daily schedule of activities on the part of the patient with names and on the part of the physician with numbers on dose regulation parameters A.

(3) FIG. 3 Shows a planning of few hours and the corresponding pump infusion for a certain adjustment of A, and and .sub.+z/t.sub.x.

(4) FIG. 4 Shows a hand bracelet with movement sensor.

(5) FIG. 5 Shows a sensor and pump battery charger with simultaneous data transfer to a server.

(6) FIG. 8 Shows a version of the electronic blocks of a movement sensor.

(7) FIG. 7 Shows the infusion results reference range from the patient

(8) FIG. 8 Shows a parameter a () possible decaying function graph per volume and FIG. 8 per time passed till morning wake up. This is a curve fit to patient's feedback by means of questions answered or sensors reporting treatment results.

A PREFERRED EMBODIMENT OF THE INVENTION

(9) The present invention provides a pharmaceutical solution for advanced Parkinson's disease, in two different versions and corresponding basic pharmaceutical substances and a different administration path for each of them, as is reported hereinabove, in combination with a prefilled bag of drug made of a flexible plastic sheet with oxygen/carbon dioxide/humidify transport protection in order to prevent drug oxidation and/or concentration change. This sheet consists of 2 or more layers, as in FIG. 1 wherein the internal side (1) is preferably EVA or polyolefin with cross-wise micro-striations for easy emptying, a connecting sheet (2) follows, an EVOH gas barrier (3) preferably follows, as well as protective structure or binder to other layers (4), the no. of layers reaching even 7 depending on the combination of materials.

(10) The planningtimetable of daily activities from the patient can be formed realistically every day FIG. 2 (5) and it may include only one rolling day changing according to the needs, or one year wherein the changes need statistical analysis and artificial intelligence support in order to merge with the existing timetable and anticipate the next day as accurately as possible and propose it to the patient for easier data entry. The patient of course can alter in real time his immediate schedule by raising or lowering the activity bar on touch screens, and its time duration by pulling it to the rightleft according to the need in hand, the places being distinguishable and having written adjacent to them the activity type for each level, in an alternative simple (no touch) screen, the type of activity is selected from a list as well as the time/duration, the simple screen then displays the altered day schedule or the next 24 hrs. The follow-up of daily activity via user as well as sensor information dispatched and recorded in the server, forms a realistic rolling, weekly or yearly, activities schedule replacing the initially planned one, with the help of algorithmic or artificial intelligence not described herein, in the data merging or not.

(11) Communication with the user can be carried out through the pump or a mobile application. The result is to program the pump using telemetry or locally as regards the real user activity and to minimise dyskinesia, trembling etc.

(12) The drug infusion for a constant activity according to the medical practice is constant and depends proportionally on the required work level.

(13) According to the invention a system is preferred wherein the controller further has access to a parameter a for a master volume control, wherein the controller controls the pump infusion Rate (pump activity) by a multiplication of the parameter a with the second Relative muscle work intensity level parameter A.sub.t that is correlated with the first activity level parameter t.sub.y.

(14) The meaning of the parameter a is a factor for infusion amount needed for a certain muscle work, as a general factor for all activity levels in ml/hr. This general factor controls overall infused volume per day by multiplication with the factors A.sub.t which change during the day according to mobility calendar.

(15) The infusion algorithm regulates transiently a higher infusion in order to increase the activity before it is realised due to the delayed drug action. Correspondingly infusion reduction before the activity reduction, e.g. higher infusion before waking up in the morning, infusion reduction before going to bed, or an increase before the daily increased activity. In addition, the user has the possibility of taking a bolus dose. After the transient part in preparing for the next activity, the infusion is constant.

(16) According to the invention the system is further preferred wherein the controller has further access to a (bolus volume) parameter b, wherein the controller controls the pump activity in case of a change of the first parameter by a multiplication of parameter b with the difference between the second parameter A.sub.t+z that is correlated with the first parameter t.sub.+z after the change and the second parameter A.sub.tx that is correlated with the first parameter t.sub.x before the change to amend the dosage z minutes prior to the change by adding the result of the multiplication (b*(A.sub.t+z-A.sub.tx) to the dosage according to A.sub.tx.

(17) The simpler form of the novelty in the technique of algorithmic planning is the following and consists of a first part of constant infusion proportional to the activity level and a transient part (replacing the bolus dose, however, not in an obligatorily manner) in preparation for the next taking into account the delayed action of the drug:
E.sub.tx=*A.sub.tx+b*(A.sub.t+z-A.sub.tx)Equation 1,
wherein

(18) E is the infusion profile including rate in ml/hr in time t.sub.x as a positive value or zero and bolus volume at z time before activity change

(19) A.sub.t is dosage of the drug relative to patient's muscle work intensity level one for each calendar patient's activity/mobility type

(20) a factor for infusion Rate needed for correct kinetic performance at any mobility level, as a general factor for ail the activity and adjustment levels in ml/hr.

(21) b Bolus factor for the automatic leading dose (increase/decrease) for the transient activity situation from one level to the next given, a time before activity change

(22) t.sub.x is the mobility type at the real present time (x according to scheduled calendar)

(23) z is the time delay of the drug action, preferably 30-45 min, being constant for each different drug and infusion path.

(24) t+z is scheduled mobility type after mobility type at real present time.

(25) a*A.sub.t is equal to the steady state infusion rate necessary for an activity t.

(26) For example, if the daily average drug consumption during 24 hours for medium-type activity is 80 ml, then the medium-type activity, e.g. seating can be A=2, and then the average infusion rate per hour is 60/24=2.5 ml/hr and a=2.5/2=1.25 ml/hr.

(27) The physician should regulate number A=2 relative to the muscle work produced in higher (3) or lower (1) activity, in order not to end up having one activity with too much drug and another with too little as for more muscle work, patient needs more drug per hour.

(28) In the example, number a=1.25 ml/hr is for the Rate of drug needed by the treatment regimen in total, i.e. this will change in case all of the activities are presented with drug deficiency or surplus. In case only one activity is in deficiency, its parameter A only is increased.

(29) Factor b regulates the onset of a subsequent activity with the proper comfort from the first instance. It increases in case the patient is slow in reaching normal functioning, and decreases in case diskinesia phenomena occur even for a short time.

(30) The pump and/or the server compute also the total drug volume that should be in the bag, for a series of parameters and a certain daily scheduling.

(31) Bolus can be positive or negative. In case it is positive, a bolus as known in the art is given at high rate, in case it is negative, infusion is suspended till the amount of Bolus volume is reached, then it continues at whatever level is needed from steady state part of the equation. The pump or server computer may indicate to the physician the value of this integral (dosage volume) for this transient dose thus enabling him to set parameter b property.

(32) FIG. 3 (5) shows a scheduled activity in time, and the infusion (7) according to the equation. The patient may be warned, if he so wishes, before the onset of the transients in case he needs to make any modifications on the daily schedulepostpone next activity about x minutes or hours.

(33) Separating the task of activity scheduling to be done by the user and the task of infusion parameters setting by the physician, enables pump programming from a distance without risks. For this reason either the parameters are being entered in the pump or via telemetry, observing however the safety limits in the pump that cannot be exceeded by teleprogramming.

(34) In the present invention as it is reported analytically below, there is provision for effectiveness of treatment feedback to the attending physician via sensors in the present invention, feedback is used as an alternative by the user himself or his family and relatives, via questions programmed in time according to the physician's needs or on demand by the patient at his own will.

(35) A report on the results (questions-answers) and on the side effects has two legs, the first one is about controlling the infusion properly, with questions on infusion control with quantification, see FIG. 7, and the second one is about the side effects recording;

(36) 1. Overall, does infusion promote satisfactory movement, difficulty or hyperkinesia? Draw the bar to the left for a little more infusion, to the right for excessive, depending on how you feel with it.

(37) 2. If a certain activity is not properly set, choose that activity from the list, and draw the bar to the left for a little more infusion, to the right for excessive, depending on how you feel with it.

(38) 3. Beginning a new activity, do you experience satisfactory mobility, more or less? Draw the bar to the left for a little more infusion in order to get prepared for the oncoming activity, to the right for excessive, depending on how you feel with it.

(39) 4. Fill in the square adjacent the word if you have the corresponding side effect with constipation, nausea, grainy tissue, dyskinesia, insomnia, nightmares at sleep stress irritation of the catheter wound.

(40) No. 1 helps configure master rote parameter a

(41) No. 2 helps configure each numberof relative activity parameter A

(42) No. 3 helps configure parameter b

(43) No. 4 helps in the recording of the general drug side effects some of which are related to a high or low infusion.

(44) The report can be dispatched to the server when the pump or any other means set to receiving the report is connected to the internet.

(45) To begin with, the physician and as an alternative an algorithmic programming may be receiving as parameters the programmed/updated activity, the administered infusion along with any requests for on demand doses and the recording of side effects (sensors and reports) depending on the dosage given during the previous time interval (case history) plus the physician's corrections from lab observations on kinesiology and personal reports, all stored on the server. The optional algorithm of artificial intelligence not described herein, is continuously being improved in analyzing the effectiveness of the infusion scheduling, towards obtaining the optimum result and suggesting to the physician the most appropriate parameters A, a, b in order to achieve the optimal patient situation.

(46) The recording of ail measurements, infusions and reports on web pages in the internet, allows the best possible follow-up in the treatment by the attending physician, plus a proof of the therapeutic effect to third parties, i.e. social security funds, companies etc.

(47) That is to say, according to the present invention a rolling schedule (calendar) on activities is created including also day or night sleep, which is configured using a first algorithm that could also contain neural networks, said algorithm learning from the user's habits, combining them with the time during which they actually fake place and in hours of the day and in anniversaries, weekends, holidays, etc. said schedule being enabled to change by the user, adding this way new data to the habits, or change through the sensor's measurements taken on the user's body monitoring its condition in real time.

(48) According to the present invention, by having the updated 24 hour schedule as input, a second algorithm can start operating that could also contain neural networks and PID (Proportional Integral Differential) algorithm for regulating different drug infusion profiles for enteral or nasal or parenteral or transdermal or intramuscular infusion, plus drug type as same or similar to Duodopa as described in the present specification, or apomorphine or the like. The PID reads the error (i.e. kinetic disorders) from the sensors on the patient's body, and remains inactive if sensors have not been activated; however it gets activated in case of reports by the user about side effects or drug activity.

(49) The pump and sensor batteries charger FIG. 5 is connected to the internet, via Ethernet (11) or WiFi (10) or GSM/GPRS, charges the pump only or the alternative battery (12) thereof, in case it is being used on a 24 hours basis, plus sensors (8) during the night, transmitting simultaneously the pump data (incidents as alarms, on demand doses etc) with a time stamp, plus the kinetic behavior daily data of the patient along with the sensor data. Locally or in the server, this data are analyzed using algorithms as described below.

(50) The sensors (8) placed on a hand or leg strap (9) or on a slipper, in the electronic part FIG. 6 preferably have rechargeable batteries (16), charger (18), USS connection (17) for data and power transfer, to/from the microcomputer (13) connected with accelerometer or gyroscope sensor (12), 18 hrs flash data memory (20), WLAN wireless connection ZigBee (14), antenna (15). Gyroscope (with all the above mentioned electronic platform) can be placed on the breast in a clip, in order to detect hyperkinesia situations (patient dancing movements) resulting from any drug overdose.

(51) The sensors preferably have 62.5 Hz sampling, in 3 dimensions x, y, z and being all synchronized, they read any movement the same moment it happens adding to the data a package of some KBs plus the time (from a synchronized clock) in order to enable data processing at a different time and in another computer. Synchronization is initially obtained in the charger base by the home base computer of FIG. 5, via USB, and continues at regular, e.g. 1 minute or more, time intervals via ZigBee, wherein, preferably, one sensor at a time, alternating with the next one, sends a real time clock synchronization signal. On the intermediate intervals the docks are based on the internal crystal for synchronized measurements.

(52) The wrist bands at the hands further may comprise sensors that may be e.g. proximity sensors to detect when wrists come close together. Inventively, when a patient feels that he has a kinetic problem he is instructed to try to raise both hands in a predetermined position e.g. in front of him close one wrist to the other, and when a beep sound is heard he moves them back normally. By doing so, an algorithm for detection of dyskinesia or bradykinesia, or ON/OFF, or tremor, can easier find the type of the kinetic problem, analysing waveforms before and after the proximity receding which for dyskinesia will have a lot of movement detection and for bradykinesia much less movement. The system records the time stamp of the hands proximity for this analysis purpose. The proximity sensor can be of any simple type like a magnet and a reed/hall effect switch, an optic sensor and light source, or simple switch pressed by the other hand therefore a single wrist sensor/switch band can be sufficient. This is a patient activated feedback when he feels bad, so doctor can better understand on a screen the time and type of patient's discomfort for therapy adjustment (parameters a,b,At). This additional option greatly facilitates the certification process of the system, as regulatory wise it is the patient who reports a problem and system analyses its type, rather than having to prove that the system correctly detects any disorder. Also in its simpler form without sensors, the switch can be a feedback of the therapy when patient feels bad, with time stamp on the event.

(53) In the charging bass, the sensors transfer the stored data of the order of 35 MB to their flash drive, in order to be processed locally by the algorithm mentioned below, or the server for processing therein. Finally the server receives the treatment feedback, i.e., whether the patient moved about without any problems or had a problem and what kind of problem, through the charging/processing base, or from its own internal algorithm (in case of dispatched data). Thus the doctor has all the information in order to be able to correct the treatment regimen, and optionally the advice from the second aforementioned treatment analysis algorithm.

(54) The sensor synchronised waveform processing algorithm, attempts to discover through relatively chaotic data, pathological disorders in patient movement owing to improper treatment/infusion. What is required is to correct the treatment with the aid of computing support

(55) For this reason an operating algorithm including neural networks able to be trained, compares the results if outputs to the results judged to be right by the expert physician, and thus the neurnal network is trained in clinical trials. The trained artificial neural networks with large clinical data bases corresponding to medical interpretation provide us with the basic factors introduced into the neuronal networks of computing units used in commercial applications.

(56) Before the supervised neural networks, the processing of the results from synchronised 3 axes waveforms is preferably carried out utilizing digital filtering (FIR) and then via a moving window, classification into tree-branching decisions and/or the Random Forest algorithm and analysis via Feature Vectors, or other neural networks with intermediate FIR filters. The objective is finding trembling, bradykinesia, dyskinesia/LID (Levodopa Induced Dyskinesia), ON/OFF situation, according to the following literature.

(57) The combination of algorithms in clinical trial showed reliable results on the patient situation with a precision in the order of 85% with a complete series of sensors and 65% with only one sensor on the hand. According to the present invention, the user in collaboration with his physician decides whether to put one, no one, or all the sensors depending on the annoyance level being able to tolerate as well as the desired treatment level.

(58) Sensor Analysis Literature An automated methodology for levodopa-induced dyskinesia; Assessment based on gyroscope and accelerometer signals. Markos G. Tsipouras, Alexandras T. Tzalias, George Rigas, Sofia Tsouti. Dimitdos I. Fotiadis, Spires Konitsiotis: Artificial intelligence in medicine 55(2): 127-135 (2012) Assessment of Tremor Activity in the Parkinson's Disease Using a Set of Wearable Sensors. George Rigas. Alexandres T. Tzalias, Markos G. Tsipouras, Panagiota Bougia, Evanthia E. Tripoliti Dina Baga, Dimitros I. Fotiadis, Sofia Tsouli, Spiros Konitsiotis: IEEE Transactions on information Technology in Biomedicine 16(3): 478-437 (2012) Assessment of Bradykinesia in Parkinson's disease patients through a multi-parametric system, Pastorino M, Canceta J, Armdondo M T, Pansera M, Pastor-Sanz L, Villagra F, Pastor M A, Martin J A, Cent Proc IEEE Eng Med Biol Soc. 2011:2011:1810-3. An automated method for Levodopa induced dyskinesia detection and severity classification M. G. Tsipouras, A T. Tzalias, G, Rigas. P. Bougia, D. I. Fotiadis, and S. Konitsiotis, IFMBA proceedings Vol. 29 On automated assessment of Levodopa-induced dyskinesia in Parkinson's disease Tzalias. A. T.; Fotiadis, D. I.; Konitsiotis, S. Engineering in Medicine and Biology Society, EMBC, 2011 Annual international Conference of the IEEE Dynamic Neural Network Detection of Tremor and Dyskinesia from Wearable Sensor Data Bryan T. Cole, Serge H. Roy, Carlo J. De Luca, Life Fellow, IEEE, and S, Hamid Nawabo, Senior Member, IEEE 32nd Annual international Conference of the IEEE EMBS Buenos Aires, Argentina, Aug. 31-Sep. 4, 2010.

Example

(59) The example depicts a scheduled day activity (and resulting pump activity) in Table 1 and the same activity table wherein after a patient's feedback the drug volume for walking (activity t.sub.3) was amended.

(60) TABLE-US-00001 TABLE 1 Half hours of a day 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Patient input 1 1 1 1 1 1 1 1 1 1 1 1 1 (Mobility calendar) Doctor A1 A2 A3 a b Al for sleep, Parameters A2 for sit, A3 for walk 1 2.2 3.3 1.3 2 a = master volume control; b = bolus volume control Patient mobility in 1 1 1 1 1 1 1 1 1 1 1 1 1 parametric terms Infusion Rates 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 ml/hr Bolus (transient) 0 0 0 0 0 0 0 0 0 0 0 0 0 Half hours of a day 6.5 7 7.5 8 8.5 9 9.5 10 10.5 11 11.5 12 12.5 Patient Input 1 1 1 1 2 2 2 2 2 3 3 2 2 (Mobility calendar) Patient mobility in 1 1 1 1 2.2 2.2 2.2 2.2 2.2 3.3 3.3 2.2 2.2 parametric terms Infusion Rates 1.3 1.3 1.3 1.3 2.86 2.86 2.86 2.86 2.86 4.29 4.29 2.86 2.86 ml/hr Bolus 0 0 0 3.12 0 0 0 0 2.86 0 2.86 0 0 (transient) Half hours of a day 13 13.5 14 14.5 15 15.5 16 16.5 17 17.5 18 18.5 19 Patient input 2 2 2 1 1 1 1 1 2 2 2 2 2 (Mobility calendar) Patient mobility in 2.2 2.2 2.2 1 1 1 1 1 2.2 2.2 2.2 2.2 2.2 parametric terms Infusion Rates 2.86 2.86 2.86 1.3 1.3 1.3 1.3 1.3 2.86 2.86 2.86 2.86 2.86 ml/hr Bolus 0 0 3.12 0 0 0 0 3.12 0 0 0 0 0 (transient) Half hours of a day 19.5 20 20.5 21 21 21.5 22 22.5 23 23.5 24 Patient Input 2 3 3 2 2 2 2 2 2 2 2 (Mobility calendar) Patient mobility in 2.2 3.3 3.3 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 parametric terms Infusion Rates 2.86 4.29 4.29 2.86 2.86 2.86 2.86 2.86 2.86 2.86 2.86 ml/hr Bolus 2.86 0 2.86 0 0 0 0 0 0 0 0 (transient) Half hours of a day Patient Input (Mobility calendar) Patient mobility SUM TOTAL in parametric Volume per day terms Infusions Rates 111.54 58.89 ml/hr Bolus 3.12 (transient) l = sleep 2 = sit 3 = walk

(61) TABLE-US-00002 Patient feedback hyperkinesia in walk (Activity level 3) New Doctor reduce Parameters A3 A1 A2 A3 a b 1 2.2 2.9 1.3 2 New Half hours of a day 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Patient mobility in 1 1 1 1 1 1 1 1 1 1 1 1 1 parametric terms Infusion Rates 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 ml/hr Bolus (transient) 0 0 0 0 0 0 0 0 0 0 0 0 0 Bold letters Input Patient and doctor Italic letters Pump calc and output Combination of 2 (infusion) inputs and formula Underlinedletters Correction after user feedback New Half hours of a day 6.5 7 7.5 8 8.5 9 9.5 10 10.5 11 11.5 12 12.5 Patient mobility in 1 1 1 1 2.2 2.2 2.2 2.2 2.2 2.9 2.9 2.2 2 2 parametric terms Infusion Rates 1.3 1.3 1.3 1.3 2.86 2.86 2.86 2.86 2.86 3.77 3.77 2.86 2.86 ml/hr Bolus 0 0 0 3.12 0 0 0 0 1.82 0 1.82 0 0 (transient) New Half hours of a day 13 13.5 14 14.5 15 15.5 16 16.5 17 17.5 18 18.5 19 Patient mobty in 2.2 2.2 2.2 1 1 1 1 1 2.2 2.2 2.2 2.2 2.2 parametric terms Infusion Rates 2.86 2.86 2.86 1.3 1.3 1.3 1.3 1.3 2.86 2.86 2.86 2.86 2.86 ml/hr Bolus 0 0 3.12 0 0 0 0 3.12 0 0 0 0 0 (transient) New Half hours of a day 19.5 20 20.5 21 21 21.5 22 22.5 23 23.5 24 Patient mobility in 2.2 2.9 29 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 parametric terms Infusion Rates 2.86 3.77 3.77 2.86 2.86 2.86 2.86 2.86 2.86 2.86 2.86 ml/hr Bolus 1.82 8 1.82 0 0 0 0 0 0 0 0 (transient) New Patient mobility SUM Total volume per day in parametric terms Infusion Rates 109.46 57.85 ml/hr Bolus 3.12 (transient) Patient feedback All OK!

EXPLANATIONS

(62) First input to pump is patient's calendar as graph representing line patient's input. More activity levels can be added such as intermediate to sit and walk, more than walk as gardening etc.

(63) Second input to pump is doctor's parameters

(64) The pump associates a parameter A1-A3 to each correspondent activity level of calendar i.e.

(65) Formula is
Et=a*At+b*(At+zAt)

(66) Infusion Basal Rate is calculated according to formula's first term in lines infusion rates

(67) Bolus here is a shot at 100 ml/hr additional infusion to the Basal Rate

(68) A negative Bolus means we reduce rate until this volume is lost from ongoing infusion

(69) Bolus is given half an hour before transition as drug needs this time to react in the body

(70) Parameter a is a master Volume control, to change easily all levels in case patient needs more or less drug overall not in one specific activity

(71) If a=1 then all activity levels A are in ml/hr as in all pumps today