Levodopa sensor for tight dose tuning

Abstract

An enzymatic sensor configured to determine a concentration of levodopa present in a sample from a current or resonant frequency generated in response to an interaction of levodopa with a L-amino acid decarboxylase present in the sensor. A processor associated with the sensor determines the levodopa concentration and generates a dosage recommendation or output in accordance with the levodopa concentration.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 976,580, filed on February 14, 2020, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to closed-loop drug delivery systems, and more specifically to systems for controlling the delivery of levodopa or other related drug compounds or formulations based on continuously monitored levels of those drugs or compounds in the body. Background Technology

[0004] Dopamine is a neurotransmitter involved in many key functions of the brain, but most notably in regulating movement. Dopamine is produced in the body through the decarboxylation of levodopa (L-Dopa), which is synthesized from the amino acid L-tyrosine by tyrosine hydroxylase. L-Dopa is a precursor to many other neurotransmitters, most notably adrenaline and noradrenaline.

[0005] Dopamine cannot cross the blood-brain barrier, while L-Dopa can, thus effectively treating dopamine deficiency disorders such as Parkinson's disease and dopamine-responsive dystonia. L-Dopa enters the central nervous system (CNS), where it is converted into dopamine, increasing dopamine levels in the CNS and activating postsynaptic dopaminergic receptors. In this way, L-Dopa administration can compensate for the reduction of endogenous dopamine.

[0006] L-Dopa exists in several pharmacological forms, administered orally or as a liquid via a duodenal pump. Gastrointestinal uptake of L-Dopa varies considerably and can be inhibited by many dietary choices, most notably fats and proteins. Proteins, in particular, directly compete with L-Dopa for uptake sites and can reduce the effective amount of L-Dopa absorbed from a given dose. Increasing the dose to address limited uptake presents its own problems. Such dose deviations increase associated risks if a patient's diet on a particular day allows for unusually high intakes. High L-Dopa spikes in the brain are especially harmful because they are associated with destructive or disabling motor and behavioral complications in patients with Parkinson's disease.

[0007] Ingested L-Dopa causes a systemic increase in L-Dopa levels throughout the body. This leads to an increase in dopamine across the entire central nervous system, not just in the therapeutic target area. Orally or intravenously administered L-Dopa outside the central nervous system can also be converted to dopamine in the peripheral nervous system, producing additional side effects. These side effects may include hypotension, arrhythmias, nausea, gastrointestinal bleeding, respiratory disturbances, hair loss, disorientation and confusion, extreme mood states (especially anxiety), vivid dreams or insomnia, auditory or visual hallucinations, effects on learning (there is evidence that it can improve working memory but impair other complex functions), drowsiness and hypersomnia, and symptoms similar to excitatory psychosis.

[0008] For some patients, deep brain stimulation (DBS) of the basal ganglia can complement L-Dopa therapy. By implanting a lead within the subthalamic nucleus or globus pallidus, dopaminergic receptors are directly stimulated, thereby reducing the patient's dopamine requirement. DBS is associated with a reduced need for the drug L-Dopa, but DBS may not completely replace L-Dopa therapy.

[0009] L-Dopa can be administered in combination with dopamine decarboxylase inhibitors (such as carbidopa) to limit its metabolism in the peripheral nervous system. Dopamine agonists can help limit the effective dose of L-Dopa required, but they do not address off-target effects in the central nervous system and require additional dose tuning in conjunction with L-Dopa dose tuning.

[0010] Therefore, the clinical management of side effects relies on careful control or “tightly tuned” dosing, but this is hampered by a lack of input regarding current body L-Dopa levels beyond the observed or experienced effects and side effects. Patient management also places a burden on providing appropriate dosing, as some patients may not be taking the appropriate amount of medication (or may be splitting pills for dispersed and timed administration). Therefore, there is a need in the art for a method of controlling L-Dopa dosing based on body L-Dopa levels. Summary of the Invention

[0011] Embodiments of this disclosure relate to apparatus and methods for the detection, measurement, and administration of L-Dopa. It should be understood that while this disclosure relates to L-Dopa throughout, the closed-loop systems and other concepts described herein can also be used for other drugs, compounds, or formulations that rely on enzymatic mechanisms for metabolism.

[0012] Embodiments of this disclosure pertain to an enzymatic L-Dopa sensor. An L-amino acid decarboxylase may be integrated or encapsulated within the sensor layer. Electrons released by the oxidation of L-Dopa by the decarboxylase can be detected via associated electrodes or harmonic circuitry. A processor can interpret the resulting current or resonant frequency to determine the L-Dopa concentration in the sample.

[0013] Embodiments of this disclosure may combine an L-Dopa sensor with an L-Dopa dosing or delivery system. The processor may be configured to determine an appropriate dose recommendation.

[0014] The above description is not intended to depict every illustrated embodiment or every implementation of the subject matter of the invention. The following figures and detailed description illustrate various embodiments in more detail. Attached Figure Description

[0015] The subject matter of the invention will be more fully understood when the following detailed description of various embodiments is considered in conjunction with the accompanying drawings, in which:

[0016] Figure 1 This is a block diagram of a closed-loop levodopa system according to an embodiment of the present disclosure.

[0017] Figures 2A-2D The reaction between L-Dopa and DOPA decarboxylase was described.

[0018] Figure 3 This is an example of a current measuring device used for enzyme-catalyzed detection.

[0019] Figures 4A-4B This is an example of an electrochemical impedance spectroscopy device used for enzyme-catalyzed detection.

[0020] Figure 5 This is an example output from an electrochemical impedance spectroscopy device used for enzyme-catalyzed detection.

[0021] While various embodiments may take various modifications and alternatives, details of this disclosure have been illustrated by way of example in the accompanying drawings and will be described in detail thereon. However, it should be understood that it is not intended to limit the claimed invention to the specific embodiments described. Rather, it is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the subject matter as defined in the claims. Detailed Implementation

[0022] Embodiments of this disclosure provide open-loop or closed-loop analytical systems for levodopa (L-Dopa). Embodiments provide oral dose recommendations and infusion rate adjustment for L-Dopa based on feedback from body concentration measurements. Embodiments provide current measurement or spectral concentration measurement combined with a closed-loop system or as a standalone measurement system. In embodiments, the system is a control system for adjusting the rate of L-Dopa infusion into a user's body based on L-Dopa concentration measurements taken from the user's body. L-Dopa infusion can be administered orally, intravenously, or otherwise. Embodiments can stimulate the user's body to produce L-Dopa, with stimulation settings varying based on feedback from an L-Dopa detection system.

[0023] Now for reference Figure 1 The block diagram depicts a closed-loop system 100 for L-Dopa detection and delivery according to embodiments of the present disclosure. The closed-loop system 100 includes an L-Dopa sensor 104, a controller 106, an L-Dopa delivery carrier 108, and a user 102. The L-Dopa sensor 104 acquires an L-Dopa concentration measurement 110 from the user 102's body. The sensor 104 converts the concentration into an electrical signal 112, which is sent to the controller 106. The controller 106 determines a dose based on the signal 112 and generates a command 114 for the delivery carrier 108. The delivery carrier 108 responds to the command 114 by delivering a dose 116 of L-Dopa to the user 102.

[0024] Sensor 104 may be an enzyme-catalyzed sensor, an impedance sensor, or otherwise used to determine the blood concentration of L-Dopa. Controller 106 may generally include a processor, memory, and software necessary for analyzing signal 112 and generating command 114. Delivery carrier 108 may generally include the oral medication L-Dopa or an infusion system for the liquid medication L-Dopa. Controller 106 may be configured to generate command 114 that produces an appropriate dose 116 based on the specific delivery carrier 108.

[0025] In one embodiment, sensor 104 and controller 106 may share a housing, which may be implantable or external to user 102.

[0026] In embodiments, the controller 106 and delivery carrier 108 may share a housing, which may be implantable or external to the user 102. For example, the delivery carrier 108 may be an infusion pump sharing a housing with the controller 106, or the delivery carrier 108 may be a screen on the housing of the controller 106 that presents oral dose 116 data to the user 102. In embodiments, the controller 106 may have its own housing, and the delivery carrier 108 may have its own housing, such as a separate infusion pump, or it may be in a form that does not require a housing at all, such as a telephone application that presents dose data to the user. When the controller 106 and delivery carrier 108 are not physically close to each other, they may communicate over a greater distance, for example, via wireless signals.

[0027] Depending on the specific needs or expectations of user 102, sensor 104 may include a point-of-care (POC) sensor, an acute sensor, or a chronic sensor. Embodiments of sensor 104 may be configured to distinguish between medications and endogenous L-Dopa.

[0028] Point-of-care (POC) sensors may be favored by users seeking discrete measurements of L-Dopa throughout use and can provide feedback regardless of the delivery medium employed. For example, users with implantable deep brain stimulation (DBS) therapy systems can use POC sensors to obtain input for initial DBS stimulation settings or update DBS stimulation settings, leading to better outcomes and improved therapy management. POC sensors can generally be manually operated or triggered by the user or by a healthcare professional. POC sensors can be used for immediate feedback, such as determining L-Dopa blood concentrations associated with a specific symptom currently being experienced.

[0029] Acute continuous measurement of L-Dopa provides real-time feedback on the user's body concentration and response to L-Dopa doses, and can be particularly useful in automated delivery scenarios. Acute monitoring typically lasts for a fixed period, such as 3–7 days. Acute monitoring can be applied to determine a user's response to a new dose of oral L-Dopa or a new DBS setting. Acute monitoring can supplement the information provided to physicians as part of longitudinal or remote monitoring tools or systems, such as in therapeutic applications, digital health platforms, or telemedicine systems.

[0030] Chronic measurement of L-Dopa can be used in true closed-loop systems to monitor a user's disease status over the long term and adjust the L-Dopa or stimulation dose based on detected L-Dopa levels and the body's response to the dose / infusion / stimulation. Chronic measurement may be associated with an automated feedback system that automatically adjusts the drug's L-Dopa dose or DBS settings based on readings. Chronic measurement can also be associated with a manual system and simply provide long-term data on the user's response to dose changes, disease progression, and treatment. Examples may incorporate sensors implanted in the brain, allowing for direct measurement of the target L-Dopa dose. Chronic monitoring can supplement information provided to physicians as part of longitudinal or remote monitoring tools or systems, such as in therapeutic applications, digital health platforms, or telemedicine systems.

[0031] L-Dopa is converted into dopamine through interaction with aromatic L-amino acid decarboxylases (DOPA decarboxylases), such as... Figure 2A As shown. By adding dopa decarboxylase to the enzymatic sensor, L-Dopa present in the application sample can be detected through its interaction with dopa decarboxylase.

[0032] Now for reference Figures 2B-2D According to embodiments of this disclosure, a series of diagrams depicting an example rigorous tuning process are shown. Figures 2B-2D Each figure depicts time along the x-axis and the blood concentration (of levodopa) along the y-axis.

[0033] Figure 2B The problem of non-responsive dosing is illustrated. Conceptually, the target dose 202 is shown in green, the upper boundary 204 represents the threshold at which a patient begins to experience side effects, and the lower boundary 206 represents the threshold below which symptoms begin to appear. The goal for patients is to maintain their medication administration above the symptom threshold but below the threshold at which side effects are seen. When a patient's dose is too high and their cerebrospinal fluid drug or blood drug concentration rises above the upper limit 204 at point 210, the severity of the side effects they experience may be sufficient to offset the relief of their symptoms and / or interfere with their daily lives. When a patient's dose is too low and their blood drug concentration drops below the lower limit 206 at point 212, they may not receive sufficient relief from their symptoms and experience disruptions related to their quality of life. Line 208 illustrates patient responses measured using point-of-care sensors, acute sensors, or continuous sensors, each as described in this disclosure.

[0034] When the dose remains constant, deviations like those seen at points 210 and 212 may be unavoidable. Deviations exceeding the upper limit 204 (such as point 210) can occur after any dose delivery, especially if the dose is periodic rather than continuous (e.g., if the oral medication L-Dopa is taken). High deviations like point 210 can also occur if the dose is canceled or if the patient's lifestyle changes, causing the dose to be metabolized more slowly than assumed when the dose was calculated. High deviations like point 210 may be associated with motor or cognitive side effects such as movement disorders, psychosis, changes in mood or mental state, or aggressive behavior, as well as a wide range of common systemic side effects, including heart rhythm abnormalities, difficulty or pain in urinating, excessive nausea or vomiting, or low blood pressure. High deviations like point 210 can also exacerbate uncommon and rare side effects, including blurred or diplopia, hot flashes, eyelid spasms, bladder incontinence, chills, fever, loss of appetite, and pain or swelling in the face or lower extremities.

[0035] A deviation below the lower limit of 206 (e.g., point 212) can occur near the end of a dose period before the next dose is administered, during which time the previous dose may be exhausted before the next dose is taken or otherwise delivered to the patient. A low deviation of point 212 may be due to a disruption in the dose delivery schedule or changes in the patient's lifestyle that lead to increased drug metabolism or elimination. A low deviation (e.g., point 212) may be associated with an increase or relapse of symptoms. For patients with Parkinson's disease, symptoms may include tremor or other muscle symptoms such as rigidity or stiffness, difficulty in movement or coordination, involuntary or slowed movements, or rhythmic contractions. Other symptoms of Parkinson's disease include sleep disturbances, restless sleep, difficulty speaking, urinary incontinence, reduced facial expression, constipation, memory difficulties, or loss or distortion of the sense of smell.

[0036] The overall pattern of line 208, where patient blood drug concentrations fluctuate between high deviations (e.g., point 210) and low deviations (e.g., point 212), is difficult to prevent in a fixed-dose model due to factors that are difficult to regulate, such as patient activity levels and diet. As a result, patients are constantly torn between the loss of their symptoms and the risk of side effects.

[0037] Figure 2C The graphs in the image illustrate the effect of electrical stimulation systems, such as deep brain stimulation (DBS), on the blood drug concentration levels of tuned patients. Region 214 is very similar to... Figure 2B The target dose region 202. When stimulation is subsequently added in the second region 216, the lower limit 206 decreases, making lower doses of L-Dopa effective for patients to relieve symptoms. Having lower effective doses has an overall positive impact on patient treatment and can prolong the timeline of concerns related to the long-term effects of L-Dopa therapy.

[0038] However, it is worth noting that the upper limit 204 was also reduced due to the effects of electrical stimulation. Therefore, although adding electrical stimulation therapy can improve L-Dopa treatment in patients, it does not effectively alleviate concerns about the side effects associated with high blood drug concentrations.

[0039] Figure 2D The graphs in the diagram illustrate the effectiveness of the disclosed closed-loop L-Dopa treatment system. Figure 2D The graphs can also be used to show how a patient or provider responds to blood drug concentration readings obtained using the disclosed point of care or acute L-Dopa sensor. Figure 2D The examples are generally discussed under the assumption of a treatment procedure combining electrical stimulation and the drug L-Dopa, but these principles also apply to treatment procedures using only L-Dopa. L-Dopa delivery can be via oral capsules, liquids, or aerosols, or via internal or external infusion pumps, or by any other method. Pump delivery can be designed with implanted pumps, external pumps, or any other infusion pump. Pump delivery is generally directed to the duodenum, but other delivery sites are also conceivable, such as intrathecal or subarachnoid spaces of the spine. In embodiments where both electrical stimulation and L-Dopa are used for treatment, both devices can be implanted in a single housing, or a single unified device can deliver both forms of treatment.

[0040] In the first region 218, the initial L-Dopa dose and electrical stimulation settings are established.

[0041] At point 220, monitoring of the patient's blood drug concentration indicates that the patient's blood L-Dopa concentration is rising, and the algorithm determines that the concentration may exceed the upper limit 204, causing the patient to experience side effects. In response, the closed-loop system may automatically reduce the electrical stimulation setting to reduce the effect of electrical stimulation, converting the brain's tuning parameters to drug concentration, thereby increasing the upper limit 204 (see second region 222), or may recommend that the patient or provider reduce the electrical stimulation setting. In an embodiment, the system may alternatively or additionally reduce or recommend a reduction in consecutive or upcoming doses of L-Dopa. In an embodiment, the provider may recommend a reduction in stimulation setting or L-Dopa dose based on readings obtained at point 220 using acute or care point blood-L-Dopa concentration measurements. In an embodiment, the patient may use acute or care point measurements to monitor their own blood drug concentration and make necessary adjustments to their stimulation setting or dose based on training or guidance received from the provider.

[0042] Similarly, at point 224, the system detects a decrease in blood drug concentration and determines that it may have crossed the lower boundary 206, potentially causing symptoms in the patient. In response, the system adapts to the lower blood drug concentration to prevent a low deviation, as at region 226. In an embodiment, the system may adapt to reduce the lower boundary 206 by increasing the electrical stimulation setting. The system may also adapt by reducing the infusion rate of the pump delivering L-Dopa to the patient, or by recommending a lower subsequent dose to the patient or provider.

[0043] The system is also configured to identify when the blood drug concentration responds within the tuning parameters, such as at point 228, and thus determine whether the current setting should be maintained.

[0044] Current measuring sensor

[0045] Now for reference Figure 3 An example of a current-measuring device 300 for enzymatic detection is depicted. L-Dopa 302 interacts with L-aminodecarboxylase 304 present in an electrochemical layer 306 associated with a working electrode 308. Electrons 310 released by the oxidation reaction are captured by the working electrode 308 and move through the working electrode 308 via a potential to generate a current 312. The potential is generated by the activity of a reference electrode and a counter electrode 314, which, in embodiments such as the example device 300, may be shorted together. The generated current is proportional to the level of L-Dopa present in the sample.

[0046] Electrochemical impedance spectroscopy (EIS)

[0047] Now for reference Figure 4AAn example of an EIS enzymatic sensor 400 is shown. L-Dopa molecules 402 in the sample interact with dopa decarboxylase 406 encapsulated in a polyimide pad 408 via a confinement membrane 404. Electrons released by the oxidation of L-Dopa generate a characteristic response from an attached harmonic oscillation (LRC) circuit 410. In embodiments, the LRC circuit 410 may be a Randles circuit or a modified Randles circuit.

[0048] Each enzyme interaction within the polyimide layer exhibits a unique LRC characteristic. This characteristic can then be translated into a resonant frequency, which can be detected and used to measure the concentration of L-Dopa using electrochemical impedance spectroscopy (EIS). The result is an "ideal" system with reliable results.

[0049]

[0050] Z F = impedance, R t =Total resistance, R D =Detecting resistance, j = √(-1), ω =Radial frequency, δ =The thickness at which diffusion should occur, and D i =Dissipation factor.

[0051] Therefore, using enzymes as molecular recognition elements and EIS as a platform, the rate of dopamine formation over time can be measured. The enzyme-catalyzed rate, read as the circuit impedance, will change over time with the concentration of L-Dopa present in the sample. These rates can be described by Faraday interactions combining Fick's flux equation and the Nernst equation for current:

[0052]

[0053] Where I is the current; n is the number of moles of electrons transferred in the half-reaction; F is the Faraday constant (C / mol); and A is the electrode area (cm²). 2 D is the diffusion coefficient; DOPA is the L-Dopa concentration; and L is the distance at which the reaction can occur (generally the thickness of the diffusion membrane used in this disclosure).

[0054] Non-Radaic interactions can be described using other electrical properties of effective capacitance, inductance, Fermi layers, and interfaces.

[0055] In this embodiment, the use of the platform's EIS provides a non-destructive, ultrasensitive, rapid, and label-free method for measuring L-Dopa concentration. The EIS applies an AC voltage with a unique potential and measures the output impedance. Now refer to... Figure 5Example circuit 506 is illustrated with example outputs 502 and 504. Example circuit 506 is a standard Randle circuit with an active electrolyte resistor (R0). S ) and double-layer capacitor (C dl ) and Faraday reaction impedance (R ct Parallel combinations of series connections of ) are used. In an embodiment, constant phase elements are used to pair C. dl Modeling. Output 504 (Nyquist plot) can be achieved using the following equation:

[0056]

[0057] Where Z is the impedance; R is the resistor in the circuit; C is the capacitor in the circuit; and ω It is the radial frequency.

[0058] By detecting the difference between the input and output signals, the system properties can be measured based on the change in phase 508 between the input potential 510 and the output current 512. Different properties can be measured depending on the different LRC circuit designs, each of which will produce different changes in the output signal relative to the sample properties.

[0059] Various embodiments of the systems, apparatus, and methods have been described herein. These embodiments are given by way of example only and are not intended to limit the scope of the claimed invention. Furthermore, it should be understood that the various features of the described embodiments can be combined in various ways to produce numerous additional embodiments. Moreover, while various materials, sizes, shapes, configurations, and positions, etc., used with the disclosed embodiments have been described, other materials, sizes, shapes, configurations, and positions, etc., besides those disclosed, may be utilized without departing from the scope of the claimed invention.

[0060] Those skilled in the art will recognize that the subject matter of this invention may include fewer features than those shown in any of the individual embodiments described above. The embodiments described herein are not intended to be an exhaustive representation of the various ways in which the various features of the subject matter of this invention can be combined. Therefore, embodiments are not mutually exclusive combinations of features; rather, various embodiments may include combinations of different individual features selected from different individual embodiments, as understood by those skilled in the art. Furthermore, unless otherwise indicated, elements described with respect to one embodiment may be implemented in other embodiments, even if the element is not described in such embodiments.

[0061] Although dependent claims may refer in the claims statement to a specific combination with one or more other claims, other embodiments may also include combinations of dependent claims with the subject matter of each other dependent claim, or combinations of one or more features with other dependent claims or independent claims. Such combinations are presented herein unless stated otherwise.

[0062] Any inclusion by reference of the foregoing documents is limited to such that no subject matter contrary to the express disclosure herein is incorporated. Any inclusion by reference of the foregoing documents is further limited to such that any claims contained in the documents are not incorporated herein by reference. Any inclusion by reference of the foregoing documents is further limited to such that any definitions provided in the documents may not be incorporated herein by reference unless expressly included herein.

Claims

1. A levodopa sensor device, comprising: processor; The working electrode includes an electrochemically reactive surface that generates an electrochemical signal in the presence of levodopa; Reference electrode; Counter electrode; Computer-readable program code having instructions that, when executed, cause the processor to: Evaluate the electrochemical signal data obtained from the working electrode; The concentration of levodopa was calculated based on the electrochemical signal data obtained from the working electrode. Provides a display of the concentration of the drug levodopa; as well as Determine whether the concentration of the drug levodopa exceeds the upper limit of the levodopa concentration that indicates the patient will experience side effects, or whether the levodopa concentration exceeds the lower limit of the levodopa concentration that indicates the patient will experience symptoms; and An electrical stimulation delivery assembly configured to modify the upper and lower boundaries based on the concentration of the drug levodopa, wherein the patient is asymptomatic when the concentration of the drug levodopa in the patient is between the upper and lower boundaries.

2. The device of claim 1, further comprising a levodopa delivery component.

3. The device of claim 2, wherein the levodopa delivery component provides a displayed oral dosage recommendation based on a calculated levodopa concentration.

4. The apparatus of claim 2, wherein the levodopa delivery component is an infusion pump.

5. The apparatus of claim 4, wherein the levodopa delivery component provides a displayed pump setting recommendation based on the calculated levodopa drug concentration.

6. The apparatus of claim 4 or 5, wherein the levodopa delivery component provides automatic adjustment of the infusion pump settings based on the calculated levodopa concentration.

7. The device according to claim 4 or 5, wherein the infusion pump is an implantable pump.

8. The apparatus of claim 7, wherein the infusion pump is a duodenal pump.

9. The apparatus of claim 7, wherein the infusion pump is an intrathecal pump.

10. The device of claim 1, wherein the electrical stimulation delivery component shares a common housing with the implanted delivery pump.

11. The apparatus of claim 1, wherein the electrical stimulation delivery component is a deep brain stimulation (DBS) system.

12. The apparatus of claim 1, wherein the electrical stimulation delivery component provides a displayed DBS system setting recommendation based on the calculated levodopa concentration.

13. The apparatus of claim 1, wherein the electrical stimulation delivery component provides automatic adjustment of the DBS system settings based on the calculated levodopa concentration.

14. The apparatus of claim 1 or 2, further comprising a monitoring application, wherein the monitoring application provides a display of longitudinal data.

15. The apparatus of claim 14, wherein the monitoring application further provides communication with a digital health system.

16. A levodopa sensor device, comprising: processor; A polyimide pad with encapsulated L-amino acid decarboxylase; The harmonic oscillation circuit associated with the polyimide pad layer causes the electrochemical signal generated by the interaction between the sample and the encapsulated L-amino acid decarboxylase to produce a resonant frequency on the circuit. Computer-readable program code having instructions that, when executed, cause the processor to: Evaluate the resonant frequency obtained from the circuit; The concentration of levodopa is calculated based on the resonant frequency obtained from the circuit; and Determine whether the concentration of the drug levodopa exceeds the upper limit of the levodopa concentration that indicates the patient will experience side effects, or whether the levodopa concentration exceeds the lower limit of the levodopa concentration that indicates the patient will experience symptoms; and An electrical stimulation delivery assembly configured to modify the upper and lower boundaries based on the concentration of the drug levodopa, wherein the patient is asymptomatic when the concentration of the drug levodopa in the patient is between the upper and lower boundaries.

17. The apparatus of claim 16, further comprising a levodopa delivery component.

18. The apparatus of claim 17, wherein the levodopa delivery component provides a displayed oral dosage recommendation based on the calculated levodopa concentration.

19. The apparatus of claim 17, wherein the levodopa delivery component is a duodenal pump.

20. The apparatus of claim 17 or 19, wherein the levodopa delivery component provides a displayed pump setting recommendation based on the calculated levodopa drug concentration.

21. The apparatus of claim 19, wherein the levodopa delivery component provides automatic adjustment of the duodenal pump settings based on the calculated levodopa concentration.

22. The apparatus of claim 16, wherein the electrical stimulation delivery component is a deep brain stimulation (DBS) system.

23. The apparatus of claim 16, wherein the electrical stimulation delivery component provides a displayed DBS system setting recommendation based on the calculated levodopa concentration.

24. The apparatus of claim 16, wherein the electrical stimulation delivery component provides automatic adjustment of the DBS system settings based on the calculated levodopa concentration.

25. A system for dose-regulating levodopa, wherein the system includes a sensor and a controller in communication with the sensor, and is configured to: Obtain the user's first blood concentration of levodopa; The dosage of levodopa to the user is calculated based on the first blood drug concentration; Provides a display of the first plasma concentration of the levodopa; Determine whether the first blood concentration exceeds the upper limit of the first blood concentration of levodopa that indicates the user will experience side effects, or whether the first blood concentration exceeds the lower limit of the first blood concentration of levodopa that indicates the user will experience symptoms. as well as The electrical stimulation settings are modified based on the first blood concentration of levodopa to modify the upper and lower boundaries, wherein the user is asymptomatic when the first blood concentration of levodopa is between the upper and lower boundaries.

26. The system of claim 25, wherein the dose of the drug levodopa is indicated as a recommended oral dose.

27. The system of claim 25, wherein the dosage of the drug levodopa is indicated as a recommended setting for the duodenal pump.

28. The system of claim 27, wherein the system is further configured to automatically adjust the duodenal pump settings according to the recommended duodenal pump settings.

29. The system of claim 25, wherein the system is further configured to calculate a recommended deep brain stimulation (DBS) system setting for the user based on the first blood drug concentration; and Provides a display of recommended settings for the DBS system.

30. The system of claim 29, wherein the system is further configured to automatically adjust the DBS system settings based on the DBS system settings recommendations.

31. The system of claim 29 or 30, wherein the system is further configured to recommend adjusting the calculation of the dose of the drug levodopa according to the settings of the DBS system.

32. The system of claim 29, wherein the system is further configured to adjust the recommended settings of the DBS system based on the calculation of the dose of the drug levodopa.

33. The system of claim 25, wherein the system is further configured to: A second blood concentration of levodopa in the user was obtained after administering the dose of levodopa to the user. Analyze the difference between the blood drug concentration of the first drug and the blood drug concentration of the second drug; The difference between the first and second blood drug concentrations is used to determine whether the dosage of levodopa should be adjusted.

34. The system of claim 33, wherein the system is further configured to calculate an adjustment to the dose of the drug levodopa.

35. A system for dose-regulating levodopa, wherein the system includes a sensor and a controller in communication with the sensor, and is configured to: Obtain the user's first blood concentration of levodopa; The deep brain stimulation settings are calculated for the user based on the first blood drug concentration; and Determine whether the first blood drug concentration exceeds the upper boundary of the first blood drug concentration of levodopa that indicates the user will experience side effects, or whether the first blood drug concentration exceeds the lower boundary of the first blood drug concentration of levodopa that indicates the user will experience symptoms. The calculated deep brain stimulation settings are used to modify the upper and lower boundaries. When the user's first blood drug concentration is between the upper and lower boundaries, the user is asymptomatic.

36. The system of claim 35, wherein the system is further configured to: The second blood concentration of levodopa in the user was obtained after the deep brain stimulation setting was applied to the user; Analyze the difference between the blood drug concentration of the first drug and the blood drug concentration of the second drug; The decision on whether to adjust the deep brain stimulation settings is based on the difference between the first blood drug concentration and the second blood drug concentration.

37. The system of claim 35 or 36, wherein the system is further configured to calculate adjustments to the deep brain stimulation settings.

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