METHOD FOR ACCELERATED TISSUE PENETRATION OF COMPOUNDS INTO BRAIN

Abstract

Disclosed is a method of increasing the rate of delivery of an active compound or agent to the brain across the blood brain barrier of a subject. In one aspect, the disclosure provides an accelerated method of providing an active compound to a targeted region of the brain of a subject, served by the cerebral medial artery, the method comprising: administering a sub-anesthetic dose of xenon as an inhalant to the subject; and administering an efficacious amount of the active compound to the bloodstream of the subject, the active compound reaching the targeted region of the brain in less time relative to a time it takes to reach the targeted region without xenon administration.

Claims

1. An accelerated method of providing an active compound to a targeted region of the brain of a subject, served by the cerebral medial artery, the method comprising: administering a sub-anesthetic dose of xenon as an inhalant to the subject; and administering an efficacious amount of the active compound to the bloodstream of the subject, the active compound reaching the targeted region of the brain in less time relative to a time it takes to reach the targeted region without xenon administration.

2. The method of claim 1, wherein the sub-anesthetic dose of xenon is from about 10% to about 43% xenon gas.

3. The method of claim 1, wherein the subject suffers from a disorder of the basal ganglia in the vascular bed of the middle cerebral artery.

4. The method of claim 3, wherein the disorder is a dopaminergic-related disorder.

5. The method of claim 1, wherein the active compound is administered intravenously to the patent.

6. The method of claim 1, wherein xenon is administered to the subject before, concomitantly with, or after the administration of the active compound.

7. The method of claim 1, wherein the active compound is an imaging or diagnostic agent.

8. The method of claim 7, wherein the imaging agent is a diagnostic imaging agent for SPECT, PET, or MRI.

9. The method of claim 7, wherein the imaging agent is DaTScan, DaT2020.

10. The method of claim 1, where in the active compound is a therapeutic compound for treating a dopaminergic disorder.

11. The method of claim 10, wherein the dopaminergic disorder is Parkinson's disease, attention deficit hyperactivity disorder, dementia, clinical depression, anxiety, narcolepsy, obesity, sexual dysfunction, schizophrenia, bipolar disorder, nausea/vomiting, addictive disorder (drugs, smoking), pheochromaocytoma, or binge eating disorder.

12. A method of evaluating an ability of a therapeutic composition to modulate a dopaminergic activity in the brain of a subject suspected of having a dopaminergic disorder, the method resulting in an accelerated delivery of the therapeutic composition across the blood brain barrier to a region of the brain served by the cerebral medial artery, the method comprising: administering to the subject a sub-anesthetic amount of xenon gas as an inhalant at about 10% to about 43% before administering to the subject a radiolabeled tropane; determining a baseline level and pattern of binding of the administered radiolabeled tropane to dopaminergic neurons in a portion of the brain of the subject; treating the subject with an initial dose of a first therapeutic composition; administering the radiolabeled tropane to the treated subject; and determining the level and pattern of radiolabeled tropane binding to the portion of the brain of the treated subject, a change in level and/or pattern of the radiolabeled tropane binding in the treated subject relative to baseline levels and/or patterns of radiolabeled tropane binding being indicative of the ability of the therapeutic composition to modulate a dopaminergic activity in the brain.

Description

EXAMPLES

Example 1

Combination Xenon—Active Compound Treatment

[0062] For studying a particular drug of concern (e.g., Azilect® (rasagiline)), first administer about 10% to about 30% xenon gas via inhalation for 10 minutes followed by administering [.sup.123I]-2-carbomethoxy-3-(4-fluorophenyl)-N-(1-iodoprop-1-en-3-yl)nortropane (a tracer) at a dose of 3.5±1.0 mCi (296 MBq) [.sup.123I]-DaT2020 (LikeMinds, Boston, Mass., followed by a 10 mL saline flush. to the subject, and by acquiring a SPECT tomograph of about 30 minutes in duration about 15 minutes after the administration. This serves as the first tomograph, from which it can be determined (1) a first density of DaT; (2) a first amount of DaT; and (3) a pattern of DaT. Each of these is informative, e.g., the pattern being comma shaped or not can indicate whether the subject has PD to begin with. The rest of the description will only refer to a level (“first level” for the first tomograph) of DaT from the tomograph. The term “level” encompasses the concepts of both the density and amount. Subsequently, the drug is administered to the subject. After a period of time post-drug administration, the tracer-administration and tomograph-acquisition steps can be repeated to obtain a second tomograph, which reveals a second level for DaT. Comparing the second level to the first level provides some indication as to if the drug is effective. For example, if the level has remained the same, this indicates that PD is at least not progressed and that the drug is efficacious. Subsequently, additional cycles of tracer-administration and tomograph-acquisition steps are performed, from which obtain additional tomographs are obtained, and thus, additional DaT levels. Ultimately, a time course for the progression of the disease is constructed, which provides data that not only more informative than what is obtained without recourse to a time course, but also is more objective than that obtained by subjective visual observations of a subject. Such a time course also enables comparisons of results across different research or clinical groups.

[0063] Creation of such time courses, which the disclosed methods enable, provides additional uses. For example, time courses for PD (or other neurological diseases) progression obtained from a number of individuals who have not been subjected to treatment. These time courses, or their various statistical averages, serve as useful controls for how progressive a disease is. A linear average value for the post-motor symptoms period slope of progression can be obtained, such as change in DaT levels divided by passed time. Alternatively, a hyperbolic, exponential, or multi-order polynomial model, can be fitted into the data to model it. Such models enable the following: (1) a prediction of how far the disease will have progressed at a certain time in the future; and (2) a forecasting of a projected DaT level for a certain time in the future, which would enable the testing of the effectiveness of a drug at that time point by comparing the DaT levels of a treated subject to those that are forecasted.

[0064] Effectively, a time course for disease progression is obtained both to assess drug effectiveness, and to gain information about the natural disease progression in the absence of any treatment. When used during a treatment regimen, a time course can be used to optimize the treatment regimen. For example, by comparing the projected values from the time course to those found from the tomograph of the treated subject, a decision to: (1) change the drug; (2) change the dosage; or (3) add or remove a drug from the regimen can be made.

Example 2

Assessment of Disease Modification

[0065] To determine if a therapeutic agent of interest is having the desired disease-slowing or disease-modifying effect on a patient, a combination of xenon delivery and DaT imaging can be used, xenon gas is administered via inhalation approximately one minute after injection of the DAT imaging agent at a concentration of 10% to 30% for a duration of 10 minutes. An initial (baseline) level and pattern of DaT is assessed. Then, determining if that level is normal or abnormal relative to the condition ids assessed. The therapeutic drug of interest is then administered, and the patient is then scanned again to determine if the DaT levels have changed (i.e., a follow-up scan). Both the baseline scan and the follow-up scan are accomplished following the steps below.

[0066] The patient has voided and is otherwise comfortable and prepared to lie still for the length of time required for xenon inhalation SPECT imaging using a SPECT camera with or without improved resolution capabilities (e.g., Discovery NM-630, GE Healthcare, Inc., Chicago, Ill. or inSPira HD®, Samsung Neurologica Corporation, Danvers, Mass.).

[0067] The subject is positioned in the camera and a peripheral 18 gauge to 22 gauge venous catheter inserted for the radiopharmaceutical infusion. A Y-system is used for optimal clearance of residual activity from the administration syringe.

[0068] The patient receives a single I.V. injection of [.sup.123I]DAT2020 with a total activity dose amounting to 3.5 (±1.0 mCi.) The total administered radioactivity is of relevance and not the volume administered to achieve this dose. This single I.V. injection contains a maximum mass dose of DAT2020 of no more than about 16 ng and a total volume of up to about 5 mL. [.sup.123I]DAT2020 must be administered manually via “slow I.V. injection”, followed by a 10 mL saline flush. As used herein “slow I.V. injection” refers to intravenous administration at about 5 ml/min to about 10 ml/min.

[0069] The exact radioactive dose administered is determined by calculating the difference between the radioactivity in the syringe and delivery system before and after injection. After the dose is delivered, the syringe is filled with a volume of saline equal to the administered dose volume. The syringe contents is recounted under the same conditions as used to determine the dose; separately. The delivery system is placed in a plastic container and counted in a dose calibrator (e.g., CRC®-25R Doe Calibrator, Capintec, Inc., Florham Park, N.J.) using the same parameters as used for the dose. Measured radioactivity values and times of measurement are documented in the source documents and recorded in the patient record, as well as the total injected volume. Injected radioactivity values outside the above stated range, i.e., values lower than about 7 mCi or higher than about 9 mCi are considered as potential sources of variation.

[0070] The single SPECT acquisition is commenced at 15 min (±2 min) post-injection for a 30 min scan. Specifically bound is required to determine striatal activity which demonstrates peak uptake during this scan time window. Thus, ensure the accuracy of the acquisition start time once the subject is injected with [.sup.123I]DAT2020. The start and end times of the [.sup.123I]DAT2020 scan are recorded on the imaging source document.

[0071] The acquisition parameters are recorded for each subject at the time of the scan on the imaging source document.

[0072] After preparing the dose as per the above, the patient is positioned in the SPECT camera as described above. Subjects are injected with 3.5±1.0 mCi (296 MBq) [.sup.123I]DAT2020. The subject is positioned in the camera at the time of injection, even though imaging will not commence until 15 min (±2 min) after radiotracer infusion. [.sup.123I]DAT2020 injection is administered by slow I.V. injection followed by a 10 mL saline flush. The start time of the injection is recorded along with the total volume injected.

[0073] Specific SPECT scan parameters, including collimation and acquisition mode, are set as follows. Raw projection data is acquired into a 128×128 matrix, stepping each head 3 degrees for a total of 120 projections into a 20% symmetric photopeak window centered on 159 keV for a total scan duration of approximately 30 min.

[0074] Tomographs of the captured photon data are then compiled and read by a radiologist skilled in assessing DaT levels using imaging.

[0075] Assessment of DaT levels in these patients prior to prescribing a drug regimen provides insight into the likely efficacy of the selected drug and hence allow for a patient-centric, individualized approach for a given patient. An initial scanning procedure to assess baseline DaT levels is conducted in the patient. The patient is then prescribed the selected drug therapy and periodic follow-up scans conducted for 2 to 3 subsequent months to assess DaT levels over time while on the drug. The results of these scans would be combined with the clinical observations of the patient by the physician to determine if the drug is having the desired biological and clinical effect.

Equivalents

[0076] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.