LOCAL ANESTHETIC FOR THE TREATMENT OF NEUROLOGICAL SYMPTOMS RESULTING FROM BRAIN DYSFUNCTIONS

Abstract

A local anesthetic chosen from the group of amino amide or amino ester, and a composition or pharmaceutical composition including the local anesthetic. The local anesthetic is for use in the treatment of neurological symptoms resulting from brain dysfunctions such as motor, cognitive, sensory, visual deficits, and/or apathetic, catatonic, vegetative and/or minimally conscious states.

Claims

1-16. (canceled)

17. A method of treatment of neurological symptoms resulting from brain dysfunctions comprising administering a local anesthetic chosen from the group consisting of amino amides, amino esters and a combination thereof.

18. The method of treatment of claim 17, comprising inducing the transient and/or partial recovery of neurological symptoms resulting from brain dysfunctions.

19. The method of treatment of claim 17, wherein the symptoms of brain dysfunctions result from stroke, tumor, head trauma, inflammatory diseases of the central nervous system, degenerative diseases, depression or psychosis.

20. The method of treatment of claim 17, wherein the brain dysfunctions result in motor, cognitive, sensory, visual deficits, and/or in apathetic, catatonic, vegetative, minimally conscious states.

21. The method of treatment of claim 17, wherein the amino-amide is chosen among bupivacaine, levo-bupivacaine, carticaine, lidocaine, prilocaine, etidocaine, levo-etidocaine, dextro-etidocaine, mepivacaine, levo-mepivacaine, ropivacaine, levo-ropivacaine, trimecaine, pyrrocaine, dibucaine, lidocaine salicylate monohydrate, octacaine, oxethazaine, pipecoloxylidides, sameridine, articaine, aptocaine, QX-314, 2-alkyl-2-alkylamino-2′, 6′acetoxylidide compounds, tertiaryalkylamino-lower acyl-xylidide; 2(ω-alkylaminoalkyl)-3-(4-substituted-benzylidene) phthalimidine compounds or 2-(ω-dialkylaminoalkyl)-3-(4-substituted-benzylidene) phthalimidine compounds; L-N-n-propylpipecolic acid-2,6-xylidide compounds; N-substituted 4-piperidinecarboxamide compounds; N-substituted 4-phenyl-4-piperidinecarboxamide compounds, compounds of formula (II): wherein a) R1 is hydrogen or a straight or branched alkyl group with 1-3 carbon atoms, and R2 is a straight or branched alkyl group with 1-3 carbon atoms, or b) R1 and R2 form together a chain —(CH2)n-, wherein n is 3, 4 or 5, or —(CH2)2O(CH2)2-; m is 0-1; p is 1-2; R3 is hydrogen or —COCH3; and R4 is hydrogen, —CH3, —OH or —OCH3, and/or analog and/or functional derivative thereof and/or a mixture thereof.

22. The method of treatment of claim 21, wherein the amino-amide is mepivacaine or mepivacaine chlorhydrate.

23. The method of treatment of claim 17, wherein the amino ester is chosen among ambucaine, amolanone, amylocaine, benoxinate, betoxycaine, biphenamine, butacaine, butamben, butethamine, butoxycaine, 2 chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dimethocaine, piperocaine, procaine, propoxycaine, pseudococaine, risocaine, proparacaine, tetracaine, ethyl aminobenzoate, dextro-eucaine, hexylcaine, hydroxyprocaine, hydroxytetracaine, isobutylp-aminobenzoate, leucinocaine mesylate, meperidine, meprylcaine, metabutoxycaine, naepaine, orthocaine, parethoxycaine, piridocaine, propanocaine, dibucaine, benzocaine, O-aminoalkylsalicylate compounds; and/or analog and/or functional derivative thereof and/or a mixture thereof.

24. The method of treatment of claim 17, wherein the local anesthetic chosen from the group consisting of amino amides and amino esters and a mixture thereof.

25. The method of treatment of claim 17, further comprising administering another active agent.

26. The method of treatment of claim 25, wherein said active agent is at least one Specific Serotonin Recapture Inhibitor (SSRI); preferably the SSRI is paroxetine.

27. The method of treatment of claim 26, wherein the SSRI is chosen among citalopram, escitalopram, fluoxetine, paroxetine, sertraline or vilazodone or any combination thereof.

28. The method of treatment of claim 17, wherein the amino amide is the mepivacaine chlorhydrate and is to be administrated from about 30 to about 600 mg per each intake, more preferably from about 40 to about 550 mg per each intake and even more preferably from about 50 to about 300 mg per each intake.

29. The method of treatment of claim 17, wherein the local anesthetic is to be administered daily, every other day, every three days, every four days, every five days, every six days, every seven days, every eight days, every nine days, every ten days, every eleven days, every twelve days, every thirteen days, every fourteen days, every fifteen days, once a month, twice a month, once a week, twice a week, at least once a day, twice, or three times a day over a period determined by the skilled man in the art such as for at least a week, at least a month, for at least two months, at least a year, or more on as needed basis for the rest of the patient's life.

30. The method of treatment of claim 17, wherein the local anesthetic is to be administered parenterally or orally, more preferably orally.

31. The method of treatment of claim 26, wherein the local anesthetic is administrated to a subject in need thereof concomitantly or in conjunction: separately or sub sequentially with a SSRI.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0099] FIG. 1 shows an assessment of the visual field with the full-threshold Humphrey visual field (HVF), 24-2 Swedish Interactive Thresholding Algorithm (SITA) (Carl Zeiss Meditec Inc., Dublin, Calif.) during on period

[0100] FIG. 2 shows an assessment of the visual field with the full-threshold Humphrey visual field (HVF), 24-2 Swedish Interactive Thresholding Algorithm (SITA) (Carl Zeiss Meditec Inc., Dublin, Calif.) during off period

[0101] FIG. 3 shows a bilateral occipital lobe infarct

[0102] FIG. 4 shows regions whose connectivity with the left calcarine cortex increased (white) or decreased (black) significantly during on—as compared to off-periods

[0103] FIG. 5 shows that the bilateral lateral occipital cortex (white), an intact part of the patient's visual cortex, increased its average functional connectivity with the rest of the brain during on—as compared to off-periods

[0104] FIG. 6 shows regions of significant increase in metabolism, as measured with 18F-FDG PET-scanner, in the intact left occipital and temporal cortex during on—as compared to off-periods.

EXAMPLES

[0105] The present invention is further illustrated by the non-limitative following examples.

Example 1: General Observation

[0106] In 2010, a patient underwent surgery for the removal of a cervical herniated intervertebral disc (C6-C7). Immediately following surgery, he suffered from a dissection of his right vertebral artery, resulting in bilateral occipital and right cerebellar infarcts. He presented initially with almost complete cortical blindness, left hemiparesis, gait instability, mild swallowing difficulties. Visual perception improved in a small peripheral part of his right visual hemifield, while all other symptoms recovered fully.

[0107] Apart from the patient's visual status, his general neurological examination was normal, either off or on Mepivacaine. He had no sensory or motor impairment, no abnormalities of the cranial nerves, no cognitive deficit (MMSE=29/30, FAB 16/18, Five Words Test 10/10). There was no psychiatric symptoms, except for a depressive mood whenever the patient was off medication and virtually blind.

Example 2: Clinical Assessment of Vision

[0108] During off periods, clinical assessment of the visual field by confrontation showed complete blindness, except for a restricted region in the periphery of the right visual hemifield. During on periods, vision returned to normal in the right hemifield while dense hemianopia persisted in the left hemifield. The patient described the transition from off to on periods as a progressive widening, over a matter of seconds, of the island of spared vision in the periphery of the right visual field, to the whole right hemifield. The inverse phenomenon took place, over about 1 minute, during the transition from on to off periods.

Example 3: Visual Field Assessment

[0109] Those clinical observations were supported and refined by assessment of the visual field with the full-threshold Humphrey visual field (HVF), 24-2 Swedish Interactive Thresholding Algorithm (SITA) (Carl Zeiss Meditec Inc., Dublin, Calif.).

[0110] FIG. 1 shows that there was no perception even at the highest stimulation intensity (black squares) during off period (left and right eyes), except for the sparing of a right homonymous peripheral area (white arrows).

[0111] FIG. 2 shows that vision returned to normal in the whole right hemifield, except for a small superior paracentral island (striped arrows). It also recovered in a small paramedial island in the left superior quadrant (gray arrows). The same pattern prevailed using Goldmann perimetry.

Example 4: Neurovisual Evaluation

[0112] As shown in the table below, during on periods, all tests involving visual perception were normal, except for a mild deficit in the Facial recognition test, with no discernible impairment of face perception in everyday life.

TABLE-US-00001 VISUOPERCEPTION, VISUOCONSTRUCTION AND VISUOSPATIAL REASONING Birmingham object recognition battery (BORB) (Riddoch et Humphreys, 1993 TEST 1: Copying  9/9 TEST 2: Length Match Task 26/30 (z = 0.56) TEST 3: Size Match Task 28/30 (z = 0.29) TEST 4: Orientation Match Task 25/30 (z = 0.08) TEST 5: Position of Gap Match Task 37/40 (z = 0.48) TEST 6: Overlapping Figures — TEST 7: Minimal Feature View Test 25/25 (z = 0.85) TEST 8: Foreshortened View Task 25/25 (z = 1.31) TEST 9: Drawing from Memory  6/6 TEST 10: Object Decision Task 26/32 (z = 0.45) TEST 11: Function Match Task 31/32 (z = 0.45) TEST 12: Associative Match Task 29/30 (z = 0.63) Other tests Benton's Judgment of Line Orientation 14/15 Hooper Test (Richardson and Marattoli, 1996) 27/30 (z = 1.30) OD 80 picture naming test (Deloche and 80/80 Hannequin, 1996) Facial recognition test (Benton, 1963) 38/54 Block design test (WAIS-IV) 53/66 (NS = 13) Matrix reasoning test (WAIS-IV) 22/26 (NS = 14)

Example 5: General Neuropsychological Status

[0113] Cognitive abilities were tested using standardized batteries. There was no impairment of attention, episodic memory, executive functioning, language, calculation.

Example 6: Brain Imaging

[0114] 1. Anatomical MRI

[0115] First, there is an infarct affecting a large part of the left mesial occipital lobe (striped arrows), including the calcarine sulcus, with cortical and white matter lesions (FIG. 3). This is the cause of the left homonymous hemianopia. Note that the ventral bank of the calcarine sulcus is less affected, with no underlying white matter FLAIR hyperintensity, which may explain why recovery under Mepivacaine extends to part of the left superior quadrant. Second, there is a smaller right occipital infarct with underlying white matter FLAIR hyperintensity (white arrow). It is located posterior and ventral relative to the calcarine sulcus, which corresponds retinotopically to the island of right visual field which is not improved by Mepivacaine.

[0116] 2. Resting State Functional MRI

[0117] Resting state fMRI is a method of functional magnetic resonance imaging (fMRI) that is used in brain mapping to evaluate regional interactions that occur in a resting or task-negative state, when an explicit task is not being performed. We gathered MRI images while the patient was at rest with his eyes closed, during off and on periods. Those data were analyzed using the CONN toolbox (https://web.conn-toolbox.org/home). We report here two results providing pathophysiological correlates of vision recovery in the patient's right visual hemifield under Mepivacaine.

[0118] a. Changes in Connectivity of the Left Primary Visual Cortex

[0119] The left early visual cortex (or calcarine cortex) is the entry gate into the brain of visual information from the right hemifield. We reasoned that this area, which showed little structural damage on anatomical MRI, should recover its function under Mepivacaine. We predicted that whatever its underlying mechanism, functional recovery implies a restoration of functional communication between the left calcarine cortex and distant cortical areas. As shown in FIG. 4, the left calcarine cortex showed an increase in connectivity with bilateral frontoparietal regions, corresponding to a network controlling attention to external events (Corbetta and Shulman, 2002). Conversely, there was a decrease in correlation with a set of mesial and lateral regions, corresponding to the so-called default-mode network involved in internally oriented cognitive processes (Raichle et al., 2001). As a control, we performed the same analysis from the symmetrical right-hemispheric calcarine region, which showed no significant differences between on and off periods.

[0120] b. Changes in Intrinsic Connectivity

[0121] We predicted that the restoration of vision should be accompanied with an overall increase of connectivity between the visual system and the rest of the brain. We computed for each voxel of the brain the average connectivity with the rest of the brain (or “intrinsic connectivity”), and studied the changes of this value between off and on periods. As shown in FIG. 5, the bilateral lateral occipital cortex (white), an intact part of the patient's visual cortex, indeed increased its functional connectivity with the rest of the brain during on—as compared to off-periods

[0122] 3. 18F-FDG PET-Scan

[0123] We observed (1) a severe and constant hypometabolism in the severely lesioned right mesial occipital cortex; and (2) regions of significant increase in metabolism in the intact left occipital and temporal cortex, during on—as compared to off-periods (FIG. 6).