WO1991001756A1 - Procede de stimulation des effets de l'electrostimulation transcranienne par courant faible - Google Patents

Procede de stimulation des effets de l'electrostimulation transcranienne par courant faible Download PDF

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WO1991001756A1
WO1991001756A1 PCT/US1990/004443 US9004443W WO9101756A1 WO 1991001756 A1 WO1991001756 A1 WO 1991001756A1 US 9004443 W US9004443 W US 9004443W WO 9101756 A1 WO9101756 A1 WO 9101756A1
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central nervous
nervous system
group
same
chemical promoter
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PCT/US1990/004443
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Malcolm H. Skolnick
David H. Malin
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Skolnick Malcolm H
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/328—Applying electric currents by contact electrodes alternating or intermittent currents for improving the appearance of the skin, e.g. facial toning or wrinkle treatment

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  • the present invention relates to the concomitant administration of transcranial electrostimulation and chemical promotors to produce greater effects when acting together then either would produce acting indi ⁇ vidually.
  • the present invention relates to a method of medical treatment of a mammal which produces greater and longer lasting analgesic, anti-abstinence, anti-withdrawal, anti-anoxiant, anxiolytic, anti-psychotic, anti-depressant, relaxant, and anti-inflammatory effects than can be produced with drugs associated with these effects with the use of the same, or even lesser, dosages needed to achieve the effect.
  • Neurotransmitters Transmission of nerve impulses between neurons is an electrochemical process in which electrical impulses reaching the neuron's terminal cause various chemicals, referred to as neurotransmitters, to be emitted. Once released by the neuron, the neurotransmitter crosses the synapse (a gap of about 20 nm) to the membrane of the next neuron in the neuronal circuit. There, the neurotransmitter interacts with specific receptors and generates a new electrical impulse, which continues the signal.
  • the chemical can be released into the general stream of extracellular fluid and subse ⁇ quently join the flow of fluid (CFS) .
  • the released chemical may simply interact locally with receptors on neurons in the immediate neighborhood (paracine action) or the chemical may travel further to interact with specific receptors positioned at relative ⁇ ly distant target sites, in adjacent brain regions or in other parts of the body (endocrine action) .
  • the released chemicals mostly act simply as neurotransmitters, but a subcategory (which may be co-released with the neurotransmitter) can also act as modulating ' agents (neuromodulators) . These agents influence the extent to which their own, or adjacent, nerve terminals can either release, or respond to the action of, neurotransmitters. Released chemicals which travel to and act at other parts of the body are generally referred to as hormones.
  • Neuromodulation is one of the most important intrinsic properties of individual neurons. Neuromodulation is generally defined as the ability of neurons to alter their electrical properties in response to intracellular biochemical changes resulting from synaptic qr hormonal stimulation. This property not only allows the nervous system to adapt its control of physiological functions to a continually changing environment, but also forms the basis for many long-lasting changes in human behavior and in the behavior of animals. Changes in behavior that can be related directly to changes in the electrical responses of specific neurons include the triggering of long-lasting, but relatively fixed and inate, behaviors such as feeding and reproduction, as well as alterations in behaviors that can be ascribed to learning.
  • Transcranial electrostimulation or TE
  • TE Transcranial electrostimulation
  • U.S. Patent No. 4,646,744 and that description is incorporated herein in its entirety by this specific reference to that patent.
  • TE may be described as the application of extremely low (on the order of 10 jaA) , pulsed, charge-balanced current across the head through electrodes of opposite polarity attached to low impedance sites on the head.
  • TCET Transcranial auricular electrostimulation
  • the present invention is characterized broadly as a method of medical treatment of a mammal involving the enhancing of the normal efforts of the central nervous system to ameliorate or otherwise compensate for such stress as pain, anxiety, addiction withdrawal symptoms, depression, and inflammation, comprising the concomitant administration of a neuroactive chemical promotor and subsensory, transcranial electrostimulation.
  • This medical treatment method is also useful in remediating imbalances or deficiences in levels of neuroactive substances that modulate neurohumoral mechanisms in living beings.
  • Concomitant administration of TE and a neuroactive chemical promoter provides a treatment modality which can replenish, initiate or invigorate production of and/or compensate for, such deficiencies and/or imbalances.
  • the present invention is characterized as a kit for providing medical treatment of a mammal, which kit comprises a neuroactive chemical promotor in a form suitable for administration to a mammal and means for concomitant administration of transcranial electrostimulation to the mammal.
  • the present invention contemplates the use of a neuroactive chemical promoter for the manufacture of a medicament for administration to a mammal to which transcranial electrostimulation is concomitantly administered.
  • the present invention is characterized as a pharmaceutical composition for providing medical treatment of a mammal in combination with transcranial electrostimulation, comprising as an active ingredient a neuroactive chemical promotor.
  • kits, compositions, and methods are characterized by a number of advantages over previously available techniques.
  • the ability to achieve analgesia to relieve chronic pain, to assist relaxation in combatting stress related disorders and to ameliorate drug withdrawal syndromes with a non-addictive modality for which tolerance does not increase is of obvious clinical significance.
  • the same effects can be achieved as are achieved by the therapeutic use of many specialized drugs, but with lower dosage levels or, in some cases, without even administering the drug (e.g., by accomplishing the same effect by using a different agent) , therefore potentially decreasing the cost and/or side effects of drug therapy.
  • Another significant advantage is that the ameliorative effects are not only more pronounced but of longer duration than the effects produced by administration of the drug alone. Such results can even be achieved using subclinical doses of the neuroactive chemical promotor of the present invention.
  • an object of the present in ⁇ vention to provide a medical treatment method for mammals for use in, for instance:
  • any of a host of stress-related disorders such as insomnia, certain forms of obesity and anorexia, post-traumatic stress disorder, and clinical depression.
  • Figure 1 is a bar graph showing the decreased TE-induced analgesia resulting from administration of p-chlorophenylalanine (pCPA) , which depletes serotonin levels, in rats as described in Example 3, below.
  • pCPA p-chlorophenylalanine
  • Figure 2 is a bar graph showing the restoration of TE-induced analgesia after restoring serotonin levels to pCPA-treated rats by administering exogenous serotonin as described in Example 3, below.
  • Figure 3 is a bar graph showing the enhancement of TE-induced analgesia in rats by concomitant administration of thiorphan as described in Example 4, below.
  • Figure 4 is a bar graph showing the enhancement of TE-induced analgesia in rats by concomitant administration of acetorphan as described in Example 5 , below.
  • Figure 5 is a bar graph showing the effect of concomitant administration of proglumide and TE in morphine addicted rats upon deprivation of morphine as described in Example 13, below.
  • the reaction to and management of pain, stress and anxiety are modulated by a host of neurotransmitters synthesized and pharmacologically active in the mammalian brain and spinal chord. These endogenous transmitters are synthesized in various regions of the brain from various chemical precursors and are broken down or metabolized by enzyme systems at various sites in the central nervous system (CNS) . Neurotransmitters have been shown to induce or be involved with analgesic, anxiolytic, sedative, hypnotic, CNS depressant, and psychotropic effects.
  • a variety of chemical agents have been discovered which interact with neurotransmitter systems. These agents may, for instance, possess a chemical structure which mimics a particular transmitter or class of transmitters and which binds to the cellular receptors uniquely associated with the transmitter family. For example, exogenous heroin or morphine cross the blood-brain barrier and displace the brain's endogenous peptidyl opiates, the endorphins and enkephalins.
  • neuroactive chemical promoters include any sub ⁇ stances which are capable of exerting an effect on the CNS which enhances the capacity of the CNS to relieve or ameliorate the effects of such stressful stimuli as pain, addiction withdrawal syndrome, and so on as listed above, or which are remedial in remediating imbalances
  • Such substances may include, but are not limited to, endorphins such as B-liptropin, adrenocortico- tropin, alpha-melanocyte-stimulating hormone, met-enkephalin, leu-enkephalin, peptides E and F, me orphamide, amidorphin, dynorphin, dynorphin B, and alpha-neo-endorphin, precursors of various endorphins such as pro-opiomelanocortin, pro-enkephalin A and pro-enkephalin B (pro-dynorphin) , enzymes active in the metabolic pathways involved in production or degradation of the above- listed endorphins and enkephalins such as endorphinase, enkephalinase, and carboxypeptidases, inhibitors of the enzymes active in the metabolic pathways involved in production or degradation of endorphins such as acetorphan, thi
  • 5-hydroxytryptophan antagonists such as the ergot alkaloids such as lysergic acid diethylamide (LSD) and methysergide (generally in the form of methysergide maleate) , H. blockers of the ethylenediamine type, various indole compounds, spiroperidol, pirenperone, cyproheptadine, phenothizaines such as chlorpromazine, J3-haloalkylamines such as phenoxybenzamine, siperone, metergoline, etitepine, ianserin, pizotyline (pizotifen) , cinanserin, and ketanserin, and substances such as clomipramine and fluoxetine which inhibit uptake, catecholamines such as noradrenalin, adrenalin, dopamine, 3, 4-dihydroxyphenylalanine (dopa) , norraetanephrine and metanep
  • neuroactive chemical promoter is intended to include a large number of substances which are not necessarily easily classified into one of the above groupings but which nonetheless are capable of exerting an effect on the central nervous system which enhances the capacity of CNS to relieve or ameliorate the effects of, for instance, the above-listed stre ⁇ ful ⁇ timuli.
  • Such substances can best be described by citation to a reference characterized the substance in detail as follows: pyrido [2,3-e]-a ⁇ -triazine derivatives as de ⁇ scribed in U.S. Patent No. 4,324,786, Messmer, heteramino benzofuran ⁇ as described in U.S. Patent No. 4,451,462, Wenk, isochro ans as described in U.S. Patent No. 4,487,774, McCall,
  • transcranial electrostimulation As noted above, an appropriate apparatus for admini ⁇ stering transcranial electrostimulation (TE) is described in U.S. Patent No. 4,646,744, incorporated herein by reference. However, the phrase "means for administration of trans ⁇ cranial electrostimulation" is used throughout this speci ⁇ fication because it is not intended that the apparatus be limited only to that which is set out in that patent.
  • TE can be de ⁇ cribed as the application of a continuous series of ⁇ ub-sen ⁇ ory electrical pulses from one side of the patient's head to the other through electrodes of opposite polarity affixed to the patient's head.
  • _E- xtensive experimentation has shown that those sites on the head having the relatively lowest impedance are the best sites for placement of the electrodes in that they are more effective in inducing a response.
  • the impedance must be low enough in an absolute sense to make it possible to achieve the desired current level (see below) at a voltage which is below the threshold of detection by the patient.
  • the electrodes be affixed to the external ears, or pinnae? however, the ma ⁇ toid process has also been used to advantage on human patients.
  • a ⁇ i ⁇ the case for other locations on the head a change in position of a ⁇ little as two millimeters can make significant difference ⁇ in impedance; preferred ⁇ ite ⁇ in humans are the ear lobe, inner ear and upper ear, on rats, the ba ⁇ e of the ear and the apex of the antihelix are preferred.
  • biphasic, charge-balanced waveform refers to a series of generally rectangular pulses having, for instance, approximately a 10 ⁇ A, 2.0 m ⁇ ec po ⁇ itive pha ⁇ e separated by 98.0 msec negative phases having an amplitude of approximately 0.2 u ⁇ . It is not intended, however, tha the method of the present invention be practiced only u ⁇ ing those parameters. Satisfactory results can be obtained by varying these parameters as follows: pulse width (duration) about 0.1 - about 8.0 mse frequency about 5 - about 50 Hz current about 5 - about 40 juA duration about 10 - about 60 min.
  • monophasic, non-charge balanced waveform ⁇ although not as efficacious as biphasic charge balanced waveform ⁇ , may also be u ⁇ ed to advantage by varying the parameter ⁇ within these same ranges.
  • the method of the present invention may be better under ⁇ tood by reference to the following examples of ⁇ everal pre ⁇ ently preferred embodiments thereof.
  • EXAMPLE 1 Effect of Amplitude, Frequency, Duratio and Repeated Stimulation Three hundred and thirty four male Sprague-Dawley rats weighing between 180 and 210 grams were used. The animals were housed in groups of four with ad lib food and water and a 12 hour alternating light/dark cycle. All animals were naive in the sense that they had no previous experience with TE; however, a day prior to each experiment, the sub ect ⁇ were placed in restraints for one hour to acclimate them to the experimental conditions.
  • a computer controlled stimulator was used to produce a continuous ⁇ erie ⁇ of biphasic, charge balanced, rectangular pulses which, unless otherwise specified, had a repetition rate or 10 Hz, first phase amplitude of 10 j_ ⁇ , and first, phase duration of 0.1 msec.
  • the second phase duration was approximately equal to the interval between consecutive first phases, and the amplitude such that the net charge delivered in any cycle was zero.
  • An essentially constant current was maintained by the stimulator during each phase, irre ⁇ spective of variations in the rat impedance.
  • the rats were placed in adjustable cylindrical plastic restrainers. Leads with a 200 K ohm resi ⁇ tor in ⁇ erie ⁇ were connected to the electrode ⁇ , with the positive lead (that deliver ⁇ ing a positive first phase) attached to the animals' right ears.
  • Each experiment included a "sham control group" consi ⁇ ting of rat ⁇ which were implanted, re- ⁇ trained and connected as above, but which did not receive any electrical stimulation.
  • Analgesia was a ⁇ se ⁇ sed using the wet tail flick method described in Mitchell, D. and R.F. Hellon, "Neuronal and behavioral respon ⁇ e in rat ⁇ during : noxiou ⁇ stimulation of the tail," Proc. Royal Soc. (Lond.) 169-194 (1977) .
  • the terminal one inch of each rat's tail was immersed in water at 50°C.
  • the time in second ⁇ measured with a stopwatch from submergence to the first flicking response was taken as the tail flick latency. If a rat did not respond within 20 second ⁇ , its tail was removed from the water to prevent ti ⁇ ue damage.
  • Four successive latencies were de ⁇ termined during both the pre- and post-te ⁇ t; in each case, the fir ⁇ t mea ⁇ urement was discarded and the last three were averaged to yield pre- and post-stimulation scores.
  • Each rat's analgesia rating was its mean post-te ⁇ t latency minus its mean pre-test latency. Results may be summarized as follows.
  • EXAMPLE 2 Effect of Pulse Width, Frequency, Polarity Charge Balance and Monolateral Stimulation
  • the stud ⁇ were in ⁇ erted into either the right or left ear only.
  • Experiment 1 tested the analgesic effects of different stimulus pulse widths in 63 rats not previously exposed to TE that were randomly assigned to seven groups of 9 rats each. These groups had 30 minutes of 10 ⁇ A, 10 Hz stimulation with, respectively, 0 (sham) , 0.1, 0.5, 1, 2, 4 and 8 m ⁇ ec first phase pulse widths. As in all the following experiments, tail flick latencies (TFLs) were determined before and after stimulus by an operator who was blind to the stimulus parameters, and the time difference in seconds determined the animals' analgesia scores.
  • TNLs tail flick latencies
  • Experiment 2 tested the analgesic effects of different stimulus frequencies in 63 rats were randomly assigned to seven groups of 9 rat ⁇ each. These groups had 30 minutes of 10 ⁇ A, 2 msec pulse width stimulation at 0 ( ⁇ ham) , 5, 7.5, 10.0, 15, 20, and 50 Hz.
  • Experiment 3 tested the neces ⁇ ity of using a charge balanced stimulus waveform in 27 rats randomly assigned to 3 groups of 9 rats each. These groups had 30 minutes of ⁇ timulu ⁇ with, re ⁇ pectively, no ⁇ timulus waveform (sham) ; 10 Hz, 2 msec, 10 ⁇ A stimulation with a charge balanced waveform; or 10 Hz, 2 msec, 10 ⁇ A stimulation with a monophasic (non charge-balanced) waveform.
  • Experiment 4 tested the effect of stimulus polarity on the analgesia produced by TE in 15 rats tested three times in a blind, triple cros ⁇ over design with 30-minute stimulus sessions. Each rat received a ses ⁇ ion of ⁇ ham stimulation; one of 10 Hz, 2 msec, 10 ⁇ A charge balanced TE with standard polarity (positive lead on the right ear) ; and one of 10 Hz, 2 msec, 10 ⁇ A TE with reversed polarity (positive lead on the left ear) . TFL analgesia score ⁇ in this experiment were determined in all animals before and after each session. Statistically weak results led to a repeat of the experiment using a further 12 ⁇ ubject ⁇ in the ⁇ ample triple crossover design.
  • Experiment 5 inve ⁇ tigated the efficacy of several electrode positioning schemes in 36 rats randomly assigned to three groups of 12 rats each. One group had one electrode in each ear, the other two groups had two electrodes in either the left or the right ear a ⁇ described. Each animal had 30 minutes of 10 Hz, 2 msec, 10 ⁇ A charge balanced TE. TFL analgesia scores were determined in the usual way under blind conditions.
  • the rats were placed in adjustable cylindrical plastic re ⁇ trainer ⁇ . Lead ⁇ were connected to the electrodes with the positive lead (that delivering a positive first pha ⁇ e) attached the animals' right ear ⁇ .
  • Each experiment included a sham control group consisting of rats which were implanted, restrained and connected as above, but which did not receive any electrical stimulation.
  • the rat ⁇ were pretreated with dl-p-chloropheny- lalanine, methyl ester (pCPA) , Sigma Chemical Co. (300 mg/kg i.p.) dissolved in 2.0 ml of saline or with saline vehicle 48 hours prior to testing, and were also treated with either 5-hydroxy-dl-tryptophan, ethyl ester, (5HTP) Sigma Chemical Co. (100 mg/kg i.p.) dissolved in 1.5 ml. of saline in a 37°C water bath or with saline vehicle 30 minutes prior to te ⁇ ting. At that time the rat ⁇ were placed in the cylindrical pla ⁇ tic re ⁇ trainer ⁇ and the elctrodes attached as de ⁇ cribed above. They then received 30 minute ⁇ of either TE or sham TE treatment (Table I) . 23
  • Analgesia was as ⁇ e ⁇ sed u ⁇ ing a pressure technique modified from that de ⁇ cribed by Randall, L.O. and J .0. Selitto, III Arch. Int. Pharmocodyn. 409-419 (1957).
  • Each rat's tail was subjected to pres ⁇ ure (1 inch from the tip) exerted by a metal wedge mounted on the end of a syringe which was pneumatically driven.
  • the amount of pressure withstood by the rat was read from a mercury manometer as the rat made the first coordinated motor response to remove its tail.
  • One experimenter operated the wedge and cut off air pressure when the rat responded as the other experimenters read the height reached by the mercury on the manometer.
  • TPP mean tolerated peak pres ⁇ ure
  • TE treatment resulted in increased tolerated peak tail pressure.
  • the average tolerated peak tail pressure was 18.2 mm Hg or 613 percent higher than in the sham treated groups collectively (p ⁇ .001, Figs. 1,2).
  • the saline-TE treated group (Group D, Table I) tolerated an average of 29 mm Hg more peak pres ⁇ ure than did the saline-sham TE group (Group H, Table I) .
  • Treatment with pCPA diminished TE induced analgesia.
  • Electrostimulation and i.e.v. Thiorphan An experiment was conducted in which the combined effect of TE and the enkephalinase inhibitor thiorphan was assessed on analgesia.
  • the subjects were 20 male Sprague-Dawley rats, weighing 200-225 grams. Subject ⁇ were maintained on ad. lib food and water and a 12 hour light/dark cycle.
  • Seven day ⁇ prior to the experiment each rat wa ⁇ placed under Innovar (tm) anesthesia, implanted with gold-plated stainless steel electrodes through the apex of the anti-helix of each pinna as described in Example 2, and stereotaxically cannulated in the third ventricle. Each cannula placement was subsequently confirmed by dye injection and histological examination.
  • each rat was habituated to a cylindrical plastic restrainer.
  • Each rat was placed in the restrainer and pretested for nociceptive sensitivity by measurement of tail flick latency on the 50°C wet tail flick te ⁇ t (average of three trials) .
  • the ear electrodes of each rat were then connected to the stimulator through leads with a 200 R ohm resistor in series.
  • Ten rats then received 30 minutes of TE stimulation (10 Hz, 10 ⁇ A, 2 msec pulse width) , while ten rats (the "sham stimulation group") received no stimulation.
  • EXAMPLE 5 Combined Effects of TE and i.p. Acetorphan - Analgesia
  • Example 4 An experiment similar to that described in Example 4 was conducted with the systemically active enkephalinase inhibitor acetorphan.
  • the subjects were 84 male Sprague-Dawley rat ⁇ weighing 180-220 gra ⁇ . Each rat wa ⁇ implanted with ear electrode ⁇ under halo- thane anesthesia and subsequently habituated and pre ⁇ tested for tail flick latency as in Example 4.
  • Forty- two rats then received i.p. injections of 15 mg/kg acetorphan (donated by J.C. Schwartz, INSERM, Paris) in a vehicle of ethanol (10%) /cremophor EL (10%) /saline (80%) .
  • Forty-two rats received the injection vehicle alone.
  • Example 4 Beginning five minutes after injection, half of the acetorphan recipients and half of the vehicle recipients received 30 min. of TE as in Example 4. The remaining half of each group received 30 min. of sham stimulation only. All rats were then immediately retested under "blind" conditions for tail flick latency and their analgesia scores were expressed as percentage increase from pretest to posttest latencies. These scores were analyzed by the same procedure ⁇ employed in Example 4.
  • L-tryptophan - Analgesia Another experiment was conducted in which the neuroaptive chemical promoter L-tryptophan, the amino acid precursor of serotonin, was administered con ⁇ comitantly with transcranial electrostimulation as follows.
  • the subjects were 40 male Sprague-Dawley rats, weighing 200-250 grams. Subjects were maintained on ad lib food and water and a 12 hour light/dark cycle.
  • each rat was placed under halothane anesthesia and implanted with gold-plated stainless steel electrodes through the apex of the anti-helix of each pinna as described in Example 2.
  • each rat wa ⁇ habituated to a cylindrical plastic restrainer.
  • each rat was placed in a restrainer and pretested for nociceptive sensitivity by measurement of tail flick latency on the 50°C wet tail flick test (average of three trials) .
  • Each rat was then injected i.p. either with 200 mg/kg L-tryptophan in a vehicle of isotonic ⁇ aline (95%) /2N HCL (5%) or with vehicle alone. This dose was selected on the basis of small pilot experiments. Beginning 40 minutes after injection, each rat was placed again in a restrainer, and the ear electrodes of each rat were connected to the stimulator through leads with a 200 K ohm resistor in series.
  • TE stimulation (10 Hz, 10 ⁇ A, 2 msec pulse width)
  • rats the "sham stimulation group”
  • a 2x2 factorial design was employed so that ten rats received L-tryptophan and TE, ten rats received L-tryptophan and sham stimulation, ten rats received vehicle only and TE and ten rats received vehicle only and sham ⁇ timulation.
  • the group receiving both TE and L-tryptophan had a significantly greater percentage increase in tail flick latency than any of the other groups, p ⁇ .05, according to Dunnett's Procedure for post-hoc comparison of a single treatment group with all others.
  • EXAMPLE 7 Combined Effects of TE with D-phenyl- alanine and Tyrosine - Analgesia
  • each rat receive ⁇ 30 minute ⁇ of either sham stimulation as de ⁇ cribed in Example 1, electrostimulation as described in Example 2, or either L-tryptophan at the dosage level set out in Example 6 or D-phenylalanine at the dosage level set out in Example 7.
  • the rats are placed in a clear plastic observation chamber with a grid floor and ob ⁇ erved for 15 minute ⁇ under blind condition ⁇ on a ⁇ tandard checkli ⁇ t of opiate ab ⁇ tinence signs (wet dog shakes, genital licks, hind foot scratches, abdominal writhes, ptosi ⁇ , dyspnea, diarrhea, and teeth chattering) as primarily based on Gianutsos, G. , et al., "The Narcotic Withdrawal Syndrome in the Rat", j in S. Ehrenement and A. Neidle (Eds.) , Methods in Narcotic Research, New York: Marcel Dekker, pp. 293-310 (1975).
  • EXAMPLE 9 Combined Effects of TE and Acetorphan - Morphine Abstinence Syndrome
  • Example 8 The experiment described in Example 8 is repeated either substituting the enkephalinase inhibitor acetor ⁇ phan for the neuroactive chemical promoters L-tryptophan and D-phenylalanine or administering acetorphan in addition to those two amino acids.
  • EXAMPLE 10 Combined Effects of TE and
  • Kelatorphin - Analgesia The experiment described in Example 5 is repeated substituting the enkephalinase inhibitor kelatorphin for the neuroactive chemical promoter acetorphan.
  • Kelator ⁇ phin is effective when given orally, consequently, the only change in the method set out in Example 5 is that the neuroactive chemical promoter is given orally in a suitable vehicle at a dosage of between approximately 25 and approximately 200 mg/kg body weight.
  • Analgesia can also be efficaciously induced with combination ⁇ of one or more neuractive chemical promoters and in combination with other substance ⁇ .
  • humans are tested for the analgesic effect of such combinations a ⁇ acetorphin and L-tryptophan, acetorphan and D-phenyl ⁇ alanine, acetorphan with L-tryptophan and a B vitamin such as niacinamide or vitamin Bb,, acetorphan with
  • D-phenylalanine and a B vitamin such as niacinamide or B_. are as follows:
  • L-tryptophan about 50 mg, twice a day for a person weighing 75 kg D-phenylalanine between about 25 mg ' and about
  • EXAMPLE 12 Combined Effects of Extended TE with Proglumide - Morphine Abstinence Syndrome
  • CCK cholecystokinin
  • EXAMPLE 13 Combined Effects of Extended TE with Proglumide - Morphine Abstinence Syndrome
  • Example 12 The experiment de ⁇ cribed in Example 12 may be extended wherein the drug-TE combination i ⁇ given repeatedly at regular intervals over a 24 hour period. TE is given every three hours with the same parameters as set out in Example 12, and proglumide is administered as described in Example 12 just prior to each TE administration. The drug-TE combination i ⁇ expected to produce fewer ab ⁇ tinence signs in the experimental subjects than would proglumide or TE given alone.
  • Analgesia, sedation, narco ⁇ i ⁇ potentiation, tetrabenzine antagonism and anti-phlogistic effects can be efficaciously induced with combined administration of TE as set out in examples 3-6 and pyrido[2,3-e]-as-triazine (PAT) derivatives of the following general formula wherein:
  • R 1and R2 each stand for a C._ 7f) alkylcarbonyl, halogenated (C. ,alkyl)-carbonyl,
  • R 1 and R2 may form, together with the adjacent nitrogen atoms, a pyrazole-2,4 ring having optionally a C- , alkyl substituent in position 3, and
  • R stands for hydrogen, halogen, C- , alkoxy, amino, mono-(C 1 _ fi alkyl) -amino, di-(C, ⁇ alkyl) -amino, hydroxy, alkylated or acylated hydroxy, morpholino, peperazino, N- (C - alkyl) -piperazino, N-benzylpiperazino or
  • Pharaceutically acceptable acid addition salts of PAT are prepared by acylating the respective 1,2 unsub ⁇ tituted 1,2 dihydro-P/.T derivative ⁇ . These ⁇ ubstances are de ⁇ cribed in U.S. Patent 4,324,786, incorporated herein by this specific reference to that patent.
  • the pharmaceutical preparations are for enteral or parental administration to warm-blooded animal (s) and contain the pharmacologically active ingredient alone or together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends on age, individual condition, method of administration and body weight. In normal patients, the estimated approximate dose in the case of oral admini ⁇ tration i ⁇ from 200 to
  • Analgesia and anti-inflammatory effects can be efficaciously induced with combined administration of TE as set out in Examples 3-6 and heteramino benzofuran derivatives of the general formula
  • R 1 represents hydrogen or an aliphatic radical
  • R_ represents an amino group di- ⁇ ubstituted by a divalent hydrocarbon 34 radical
  • the aromatic ring A may be additionally ⁇ ub ⁇ tituted, and their ⁇ alt ⁇ and/or isomers.
  • the pharmaceutical preparations are for enteral or parental administration to warm-blooded animal( ⁇ ) and contain the pharmacologically active ingredient alone or together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends on age, individual condition, method of administration and body weight. In normal humans, the estimated approximate dose in the case of oral administration is from 2 to 10 mg/kg of body weignt.
  • Antipsychotic and hypotensive effects can be efficaciously induced with combined administration of TE and amino derivatives of isochromans of the general formula given in U.S. Patent 4,487,774, incorporated herein by this specific reference to that patent.
  • the pharmaceutical preparations are for enteral or parental administration to warm-blooded animal ( ⁇ ) and contain the pharmacologically active ingredient alone or together with a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends on age, individual condition, method of administration and body weight. In normal humans, the estimated approximate dose in the case of oral administration is from 2 to 10 mg/kg of body weigh.
  • Example 3 protocols set out in Example 3, and tested for the combined effects of TE and these neuroactive chemical promoters using the tail flick latency model described in that same example.
  • TE is given a ⁇ set out in Exampl 4 and acetorphan dosages are the same as set out in Example 4.
  • L-tryptophan is administered t the rats in the dosages de ⁇ cribed in Example 5. It i ⁇ expected that the re ⁇ ults seen in both Examples 4 and 5 a ⁇ de ⁇ cribed above will be even more dramatic when both neuroactive chemical promoter ⁇ are administered concurrently with TE.
  • the 80 subjects participating in this study all ha intractable low back pain. This type of pain limits musculo-skeletal output, and is therefore subject to a more objective measurement of the analgesic measures which may be applied.
  • An isokinetic, automated exercis device (Kin-Corn m ) wa ⁇ used to test the subjects' ability to output musculo-skeletal torque before and after administration of TE. Because of the varying nature of each subject' ⁇ pain, the ability to trigger pain in each subject, each subject's idiosyncratic use ⁇ f drugs, and each subject's differing physical condition, an experimental design was implemented in which each subject served as his own control.
  • Volunteering subjects were randomized into two matched groups. Each subject participated in a 2 x 2 cross-over design in which he received two randomly as ⁇ igned analge ⁇ ic treatments and two ⁇ ham treatments (placebos) .
  • the analgesic treatment was application of low current, transcranial electrostimulation therapy (TE) .
  • TE transcranial electrostimulation therapy
  • EXAMPLE 19 Effect of TE to Relieve Nicotine Withdrawal Systoms - Smoking Cessation
  • Transcranial electrostimulation has been applied in double blind clinical trails to long term smokers (at least one pack per day) who indicated they wished to quit smoking.
  • Three different portocols were investigated—one treatment per day for eight days, two treatments per day for five days, or one treatment per day combined with a behavior modification program. In the first protocol, treatments were given Monday through Friday and then the following Monday through Wednesday. In the second protocol, treatments were delivered Monday through Friday.
  • the behavior modification program used in the third protocol was applied in the recognition that TE served to assist in overcoming short term withdrawal symptoms, but that psychological craving required address by behavior modification to induce long term support against recidivism.
  • the subjects selected for participation in the study smoked at least one pack of cigarettes per day for at least five years, were between the ages of 18 and 55, were not pregnant, had no known threatening medical conditions, had tested negative for cannaboids and other confounding drugs.
  • the subjects supplied information on the base cigarette count and brand of cigarette smoked and were prospectively randomized into two groups—treatment and placebo.
  • TE consisted of low current (less than 40 ⁇ A) , pulsed sugnals delivered through electrodes attached to the earlobes.
  • the stimulu ⁇ was delivered below perception levels of the subjects.
  • the duration of each treatment was approximately one hour.
  • Subjects provided a daily record of the number of cigarettes and the time that they smoked, and completed questionaire ⁇ to assess withdrawal symptoms.
  • Saliva samples were collected at the clinic from each subject at orientation before the study began and on each day of treatment. Cotinine levels were determined using a monoclonal antibody enzyme linked immunosorbent assay (ELISA) .
  • ELISA monoclonal antibody enzyme linked immunosorbent assay
  • the Shiffman Withdrawal Scale, Analog Craving Scale and an instrument to assess withdrawal symptoms were administered regularly throughout the study. Subjects provided urine samples at orientation and on demand during the study. These samples were assayed to detect marijuana, cocaine or other drugs whose use could confound the analysis of study results. Subjects whose drug test was positive were excluded from the study.
  • the subjects involved in the third protocol were randomly assigned to one of four groups: treatment + behavior modification, treatment only (behavior modification was promised after the initial experimental period) , behavior modification only (treatment was promised ' after the initial experimental period) , and placebo + behavior modification.
  • treatment + behavior modification had a statistically significant greater quit rate than the other three groups.
  • Example 20 Separate and Combined Effects of Transcranial Electrostimulation and Acetorphan, with L-tryptophan, D-phenylalanine, B complex vitamins and Nicotinic acid
  • the experiment described in Example 11 can be repeated using additional chemical promotors which assist the synthesis, inhibit the degradation, and facilitate uptake, distribution and metabolism of neuroactive substances. Nicotinic acid in the form of niacinamide (50 mg given once per day), vitamin B fi , puridoxin (50 mg given once per day) and monoamine oxidase inhibitors such as D-L-phenylalanine (500 mg given once per day) , L-glutamine, or pyridoxal ⁇ -phosphate (10 mg given once per day) assist in producing enhanced analgesic effects.
  • niacinamide 50 mg given once per day
  • vitamin B fi puridoxin
  • monoamine oxidase inhibitors such as D-L-phenylalanine (500 mg given once per day) , L-glutamine, or

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Abstract

Procédé assurant un soulagement des stimuli douloureux et stressant ou remédiant à des déséquilibres ou à des carences des substances neuro-actives modulant les mécanismes neurohumoraux, consistant à administrer de manière concomitante un stimulant chimique neuroactif et une électrostimulation transcrânienne. Cette combinaison augmente la capacité du système nerveux central à assurer un soulagement par exemple de la douleur, de la suppression de l'accoutumance, de l'anxiété et de la dépression.
PCT/US1990/004443 1989-08-11 1990-08-08 Procede de stimulation des effets de l'electrostimulation transcranienne par courant faible WO1991001756A1 (fr)

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WO1997039797A1 (fr) * 1996-04-25 1997-10-30 Medtronic, Inc. Procede de traitement des dyskinesies par stimulation cerebrale et infusion de medicament
GB2314273A (en) * 1996-06-17 1997-12-24 Spes Transcranial electrotherapy for prophylaxis and treatment of allergies
US7781486B2 (en) 2003-11-04 2010-08-24 Josef Constantin Szeles Punctual stimulation therapy
US8267851B1 (en) 2009-06-16 2012-09-18 James M Kroll Method and apparatus for electrically generating signal for inducing lucid dreaming
EP2841946A4 (fr) * 2012-04-27 2015-12-09 Rhode Island Education Systèmes de commande électrique automatisés non invasifs et procédés de surveillance des conditions d'un animal
US11724985B2 (en) 2020-05-19 2023-08-15 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use

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US4646744A (en) * 1984-06-29 1987-03-03 Zion Foundation Method and treatment with transcranially applied electrical signals

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US4646744A (en) * 1984-06-29 1987-03-03 Zion Foundation Method and treatment with transcranially applied electrical signals

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CHEMICAL ABSTRACTS, Volume 110, No. 23, 5 June 1989, (Columbus, Ohio, US), D.H. MALIN et al.: "Augmented Analgesic Effects of Enkephalinase Inhibitors Combined with Transcranial Electrostimulation", see page 64, Abstract 205560u & Life Sci. 1989, 44(19), 1371-6 (Eng). *
CHEMICAL ABSTRACTS, Volume 113, No. 13, (Columbus, Ohio, US), D.H. MALIN et al.: "Augmented Analgesic Effects of L-Tryptophan Combined with Low Current Transcranial Electrosimulation", see page 73, Abstract 10923k & Life Sci. 1990, 47(4), 263-7 (Eng). *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997039797A1 (fr) * 1996-04-25 1997-10-30 Medtronic, Inc. Procede de traitement des dyskinesies par stimulation cerebrale et infusion de medicament
US6094598A (en) * 1996-04-25 2000-07-25 Medtronics, Inc. Method of treating movement disorders by brain stimulation and drug infusion
GB2314273A (en) * 1996-06-17 1997-12-24 Spes Transcranial electrotherapy for prophylaxis and treatment of allergies
GB2314273B (en) * 1996-06-17 2000-09-27 Spes The use of TCET in the prophylaxis and treatment of allergies
US7781486B2 (en) 2003-11-04 2010-08-24 Josef Constantin Szeles Punctual stimulation therapy
US8267851B1 (en) 2009-06-16 2012-09-18 James M Kroll Method and apparatus for electrically generating signal for inducing lucid dreaming
EP2841946A4 (fr) * 2012-04-27 2015-12-09 Rhode Island Education Systèmes de commande électrique automatisés non invasifs et procédés de surveillance des conditions d'un animal
US9399133B2 (en) 2012-04-27 2016-07-26 Rhode Island Board Of Education, State Of Rhode Island And Providence Plantations Non-invasive automated electrical control systems and methods for monitoring animal conditions
US11724985B2 (en) 2020-05-19 2023-08-15 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use
US11746088B2 (en) 2020-05-19 2023-09-05 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use
US11834410B2 (en) 2020-05-19 2023-12-05 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use
US11958807B2 (en) 2020-05-19 2024-04-16 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use

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