CN102083399A

CN102083399A - Treatment of movement disorders by a combined use of botulinum toxin and muscle stimulation

Info

Publication number: CN102083399A
Application number: CN2008800135923A
Authority: CN
Inventors: 苏珊·格拉夫; 弗洛里安·埃南; 斯特芬·博维克; 英戈·博格格雷费
Original assignee: Merz Pharma GmbH and Co KGaA
Current assignee: Merz Pharma GmbH and Co KGaA
Priority date: 2007-04-26
Filing date: 2008-04-25
Publication date: 2011-06-01

Abstract

The present invention relates to a method of treating a movement disorder in a patient, comprising administering a medicament comprising an effective amount of chemodenervating agent to the patient, wherein the patient is subjected to a muscle stimulation therapy, for example an movement therapy or an muscle activation therapy, and the medicament is administered prior to and/or during and/or after the movement therapy ; and a kit for the treatment of patients suffering from movement disorders comprising a medicament comprising an effective amount of a chemodenervating agent, and a device for carrying out automated movement therapy.

Description

Botulinum toxin and the muscular irritation coupling application in dyskinesia treatment

Technical field

The present invention relates to chemical denervation medicine and the automatically method in the treatment dyskinesia, used of muscle stimulation treatment coupling, the equipment that contains the test kit of described medicine and arbitrarily automatically carry out muscular irritation (for example motion) treatment.

Background technology

A. chemical denervation medicine

Chemodenervation relates to the application of the preparation that stops its target tissue of nerve stimulation (for example muscle, body of gland or other nerves).For example, adopt phenol, ethanol or botulinum toxin to carry out Chemodenervation.For example, Chemodenervation is applicable to the idiospastic patient of the little muscle of one or two place's big muscles or a few place.This method can be used for relief of symptoms, such as muscle spasm and pain, and hyperreflexia.Can disturb the chemical denervation medicine of muscle innovation also can be called as " muscular flaccidity agent ".

Term used herein " muscular flaccidity agent " relates at least two main treatment groups: neuromuscular blocking agent and spasmolytic.Neuromuscular blocking agent works by the conduction of disturbing neuromuscular soleplate place, and does not have the CNS activity.They in the operation process of being everlasting, in Intensive Care Therapy and emergency medicine, use, to cause part or paralysis fully respectively, perhaps dose dependent paresis (promptly as the muscular tone regulator).Spasmolytic also is known as the agent of " central action " muscular flaccidity, is used to alleviate musculoskeletal pain and spasm, to reduce the spasm in the multiple nervous system disease.

Neuromuscular blocking agent and spasmolytic are often used together as the muscular flaccidity agent, and these two terms are meant different preparation groups.

The neuromuscular blocking drug thing can block nerves the neuromuscular conduction at neuromuscular junction place, cause paralysing or the paresis of the skeletal muscle of getting involved.This can work in the presynaptic that be suppressed at synthetic by acetylcholine (ACh) or that discharge, perhaps works and finishes by be in the postsynaptic at acetylcholinergic receptor.The embodiment of the medicine that works in the presynaptic has botulinum toxin, Fugu ocellatus toxin and tetanus toxin.

Term " Chemodenervation " also comprises the effect that all are directly or indirectly risen by chemical denervation guiding drug, therefore also comprises upstream, downstream or the secular effect of described chemical denervation medicine.Therefore presynaptic effect and postsynaptic effect, organizational effect and/or be also included within by the indirect effect that spinal cord or afferent neuron cause in.

A kind of chemical denervation medicine-botulinum toxin although be one of at present known toxic chemical compound of tool, has been used for the treatment of multiple disease and malfunction in the past, and for example some of them have description in PCT/EP 2007/005754.And based on the botulinum toxin type A of botulinum toxin type A albumen composition, its trade name is respectively

(Allergan Inc.) and trade name Dysport (

Ltd.), be commercially available.It is by name to obtain commercially available commodity from German Merz PharmaceuticalsGmbH

Pharmaceutical composition, this pharmaceutical composition is based on the toxin goods of high purification, and contains the neurotoxicity composition botulinum toxin type A that has or not compound protein, exists with form independently.

Muscle stimulation treatment

Known multiple muscle stimulation treatment in this area.Particularly, we refer to herein the B part in " specific embodiment " chapters and sections.

An embodiment preferred is the treatment (locomotion therapy) of advancing.

In (again) rehabilitation course of maincenter gait disorder patient, utilize and strengthen the neural plasticity principle, by carrying out special training mission, complete foundation be used to recover locomotor activity (for example advance treatment, see Hesse S. (2001) Locomotor therapy inneurorehabilitation, NeuroRehabilitation 16:133-139); Borgraefe etc.-(2007) Movement Disorders, 23,280-282; Meyer-Heim etc. (2007) Developmental Medicine ﹠amp; Child Neurology 2007,49,900,906.

Traditional ground gait training (the Conventional over-ground gaittraining that is applied to be grown up, COGT) by loss of weight gait training method (body weight supported treadmilltraining, BWSTT) support, because of it can increase functional benefits, such as symmetry and the increase speed of travel (Barbeau H, Visintin M. (2003) Optimal outcomesobtained with body-weight support combined with treadmill training instroke subjects, Arch Phys Med Rehabil 84:1458-1465; McNevin NH, Coraci L, Schafer J. (2000) Gait in adolescent cerebral palsy:the effect ofpartial unweighting, Arch Phys Med Rehabil 81:525-528).Therefore, the resource of considering to dispose available manpower in these methods is used for auxiliary the guidance.By adopting BWSTT and COGT, carried out controlled trial (the Dobkin B of traumatic brain injury (TBI) or incomplete spinal cord injury (SCI) adult patient, Apple D, Barbeau H, Basso M, BehrmanA, Deforge D, Deng. (2006) Weight-supported treadmill vs over-groundtraining for walking after acute incom-plete SCI, Neurology 66:484-493; Wilson DJ, Powell M, Gorham JL, Childers MK (2006) Ambulationtraining with and without partial weightbearing after traumatic braininjury:results of a randomized, controlled trail, Am J Phys Med Rehabil85:68-74).

For the child of cerebral palsy (CP), find that general functional strength training can effectively improve the function performance.Challenging evidence shows, the BWSTT that strengthens can improve these children's locomotor activity (Song WH S1, Kim YJ, Yoo JY, (2003) Treadmill trainingwith partial body weight support in children with cerebral palsy, ArchPhys Med Rehabil 84 (E2)).

In order to recover or to develop locomotor activity, seemingly start the key point of (again) study repeatedly with violent training.Therefore, developed automatic gait training equipment in the past 10 years, with further gait training (the Colombo G that improves, Joerg M, Schreier R, Dietz V. (2000) Treadmill training of paraplegic patients using a robotic orthosis, JRehabil Res Dev 37:693-700; Hesse S, Schmidt H, Werner C, BardelebenA (2003), Upper and lower extremity robotic devices for rehabilitationand for studying motor control, Curr Opin Neurol 16:705-710).

U.S. Patent No. 6,821 is described this equipment in detail in 233.This patent relates to a kind of automatic machine, is used for paraparesis and hemiparesis patient's treadmill treatment, and it can automatically instruct the lower limb on treadmill.Machine in the claim is made up of driving and control orthotic device, treadmill and the relief mechanism (reliefmechanism) that can instruct lower limb to be in the physiology of exercise pattern.The theme of European patent No.1586291 is a kind of improved relief mechanism, and it helps support the patient by unloading at least a portion body weight.U.S. Patent No. 6,059,506 and the theme of U.S. Patent No. 6,685,658 be respectively to be used to advance other equipment of treatment.

It is by name to obtain commercially available for example commodity from Ho-coma AG Advance automatically the treatment usefulness equipment.Developed DGO recently Child's model, its can allow from about 4 years old and more than begin to train the child.

According to the present invention, need a dyskinetic concrete aspect of treatment to relate to children cerebral palsy (CP).CP is the modal dyskinesia among the child.Just there are 1.5 to 2.5 cerebral palsy takes place among per 1000 children.CP is the development obstacle of a kind of motion and performance, because due to the young brain that waits to grow impaired (early stage brain injury).Just because of this, CP is a general name, and it has provided by the situation scope due to the early stage brain injury for example, and early stage brain injury may occur in utero, when be born or about being born or 1 year of life.CP used herein also comprises any disease and obstacle that is caused the muscle overacfivity by other reasons.Brain injury may be by due to the multiple situation, for example premature labor.Although causing the brain injury of cerebral palsy is the damage of non-carrying out property, along with patient's growth, its meeting that influences changes to some extent.This may cause the dynamic contracture of muscle, and it be along with the time will be varied to fixed contracture, and can damage or suppress the ability that the patient uses impaired muscle fully.

Except the above-mentioned treatment of mentioning of advancing, the method for selected treatment CP is performed the operation exactly in most of traditionally cases.In recent years, botulinum toxin has been used to treat cerebral palsy as bacteriotoxin.Utilize the general introduction of botulinum toxin treatments CP to be recorded in European patent No.0605501, and " the Europe common recognition table with the botulinum toxin treatments children with cerebral palsy in 2006 " European Journalof Pediatric Neurology 10 (2006), 215-225, and the document of wherein quoting.

In view of the above-mentioned prior art of quoting, the purpose of this invention is to provide the application of dyskinesia alternative treatment method, for example the application of child CP associated movement treating dysfunction method.Further aim of the present invention provides the application of the improvement treatment of these obstacles, relates to individual actions in one embodiment and grows (individual motor development).

A further object of the invention provides a kind of test kit, is designed for the dyskinetic patient of pretreat herein especially.

Summary of the invention

In one embodiment, by with a kind of drug administration patient of containing effective dose chemistry denervation medicine, treat described patient's the dyskinesia, above-mentioned purpose and other purposes have been solved, wherein said patient is the patient that maybe will accept muscle stimulation treatment, and wherein said medicine be before the described muscle stimulation treatment and/or during and/or bestow afterwards.

In another embodiment, be used for bestowing the application of the medicine patient, the described patient moving obstacle of treatment in preparation by the chemical denervation medicine of effective dose, above-mentioned purpose and other purposes have been solved, wherein said patient is the patient that maybe will accept automatic muscle stimulation treatment, and wherein said medicine be before the described muscle stimulation treatment and/or during and/or bestow afterwards.

Described muscle stimulation treatment is automatic muscle stimulation treatment.Described automatic muscle stimulation treatment is that muscle activates treatment, and wherein said muscle activates the quiescent condition that is better than described muscle that is meant muscle metabolism.In another embodiment, described automatic muscle stimulation treatment is the muscular movement treatment.

In one embodiment, described muscle stimulation treatment is automatic exercise therapy.

In further embodiment, described muscle activates and comprises that thermal stimulus, electricity irritation, vibration, sound wave activation, the activation of statics device, electromagnetic wave or magnetic field are activated, pharmacy activates, or the combination of its any way.In one embodiment, described thermal stimulus is with more than 40 ℃, or more than 45 ℃, or more than 50 ℃, rises to 55 ℃, rises to 60 ℃, rises to 70 ℃ or rise to 80 ℃ temperature target muscle is heated.

In another embodiment, it is with below 35 ℃ that the described automatic muscle by thermal stimulus activates, or below 30 ℃, or below 25 ℃, or below 20 ℃, or below 10 ℃, reduce to 0 ℃, reduce to-5 ℃, reduce to-10 ℃ or reduce to-20 ℃ temperature target muscle is cooled off.In another embodiment, described electricity irritation is the target muscle at the domination of exciting nerve.

In another embodiment, described electricity irritation is at stimulating target muscle itself.

In another embodiment, described vibration is directly at whole body.In another embodiment, described vibration is directly at single muscle, muscle group or limbs.In another embodiment, described sound wave is ultrasound wave or audible sound.In another embodiment, described ultrasound wave or audible sound are directly at single muscle, muscle group or limbs.

In another embodiment, described statics device comprises water jet (water-jets).In another embodiment, described water jet is directly at single muscle, muscle group or limbs.

In another embodiment, described electromagnetic wave comprises microwave.In another embodiment, described electromagnetic wave is directly at single muscle, muscle group or limbs.

In another embodiment, described magnetic field comprises that magnetic stimulates.

In further embodiment, described pharmacy activate the material that comprises the material of bestowing analeptic, muscle contraction agent, increasing blood flow in the muscle, the muscular temperature that can raise, can be by allowing the combination of chemical denervation medicine and enter the material that cell raises surface protein quantity, or its any combination.

In one embodiment, described analeptic is selected from by β ₃The group that receptor stimulating agent, caffeine, ephedrine, amfetamine, methamphetamine, methylphenidate, cocaine derivatives and any combination thereof are formed.

In another embodiment, described muscle contraction agent is selected from by the material with sympathesis, has anti-β ₂The material of adrenoceptor effect, caffeine, acetylcholine, nicotine, epibatidine derivant, ABT-594, dimethylphenylpiperazinium, succinylcholine, the group that isolating muscular irritation saponin derivative, calcium, potassium, norepinephrine, epinephrine, leukotriene, the allene that contains arachidonic acid derivatives and any combination thereof are formed from dalbergia saxatilis (Dalbergia).

In another embodiment, describedly can increase that the material of blood flow is selected from by EDHF, a matter K in the muscle ⁺(interstitial K ⁺), nitric oxide, β ₂Adrenoceptor agonists, histamine, prostacyclin, prostaglandin, VIP, extracellular adenosine, effect of extracellular ATP, extracellular ADP, L-arginine, Kallidin I, P material, niacin usp (nicotinic acid), platelet activating factor (PAF), CO ₂, a matter lactic acid, adenosine (Adeno-

), the alpha receptor blocking agent, amyl nitrite, atrial natriuretic peptide, ethanol, the histamine derivant, complement protein C3a, C4a, C5a, the nitric oxide derivant, glyceryl trinitrate (nitroglycerin), isosorbide mononitrate, Dilatrate-SR, pentaerythritol tetranitrate (PETN), sodium nitroprusside, the PED5 inhibitor, increase the preparation of nitric oxide effect indirectly, sldenafil, tadanafil, Vardenafil (tardenafil), tetrahydrocannabinol, theobromine, papaverine, and the group of any combination composition.In another embodiment, the described material that can raise muscular temperature is selected from the group of being made up of Herba Ephedrae, Citrus aurantium Linn. (Neosynephrine), Fructus Capsici, Rhizoma Zingiberis Recens, sibutramine and metabolite, caffeine and any combination thereof.

In another embodiment, the described albumen that shows is selected from the group of being made up of the material that contains rise SV2, GT1b, GD1b, GQ1b, synaptotagmin polypeptide, Syt1 and Syt2.

In another embodiment, the material of described rise surface protein quantity is selected from the group of being made up of blocking-up material, the proteic inhibitor of inhibition G-, competitive receptor antagonist and the neurotransmitter degradation agent of the blocking-up material of hormone, somatomedin, neurotrophic factor, receptor-endocytosis (intemalization), the factor that strengthens the receptor surface expression, Profilin-inhibitor, protease inhibitor, receptor degraded.

In another embodiment, described automatic exercise therapy is supported by automatic gait orthosis or arm pusher (arm mover).

In one embodiment, described automatic gait orthosis and treadmill coupling.

In another embodiment, comprise the equipment that drives and control orthotic device by employing and implement described automatic exercise therapy, described device can instruct described patient's lower limb to be in the physiology of exercise pattern, in one embodiment, the relief mechanism that has adopted treadmill and described patient's body weight is worked.

In another embodiment, relief mechanism comprises the off-loading power that is used to regulate patient's height and acts on patient's weight, wherein said weight is by the cable support, the first cable length adjusting device provides the adjusting of cable length, to limit the height of described weight suspension, the second cable length adjusting device provides the adjusting of cable length, acts on the off-loading power of described weight suspension with qualification.

In another embodiment, wherein the apparatus that is used for treadmill training by application is implemented described automatic exercise therapy, this apparatus comprises treadmill, patient's relief mechanism and driving orthotic device, wherein on treadmill, be provided with an adjustable for height parallelogram, to stablize orthotic device and to prevent that the patient forward, topple over backward and to both sides, this parallelogram is connected on the orthotic device, this orthotic device comprises hip orthotic device and two shank parts, provide two hip drivers with mobile hip orthotic device, provide two knee actuator with mobile shank parts; Hip orthotic device and shank parts all are adjustable, the shank parts scalable size and the position that have running-on that provide; Provide control unit to be used for controlling the speed that moves and control treadmill of orthotic device.

In another embodiment, implement automatic exercise therapy by the dull and stereotyped exercising device of application activity, this apparatus comprises treadmill, the patient's relief mechanism that has handrail and drives orthotic device, wherein provide the equipment that is used for stablizing orthotic device, to prevent that the patient forward, topple over backward and to both sides; This orthotic device comprises hip orthotic device and two shank parts, provides two hip drivers with mobile hip orthotic device, provides two knee actuator with mobile shank parts; Provide ball screw thick stick axle driver (a ball screw spindle drive) to be used for each knee joint driving and hip driving, orthotic device and shank parts all are adjustable, the shank parts scalable size and the position that have running-on that provide; Provide control unit to be used for controlling the speed that moves and control treadmill of orthotic device.

In another embodiment, implement automatic exercise therapy by application be used to the to advance apparatus of treatment, this treatment of advancing is meant the rehabilitation or the rehabilitation of paraparesis or hemiparesis patient bilateral or one-sided spasm situation, described apparatus comprises height and the adjustable vertical table of gradient, the restraint zone that the clamping device that the patient uses is arranged on vertical table, the actuating device that patient's leg exercise is used, it is made up of knee device and foot's device, shank for trochoid, vertical table has interchangeable head, trochoid provides an adjustable hip extension angle whereby, and therefore an adjusting device is provided; Knee and foot be replaceable to be arranged on the handrail of shank device; Knee joint between extensin period foot's device can be used for sole is applied power; Provide control unit to be used for moving of control device.

In another embodiment, by using the equipment that applies power between the first of life entity and the second portion is implemented automatic exercise therapy, described equipment comprises: with first and second coupling assemblings of first and second part correlations connection, each described first and second coupling assembling comprises respectively:

A. fixed support structure on the position of described part, each supporting construction all is support and connection; With

B. be connected the articulated element of each described support and connection by the joint; The described articulated element of wherein said first and second coupling assemblings is connected to each other by trochoid, and the described articulated element of described second assembly extends to described trochoid; Be connected first and second sleeve pipes on the member in described first coupling assembling; Respectively by described first and second sleeve pipes first and second tendons that stretch, in described second coupling assembling, be connected on the member, wherein in second coupling assembling in a side of described trochoid, one of described tendon is connected on the described articulated element, and at the opposite side of described trochoid, another tendon is connected on the described articulated element in described second coupling assembling.

In another embodiment, the equipment that applies power by first and second parts that are applied in hands is implemented automatic exercise therapy, one of described part is a phalanges, and described equipment comprises: with first and second coupling assemblings of first and second part correlations connection, each coupling assembling comprises respectively:

In another embodiment, the dyskinesia is the hyperkinetic and/or hypokinetic dyskinesia, and wherein unbalance between agonist and the antagonist disturbed this function.In another embodiment, the dyskinesia is accompanied by cerebral palsy, M. parkinson, maincenter gait disorder, spinal cord injury, myodystonia, traumatic brain injury, hereditary, metabolism disorder, dynamic muscle contracture and/or apoplexy.In another embodiment, the dyskinesia be selected from strephenopodia, strephexopodia, the lower limb spasm, the upper limb spasm, adductor spasm, the arm dystonia, the hands dystonia, the hip joint flexion contracture, receive in the hip joint, knee sprung spasm (rolling up gait), the ankle sole of the foot is bent, the condyle hypozygal revolve preceding or supination, writers spasm, knot like the musician, knot like the linksman, the shank myodystonia, adduction of the hip joint, abduction of the hip joint, go down on one's knees, knee extends, equinvoarus, the foot myodystonia, the striatum toe, the toe flexing, at least a being correlated with during toe prolongs.

In one embodiment, described patient is the adult.In another embodiment, described patient does not finish its action and grows, and fixedly muscle contracture does not take place.In another embodiment, described patient is to be six years old child at the maximum age.

In another embodiment, by injection administration chemistry denervation medicine, for example botulinum toxin.

In another embodiment, described preparation is bestowed in therapeutic process for several times.

In another embodiment, before beginning, bestows exercise therapy described preparation for the first time.

In another embodiment, bestow described preparation once more 3 to 6 months interval.

In another embodiment, bestow described preparation once more in 2 week to the intervals that are less than 3 months.

In another embodiment, the time point that disturbs automatic muscle to activate treatment in musculation is bestowed described preparation once more.

In one embodiment, chemical denervation medicine is a botulinum toxin.

The effective dose of the botulinum toxin of bestowing in one embodiment, surpasses the 500U of neurotoxicity composition or surpass the 15U/kg body weight in the child in the adult.

In another embodiment, botulinum toxin is the botulinum toxin type A complex.

In another embodiment, botulinum toxin is the neurotoxicity composition in the clostridium botulinum toxin complex.

In another embodiment, botulinum toxin is selected from the group of being made up of serotype A, B, C, D, E, F, G and composition thereof.In another embodiment, the neurotoxicity composition is the A type.

In addition, the present invention relates to a kind of test kit that is used for dyskinesia patient's treatment, it comprises the medicine that contains effective dose chemistry denervation medicine, and the device that is used to carry out muscle stimulation treatment, such as the equipment that is used to carry out automatic exercise therapy.

In one embodiment, the described device that is used to carry out muscle stimulation treatment is selected from by thermal stimulus device, electrical stimulation device, vibrating device, sound wave active device, statics device, electromagnetic wave device and magnetic field device, or combinations thereof group.

In another embodiment, the described device that is used to carry out muscle stimulation treatment is automatic exercise therapy, it comprise drive and the control gait orthosis and/or can instruct under patient's extremity be in the arm pusher of physiology of exercise pattern.

In another embodiment, chemical denervation medicine is a botulinum toxin.

In another embodiment, botulinum toxin is the neurotoxicity composition of clostridium botulinum toxin complex.

The specific embodiment

The chemical denervation medicine that the present invention relates to effective dose is used for bestowing the application of the medicine patient, the described patient moving obstacle of treatment in preparation, wherein said patient accepts arbitrarily automatically muscle stimulation treatment, and wherein said medicine be before the described muscle stimulation treatment and/or during and/or bestow afterwards.

Term " (automatically) muscle stimulation treatment " is defined as the automatic muscular irritation by automatic muscular movement or other modes of passing through herein, can excite any (automatically) method of muscle.

A. the patient organizes

The patient who accepts the treatment of the inventive method and test kit can be animal or natural person.In one embodiment, described patient is the people.In another embodiment, described and desired treatment is at young patient, especially about following the dyskinetic patient of cerebral palsy.At this on the one hand, term " youth " is meant that not finishing its action grows, and does not have to take place the fixedly patient of muscle contracture.In another embodiment, described patient be that not execution grows and move sophisticated, the maximum age is the child in 6-8 year.In another embodiment, the child who receives treatment is six years old at the maximum age.

In another embodiment, described treatment of dyskinesias comprises the symptom of following condition, and CP for example comprises that especially finishing fine movement (such as writing or using shears) has any problem, and keeps balance or the inconvenient symptom of non-autonomic movement.Described symptom varies with each individual, and can change to some extent in time.

In another embodiment, the described dyskinesia is the hyperkinesis and/or the hypokinetic dyskinesia, and wherein agonist and antagonist unbalance disturbed this muscle function.

In one embodiment of the invention, the described dyskinesia comprises muscle spasm.In another embodiment of the invention, described spasm is or is relevant with spasm or the spasm that caused by cerebral palsy after the apoplexy.

" spasm " is defined as increasing to speed-dependency of following exaggerative tendon to twitch the dyskinesias of feature in tetanic stretching reflection (muscular tension), its reason be to stretch hyperexcitability of reflection is the syndromic ingredient of upper motor neuron.In some patients, spasm is useful, because under the situation of hip and KE spasm, can allow body weight to bear a heavy burden, and makes affected limbs play the effect of picture clamping plate.Yet the spasm of Most patients can cause the movable difficulty of daily life, such as wearing the clothes and cleaning the palm of the hands of holding.Below table 1 exemplary provided some spasm situations, comprise the dyskinesia that the present invention will treat:

Table 1 spasm situation (optional)

Term " spasm after the apoplexy " is meant the spasm that occurs in after the apoplexy incident.Apoplexy is the reason that causes long term disability, and spasm (Watkins CL, Leathley MJ can take place 19% to 38% patient, Gregson JM, Moore AP, Smith TL, Sharma AK, Prevalenceof spasticity post stroke, Clin Rehabil 2002; 16 (5): 515-522. (ID1915001)).

Cerebral palsy is the term (umbrella-like term) of a umbrella, is used for describing one group of impaired chronic disease of motor control, and it occurs in 1 year of life, and generally can As time goes on not become even worse.This disease is to be caused by the ability that brain controlled motion and posture have been interrupted in the damage of defective growth or brain motor region.

As far as we know, cerebral palsy is irremediable, and promptly this damage to brain can not be eliminated.Yet our purpose is the symptom of some cerebral palsy of treatment, and especially those are about dyskinetic symptom.These symptoms be by the muscle ability unusual or disturbed due to, unusual or be subjected to interferential muscle ability can stop affected loosening all muscles.What " cerebral palsy " described is the generalized cone dysfunction that causes paresis, causes the extrapyramidal system dysfunction of dystonia, tetanic, spasm and tic, akinesia and coordination function obstacle.Cerebral palsy (Koman LA ₁Mooney JF, Smith BP, Goodman A, Mulvaney T.Management ofspasticity in cerebral palsy with botulinum-A toxin:report of apreliminary, randomized, double-blind trial, J Pediatr Orthop 1994; 14 (3): 299-303. (ID 1767458); Pidcock FS, The emerging role of therapeuticbotulinum toxin in the treatment of cerebral palsy, J Pediatry 2004; 145 (2Suppl): S33-S35. (ID 2994781)) may occur in cerebral hemorrhage, suffocate, after premature infant's birth or other perinatal stage complication.It is a kind of lifelong situation that causes asynergic movement, paresis and various forms muscle function hyperfunction.The patient who influenced by cerebral palsy when treating according to method disclosed by the invention, needs carry out functional improvement training to hyperfunction muscle.Yet, in the present invention improves the scope of musculation of muscle, also can not be subjected to the influence of spasm.This also comprises the coordination between the different muscle groups.Term " muscle group " not only comprises adjacent muscle, also comprises the muscle of different body parts.

According to instruction of the present invention, the dyskinesia relevant in corresponding muscle group with spasm, or the dyskinetic common Clinical types relevant with cerebral palsy treat by method of the present invention, promptly advances/exercise therapy and bestow the botulinum toxin coupling.

Preferably, treated and cerebral palsy, M. parkinson, the maincenter gait disorder, spinal cord injury, myodystonia, traumatic brain injury, hereditary, metabolism disorder, the dyskinesia that dynamic muscle contracture and/or apoplexy are relevant, for example, the dyskinesia be selected from strephenopodia, strephexopodia, the lower limb spasm, the upper limb spasm, adductor spasm, the hip joint flexion contracture, receive in the hip joint, knee sprung spasm (rolling up gait), the ankle sole of the foot is bent, the condyle hypozygal revolve preceding or supination, writers spasm, knot like the musician, knot like the linksman, the shank myodystonia, adduction of the hip joint, abduction of the hip joint, go down on one's knees, knee extends, equinvoarus, the foot myodystonia, the striatum toe, the toe flexing, at least a being correlated with during toe prolongs.

B. muscle stimulation treatment

In described embodiment, can use to produce stimulation, for example activate described any device of target muscle.

Term " muscle activation " is meant any treatment to muscle or muscle group, can increase the metabolism of this muscle or muscle group, the average metaboilic level when making it be better than identical muscle tranquillization.In order to estimate muscle metabolism, those skilled in the art can for example measure the output of ATP in the muscle, the activity of creatine kinase, inversion rate of glucose and/or fatty conversion ratio.Can also use indirect method, for example rising of muscular temperature, the rising of blood flow or measurement muscle volume.Yet this need be tested by those skilled in the art's application activating according to the accessibility of the activated form of muscle, muscle and disease to be treated.Term " muscle activation " also comprises the activation of motor neuron, and promptly the presynaptic is carried the raising of the ability of chemical denervation medicine.Surface protein-for example chemical denervation medicine can bonded receptor-quantity rising, can make this activation highly significant.The embodiment of this surface protein can be for example SV2 albumen (all hypotypes are such as A, B or C), polysialoganglioside (for example GT1b, GD1b, GQ1b) or synapsin in conjunction with polypeptide (for example Syt1 or Syt2).Those skilled in the art are very clear, and different chemical denervation medicines can be in conjunction with different surface proteins.For example think that botulinum toxin type A combines with all SV2-hypotypes, and think that botulinum toxin B and G combine with syt1 and syt2.Can adopt for example biopsy and follow-up antibody or the raising of the mRNA level by the encoding said proteins rising of measuring surperficial protein expression to described protein staining.

Term " muscle activates automatically " is meant the process that activates muscle with technical equipment.Usually, this muscle activates and does not require the muscular movement that the patient enlivens, but requires to activate the less muscle that enlivens by described technical equipment.

Term " is used to activate the device of muscle " and is meant any device that is suitable for activating muscle, as disclosed device below this paper.Therefore " device " comprises a kind of technical equipment, and the physical stimulation of a kind of preparation or a kind of muscle is for example by massage, temperature, electricity irritation, electromagnetic wave, sound wave, vibration etc.

Hereinafter summarized the certain methods of stimulated muscle, but be not used for limiting the scope of the invention.

B.1 thermal stimulus activates

Can change temperature conditions and activate muscle by way of expectations.Known low temperature can cause little contraction of muscle, to keep body temperature in certain scope.On the other hand, elevated temperature can cause vasodilation, can better supply oxygen and nutrient for muscle, therefore also can make muscle more active.Usually, can regulate the temperature of muscle by any device that can heat and/or cool off muscle.

In one embodiment, by infrared light muscle is heated.Employing can be sent the normal bulb of IR-A-light (wavelength is between 700nm-1400nm), and warm local organization and blood flow increasing and loosen stimulate and activate muscle.

In another embodiment, by using water-bath to be easy to cooling and heating muscle.In another embodiment, use steam to heat or cooled target muscle.

In another embodiment, by skin surface being bestowed the effect that chemicals is strengthened heating and cooling, therefore allow faster and more concentrated target muscle is cooled off or heats.Being used for refrigerative feasible chemicals for example can be that skin is produced those chemicalses (the ice spray or the cooling gel of for example ethyl chloride spraying, ethanol) that strengthen evaporation.The feasible chemicals that is used to heat for example can be the chemicals (for example capsaicin (Capsicain), capsaicin (Nonivamid) etc.) that skin is produced blood flow increasing and/or hotness

In another embodiment, help heating and/or cooling muscle by compression or " heat-parcel " or " cold-parcel " (" heating-" or " cooling-packs "), promptly heat from the outside or coolant, and in certain period, can keep stable temperature (for example sludge parcel (fango-packs), constant temperature (temperature)), the perhaps hot and cold (for example neither endothermic nor exothermic reaction) that produces by chemicals or physical reactions.

In another embodiment, temperature levels can periodic transformation between the temperature of cold-peace heat.Usually, herein " heating " be defined as the temperature that makes muscle and raise more than 40 ℃, or more than 45 ℃, or more than 50 ℃, rise to 55 ℃, rise to 60 ℃, rise to 70 ℃ or rise to 80 ℃.On the other hand, herein " cooling " of muscle be defined as and reduce below the temperature to 35 ℃, below 30 ℃, below 25 ℃, below 20 ℃, below 10 ℃, reduce to 0 ℃, reduce to-10 ℃ or reduce to-20 ℃.Decide which kind of hot and cold to have Application feasibility according to the size of the sensitivity of individual patients, muscle and the time of using.

B.2 electricity irritation activates

Within the scope of the invention, can use can electricity irritation muscle any method, device.Hereinafter more specifically narrated some embodiment:

In one embodiment, function of use electricity irritation (being abbreviated as FES usually) can be easy to activate muscle.This is a kind of technology of using electric current to activate innerv extremity, is used to recover disabled's function, and above-mentioned extremity are subjected to the influence of the paralysis that caused by spinal cord injury (SCI), head injury, apoplexy or other nervous system disease.

Usually can use two kinds of functional electric stimulation approach:

-excite nerve in one embodiment.In this case, gradient strengthens electric field intensity to being enough to produce action potential in target nervus motorius (targeted motoric nerve).

-direct in another embodiment stimulated muscle.Compare with the activation that produces muscle of exciting nerve, this situation needs strong and long stimulation electric wave.

In both cases, can stimulate (for example under the situation of chronic spasm) by the electrode of surface electrode or implantation.Can adopt suitable emulsifiable paste to increase conductivity from the electrode to skin.Electrode in the determining positions of skin stimulate which N﹠M.

In another embodiment,, electricity irritation is become be easy to, more commonly refer to TENS by adopting Percutaneou transcutaneous electrical nerve analeptic.This is a kind of electric equipment, can produce the signal of telecommunication by continual skin and be used to excite nerve.This unit can adopt two or more electrodes to be connected on the skin.A kind of typical battery powered TENS unit by pulse generator, small transformers, frequency and intensity controller, and a plurality of electrodes form.Electrode is connected on the receptor of implantation, and this receptor is accepted power from the antenna that is installed in skin surface.The application of this implantation equipment for the patient of chronic spasm of great use.

In another embodiment, stimulate, electricity irritation is become be easy to by high-frequency muscle.Can use 4 to about 30kHz (thousand-Hz) high-frequency ac electric fields.In addition, the frequency of these two kinds of intensity and electric current is adjustable.This has caused the effect of stimulation to neural and adjacent muscle.

In another embodiment, by interventional therapy (being also referred to as the NEMEC treatment), electricity irritation being become be easy to.In this case, use the electric current of intermediate frequency, it can be at the internal interference target tissue, and be considered to can be to muscle and the neural endogenous stimulus that produces.

B.3 vibration activates

According to the present invention, can pass through whole body or local excitation muscle, promptly stimulate single muscle or muscle group.

In one embodiment, import intravital technical equipment and can make muscle activate to become to be easy to by vibrating.

In one embodiment, adopt whole body vibration (WBV).WBV makes the people place vibration by foot, buttocks and/or back.(in WBV, whole health all places vibration for biomechanics stimulation, BMS) difference, stimulates independent muscle or muscle group by using vibratory equipment with local vibration.The conduct vibrations that engine produces is to standing in, be sitting in or lying on the person of machine.The intensity of these vibrations and direction are very important to their result.One skilled in the art will appreciate that he will regulate the intensity and the direction of vibration according to muscle to be treated.

In order to make muscle produce stretch reflex, it is most important moving up and down.Because gravitational effect, human body is easier to absorb vertical vibration.Yet many mechanical vibration are in three different directions: side (x), preceding and back (y), and upper and lower (z) can cause serious adverse like this after long-time the use.The z-axle has maximum amplitude, and can define the component that produces and guide muscle contraction.Move about z-, need to distinguish the principle type of two systems: one is the direction alternate system as seesaw (see-saw) operation, so apish gait, promptly always a foot moves forward, and the another foot moves backward, another is the system that whole platform is mainly done same movement, and two feet are all distinguished simultaneously motion up or down.System with direction alternate functions provides the frequency range of a bigger vibration amplitude and about 5Hz to 35Hz, and another system provides lower amplitude, but the lower frequency range of 20Hz to 50Hz is provided.Although the direction alternate system has bigger amplitude, the vibration (acceleration) that is transmitted to head significantly is lower than non-direction alternate system.

Mechanical stimulus has produced acceleration to health, can think that these power cause the muscle lengthening, and this signal is received by an organella in the muscle-muscle-spindle.This muscle-spindle passes to related muscles by the central nervous system with signal.Compare with conscious, voluntary motion, because this subconscious contraction of muscle makes more meat fiber participate in motion.

In another embodiment, vibratory equipment can be for example hands-arm vibration (HAV), wherein vibrates by limbs and shifts, be i.e. hands and arm or foot and lower limb.In another embodiment, by the very little muscle of local vibration device activation, the muscle of face for example promptly stimulates the small size muscle of several centimetres of diameters.

Typically, produce muscular irritation 8 to 45Hz the time.

With three groups of vibrations is example:

-below 10-12Hz, activate Semen Pisi sativi (postular) stabilitrak, therefore activated the muscle of Semen Pisi sativi (postular) system.

-between 12Hz to 20Hz, activate to be reflected into basic system (by muscle-spindle and spinal cord feedback).This makes and forms contraction and loosen circulation in muscle.

-when being higher than 20Hz, the time of loosening all muscles is too short, and therefore the contraction of muscle will increase during treating.Only have the only a few case to be fit to frequency and be increased to more than the 40Hz, normal range be 20 to 30Hz, 20 to 35Hz.

B.4 sound wave activates

In one embodiment, adopting sound wave can be easy to carry out muscle activates.

In one embodiment, described sound wave is therapeutic ultrasound (scope is 20kHz to 10GHz).

In one embodiment, employed therapeutic ultrasound is between 1 to 3MHz.Under this frequency, the ripple trend is passed and is contained high moisture content or low proteic tissue, by cartilage and bone reflex.Their main connected tissues absorb: ligament, tendon and fascia (can also be absorbed by scar tissue).In this embodiment, as if therapeutic ultrasound has two types benefit.

-the heat effect that contains the energy that absorbs from sound wave can heat target tissue, and causes its activation.

-can cause forming the microcosmic bubble by the cavitation effect (Cavitational effects) of organizing vibration to form, can be with mode conduction vibration at the stimulated muscle cell membrane, this also can cause the activation of muscle.

Use HIFU (high intensity focused ultrasound) (using FUS or HIFUS sometimes) in another embodiment.In HIFU, use height-intensity focus supersonic to come the Fast Heating tissue.Although use it for destroy pathogenic tissue usually, it can also be used for Fast Heating muscle (not destroying muscle) with low-intensity, therefore activates described muscle.In case of necessity, can instruct this activation by computer MRI.In these situations, it is called as the magnetic guiding concentration ultrasonic that shakes, and often is abbreviated as MRgFUS.

In another embodiment, the sound wave of application is an audible sound, and for example frequency is between 20Hz to 20000Hz.In this frequency range, with the effect guiding muscular movement of acoustical vibration.

In one embodiment, standing wave (being also referred to as set wave) is used to guide the cell movement of meat fiber.This phenomenon is seemingly because medium (muscle, tissue-body fluid etc.) moves and takes place to the direction opposite with sound wave.This activation also is interferential result between two ripples of propagating in the opposite direction.According to the length of target muscle and size can adjusting sound intensity and frequency.

In another embodiment, use ultrasonic equipment, not only be used to activate muscle, and the entry needle that can also will contain chemical denervation medicine guides to application site with assisting.In this embodiment, the application of chemical denervation medicine can be divided into three steps:

-differentiate muscle spasm by normal ultrasonic image technology.

-application focus supersonic activates the muscle at spasm position.

-by normal ultrasonic image technology, the pin that will contain injection chemistry denervation medicine guides to through the position of discriminating, for example is with or without spasm or Fibrotic muscle.

B.5 the statics device activates

In one embodiment, adopting the statics device can make muscle activate to become is easy to.In one embodiment, described statics device is to be used for the activated water jet of muscle.In another embodiment, described machinery be pressure current massage under water (Unterwasserdruckstrahlmassage, UWM).In this embodiment, use the special bathtub be connected to pump, described pump can be by circulate water in the bathtub of water pipe.Therefore, the jet temperature is identical with the temperature of water in the bathtub.Yet by the pump unit, additional water can add in the steam to change the effusive temperature of massage.The common applied pressure of pump is 0.5 to 3bar, and this can use different massage technique according to the diameter of institute's water pipe and the type of nozzle.Consider the adjusting to target muscle, the diameter of effusive intensity and/or water pipe and nozzle also can be regulated.

B.6 electromagnetic wave or magnetic field are activated

In one embodiment, can make muscle activate to become by electromagnetic wave is easy to.

In one embodiment, use low intensive microwave that heat is introduced in the muscle, therefore activate muscle.Microwave is a wavelength less than one meter and greater than one millimeter electromagnetic wave, or frequency is between 300 megahertz to 3 gigahertzs.

In another embodiment, muscular irritation is become be easy to by repeating the magnetic muscular irritation (for example, with reference to Swallow etc., J.Appl.Physio1.2007; 103:739-746).In this embodiment, use a kind of large-scale, oval coil flexibly, can be safely around the front of thigh.This coil is the overheated to prevent of liquid cools.In magnetic stimulated, the current impulse by the flowing through coil line produced fast-changing magnetic field.Magnetic field produces electric current in vivo successively, and this depolarization aixs cylinder is in an identical manner as a kind of electricity irritation.The advantage of this method is that electric current does not need by higher relatively skin resistance, so do not activate the sensor in the skin when adopting magnetic to stimulate.In order to stimulate quadriceps femoris, the intensity of for example using 30Hz just is enough to produce 30% maximum tic power, and the pattern of shrinking and loosening in 3 seconds in 2 seconds.

In another embodiment, use transcranial magnetic stimulation (TMS) to activate target muscle.TMS is a kind of method of non-invasive stimulation cerebral neuron: introduce weak current by quick change magnetic field (electromagnetically induced) in tissue.For example at the muscular movement center of brain, this mode activates relevant muscle with the activity of minimum discomfort triggering brain.In another embodiment, multiple transcranial magnetic stimulation, as if just rTMS can produce long sustained activation to muscle, therefore more feasible concerning specific patient's situation.

B.7 medicine muscle stimulation treatment

In another embodiment, can also activate by the muscle drug application being reached above-mentioned muscle.Described " muscle activation medicine " be can set up muscle as defined among the following C " muscle active " state.It can be any material of active state with the condition changing of described muscle that term herein " medicine " is defined as.

In one embodiment, described muscle activation medicine is an analeptic.Term " analeptic " is defined as any material, especially temporarily causes or quickens physiology or organic active chemicals, for example β ₃Receptor stimulating agent, caffeine, ephedrine (for example Herba Ephedrae), amfetamine, methamphetamine, methylphenidate and/or cocaine derivatives.

In another embodiment, described muscle activation medicine is the muscle contraction agent.Term herein " muscle contraction agent " is defined as any material that can cause muscle contraction, for example have sympathesis any material, have β ₂Any material of adrenoceptor antagonistic effect, caffeine, acetylcholine, nicotine, epibatidine derivant (for example ABT-594), dimethylphenylpiperazinium, succinylcholine, muscular irritation saponin derivative (for example isolating from Dalbergia saxatilis (Dalbergia)), with reference to C.N.Uchendu ^a' And B.F.Leek ^bFitoterapia Volume 70, Issue 1, and 1February 1999, Pages50-53, calcium, potassium, norepinephrine, epinephrine, leukotriene, contain the allene of arachidonic acid derivatives.

In further embodiment, it is the material that can increase blood flow in the muscle that described muscle activates medicine, for example EDHF, a matter K ⁺(interstitial K ⁺), nitric oxide, β ₂Adrenoceptor agonists, histamine, prostacyclin, prostaglandin, VIP, (extracellular) adenosine, (extracellular) ATP, (extracellular) ADP, L-arginine, Kallidin I, P material, niacin usp (nicotinic acid), platelet activating factor (PAF), CO ₂, a matter lactic acid (interstitiallactic acid), adenosine (Adeno-

), alpha receptor blocking agent, amyl nitrite, atrial natriuretic peptide, ethanol, histamine derivant (for example complement protein C3a, C4a and C5a), nitric oxide derivant (for example glyceryl trinitrate (being generally nitroglycerin)), isosorbide mononitrate, Dilatrate-SR, pentaerythritol tetranitrate (PETN), sodium nitroprusside, PED5 inhibitor, increase the preparation (sldenafil for example of nitric oxide effect indirectly

Tadanafil, Vardenafil (tardenafil)), tetrahydrocannabinol, theobromine and/or papaverine.

In another embodiment, it is the material (promptly by increasing core temperature) that can directly or indirectly increase muscular temperature that described muscle activates medicine, promptly plays the material of themogenesis in the patient.The example of these materials has Herba Ephedrae, Citrus aurantium Linn. (Neosynephrine), Fructus Capsici, Rhizoma Zingiberis Recens, sibutramine and metabolite and/or caffeine.

In another embodiment, it is the material (for example receptor) that can raise surface protein quantity that described muscle activates medicine, thereby allows chemical denervation medicine to combine and enter cell, presynaptic cell typically with cell.In one embodiment, the SV2 albumen of described material rise muscle weakens presynaptic neuron.In another embodiment, raise polysialoganglioside (for example GT1b, GD1b, GQ1b) or synapsin in conjunction with polypeptide (for example Syt1 or Syt2).The example of these materials has blocking-up material, the proteic inhibitor of inhibition G-, competitive receptor antagonist and the neurotransmitter degradation agent of the blocking-up material of hormone, somatomedin, neurotrophic factor, receptor-endocytosis (intemalization), the factor that strengthens the receptor surface expression, Profilin-inhibitor, protease inhibitor, receptor degraded.

B.8 automatic exercise therapy

In one embodiment, the part of described treatment is alleged automatic exercise therapy.Term " exercise therapy " is meant the treatment of any kind of, wherein trains the patient to move its extremity in " normally " mode, i.e. physiological movement or an action sequence.The treatment of upper limb and lower limb should be included in the scope of term " exercise therapy ".Term " exercise therapy automatically " is meant the exercise therapy of any kind of, and wherein by automatic (driving) orthopedic equipment, the training patient uses its muscle in " normally " mode, promptly physiological action (sequence).A part-exercise therapy of the present invention includes but not limited to the selection campaign of upper limb and lower limb and/or its part, such as arm and lower limb and shoulder, elbow, wrist, hands, finger, thumb, knee joint, foot and toe joint in many ways, independently or be included in motion in the kinematic chain.

Usually, the equipment that uses in the inventive method and test kit comprises driving and control orthotic device, and this device can instruct extremity, and for example patient's lower limb and arm are in the physiology of exercise pattern.Preferably, this equipment is supported by automatic gait orthosis or arm pusher.

For the in-problem patient of leg exercise, preferably, described equipment comprises automatic gait orthosis, more preferably combines with treadmill.Automatically the relevant device of motion (advancing) treatment all is commercially available, Hocoma AG company for example, and commodity are by name Equipment.This equipment based on treadmill treatment is specified in U.S. Patent No. 6,821,233 and the prior art of this paper in, all be incorporated into herein by reference.

Therefore, can comprise by employing and driving and control orthotic device, treadmill, the equipment that preferably also comprises relief mechanism are implemented described automatic exercise therapy, wherein said driving and control orthotic device can instruct described patient's lower limb to be in the physiology of exercise pattern, and described relief mechanism can work to described patient's body weight.Preferably, described equipment is used to train the gait motion obstacle.

Preferably, in the scope of this paper method, by U.S. Patent No. 6,821,233 described use equipment.Equipment is the apparatus that is used for treadmill training, comprise treadmill, patient's relief mechanism and drive orthotic device, wherein on treadmill, be provided with an adjustable for height parallelogram, to stablize orthotic device and to prevent the patient forward, topple over backward and to both sides, this parallelogram is connected on the orthotic device.Preferably, this orthotic device comprises hip orthotic device and two shank parts, provides two hip drivers with mobile hip orthotic device, provides two knee actuator with mobile shank parts; Hip orthotic device and shank parts all are adjustable, the shank parts scalable size and the position that have running-on that provide; Provide control unit to be used for controlling the speed that moves and control treadmill of orthotic device.

Alternatively, another kind of equipment is the apparatus that is used for treadmill training, comprises the treadmill that has handrail, patient's relief mechanism and drives orthotic device, and the measure that is used for stablizing orthotic device wherein is provided, to prevent that the patient forward, topple over backward and to both sides.Preferably, this orthotic device comprises hip orthotic device and two shank parts, provides two hip drivers with mobile hip orthotic device, provides two knee actuator with mobile shank parts; Provide ball screw thick stick axle driver (a ball screw spindle drive) to be used for each knee joint driving and hip driving, orthotic device and shank parts all are adjustable, the shank parts scalable size and the position that have running-on that provide; Provide control unit to be used for controlling the speed that moves and control treadmill of orthotic device.Above-mentioned these two kinds of equipment are all in U.S. Patent No. 6,821, are described in detail in 233.

In these equipment, provide off-loading power by roller bearing of connection on basic framework, the live wire cable passes through on roller bearing, be connected near the bearing, the opposite side that utilizes a counterweight (counterweight) to be loaded into parallelogram (is seen U.S. Patent No. 6, Fig. 1 of 821,233).The theme of European patent No.1 586 291 A1 is a kind of improved equipment, and the off-loading power that is used to regulate patient's height and acts on patient's weight also is incorporated into herein by reference.The equipment that is used to regulate patient's height and acts on the off-loading power of patient's weight, it is characterized in that described weight is by the cable support, the first cable length adjusting device provides the adjusting of cable length, to limit the height of described weight suspension, the second cable length adjusting device provides the adjusting of cable length, acts on the off-loading power of described weight suspension with qualification.

In the further embodiment of the present invention, implement automatic exercise therapy by application be used to the to advance apparatus of treatment, this treatment of advancing is meant paraparesis or hemiparesis patient's rehabilitation, described apparatus comprises height and the adjustable vertical table of gradient, the restraint zone that the clamping device that the patient uses is arranged on vertical table, the actuating device that patient's leg exercise is used, it is made up of knee device and foot's device, shank for trochoid, vertical table has interchangeable head, trochoid provides an adjustable hip extension angle whereby, and therefore an adjusting device is provided.Preferably, on the replaceable handrail that is arranged on the shank device of knee and foot.Preferably, knee joint between extensin period foot's device can be used for sole is applied power.Preferably, provide control unit to be used for moving of control device.Further detail and operational approach thereof about described apparatus can be with reference to U.S. Patent No.s 6,685,658, and it is incorporated into herein by quoting in full.

In another embodiment of the invention, by using the equipment that applies power between the first of life entity and the second portion is implemented automatic exercise therapy, described equipment comprises: respectively with first and second coupling assemblings of first and second part correlations connection, each described first and second coupling assembling comprises: (a) fixed support structure on the position of described part, each supporting construction all are support and connection; (b) be connected the articulated element of each described support and connection by the joint; The described articulated element of wherein said first and second coupling assemblings is connected to each other by trochoid, and the described articulated element of described second assembly extends to described trochoid; Be connected first and second sleeve pipes on the member in described first coupling assembling; Respectively by described first and second sleeve pipes first and second tendons that stretch, in described second coupling assembling, be connected on the member, wherein in second coupling assembling in a side of described trochoid, one of described tendon is connected on the described articulated element, and at the opposite side of described trochoid, another tendon is connected on the described articulated element in described second coupling assembling.

Perhaps, the equipment that applies power by first and second parts at hands is implemented automatic exercise therapy, one of described part is a phalanges, described equipment comprises: respectively with first and second coupling assemblings of first and second part correlations connection, each coupling assembling preferably includes: (a) fixed support structure on the position of described part, each supporting construction all are support and connection; (b) be connected the articulated element of each described support and connection by the joint; The described articulated element of wherein said first and second coupling assemblings is connected to each other by trochoid, and the described articulated element of described second assembly extends to described trochoid; Be connected first and second sleeve pipes on the member in described first coupling assembling; Respectively by described first and second sleeve pipes first and second tendons that stretch, in described second coupling assembling, be connected on the member, wherein in second coupling assembling in a side of described trochoid, one of described tendon is connected on the described articulated element, and at the opposite side of described trochoid, another tendon is connected on the described articulated element in described second coupling assembling.Come from US 6,059,506 about the further detailed content of this equipment, be incorporated into herein by quoting in full.

Within the scope of the present invention, can adopt the device of any other commercially available acquisition or any that in academic institution, develop and be applicable to the equipment of automatic exercise therapy.In this respect, can relate to " MIT-Manus " device, " Mirror-Image Motion Enabler " (MIME) robot, " ARM guide ", the training aids of " Bi-Manu-Track " arm, GTI and dynamo-electric gait training device, and NeRobot and REHAROB equipment.Come from Hesse S about the more details of these equipment, Schmidt H, Werner C, Bardeleben A. (2003), the upper and lower extremities robot device, Curr Opin Neurol 16:705-710 and the document of quoting thereof that are used for rehabilitation and research Electric Machine Control.

More preferably, adopt equipment from the commercial acquisition of Hocoma AG company, especially those when the application submits to trade mark

With

The equipment of selling.

B.9 the activated combination of muscle

To those skilled in the art, the special requirement according to the patient is conspicuous with the above-mentioned muscle active device coupling of mentioning.For example statics activates to activate with muscular temperature and combines, and electric activation can activate with medicine and combine, and magnetic activates to activate with muscular movement and combines, or the like.

In addition, interval that can be different uses the muscle active device, for example at 1 to 100 millisecond, 100 milliseconds to 1 second, 1 second to 5 seconds, 5 seconds to 30 seconds, 30 seconds to 1 minute, 1 minute to 10 minutes, 10 minutes to 30 minutes, 30 minutes to 1 hour, 1 hour to 12 hours, 12 hours to 1 day, by 10 days, by 1 month, by 1 year.These intervals only as the usefulness of example, therefore, also comprise any time interval in the meantime.

C. bestowing of chemical denervation medicine

As mentioned above, according to the present invention, with muscular irritation, for example exercise therapy or automatic muscle activate treatment and the chemical denervation medicine coupling of bestowing patient's effective dose automatically, in one embodiment, the botulinum toxin that chemical denervation medicine for example exists with pharmaceutical composition/medicament forms is bestowed described patient, wherein in muscular irritation, for example motion or activate before the treatment and/or during the treatment and/or after the treatment and bestow.

D.1 chemical denervation medicine

In one embodiment, chemical denervation medicine is a clostridial neurotoxins, and in another embodiment, this clostridial neurotoxins is the botulinum toxin of the different serotype A of antigen, B, C, D, E, F or G.In any place of mentioning botulinum toxin serotype A, B, C, D, E, F or G, the variant that also comprises known serotype, for example serotype A 1, A2, A3, B1, B2, B3, C1, C2, C3, D1, D2, D3, E1, E2, E3, F1, F2, F3 or G1, G2, G3.In one embodiment, botulinum toxin is a botulinum toxin type A.

In another embodiment, also comprise hypotype, homologue, direct congener and the indirect congener of botulinum toxin, its demonstration has 50% at least, has 60% at least, has 70% at least, has 80% at least, has 90% or 100% sequence homogeneity at least.Can use any suitable algorithm sequence of calculation homogeneity to obtain reliable result.For example use fasta algorithm (W.R.Pearson ﹠amp; D.J.Lipman PNAS (1988) 85:2444-2448).

When botulinum toxin is disengaged from dissolved clostridium culture fluid, usually and other bacterioproteins interrelated, form toxin complex jointly.Described in another embodiment botulinum toxin does not contain any compound protein, and for example, it is pure neurotoxin serotype A.Comprise separately in addition suddenly change, the neurotoxicity composition of botulinum toxin that modification such as disappearance and reorganization prepare also within the scope of the invention.As for suitable mutant, can consult WO 2006/027207A1, WO 2006/114308A1 and EP07014785.5 (by the patent application of Merz) in 27 submissions July in 2007, these documents are incorporated into herein by quoting in full all.Can adopt the mixture (neurotoxicity composition or recombinant forms or its mixed form, for example mixture of A type and botulinum toxin type B) of different serotypes in addition in the present invention.Yet, the invention still further relates to through chemical modification, for example the aminoacid that exposes of neurotoxin, especially one or more surfaces or the solvent by Pegylation (peylation), glycosylation, sulphation, phosphorylation or any other modification.

The term that the present invention uses in the whole text " botulinum toxin " or " botulinum toxin class " refer to and do not contain the proteic neurotoxicity composition of any other clostridium, also refer to " botulinum toxin complex ": when indifference XOR neurotoxicity composition between the complex be necessary or the situation of needs under use term " botulinum toxin ", " BoNT " or " NT " is the abbreviation of using always.Complex comprises other what is called " nontoxic " albumen usually, and we are referred to as it " compound protein " or " bacterioprotein ".

The complex of neurotoxicity composition and bacterioprotein is called as " clostridium botulinum toxin complex " or " botulinum toxin complex ".The molecular weight of this complex may be different, and from 300,000 to 900,000Da does not wait.Compound protein is, for example, and various hemagglutinins.The albumen of this toxin complex itself does not have toxicity, but can keep the stability of nerve component by gastrointestinal tract the time.Based on the commercially available acquisition of medicine of A, B and C BOTULINUM TOXIN TYPE A A complex, (trade mark is botulinum toxin type A available from lpsen

) and Allergan Inc. (trade mark is

).

In the present invention, the neurotoxin subunit of described complex is called as botulinum toxin complex " neurotoxicity composition ".The neurotoxicity composition of botulinum toxin complex begins to take shape and is single polypeptide chain, and under the situation of serotype A, molecular weight is about 150kDa.In another kind of serotype,, observe the neurotoxicity composition and between about 145kDa and about 170kDa, change according to the difference of bacterial origin.

Under the situation of serotype A, for example, the processing of the proteolysis of polypeptide produces activated polypeptides, and this polypeptide is double-stranded, is made up of a heavy chain and a light chain, connects by disulfide bond.In human body, heavy chain mediation be attached to the presynaptic cholinergic nerve cell terminal and with the toxin endocytosis to cell.It is relevant with toxic action that light chain is considered to, play zinc-endopeptidase and cutting and be responsible for film fused specificity albumen (SNARE complex) (referring to for example MontecuccoC1 Shiavo G., Rosetto O:The mechanism of action of tetanus andbotulinum neurotoxins, Arch Toxicol.1996; 18 (Suppl.): 342-354).

By destroying intracellular film fusion process, botulinum toxin stops acetylcholine to discharge into synaptic space.Botulinum toxin is to interrupt the neuromuscular transmission, and actually, makes the muscle denervation total effect of neuromuscular intersection.Botulinum toxin also has activity to other peripheral cholinergic nerve synapses, causes sialorrhea or the minimizing of perspiring.

Every kind of serotype of botulinum toxin combines with the serotype specificity acceptor site at the pre-synapse teleneuron.Botulinum toxin is based on heavy chain to the specificity of cholinergic neuron the high-affinity of the acceptor site of these teleneurons (is consulted: Katsekas S., Gremminloh G., Pich E.M.:Nerve terminal proteins; To fuse to learn.Transneuro Science 1994; 17:368-379).

Term " neurotoxicity composition " is also included within the functional homologue of finding in other serotypes of bacillus botulinus.In one embodiment, the neurotoxicity composition does not contain any other bacillus botulinus albumen, does not also contain RNA in one embodiment, and this may have potential relation with the neurotoxicity composition.The neurotoxicity composition may be strand precursor protein or the finished neurotoxicity composition of proteolysis of about 150kDa, comprises light chain (L _c) about 50kDa and the about 100kDa of heavy chain, may be to connect by one or more disulfide bond (to see also for example Simpson LL, Ann Rev Pharmacol Toxicol.2004; 44:167-93).

In the present invention, can use the botulinum toxin of form of ownership, particularly various serotypes, the various complex of the neurotoxicity composition in the botulinum toxin and the compound neurotoxicity composition of following albumen and these botulinum toxins thereof.In addition, comprise because of suddenly change separately, botulinum toxin that modification such as disappearance and/or reorganization prepare or the neurotoxicity composition of botulinum toxin, these also belong to scope of the present invention.About suitable mutant, can consult WO 2006/027207A1, it is incorporated into herein by quoting in full.In addition, in the present invention, can use each serotype mixture (composite form, neurotoxicity composition and/or recombinant forms), as: the mixture of the mixture of A type and botulinum toxin type B or A type and Type B botulinum neurotoxin.

According to instruction of the present invention, medicine can not contain the albumen of finding from the botulinum toxin complex, except the neurotoxicity composition.The precursor of neurotoxicity composition is cut into heavy chain and light chain.As other are pointed Anywhere in the present invention, polypeptide can be that wild-type sequence maybe can be modified one or more residues.Modification comprises chemical modification, for example by glycosylation, and acetylation, acidylate or the like, this may be useful to stablizing of for example picked-up or polypeptide.Yet the polypeptide chain of neurotoxicity composition can be by increasing, substitute or lacking that one or more amino acid residues carry out optionally or other modifications.

D.2 pharmaceutical composition

D.2.1 neurotoxicity composition

The above-mentioned neurotoxicity composition of mentioning of the present invention can be compositions or part of pharmaceutical compositions.Pharmaceutical composition used in the present invention can comprise botulinum toxin; for example; the active constituents of medicine that maybe can comprise other with the neurotoxicity composition as unique active component; for example hyaluronic acid or polyethylene or Polyethylene Glycol; said composition can be by the stable any pH value of suitable pH buffer, preferred sodium-acetate buffer and/or cryoprotective agent polyhydric alcohol.

In one embodiment, according to the median lethal dose(LD 50) (LD of mice ₅₀) determination experiment, the biological activity of every ng neurotoxicity composition is 50 to 250 LD ₅₀Unit.In another embodiment, the biological activity of neurotoxicity composition is 150 LD of every nanogram ₅₀Unit.Common pharmaceutical composition of the present invention comprises the neurotoxicity composition of about 6pg to 30ng.

" pharmaceutical composition " is a kind of preparation, wherein contains or comprise the active component as medicine or diagnostic medicament.This pharmaceutical composition is applicable to that diagnostic or therapeutic bestow the human patients of (promptly by intramuscular injection or subcutaneous injection).

The pharmaceutical composition of neurotoxicity composition of branch amorph that contains botulinum toxin type A is commercially available in the Merz of Germany Pharmaceuticals GmbH, and trade mark is

The preparation method of the neurotoxicity composition of A type and botulinum toxin type B is described in, and for example, publication number is the international patent application of WO00/74703 and WO 2006/133818.In one embodiment, described compositions comprises the neurotoxicity composition of botulinum toxin type A.In another embodiment, said composition further comprises sucrose or human serum albumin or both to be had, and the ratio of human serum albumin and sucrose is 1: 5 in another embodiment.In one embodiment, compositions is

In another embodiment, described human serum albumin is a recombination human serum albumin.Perhaps, described compositions does not contain the albumen that is produced by mammal, as the human serum albumin.Any solution can be by with other non-protein stabilized dose of (infra) alternative serum albumin, thereby provide enough stability for neurotoxin.

In present patent application, use medicine based on the neurotoxicity composition of botulinum toxin type A, in another embodiment, can use product by Merz Pharmaceutical preparation, trade mark is

This is because compare with the medicine of bestowing based on the botulinum toxin type A complex, when the pharmaceutical composition that uses based on the neurotoxicity composition of botulinum toxin, for example

The time, find that the tendentiousness that produces antibody in patient's body reduces.Be not bound by any theory, think that the hemagglutinin in the botulinum toxin type A complex has activation capacity to immune system.

For composition and dosage, and relevant, based on the applied dose of the medicine of the neurotoxicity composition of botulinum toxin with bestow frequency, can consult PCT/EP2007/005754 with compositions based on the medicine of botulinum toxin.

But it is pharmaceutical composition lyophilizing of the present invention or vacuum drying, reorganization, or dominant in solution.When by reorganization, in one embodiment, add physiological saline solution (0.9% sodium chloride) with preparation reorganization solution.

D.2.2 other compositions (" adjuvant ")

Said composition can comprise other adjuvants.Term " adjuvant " material refers to the material that exists except active pharmaceutical ingredient in pharmaceutical composition.Adjuvant can be buffer, carrier, antiplastering aid, analgesics, binding agent, disintegrating agent, filler, diluent, antiseptic, carrier, cyclodextrin and/or extender, as albumin, and gelatin, collagen protein, sodium chloride, antiseptic, antifreeze and/or stabilizing agent.

D.2.3pH-buffer

" pH buffer " is meant and a kind ofly the pH value of compositions, solution etc. can be transferred to certain value or certain pH range of chemical substances.In one embodiment, the pH value scope can be between 5 to 8, and pH value is 7 to 8 in another embodiment.In another embodiment pH value be 7.2 to 7.6 and another embodiment in pH value be 7.4.In another embodiment, after when reorganization or injection, the pH value of pharmaceutical composition is between 4 and 7.5, and in another embodiment, pH value is 6.8 and 7.6, and in another embodiment pH value between 7.4 and 7.6.

In one embodiment, compositions also contains the 1-100mM sodium-acetate buffer, contains the 10mM sodium-acetate buffer in another embodiment.

The above-mentioned pH value scope that provides is typical example, and actual value may comprise any interval between the above-mentioned numerical value.According to instruction of the present invention, suitable buffer is a sodium phosphate buffer for example, sodium-acetate buffer, and TRIS buffer, these buffer are suitable for cushioning the above-mentioned pH value scope that obtains.

D.2.4 stabilizing agent

Before being added into pharmaceutical composition, " make stable ", " stablizing " or " stabilisation " be meant effective ingredient, promptly the neurotoxicity composition in reorganization or aqueous solution pharmaceutical composition has above about 20%, 30%, 40% of biological activity neurotoxicity composition, 50%, 60%, 70%, 80%, 90%, the toxicity up to about 100%.

In one embodiment, the example of stabilizing agent is gelatin or the albumin that humanized or recombinant sources obtain.In non-human or non-protein for animal are also included within.This stabilizing agent can pass through chemical method or gene recombinaton modification.In one embodiment of the invention, imagination is with alcohol, for example, inositol, mannitol is stablized protein in the freezing dry process as the cryoprotective agent adjuvant.

In another embodiment, stabilizing agent can be non-protein stabiliser, comprises hyaluronic acid or polyvinylpyrrolidone

Hetastarch, alginate or Polyethylene Glycol or its any combination, said composition can be by the stable any pH value of suitable pH buffer, preferred sodium-acetate buffer, or cryoprotective agent, or both have both at the same time.Except that the aforementioned stable agent, described compositions can comprise water and at least a polyhydric alcohol, for example mannitol, or Sorbitol or its mixture.It also can comprise monosaccharide, disaccharidase or higher polysaccharide, as glucose, and sucrose or fructose.This compositions is considered to a kind of safer and highly stable compositions.

In one embodiment, with 0.1 to 10 milligram every milliliter, particularly combine by every milliliter of 1 milligram of hyaluronic acid and neurotoxicity composition in the botulinum toxin solution of 200U/ml for the hyaluronic acid in the pharmaceutical composition of the present invention.

With the polyvinylpyrrolidone that exists in the pharmaceutical composition of the present invention

Combine so that reorganization solution to be provided with the neurotoxicity composition with a certain amount of, the every ml of this solution contains 10-500mg, and especially every ml contains the 100mg polyvinylpyrrolidone, for being total to the botulinum toxin solution that 200U/ml contains the neurotoxicity composition.In another embodiment, in reaching the solution of 8ml, recombinate.This causes in 25U/ml neurotoxicity composition solution, and concentration is reduced to every milliliter and contained 12.5 milligrams of polyvinylpyrrolidones.

In one embodiment, with 10 to 500 milligrams every milliliter, particularly every milliliter of 100 milligrams of Polyethylene Glycol are combined into the botulinum toxin solution of 200U/ml with the Polyethylene Glycol in the pharmaceutical composition of the present invention.In another embodiment, the botulinum toxin solution that contains the neurotoxicity composition.In another embodiment, theme solution also comprises the 1-100mM sodium-acetate buffer, contains the 10mM sodium-acetate buffer in another embodiment.

In one embodiment, when be stored in approximately+temperature of 8 ℃ of peace treaties-20 ℃ under, according to pharmaceutical composition of the present invention can keep effectiveness constantly substantially reach 6 months, 1 year, 2 years, 3 years and/or 4 years.In addition, described pharmaceutical composition has potent or returns to about 20% and about 100% after reorganization.

D.2.5 cryoprotective agent

" cryoprotective agent " is meant adjuvant; can cause active ingredient in pharmaceutical, promptly the neurotoxicity composition in reorganization or aqueous solution in compositions by lyophilizing before, have and surpass 20%; 30%; 40%, 50%, 60%; 70%; 80%, 90%, the toxicity of biological activity neurotoxicity composition up to about 100%.

In another embodiment, compositions can contain polyol, and for example as protectant polyhydric alcohol, spendable examples of polyhydric alcohols comprises, for example, and inositol, mannitol and other non-reduced alcohol.Some embodiment of compositions does not comprise protein stabilizing agent, or the saccharide compound that does not contain trehalose or Fructus Hordei Germinatus or lactose or sucrose or associated sugars or use as protective agent sometimes.

D.2.6 antiseptic

Term " antiseptic " and " antiseptic kind " are meant a kind of material or one group of material respectively, and it prevents microorganism, insecticide in the described compositions, the growth of antibacterial or other contaminating microorganisms or survival.Antiseptic can also prevent that described compositions from undesirable chemical change taking place.The antiseptic that uses in the scope of this patent is state-of-the-art antiseptic to those skilled in the art.The example of spendable antiseptic comprises, wherein, and for example: benzyl alcohol, benzoic acid, benzalkonium chloride, calcium propionate, Chile saltpeter, sodium nitrite, sulphite (sulfur dioxide, sodium sulfite, Potassium acid sulfite etc.), two sodium edtas ₁Formaldehyde, glutaraldehyde, kieselguhr, ethanol, methanol chloro isothiazolone, butyl ester, butylatedhydroxyanisole and/or dibenzylatiooluene.

D.2.7 analgesic

Term " analgesia " relates to the analgesic that acts on periphery and central nervous system in every way, comprises particularly acetaminophen (acetaminophen), NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) be salicylic acid for example, and narcotics is morphine for example, has the synthetic drug such as the tramadol of anesthesia character

, and other.Also comprise any chemical compound that the topical pain relief effect is arranged, lignocaine for example, benzylalcohol, benzoic acid etc.

In one embodiment, analgesic is the part of compositions, in another embodiment, before with the treatment of chemical denervation medicine, during or bestow analgesic afterwards.

D.3 administration

As mentioned above, in one embodiment, before the described exercise therapy and/or during and/or afterwards, the pharmaceutical composition that will comprise botulinum toxin is repeatedly bestowed to improve patient's symptom with effective dose.In one embodiment, during exercise therapy, repeatedly bestow the botulinum toxin of effective dose, and before any motion of beginning/mobile treatment, bestow said composition for the first time.

Usually, the dosage of bestowing to the patient will reach about 1000 units, but every patient generally should not surpass 400 units.In one embodiment, dosage range is between about 80-400 unit.In one embodiment, these values are invalid for adult patient.For the child, from 25 to 800 units of dosage range separately, and be 50 to 400 units in another embodiment.

Though above-mentioned scope relates to the highest accumulated dose, in one embodiment, every intramuscular dosage scope is between 3 to 6 units/kg body weight (b.w.), to fritter muscle is 0.5-2 unit/kg body weight, in another embodiment, for the dosage of general each injection site of 0.1-1U/kg b.w. should not surpass 50U and every muscle should not surpass 100U.

In one embodiment of the invention, the botulinum toxin of the effective dose that gives surpasses the neural poison of 500U in the adult, surpass the 15U/kg body weight in the child.

As for administration frequency, in one embodiment, the injection interval frequency was greater than 3 months again.Especially true when the medicine that uses based on the botulinum toxin complex, at this moment the probability that exists of antibody increases to some extent.

When the medicine that uses based on the botulinum toxin complex, for example The time, more frequent dosage also is possible.Therefore, according to the present invention, the medicine that use is bestowed again with 3 to 6 months interval.In another embodiment, especially when using the neurotoxicity composition of botulinum toxin, in another embodiment, use

Thoughtful with 2 less than trimestral interval dispenser again.In another embodiment, interfere with the time point administration again of automatic exercise therapy in musculation.

About composition with to drug dose on the basis of botulinum toxin type A, and relevant composition, dosage and about on the basis to botulinum toxin type A neurotoxicity composition medicament medicine frequency can be with reference to US 60/817756, and this patent is incorporated into herein by quoting in full.

In another embodiment described compositions only comprise botulinum toxin as active component.In another embodiment, other volume active component, for example analgesic, described muscle activator or the like are the parts of compositions.

Though should understand the value of above-mentioned expression as the general policy of using the medicine that the present invention uses.Yet final doctor is responsible for treatment, the toxin amount and the administration frequency that are given by its decision.In an embodiment of the inventive method, compare when obtaining greatest treatment efficacy with botulinum toxin, when to be ready weakening, patient's motor capacity gives medicine again based on botulinum toxin.On the basis about botulinum toxin type A, can directly inject the medicine that gives botulinum toxin to affected medicine.In order to find suitable injection site, exist some means and can help the doctor to find suitable injection site.In the scope of the present invention, all methods of seeking best injection site all are suitable for, as electromyogram (EMG), and palpation guiding injection, through the injection of CT/ guided by magnetic resonance, and injection is instructed in the ultrasonic guidance injection.In these methods, in one embodiment, the method that the latter selects when being the treatment child.About to inject further details by ultrasonic guidance, we refer to Berweck " Sonography-guided injection of botulinumtoxin A in children with cerebral palsy " Neuropediatric 2002 (33), 221-223.

The D4 test kit

In addition, the present invention relates to be used for the treatment of and suffer from dyskinetic patient's test kit, comprise the chemical denervation medicine that contains effective dose, and be used to carry out the device that muscle activates treatment.

In one embodiment, being used to carry out the device that muscle activates treatment is the disclosed devices of one or more B parts.In one embodiment, described chemical denervation medicine is a botulinum toxin type A.Be used for the device of muscle stimulation treatment or provide or the form of description provides with chemical denervation medicine.

In one embodiment, the described muscle that carries out activates the device of treatment for wherein carrying out the device of muscle stimulation treatment.Described test kit comprises that one drives and the gait orthosis of control and/or can guide patient's lower limb to be in the arm pusher of physiology of exercise pattern.In another embodiment, it is in the device of detailed earlier herein one.In test kit, medicine in one embodiment contains botulinum toxin as chemical denervation medicine.In another embodiment, described device is based on the medicine of the neurotoxicity composition of botulinum toxin type A.

In described test kit, with medicine carry out specific adaptation with the treatment coupling of advancing, in one embodiment, with the device coupling that is respectively applied for described treatment.This specific adaptation can in the medicine that can buy, by the specific enforcement of test kit, and can obtain by the operation instructions of specific suitability packing and/or package insert and/or medicine of the present invention like this according to the present invention.

D5 further defines

The term that uses in the presents " lyophilizing " is used to handle the solution that contains chemical denervation medicine, for example, the neurotoxicity composition of botulinum toxin, wherein icing the and dry solid constituent up to compositions of this solution stays.Therefore the lyophilized products that processing obtains is defined as " lyophilization ".

Term " reorganization " is defined as chemical denervation medicine, the solubilising process of the freeze-dried composition of neurotoxicity composition for example, and this can finish by increasing an amount of sterilized water, and for example, all necessary components all are included in the lyophilized products.Perhaps, if not so, can be by adding separately physiological saline solution, if or be suitable for, add following compositions and comprise for example pH buffer, adjuvant, cryoprotective agent, antiseptic, stabilizing agent, analgesic or its any combination." saline " before mentioned is a kind of saline solution, in another embodiment, is sodium chloride (NaCl) solution, is isotonic sodium chlorrde solution (that is, the concentration of sodium chloride is 0.9%) in another embodiment.Implement solubilising in this way, make that last " reorganization " is directly or indirectly, after promptly for example diluting, bestow the patient.Neurotoxin is recombinated waiting to ooze in the medium, for example in isotonic saline solution or normal saline.

The term " paralysis " of the present invention definition, with forfeiture componental movement energy or motor capacity impaired be classical symptom.

The E remarks

About above-mentioned situation, the content of all prior aries of being mentioned above should be understood that (published in the past and do not publish in the past) is incorporated into herein by quoting in full.

Should be appreciated that the term that the present invention uses only is in order to describe specific embodiment, and is not intended to limit the present invention.It must be noted that, indicate that as " (a) " of singulative used in description and the appending claims, " a kind of (an) " and " described (the) " comprises plural form unless have clearly in addition in the literary composition.

Following sets forth in detail non-limiting instance of the present invention.

Embodiment

Embodiment 1

Children's's nerve and developmental medicine portion (Germany) in Dr.von Haunersches Munich children's hospital are studied 9 routine patients.This research has obtained the approval of local Ethics Committee.

If the patient causes suffering from the maincenter gait disorder because of congenital or posteriority brain or spinal cord injury, they are with regard to the qualified research that enters us.Femur length must have 21 centimetres at least, and it is applicable to about 4 years old child.Obtaining locomotor activity must be the real-world objects of rehabilitation training project.The patient must send misery, frightened or uncomfortable signal reliably.Father and mother's written informed consent is a prerequisite.

Exclusion standard: seriously descend acrocontracture, fracture, the bone unstability, osteoporosis, the systemic load taboo that operation causes, serious out-of-proportion bone growth, the skin injury of disunion in the lower limb, thrombotic disease, cardiovascular instability, acute or that progressive nerve is disorderly and positive or self-injury behavior.

8 children and 1 teenager are assigned to our outpatient clinic of section and participate in driving gait orthosis (office) year 8 monthly training plans in January to 2006.8 years old two months mean age that begins to train (standard deviation 2 years old 10 months, scope 5 years old two months-14 years old 4 months).All patients train (seeing Table 2) in child's module of DGO except one.

Automatically the motor capacity training is by commercial acquisition

(Hocoma company, Fu Erkeciweier, Switzerland) carries out.Use DGO adult-and new children's's version.DGO by two legs or-form at adjustable those of different patients' skeleton.It is fixed at lower limb by several suspender belts.The orthotic width of hip, the length of thigh and calf, and the size of lower limb suspender belt and position can change.The main distinction of (210 millimeters to 350 millimeters) is the length of thigh between adult's module (femur length＞350 millimeter) and the child's module.By a quadric chain this DGO is connected to an individual weight back-up system framework.This makes orthosis in movement in vertical direction, and extra vertical stability is provided.On every lower limb, two Linear actuators move orthotic buttocks and knee endoprosthesis.These drivers are controlled the motor pattern of the similar normal walking of (real-time system of carrying out) operation on PC by positioner.Motion and the treadmill of this DGO are synchronous.The speed of walking can be set to 1 to 3.2 kilometer/hour.In order to ensure safety training, multinomial security function is integrated in this system.These are included as stop button that therapist and patient provide and the power on the driver of not only having limited is excessive, but also limit the controller of the deviation of joint angle and ideal position.For ankle dorsal flexion provides an elasticity footmuff.In order to ensure the most approaching physiological gait pattern, and prevent the skin scaling, it is very important that the patient suitably is fixed on the DGO.In order to support body weight, can use counterweight.This makes that the body weight support is in the 5-80 kilogram scope in the 5kg gait.

The off-load amount is made as is at first carrying that 50%, will reduce (too much not going down on one's knees when standing) according to the increase of muscular strength successively.Select the training leg speed at initial stage according to child's ability.

Training on the DGO comprises 3 to 4 times training session in 25-45 minute weekly.Carry out 10 to 13 training session.Because time restriction, nearly all patient has stopped their physiotherapy training class weekly usually.The 8 routine recommended botulinum toxins of using are arranged among the 10 routine patients

Treatment lower limb muscles (table 2).

In order to assess the feasibility of DGO training, to the walking time, the gait speed of walking distance and each training session has been made record.Before training program and when finishing to motion performance assess.With 10 meters gait tests (10MWT) assessment gait speed.Children are instructed to the speed walking that feels comfortably cool with them.

Be the variation of assessment motor function, the therapist who is authenticated by GMFM (big motor function test) operates standing (two-dimentional D) of GMFM-66 and running gear (two-dimentional E).In addition, the child of Inpatient Admissions has carried out 6 minutes gait test (6MWT) evaluation gait endurance.For determining, can adopt functional ambulation classification (FAC) in the required help size of child therebetween of walking.All use identical auxiliary device to finish in all tests of patients before and after intervention.

Check parameter and normal distribution separately thereof.This is applicable to the result of gait speed and 6MWT.Therefore, use the difference of t check analysis training front and back repeatedly.Adopt nonparametric order signed rank test that every other parameter is carried out statistical analysis.

There are 8 examples to finish training on DGO among the 9 routine patients.1 example has been dropped by the wayside after the training owing to compliance is reduced in for the third time.The training session of carrying out on DGO adds up to 12 (SD1.0, scope 10-13).The participant on average walks 1,158 meters (standard deviation 371m, scope 410-1675 rice) every joints.The average training time is 28:42 branch (standard deviation 3:30 minute, scope 23-32 minute).Walking speed average out to 1.7km/h (standard deviation 0.17km/h, scope 1.5-2.1km/h), off-load 14.4% (standard deviation is 12.6% of a body weight, scope 0-30%) (Fig. 2 c, d).

Assessed 7 example patients' ground walking parameter, all made moderate progress.Average leg speed obviously increases, from 0.87 meter per second (0.32 meter/s) be increased to a bit 09 meter per seconds (standard deviation 0.31 meter per second,

), p=0.01 (Fig. 3 e).There are 7 examples making moderate progress aspect two-dimentional D and the E among the 8 routine patients.The two dimension D average mark change obviously, be increased to 52.0 (standard deviations 28.8) from 46.7 (standard deviations 34.1), although statistical results show do not have significant difference (Z=-1.820, p=0.69).The average mark of two dimension E increases slightly but significant difference is arranged, from 42.2 (standard deviations 34.6) (Z=-2,366, p＜0.05) of 39.5 (standard deviations 32.6) after train.(Fig. 3 f+g) walking ability, with the FAC evaluation, the result shows not variation.

Speed of walking and GMFM scoring significantly improve.The result of running gear shows in GMFM, compares with the not obvious result of the part of standing to be significantly improved.The overview of this research is as shown in table 2.

Table 2:

Patient number

Sex

Age (year: month)

Diagnosis

Type of sports

Frequency of training

Total walking distance (km)

Before the botulinum toxin type A treatment

1

F

6:4

CP(I)

CM

13

17.2

Y

2

F

9:10

CP(II)

CM

12

13.6

Y

3

F

10:10

CP(II)

CM

13

18.6

N

4

M

6:2

CP(III)

CM

10

9.9

Y

5

M

6:4

CP(III)

CM

12

13.3

Y

6

M

14:4

CP(II)

AM

12

12.5

Y

7

F

7:0

CP(IV)

CM

3

0.9

Y

8

M，

8:0

CP(IV)

CM

10

5.0

N/Y

9

M

5:2

CP(III)

CM

10

6.7

Y

Embodiment 2

A 8 years old male patient's who suffers from bilateral spastic cerebral palsy owing to the relevant brain injury of premature labor, use children's

No. 12 the auxiliary treadmill training of robot have been carried out.Because robot device's internal control is owing to the relevant muscular hypertonia of drug resistance stops training, the patient can't carry out surpassing twice training.By comprising the hip musculus flexor, KF, the multi-level method of the lower limb of adductor and gastrocnemius is carried out botulinum toxin treatments and (is add up to 15U/ kilogram botulinum toxin

).After this was intervened, the auxiliary ambulation training of robot was easy to be continued, and the patient can carry out whole 12 interventions of suggestion.After these were intervened, endurance (was from 344-751 rice in the operation test at 6 minutes) and motor function (from increasing by 2.5% to 10% aspect the big motor function test of walking) had clear improvement.

Present embodiment shows: give at least can the respite muscular spasm the denervation agent for example the synergism that is used in combination of botulinum toxin and exercise therapy can act on the muscle of partial relaxation at least effectively.Then, the bronze drum exercise therapy strengthens or the muscle of adjusting can contact with the denervation agent of higher potential metering, thereby causes further cooperative effect.

Embodiment 3

Before comprising that muscle to the heating and cooling of cervical region sternocleidomastoid alternate cycles ground activates treatment, during and be the neurotoxicity composition that a spasmodic torticollis patient of 25 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Embodiment 4

Before comprising that to the cervical region sternocleidomastoid muscle of electricity irritation activates treatment repeatedly, during and be the neurotoxicity composition that a spasmodic torticollis patient of 44 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Embodiment 5

Comprise the patient is placed on one activate treatment with the muscle on the platform of 12 hertz and 20 hertz vibrations before, during and be the neurotoxicity composition that a spasmodic torticollis patient of 24 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Embodiment 6

Before comprising that with 40 kilo hertzs ultrasonic applications sternocleidomastoid muscle activates treatment to cervical region, during and be the neurotoxicity composition that a spasmodic torticollis patient of 37 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Embodiment 7

Before the sternocleidomastoid muscle that comprises hydraulic pressure massage cervical region activates treatment, during and be the neurotoxicity composition that a spasmodic torticollis patient of 34 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Embodiment 8

Before comprising that the sternocleidomastoid muscle that low-intensity microwave is applied to cervical region activates treatment, during and be the neurotoxicity composition that a spasmodic torticollis patient of 43 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Embodiment 9

In that comprise will be applied to before the sternocleidomastoid muscle of cervical region activates treatment by the isolated saponin of yellow wingceltis root (DSS), during and be the neurotoxicity composition that a spasmodic torticollis patient of 49 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Embodiment 10

Before comprising that the sternocleidomastoid muscle that casein kinase is applied to cervical region activates treatment, during and be the neurotoxicity composition that a spasmodic torticollis patient of 33 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Embodiment 11

Comprising potassium (K ⁺) the sternocleidomastoid muscle that is applied to cervical region activates before the treatment, during and be the neurotoxicity composition that a spasmodic torticollis patient of 56 years old injects the botulinum toxin type A of 0.1-1000 unit/kg body weight afterwards.After the intervention, west, Toronto spasmodic torticollis scale shows significant improvement the (TWSTRS).

Claims

1. be used to bestow the patient to treat its dyskinetic chemical denervation medicine, wherein said patient has accepted and/or will accept muscle stimulation treatment, and wherein said medicine is bestowed before described muscle stimulation treatment and/or during the treatment and/or after the treatment.

2. the chemical denervation medicine of effective dose is used for bestowing the patient to treat the application of its dyskinetic medicine in preparation, wherein said patient has accepted and/or will accept muscle stimulation treatment, and wherein said medicine is bestowed before described muscle stimulation treatment and/or during the treatment and/or after the treatment.

3. medicine according to claim 1 and 2 or application, wherein said muscle stimulation treatment are a kind of automatic muscle stimulation treatments.

4. according to described medicine of aforementioned each claim or application, wherein said muscle stimulation treatment is that a kind of muscle activates treatment, and wherein said muscle activates and is meant that the metabolism of described muscle is better than quiescent condition.

5. medicine according to claim 3 or application, wherein said muscle stimulation treatment are a kind of automatic exercise therapies.

6. medicine according to claim 4 or application, wherein said muscle activate comprise that thermal stimulus, electricity irritation, vibration, sound wave activate, the statics mode activates, electromagnetic wave or magnetic field activates, medicine activates or its any combination.

7. medicine according to claim 6 or application, wherein said thermal stimulus are that target muscle is heated to more than 40 ℃, or more than 45 ℃, or more than 50 ℃, reach 55 ℃, reach 60 ℃, reach 70 ℃ or reach 80 ℃.

8. according to claim 6 to 7 each described medicine or application, wherein to activate be to be cooled to target muscle below 35 ℃ or below 30 ℃ to the automatic muscle that is undertaken by thermal stimulus, or below 25 ℃, or below 20 ℃, or below 10 ℃, reduce to 0 ℃, reduce to-5 ℃, reduce to-10 ℃ or reduce to-20 ℃.

9. according to claim 6 to 8 each described medicine or application, wherein said electricity irritation is the nerve at the domination target muscle.

10. according to claim 6 to 9 each described medicine or application, wherein said electricity irritation is at target muscle itself.

11. according to claim 6 to 10 each described medicine or application, wherein said vibration is at whole health.

12. according to claim 6 to 11 each described medicine or application, wherein said vibration is at single muscle, muscle group or limbs.

13. according to claim 6 to 12 each described medicine or application, wherein said sound wave is ultrasound wave or audible sound.

14. according to claim 6 to 13 each described medicine or application, wherein said statics mode comprises water jet.

15. according to claim 6 to 14 each described medicine or application, wherein said electromagnetic wave comprises microwave.

16. according to claim 6 to 15 each described medicine or application, wherein said magnetic field comprises that magnetic stimulates.

17. medicine according to claim 6 or application, make chemical denervation medicine combine and enter the material of cell or its any combination with cell thereby wherein said medicine activates the material that comprises the material of bestowing analeptic, muscle contraction agent, increasing the intramuscular blood flow, the muscular temperature that can raise, can raise surface protein quantity.

18. medicine according to claim 17 or application, wherein said analeptic is selected from by β ₃The group that receptor stimulating agent, caffeine, ephedrine, amfetamine, methamphetamine, methylphenidate, cocaine derivatives and any combination thereof are formed.

19. according to claim 17 or 18 described medicine or application, wherein said muscle contraction agent is selected from by the material with sympathesis, to β ₂-adrenoceptor has the material, caffeine, acetylcholine, nicotine, epibatidine (epibatidine) derivant, ABT-594, dimethylphenylpiperazinium, succinylcholine of agonism, separates muscular irritation saponin derivative, calcium, potassium, norepinephrine, epinephrine, the leukotriene that obtains, the allene that contains arachidonic acid derivatives from dalbergia saxatilis (Dalbergia), and the group formed of any combination.

20. according to claim 17 to 19 each described medicine or application, the wherein said material that can increase the intramuscular blood flow be selected from by the endothelium hyperpolarization factor (EDHF), a matter K＜+, nitric oxide, β ₂Adrenoceptor agonists, histamine, prostacyclin, prostaglandin, VIP, extracellular adenosine, effect of extracellular ATP, extracellular ADP, L-arginine, Kallidin I, P material, niacin usp (nicotinic acid), platelet activating factor (PAF), carbon dioxide, a matter lactic acid, adenosine

Alpha receptor blocking agent, amyl nitrite, atrial natriuretic peptide, ethanol, histamine-derivant, complement protein C3a, C4a, C5a, nitric oxide derivant, glyceryl trinitrate (nitroglycerin), isosorbide mononitrate, Dilatrate-SR, pentaerythritol tetranitrate (PETN), sodium nitroprusside, phosphodiesterase (PDE5) inhibitor, strengthen preparation, sldenafil, tadanafil, Vardenafil (tardenafil), tetrahydrocannabinol, theobromine, the papaverine of nitric oxide effect indirectly, and the group formed of any combination.

21. according to claim 17 to 20 each described medicine or application, the wherein said material that can raise muscular temperature is selected from by Herba Ephedrae, Citrus aurantium Linn. (Neosynephrine), Fructus Capsici, Rhizoma Zingiberis Recens, sibutramine and metabolite thereof, caffeine, and the group of any combination composition.

22. according to claim 17 to 21 each described medicine or application, the group that the material that wherein said surface protein selects free energy to raise SV2, GT1b, GD1b, GQ1b, synaptotagmin polypeptide, Syt1 and Syt2 is formed.

23. according to claim 17 to 22 each described medicine or application, the wherein said material that can raise surface protein quantity is selected from by the blocking-up material of the blocking-up material of hormone, somatomedin, neurotrophic factor, receptor-endocytosis, the factor that increases the receptor surface expression, Profilin-inhibitor, protease inhibitor, receptor degraded, suppresses the group that the proteic inhibitor of G-, competitive receptor antagonist and neurotransmitter degradation agent are formed.

24. according to claim 5 or 6 described medicine or application, wherein said automatic exercise therapy is supported by automatic gait orthosis or arm pusher.

25. medicine according to claim 24 or application, wherein said automatic gait orthosis and treadmill coupling.

26. according to claim 5 to 25 each described medicine or application, wherein said automatic exercise therapy is undertaken by equipment, this equipment comprises the orthotic device that drives and control, it can guide described patient's lower limb to be in the physiology of exercise pattern, in one embodiment, the relief mechanism that uses treadmill and described weight in patients is worked.

27. medicine according to claim 26 or application, wherein relief mechanism comprises the off-loading power (relief force) of regulating height and patient's weight being worked, wherein said weight is by cable support, the first cable length adjusting device provides the adjusting of cable length to limit the height of weight suspension, and the second cable length adjusting device provides the adjusting of cable length to limit the off-loading power that weight suspension is worked.

28. according to claim 26 or 27 described medicine or application, wherein by adopting the treadmill training device to carry out automatic exercise therapy, this device comprises treadmill, relief mechanism that the patient uses and driving orthotic device, wherein on treadmill, be provided with an adjustable for height parallelogram, to stablize orthotic device and to prevent that the patient forward, topple over backward and to both sides, this parallelogram is connected on the orthotic device, this orthotic device comprises hip orthotic device and two shank parts, provide two hip drivers with mobile hip orthotic device whereby, provide two knee actuator with mobile shank parts; Hip orthotic device and shank parts are adjustable, the shank parts scalable size and the position that have running-on that provide; The speed that moves and control treadmill of control unit with the control orthotic device is provided.

29. according to claim 26 or 27 described medicine or application, wherein by adopting the treadmill training device to carry out automatic exercise therapy, this device comprises the treadmill that has handrail, the relief mechanism that the patient uses and drive orthotic device wherein provides the equipment that is used for stablizing orthotic device to prevent that the patient forward, topple over backward and to both sides; Orthotic device comprises hip orthotic device and two shank parts, provides two hip drivers with mobile hip orthotic device, and provides two knee actuator with mobile shank parts; For each knee actuator and hip driver provide a ballscrew shaft driver, orthotic device and shank parts are adjustable, the shank parts scalable size and the position that have running-on that provide; The speed that moves and control treadmill of control unit with the control orthotic device is provided.

30. according to claim 5 to 29 each described medicine or application, wherein implement automatic exercise therapy by application be used to the to advance apparatus of treatment, this treatment of advancing is meant the rehabilitation or the rehabilitation of paraparesis or hemiparesis patient bilateral or one-sided spasm situation, described apparatus comprises height and the adjustable vertical table of gradient, the restraint zone that the clamping device that the patient uses is arranged on vertical table, the actuating device that patient's leg exercise is used, it is made up of knee device and foot's device, shank for trochoid, vertical table has interchangeable head, trochoid provides an adjustable hip extension angle whereby, and therefore an adjusting device is provided; Knee and foot be replaceable to be arranged on the handrail of shank device; Knee joint between extensin period foot's device can be used for sole is applied power; Provide control unit to be used for moving of control device.

31. according to claim 5 to 30 each described medicine or application, wherein the equipment of the application of force carries out automatic exercise therapy between first and second parts of life entity (animate body) by adopting, described equipment comprises: with first and second coupling assemblings of first and second part correlations, each described first and second coupling assembling comprises respectively:

A. fixed support structure on the position of described part, each supporting construction all is support and connection; Be connected the articulated element of each described support and connection by the joint with b.; The described articulated element of wherein said first and second coupling assemblings is connected to each other by trochoid, and the described articulated element of described second assembly extends to described trochoid; Be connected first and second sleeve pipes on the member in described first coupling assembling; Respectively by described first and second sleeve pipes first and second tendons that stretch, in described second coupling assembling, be connected on the member, wherein in second coupling assembling in a side of described trochoid, one of described tendon is connected on the described articulated element, and at the opposite side of described trochoid, another tendon is connected on the described articulated element in described second coupling assembling.

32. according to claim 5 to 30 each described medicine or application, wherein use the equipment of the power that between first and second parts of hands, applies to implement automatic exercise therapy, one of described part is a phalanges, described equipment comprises: with first and second coupling assemblings of first and second part correlations connection, each coupling assembling comprises respectively:

33. according to aforementioned claim each described medicine or application, wherein the dyskinesia is the hyperkinetic and/or hypokinetic dyskinesia, wherein unbalance between agonist and the antagonist disturbed this function.

34. medicine according to claim 33 or application, the wherein dyskinesia and cerebral palsy, the M. parkinson, the maincenter gait disorder, spinal cord injury, myodystonia, traumatic brain injury, hereditary, metabolism disorder, the dynamic muscle contracture and/or apoplexy relevant.

35. medicine according to claim 34 or application, wherein the dyskinesia be selected from down the group at least a relevant: strephexopodia, strephenopodia, the lower limb spasm, upper limb spasm, adductor spasm, receive knee sprung spasm (rolling up gait) in the hip joint flexion contracture, hip joint, the ankle sole of the foot is bent, the supination of condyle hypozygal and revolve before, writers spasm, knot like the musician, knot shank myodystonia, adduction of the hip joint like the linksman, abduction of the hip joint, go down on one's knees, knee extends, equinvoarus, the foot myodystonia, the striatum toe, the toe flexing, toe prolongs.

36. according to described medicine of aforementioned each claim or application, wherein said patient is the people.

37. medicine according to claim 36 or application, wherein said patient does not finish its action and grows, and as yet fixedly muscle contracture does not take place.

38. according to described medicine of claim 37 or application, wherein said patient is 6 years old child.

39. according to described medicine of aforementioned each claim or application, wherein chemical denervation medicine is a botulinum toxin.

40. according to described medicine of aforementioned each claim or application, wherein said medicine passes through injection administration.

41. according to described medicine of aforementioned each claim or application, wherein said medicine is bestowed in therapeutic process for several times.

42. according to described medicine of aforementioned each claim or application, wherein said medicine is bestowed before exercise therapy begins for the first time.

43. according to described medicine of aforementioned each claim or application, wherein said medicine is to bestow once more 3 to 6 months interval.

44. according to described medicine of aforementioned each claim or application, wherein said medicine was bestowed to being less than trimestral interval once more with two weeks.

45. according to described medicine of aforementioned each claim or application, the time point that wherein said medicine disturbs automatic muscle to activate treatment in musculation is bestowed once more.

46. according to claim 39 to 45 each described medicine or application, the botulinum toxin of wherein bestowing effective dose, the neurotoxicity composition surpasses and surpasses the 15U/kg body weight among 500U or the child among the adult.

47. according to claim 39 to 46 each described medicine or application, wherein botulinum toxin is the botulinum toxin type A complex.

48. according to claim 39 to 47 each described medicine or application, wherein Botulinum toxin is the neurotoxicity composition in the botulinum toxin complex.

49. according to described medicine of claim 48 or application, wherein botulinum toxin is selected from the group of being made up of serotype A, B, C, D, E, F, G and composition thereof.

50. according to described medicine of claim 49 or application, neurotoxicity composition wherein is the A type.

51. one kind is used for the treatment of the test kit of suffering from dyskinetic patient, comprises:

A. the medicine that contains the chemical denervation medicine of effective dose; Carry out the device of muscle stimulation treatment with b.

52. according to the described test kit of claim 51, the device that wherein carries out muscle stimulation treatment is selected from by thermal stimulus device, electrical stimulation device, vibrating device, sound wave active device, statics active device, electromagnetic wave device and magnetic field device, or the group of its any combination composition.

53. according to the described test kit of claim 51, the device that wherein carries out muscle stimulation treatment is automatic exercise therapy, this device comprises that one drives and the gait orthosis of control and/or can guide patient's lower limb to be in the arm pusher of physiology of exercise pattern.

54. according to claim 52 or 53 described test kits, wherein chemical denervation medicine is a botulinum toxin.

55. according to the described test kit of claim 54, wherein botulinum toxin is the neurotoxicity composition of botulinum toxin complex.