CN109069609A - Use the botulin toxin for primary mood and the disturbance of emotion of neurotransmitter - Google Patents

Abstract

The present invention is provided to treat primary mood and the disturbance of emotion, the method including depressive disorder, anxiety and sleep disturbance and CNS obstacle, including administration neurotoxin.

Description

Use the botulin toxin for primary mood and the disturbance of emotion of neurotransmitter

This application claims the equity for the U.S. Patent Application Serial 14/464,740 that August in 2014 is submitted on the 21st, The priority for the U.S. Patent Application Serial 11/447,984 for asking on June 7th, 2006 to submit, this application requirement four are preferential Power: the U.S. Provisional Application No. 60/690,162 that on June 14th, 2005 submits；The interim Shen in the U.S. that on June 27th, 2005 submits It please number 60/693,771；The U.S. Provisional Application No. 60/721,060 that September in 2005 is submitted on the 28th；On November 23rd, 2005 submits U.S. Provisional Application No. 60/738,981, all these full contents is incorporated herein by quoting.

Invention field

The present invention relates to treat primary mood and the disturbance of emotion, including depression and anxiety and sleep disturbance with neurotoxin And other CNS obstacles.The present invention relates to the imagings of the neurotransmitter of brain and central nervous system part for selecting clostridium botulinum (botulinum) be administered patient and for selecting close to outside the cranium of the target brain and the region CNS expressed with abnormal neuron mediator The purposes of the suitable region of anatomy in region.The method can make botulin toxin diffuse through blood-brain barrier and dissection table Face brain barrier generates the work of block nerves mediator function safely and effectively to deliver the clostridium botulinum to central nervous system With.

Background of invention

Depression is one of most universal and extensive mental disease form, and the individual influenced crosses over age and gender. (Gainotti et al.(2001)J.Neural Neurosurg.Psychiatr.71:258-261；Wong et al. (2001)Nature Rev.Neurosci.2:343-351；Nestler et al.(2002)Neuron 34:13-25).It is logical Often, people suffers from the risk of major depression in life, and male is about 12%, and women is about 25% (Kessler et al. (1994) Arch.Gen.Psychiatry 51:8).In addition, about 5 to 10% have serious suppression in all patients under primary care environment It is strongly fragrant, and about 3 to 5% patient is diagnosed as dysthymia (dysthymia) (Barrett et al. (1988) Arch.Gen.Psychiatry 45:1100).However, 10 to 14% in all patients are diagnosed in inpatient situation For major depression (Blackburn et al. (1997) Br.J.Psychiatry 171:328).Major depression is especially to disable With it is harmful, being partly because it is recurrent.After first time breaks out, the patient with major depression is through during 2 years Recurrence rate be about 40%.After being diagnosed as second of major depression breaking out, the incidence recurred during 5 years increases To about 75% (Solomon et al. (2000) Am.J.Psychiatry 157:229).

The most frequently used three kinds of major type of compounds treat depression: 1) monoamine oxidase inhibitors；2) heterocycle antidepression Medicine；With 3) selective serotonin reuptake inhibitor (SSRIs).There are many pairs for the antidepressants of known and current prescription Effect.Monoamine oxidase inhibitors is the antidepressants of first kind clinical use.Monoamine oxidase inhibitors, including different card wave Hydrazine, nardil (pheneizine) and parnitene inhibit the metabolism of phenyl ethylamine and dopamine, serotonin and remove first kidney The catabolism of upper parathyrine.Due to many diet restrictions related with monoamine oxidase inhibitors is used, extensive side effect packet Hypertension, headache, myoclonic twitch (myoclonic jerk), interruptions of sleep and gastrointestinal complication are included, currently, monoamine oxygen Change enzyme inhibitor and is not used as a line antidepressants.Tricyclics, including imipramine, desipramine, nortriptyline (nortrypline), amitriptyline (amitrypline), doxepin and protriptyline (protrypline) generate a variety of anti- Cholinergic side effect, sleepy, orthostatic hypotension, arrhythmia cordis and weight gain.Although SSRIs usually presses down than monoamine oxidase Preparation and tricyclics are mild, but also generate many side effects.For example, SSRIs, including Prozac, Paxil, fluorine Fu Shaming, Sertraline and Citalopram, with gastrointestinal discomfort (gastrointestinal distress), neuroticism, excitement It is related with interruptions of sleep.

Other than many side effects related with traditional antidepressants, these treatments are further characterized in that edge effect (marginal efficacy).About to some of major depression antidepressant therapy validity studies have shown that treatment acute illness Or maintenance therapy has the response rate of 50-60%.(Schulberg et al.(1998)Arch.Gen.Psychiatry 55: 1121).Average absolute response rate between antidepressants and placebo is about 20-25% (Williams et al. (2000) Ann.Intern.Med.132:743).Therefore, new antidepressant therapy is needed at present.

In view of serious adverse side effect and the edge effect sometimes of many antidepressant therapies, it is also very desirable to improved medicine Object can effectively treat depressive disorder and sleep disturbance without generating pair relevant to treatment depression and/or sleep disturbance Effect.The present invention provides the composition comprising botulin toxin neurotoxin, for treat depression and/or sleep disturbance with And other CNS obstacles.

The effect of the drug based on botulin toxin for medical application is traditionally still to peripheric movement and to dive Sensory nerve work.This effect of these medicaments is usually used in explaining most of beneficial effect to various indications, The indication includes dyskinesia, pain syndrome, syndrome (the autonomic based based on autonomic nerve ) and spasm obstacle syndromes.So far, the present inventor carry out clinical observation, instruction involve central nervous system and It cannot be explained by peripheral action.Even if when botulin toxin is administered to scalp, face or neck area, including by removing Any injection form administration except intracranial injection, all observes the effect for central nervous system.This kind of observation result It include: using improvement of the periocular injections to photophobia；The alleviation of improvement and the insomnia of sleep pattern；It is corrected with body/muscle damage (corrected) the problem of incoherent anxiety improvement；The incoherent depression of the problem of causing with body/muscle damage changes It is kind；With the effect for dysmenorrhea symptom and for the latent effect of promoting sexual gland hormone or other pituitrins.

In addition, botulin toxin has shown that for nervous centralis when medicament to be injected directly into brain parenchym The influence of neurotransmission within system.Change include the inhibition of electrode depolarization, the inhibition of glutamic neuron, GABA dyeing, With the cracking of SNAP-25, the duration is consistent with the effect of botulin toxin.Draw when by the induction of harsh chemicals injection When playing cicatrization breaking-out, injection is suppressed related with the seizure activity within cerebral hemisphere in brain parenchym.It is directly injected into brain Inside unpractiaca, in fact, usually this field doctor treatment breaking-out obstacle on be less likely implement because in the presence of with induction It a possibility that bleeding, cicatrization, neuron loss and location difficulty, infection (meningitis) are related and risk and is passed with necessity Send device related inconvenience.Due to such complication relevant to the operation of invasive encephalic, being injected directly into CNS is It is highly unpractical.This document describes it is a kind of for will the drug delivery based on botulin toxin to central nervous system (via obviously not including through cranium (transcranial), intrathecal or intraspinal injection administration and injecting method), can penetrate into In central nervous system, with increased convenience and safety, almost without or mitigate bad work relevant to directly delivering With.

The present inventor astoundingly and have been surprisingly found that with botulin toxin treatment pain syndrome by The selection criteria of examination person.The present invention is provided to identify to have responsiveness increased tested to botulin toxin treatment pain The method of person.Particularly, the inventors discovered that atopic diseases are related with various pain syndromes, the appearance of atopic diseases and (gesture antagonism (geste antagoniste) phenomenon) is relieved pain by haptic stimulus, it appears that in prediction for clostridium botulinum There is predictive value in terms of the painful response of toxin.

Using botulin toxin treat myofacial pain, initially include tension headache (tension headaches), Bruxism, temporal-mandible joint syndrome, lumbago (lower-back pain), and treatment acoustic neurinoma (posterior fossa tumor (posterior fossa brain tumor)) neck surgical incision after postoperative pain.It is eliminated with botulin toxin After the consistent observation result that migraine is eased after face's gauffer of forehead, migraine is treated using botulin toxin It catches on.

Multiple case reports show the flesh muscle of botulin toxin treatment tension headache and migraine and multiple forms Film pain syndrome is effective.Despite the presence of the introduction, fail to confirm using the check experiment of a small amount of patient in study group Botulin toxin treats validity (Wheeler et al. (1998) A of muscular fascia and other forms pain randomized,double-blind,prospective pilot study of botulinum toxin injection for refractory,unilateral,cervicothoracic,paraspinal,myofascial pain syndrome.Spine 23(15):1662-6).In check experiment, it is invalid that botulin toxin treats various pain syndromes It is small relatively low with statistics efficiency to be attributed to sample size.For the demand pair of a greater amount of patients and further multicenter study It is considered required in the evidence for providing stronger validity.

In view of showing botulin toxin in practice for treatment migraine-effective medical record of headache-pain syndrome Report, effort have carried out more massive research.By Allergan Pharmaceutical Company (clostridium botulinum poison One of maximum supplier of plain A (BOTOX.TM)) patronage initial Multicenter controlled study in, it is pre- to show botulin toxin Anti- common migraine (as International Headache Classification-1988 is defined) repeatability occurs Validity.However, the statistical significance of these results be it is uncertain, there are contradictions between processing group, show no method interpretation Inversion dose-effect curve (Silberstein et al. (2000) Botulinum toxin type A as a migraine preventive treatment.Headache 40(6):445-50)。

Migraine, tension headache, the myofacial pain on head and chronic atypical head (chronic bitterly Atypical facial headaches) it is (the headache unrelated with the structure pathology in head or not of primary headaches obstacle That other diseases process is secondary) representative.The treatment of these illnesss has very high placebo response rate (at most 35%) a large amount of patients, is needed to detect the marked difference between study group and control group in clinical test.Utilize the stronger response of identification Property patient population selection criteria (research-induction standard) increase comparative study processing group within subject response rate, from And allow smaller test sample originally determine check experiment therapeutic effect.More importantly, selection criteria (diagnostic criteria) is base In the basis of the accurate effective medical therapy of any illness.Identify be more likely to respond the patient of given treatment parameter can: 1) when there are a variety of therapeutic choices, the order of priority between therapy；2) avoiding can not successful therapy；With 3) facilitate to examine The patient for considering the ratio between risk and benefit signs informed consent form.Effective selection criteria facilitates researcher and is based on clinical evidence Further understand mechanism of action.

The present invention provides the method for patient of the selection with various pain syndromes, and the pain syndrome includes but unlimited In myofacial pain, muscle tone headache and chronic wound after surgery syndrome, based on using botulin toxin treatment packet Include the review and predictive analysis of the pain syndrome of incidence.

Invention summary

The present invention provides the method for the treatment of depression and anxiety and sleep disturbance, including the medicine group comprising neurotoxin is administered Close object.

The present invention provides the method for the treatment of depression, comprising the following steps: a) identifies subject or mirror with depressive disorder Not Ju You one or more depressive disorder symptoms subject；And b) a effective amount of to the snibject includes clostridium botulinum The composition of toxin and pharmaceutical acceptable carrier.

The present invention also provides treatment anxiety method, comprising the following steps: a) identify with anxiety disorder subject or Identify the subject at least one anxiety disorder symptom；And b) a effective amount of to the snibject includes clostridium botulinum The composition of toxin and pharmaceutical acceptable carrier.

The present invention also provides the methods for the treatment of sleep disturbance, comprising the following steps: a) identifies tested with sleep disturbance Person or identification show the subject of at least one sleep disturbance symptom；And b) a effective amount of to the snibject includes meat The composition of bacillus venenosus toxin and pharmaceutical acceptable carrier.

The present invention also provides the methods for the treatment of circadian disorders, comprising the following steps: a) identifies and hinders with circadian rhythm The subject hindered；And b) to a effective amount of composition comprising botulin toxin and pharmaceutical acceptable carrier of the snibject.

The present invention also provides the methods that delivery of botulinum toxins passes through blood-brain barrier, comprising the following steps: a) identifies and suffers from There is the subject of at least one methanone derivatives；And b) it is enough to deliver the neurotoxin to the snibject Across the composition comprising neurotoxin and pharmaceutical acceptable carrier of the amount of blood-brain barrier.

The present invention also provides the methods that delivery of botulinum toxins passes through blood-brain barrier, comprising the following steps: a) identifies and suffers from There is the subject of at least one methanone derivatives；And b) it is enough to deliver the neurotoxin to the snibject Across the composition comprising neurotoxin and pharmaceutical acceptable carrier of the amount of blood-brain barrier, wherein the administration neurotoxin note It penetrates agent and has blocked at least one neurotransmitter.In a preferred embodiment, neurotransmitter is acetylcholine.

The present invention also provides the methods for the treatment of anxiety disorder, comprising the following steps: a) identification is at least one anxiety barrier The subject or identification that hinder have the subject of one or more anxiety disorder symptoms；And it includes nerve that the subject, which b) is administered, The composition of toxin and pharmaceutical acceptable carrier, the composition are delivered through blood brain with the amount for being enough to reduce cholinergic neuron transmitting Barrier.

The present invention also provides the methods for the treatment of sleep disturbance, comprising the following steps: a) identification is at least one sleep barrier The subject or identification that hinder have the subject of one or more sleep disturbance symptoms；And it includes nerve that the subject, which b) is administered, The composition of toxin and pharmaceutical acceptable carrier, the composition are delivered through blood brain with the amount for being enough to reduce cholinergic neuron transmitting Barrier.In a preferred embodiment, the composition reduces choline acetyl transfers enzyme activity.It is preferred real at another It applies in scheme, the composition reduces the synthesis of acetylcholine.In another preferred embodiment, sleep disturbance is to lose It sleeps.In another preferred embodiment, sleep disturbance is that narcolepsy, restless leg syndrome or the breathing of sleep property are temporary Stop.

The present invention also provides the methods for the treatment of circadian disorders, comprising the following steps: a) identifies at least one daytime The subject of circadian rhythm obstacle identifies the subject with one or more circadian disorders symptoms；And b) administration it is described by Examination person includes the composition of neurotoxin and pharmaceutical acceptable carrier, and the composition is to be enough to reduce the amount of cholinergic neuron transmitting It is delivered through blood-brain barrier.In a preferred embodiment, the composition reduces choline acetyl transfers enzyme activity.Another In one preferred embodiment, the composition reduces the synthesis of acetylcholine.

The present invention also provides the methods for the treatment of depressive disorder, comprising the following steps: a) identifies at least one depression barrier The subject or identification that hinder have the subject of one or more depressive disorder symptoms；And it includes nerve that the subject, which b) is administered, The composition of toxin and pharmaceutical acceptable carrier, the composition are delivered through blood brain with the amount for being enough to reduce cholinergic neuron transmitting Barrier.In a preferred embodiment, the composition reduces choline acetyl transfers enzyme activity.It is preferred real at another It applies in scheme, the composition reduces the synthesis of acetylcholine.

The present invention provides the method that the subject of pain is treated in selection with botulin toxin, comprising the following steps: identifies It seeks peace the subject of the illness selected from depressive disorder, anxiety disorder and sleep disturbance with pain syndrome, wherein identifying with pain The subject of pain syndrome and the illness selected from depressive disorder, anxiety disorder and sleep disturbance with botulin toxin for being treated The responsiveness increase of pain is predictive.In a preferred embodiment, pain syndrome is selected from following any Kind pain syndrome or combinations thereof: myofacial pain；Migraine；Wound after surgery pain；The relevant headache of nasosinusitis；Muscle is tight Extensional pain；Chronic post-traumatic headache；Cluster headache；Temporal-mandible joint syndrome (temporal mandibular joint syndrome)；Fibromyalgia；Atypical facial pain；Wound pain after incision；Cervical vertebra radiculopathy (cervical radiculopathy)；With acute neck sprain (whiplash).

In another embodiment of the present invention, by determine subject suffer from respectively depressive disorder, anxiety disorder or The medical history of sleep disturbance identifies the subject with the illness selected from depressive disorder, anxiety disorder and sleep disturbance.

The present invention also provides have responsiveness increased tested to botulin toxin treatment pain disorder for identifying The method of person, comprising the following steps: screening subject group is sought peace with pain syndrome selected from depressive disorder, anxiety disorder with identifying With those of the illness of sleep disturbance subject, wherein identify with pain syndrome seek peace selected from depressive disorder, anxiety disorder and The subject of the illness of sleep disturbance is for being predictive with the responsiveness increase of botulin toxin treatment pain.At one In preferred embodiment, pain syndrome is selected from following any pain syndromes or combinations thereof: myofacial pain；Partially Headache；Wound after surgery pain；The relevant headache of nasosinusitis；Muscle tone pain；Chronic post-traumatic headache；Cluster headache；Temporo Mandibular joint syndrome；Fibromyalgia；Atypical facial pain；Wound pain after incision；Cervical vertebra radiculopathy；And acute complete cervical Sprain (whiplash) in portion.

The present invention provides a kind of method, comprising the following steps: identifies or diagnose pain syndrome；It diagnoses or leans out and be selected from down The medical history stated: depressive disorder, anxiety disorder and sleep disturbance；And the pain syndrome identified is classified as with meat poisoning bar The increased one kind of verticillium toxin treatment responsiveness.In one embodiment, according to International Headache classification system (International Headache Classification System)(The International Headache Society (I.H.S.)) identify pain syndrome.

The present invention provides the method for selection patient with the drug therapy number of people pain obstacle based on botulin toxin a kind of, Depressive disorder, anxiety disorder, mandatory mandatory conduct characteristics (obsessive compulsive are suffered from including diagnosis Behavioral traits) or the patient of sleep disturbance in the headache type that occurs, and the clostridium botulinum of dosage treatment effective amount Toxin.In one embodiment, head pain conditions are migraine, tension headache, tension headache merging migraine (combined tension and migraine headache), myofascial headaches, Sinus headaches and remporomandibular joint are comprehensive Levy relevant headache, headache relevant to fibromyalgia or headache relevant with neuralgia.

The present invention also provides a kind of selection patients with drug therapy human face's pain disorder based on botulin toxin Method, including diagnose with depressive disorder, anxiety disorder, mandatory mandatory conduct characteristics or sleep disturbance patient in go out Existing facial pain type, and the botulin toxin of dosage treatment effective amount.In one embodiment, the facial pain Obstacle is that trigeminal neuralgia, facial pain obstacle relevant to bruxism or the facial pain illness are chronic after performing the operation Operation wound pain.

Composition of the invention includes botulin toxin and pharmaceutical acceptable carrier.In a preferred embodiment, meat Bacillus venenosus toxin is immunophenotyping (immunotype) A, B, C, D, E, F or G.In a further preferred embodiment, meat poisoning Bacillus toxin is the A type meat poisoning bar from Hall bacterial strain clostridium botulinum (Hall strain Clostridium botulinum) Verticillium toxin.

Method of the invention can preferably be implemented by botulinum toxin composition described in drug administration by injection, the note Penetrate including in percutaneous (transcutaneous), percutaneous (percutaneous), subcutaneous, peritonaeum, transdermal (transdermal), In intramuscular and bone, but it is clear be not encephalic, wear cranium, intrathecal or intraspinal injection or administration.In one embodiment, exist At least two injection sites.In another embodiment, injection is more stoves (multifocal).Botulin toxin can be with It is preferably administered to forehead, scalp or neck or other positions, such as the region and the other regions of face of eye circumference, is enhanced by giving Medicine position to central nervous system (CNS) venous drainage.In another embodiment, botulin toxin can be administered to Soft tissue outside brainpan.In another embodiment, botulin toxin can drain maximum intake by door hypophysis Position administration.

The example of the compound and preparation that can be used in the present invention includes with protein such as seralbumin or transparent The stable botulin toxin of matter acid enzyme.In a preferred embodiment, seralbumin or hyaluronidase are recombinations 's.It is in another embodiment, sero-abluminous that there are concentration to be greater than 500.mu.g/100LD₅₀The clostridium botulinum poison of unit Element.Botulin toxin drug can be further steady with simple stability sugar or polysaccharide (for example, sucrose, lactose or trehalose) It is fixed.Botulin toxin is preferably the one pack system neurotoxin of 150,000 dalton of molecular weight, is free of compound meat poisoning bar Bacterium fibroin.Compositions disclosed herein also may include polyethylene glycol polymer；The nanoemulsions on plant fat basis；With Use one or more single unsaturated oils or any nanoemulsions of polyunsaturated oil.In a preferred embodiment, originally Botulinum toxin composition used in the method for invention is formulated into enhancing botulin toxin and penetrates into and pass through skin Skin.

The new development of pharmaceutical technology concentrates on the delivery system of enhancing, such as transdermal or transdermal delivery system.Such system System is considered more convenient and has smaller pain.The problem related with such system includes that substance passes through wearing for epidermis and corium It is thoroughly poor.Hyaluronidase provides penetrating for improvement.

Pharmaceutical composition including botulic neurotoxin, hyaluronidase and sugar (monosaccharide and oligosaccharides) is suitable for the present invention Method.The botulin toxin pharmaceutical preparation for being suitable for the invention method is preferably free of any human blood or recombination blood Product, and be stable rapid draing or freeze-dried.PH is preferably between pH 3.0 to 7.4, and prepared product It may be used as injection, transdermal or topical agent.The botulin toxin pharmaceutical preparation for being suitable for the invention method can pass through Injection, needle-free delivery system and the method such as electroporation, ultrasonic treatment and high pressure sky that need to intervene (disruption) technology The injection of gas air-flow is administered in the form of micropin.Micropin is usually 150 to 600 microns.Further, it is suitable for the invention method Botulin toxin pharmaceutical preparation may further include polycation albumen.

Currently, hyaluronidase can be applied with various given activities (specific activities).For example, based on silk floss The substance of sheep can have the specific activity of 1,500Upper mg or 1.5Upper mcg.Generally, 75-300U is used to inject, than Such as intraocular surgery is carried out with Peribulbar anesthesia.This will correspond to the zymoprotein of about 100-450mg mass, it is sufficient to rise and stablize figuration The effect of agent.

It is existing research shows that protein excipient, such as human serum albumins can stablize botulin toxin.It carries out Experimental study confirm hyaluronidase also with the identical horizontal stable botulin toxin observed for human serum albumins.

Compositions disclosed herein can make dosage formulation at being suitable for eye drops administration in order to penetrating into through conjunctiva The concentration for treating diseases of eye surface.Compositions disclosed herein can make LD₅₀Unit range is 1.25U-3,000 unit Botox.Compositions disclosed herein can make LD₅₀Unit range is the Type B meat poisoning bar of 1.25-20,000U Bacterium.Compositions disclosed herein can make preparation by as in Aerosol delivery to nose or oral cavity, be based on meat poisoning bar with promotion The intracranial delivery of the drug of verticillium toxin.Compositions disclosed herein can make preparation as Aerosol delivery into ear canal, with Promote the intracranial delivery of the drug based on clostridium botulinum.

The present invention provides through any injection or methods of use for topical application, in addition to encephalic, wear cranium, intrathecal or intraspinal injection, For by the method for the central nervous system based on the drug delivery of botulin toxin to subject of therapeutically effective amount, and not The subject for the treatment of compares, and the therapeutically effective amount is enough to reduce at least one central nervous system nerve mediator.It is excellent at one In the embodiment of choosing, at least one central nervous system nerve mediator is glutamic acid, norepinephrine or acetylcholine.? In one further preferred embodiment, at least one central nervous system nerve mediator is glutamic acid.In another embodiment In, when compared with untreated subject, method of the invention reduces at least one central nervous system nerve mediator, foot To reduce insomnia, sleep disturbance, anxiety disorder, depressive disorder, dysmenorrhea, at least one of appetite eating disorder or the obstacle that breaks out Symptom.In a preferred embodiment, breaking-out obstacle is systemic, focal motility or complicated part.

Glutamic acid is to show the active neurotransmitter of endogenous neurotoxic, in a large amount of neurodegenerative diseases and barrier Hinder, observe and obtain in the unexpected such as apoplexy of blood vessel and breaking-out obstacle.For example, with slightly to moderate dementia and possible A Erci The subject of the silent disease in sea has shown that showing the horizontal of central nervous system Glutamic Acid increases.Paddy ammonia in central nervous system Horizontal increase of acid reflects that the early stage glutamatergic activity of Alzheimer disease increases.In Alzheimer disease and other nerves The progressive neuronal observed in degenerative disorder and disease, which is lost, to be increased with glutamic acid and increases with the level of the neurotransmitter Relevant exitotoxicity enhancing is related.

The present invention provides the method for reducing the glutamate levels of central nervous system, brain or part brain, including following Step: by any injection or methods of use for topical application, in addition to encephalic, cranium, intrathecal or intraspinal injection are worn, to snibject one Quantitative botulin toxin drug, compared with untreated subject, the amount be enough to reduce central nervous system, brain or The glutamate levels of part brain.

The present invention is provided to the methods of neuroprotection, comprising the following steps: by any injection or methods of use for topical application, In addition to encephalic, cranium, intrathecal or intraspinal injection are worn, to a certain amount of botulin toxin drug of snibject, and is not treated Subject compare, the amount is enough to reduce the neuron loss of central nervous system, brain or part brain.

The present invention also provides the bases for delivering therapeutically effective amount in nasal sinus to the central nervous system of subject by being injected into In the method for the drug of botulin toxin, compared with untreated subject, the therapeutically effective amount is enough to reduce at least one A central nervous system nerve mediator.In a preferred embodiment, at least one central nervous system nerve mediator is Glutamic acid, norepinephrine or acetylcholine.In a further preferred embodiment, at least one central nervous system mind It is glutamic acid through mediator.In another embodiment, when compared with untreated subject, method of the invention reduce to Few a kind of central nervous system nerve mediator, it is sufficient to reduce insomnia, sleep disturbance, anxiety disorder, depressive disorder, dysmenorrhea or hair Make at least one symptom of obstacle.In a preferred embodiment, breaking-out obstacle is systemic, focal motility or answers Hetero moiety.

The present invention also provides by any injection or methods of use for topical application, in addition to encephalic, cranium, intrathecal or intraspinal note are worn It penetrates, for by the method for the central nervous system based on the drug delivery of botulin toxin to subject of therapeutically effective amount, Compared with untreated subject, the therapeutically effective amount is enough to reduce at least one central nervous system nerve mediator.One In a preferred embodiment, at least one central nervous system nerve mediator is glutamic acid, norepinephrine or acetyl gallbladder Alkali.In a further preferred embodiment, at least one central nervous system nerve mediator is glutamic acid.In another implementation In scheme, when compared with untreated subject, method of the invention reduces at least one central nervous system nerve mediator, It is enough to reduce agitated behavior relevant to mental retardation, schizophrenia, hungtington's chorea or Alzheimer disease.

The present invention also provides by any injection or methods of use for topical application, in addition to encephalic, cranium, intrathecal or intraspinal note are worn It penetrates, for by the method for the central nervous system based on the drug delivery of botulin toxin to subject of therapeutically effective amount, Compared with untreated subject, the therapeutically effective amount is enough to reduce at least one central nervous system nerve mediator.One In a preferred embodiment, at least one central nervous system nerve mediator is glutamic acid, norepinephrine or acetyl gallbladder Alkali.In a further preferred embodiment, at least one central nervous system nerve mediator is glutamic acid.In another implementation In scheme, when compared with untreated subject, method of the invention reduces at least one central nervous system nerve mediator, It is enough to reduce at least one symptom of neurodegenerative disease relevant to inflammation.

The present invention also provides botulin toxin of the invention or botulinum toxin composition in preparation for treating this Purposes in any one obstacle, disease or illness disclosed in text and the drug for treating pain, the obstacle, disease or disease Disease includes depressive disorder, anxiety disorder, sleep disturbance, circadian disorders, methanone derivatives, Alzheimer disease It is such as various headaches, pain relevant to pain syndrome Deng, the pain.

Brief description

Fig. 1 is depicted compared with untreated mouse, the paddy ammonia in the neostriatum of the mouse of clostridium botulinum toxicity processing Acid acceptor activity reduces.

The image technique of Fig. 2 display positioning glutamic acid deviation.

Fig. 3 shows the area of cortex of frontal lobe and cortex of temporal lobe, shows the excessive glutamic acid of expression.

Fig. 4 shows the area of partial analysis brain area excess GABA neurotransmission, and injects strategy outside cranium and target Treat these regions.

Detailed description of the invention

A. it defines

" administration " of composition as used herein refers to any administration route, including but not limited to oral, nasal cavity, percutaneous (transcutaneous), percutaneous (percutaneous), in subcutaneous, peritonaeum, transdermal (transdermal), in intramuscular and bone, But it clearly excludes encephalic, wear cranium, intrathecal or intraspinal injection any medication.

" botulin toxin " refers to from clostridium botulinum bacterial strain, including various immunophenotypings as used herein, such as A, B, C1, C2, C3, D, E, F and G, isolated proteotoxin and its compound.

" depressive disorder " refers to major depression, dysthymia and Atypical depression or unclassified suppression as used herein Strongly fragrant (depression not otherwise specified).

" effective quantity " is to be enough to reduce and depression and anxiety or sleep disturbance or described herein any as used herein One or more symptoms of obstacle.

Term " pharmaceutical acceptable carrier " as used herein refers to that active constituent can be in combination and can be used for after the combination To the Chemical composition that of snibject's active constituent." pharmaceutical acceptable carrier " also includes but is not limited to one or more following objects Matter: excipient；Surfactant；Dispersing agent；Inert diluent；Granulating agent and disintegrating agent；Adhesive；Lubricant；Sweetener；It adjusts Taste agent；Colorant；Preservative；The degradable composition of physiology, such as gelatin；Aqueous vehicles and solvent；Oiliness solvent and solvent； Suspending agent；Dispersing agent or wetting agent；Emulsifier, moderator；Buffer；Salt；Thickener；Filler；Emulsifier；Antioxidant；Antibiosis Element；Antifungal agent；Stabilizer；With pharmaceutical acceptable polymer matter or lyophobic dust.It may include in pharmaceutical composition of the invention In other " ingredients in addition " be known in the art, such as description in Genaro, ed., 1985, Remington's In Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., it is incorporated herein by quoting In.

" responsiveness increase " refers to as used herein has the subject of response to complete to botulin toxin treatment pain The ratio of portion subject (having response to botulin toxin and without response) increases.

" response ratio " refers to as used herein has the subject of response to whole to botulin toxin treatment pain The ratio of subject's (having response to botulin toxin and without response).

Term " screening crowd " as used herein refers to that retrospective examination and analysis subject's medical history or identification specificity are same Period diagnosis.

The preparation of pharmaceutical composition described herein can be by any method for known to area of pharmacology or hereafter developing Preparation.In general, such preparation method includes the step for mixing active constituent with carrier or one or more other auxiliary elements Suddenly, then if necessary or expectation, product is made or is packaged into desired single dose or multi-dose unit form.

Although the explanation of pharmaceutical composition provided herein relates generally to the pharmaceutical composition for being suitable for ethically being administered to the mankind Object, but it should be understood by those skilled in the art that such composition is typically suitable for being administered to the animal of all kinds.It will be applicable in Being improved in the pharmaceutical composition for being administered to the mankind to make the composition be suitable for being administered to various animals is good understanding, usually This field veterinary pharmacology man can design and carry out such improvement only with routine experimentation (if any).This hair is administered The expected subject of bright pharmaceutical composition includes but is not limited to the mankind and other primates and other mammals.

The relative quantity of active constituent, pharmaceutical acceptable carrier and any other ingredient in pharmaceutical composition of the invention is by basis Identity, size and the illness variation of subject to be treated, and further changed according to the approach of administration composition.Citing comes It says, composition may include the active constituent in 0.1% to 100% (w/w).In addition to the active ingredient, drug of the invention Composition may further include one or more other forms of pharmacologically active agents.Especially expected other medicament includes antiemetic And scavenger, such as cyanide and cyanate scavenger.The controlled or sustained release formulations of pharmaceutical composition of the invention can be used Routine techniques preparation.

Term " physiology is acceptable " ester or salt as used herein refer to any other at split-phase with pharmaceutical composition The ester or salt form of the active constituent of appearance, it is harmless for the subject of composition to be administered.

B. depressive disorder

Depressive disorder includes being diagnosed as major depression, dysthymia and Atypical depression or unclassified depression (" slightly Depression ").Diagnosis and statistics handbook (Diagnostic and of the depressive disorder of different subgroups by mental disease Statistical Manual of Mental Disorders), fourth edition (DSM-IV) (American Psychiatric Association.Diagnostic and Statistical Manual of Mental Disorders,4.sup.th Ed.,Primary Care Version(DSM-IV-PC).American Psychiatric Association Press, Washington, D.C.1995) classified and is defined.According to DSM-IV, diagnoses " major depression " and need in entire diagnostic period Between patient there are at least five kinds in following nine kinds of symptoms: 1) the most of time hypothymergasia in one day (morning most serious)；2) In nearly all activity, interest and happy (anhedonia) is significantly reduced；3) weight significantly mitigates or increases；4) it has a sleepless night or sleeps It sleeps excessive；5) psychomotor agitation or slow；6) fatigue or energy losses；7) sense of guilt or value missing sense；8) attention by Damage is irresolute；Dead or suicide is expected with 9) continuous.In order to support the diagnosis of severe depression, five kinds of symptoms observed In must to have one be hypothymergasia or anhedonia (anhedonia).On the contrary, most common form " the atypical suppression of depression It is strongly fragrant " or " unclassified depression " (also referred to as " minor depressive ") diagnosis need daily or one day in most of time exist 2 to 4 kinds of depressive symptoms continue at least two weeks.Dysthymia is chronic, the low-intensity disturbance of emotion, feature be anhedonia, Low self esteem and energy are insufficient, and continued presence is more than 2 years.Think that seasonal Emotional Disorders are characterized by seasonal variety A kind of form of major depression.

Depressive disorder does not include normal emotional reactions, normal grieved reaction or organic reason such as body illness it is secondary Property reaction or drug exposure.Depressive disorder as used herein refers to primary mood and sleep pattern obstacle, and not secondary Property or reaction sexual dysfunction.Such reaction sexual dysfunction is more secondary than other medical disorders described as follows: ephidrosis, cervical muscle Power obstacle, migraine, tension headache, various pain syndromes, gnathospasmus, blepharospasm, strabismus, it is inflammatory locally and systemically Disease, postoperative pain syndrome, hemifacial spasm, cancer, myocardial infarction, apoplexy, neurodegenerative disease disease are drawn Play any other body illness of emotional reactions.

C. anxiety

Anxiety is that one group of feature is a large amount of mind & body symptoms without the obstacle obviously explained.Fear is feared to lose It controls, fears " going mad ", fears death (pending death), extremely urgent danger (impending danger) i.e. Or uneasiness is the most common mental symptom.Common physical symptom includes dizziness, feels dizzy, the increasing of pectoralgia, abdominal pain, nausea, heart rate Add or diarrhea.Chronic anxiety, also referred to as generalized anxiety disorder show as persistent fear, fear and negative ideas and continue at least Six months.Chronic anxiety typically results in undue worries, headache and nausea during daily activity.It is sleep disturbance or early awakening, depression, tight , courbature and fatigue can all accompanied by long-term anxieties.

Acute anxiety or panic disorder, in breaking out or fear starts, with the disease that can be similar to heart attack Shape, such as palpitaition, pectoralgia and dizziness.It is short of breath, has a stomach upset, feeling cold, cold sweat, hot flash or not fearing that death can rationally The individual for undergoing them is set to generate frightening impression together with these symptoms.It is increased it was found that noradrenaline level is excessively high The respiratory rate and pulse frequency of patients with panic attacks.Posttraumatic stress disorder is also categorized as anxiety disorder, can be by any experience Or anyone triggering of the deep traumatic event of witness.Some symptoms of posttraumatic stress disorder can be indignation, depression, mood Numbness, flashback (flashbacks), nightmare and have the tendency that being easy to terrified.

Phobia or unreasonable fear and compulsive disorder are (a kind of to tend to becoming for repeatability or uncontrollable sexual behaviour Gesture) also it is classified as anxiety disorder.These can cooperatively exist because many individuals with compulsive disorder have bacterium or Unclean phobia can excessively clean their hand or shower.

Anxiety disorder does not include that normal emotional reactions, normal stress reaction or organic reason such as body illness are secondary Reaction or drug exposure.

D. sleep disturbance

Circadian rhythm describes 24 hour period of approximation of organism generation.Most of physiology systems confirm circadian rhythm Variation.System with most of significant changes is sleep-wake cycle, body heat regulation and endocrine system.Circadian rhythm is disorderly Disorderly can be classified as two main Types: temporary sexual dysfunction is (for example, jet lag, work of being slept due to caused by work, social responsibility Breath changes and disease) and long-term obstacle.The most common long-term obstacle is the sleep phase syndrome (delayedsleep- of delay Phasesyndrome, DSPS), in advance sleep phase syndrome (advanced sleep-phase syndrome, ASPS) With irregular sleep-wake cycle.The genetic correlation for circadian pattern has been proposed in Katzenberg et al. (i.e. clock polymorphism (clock polymorphisms)).DSPS is characterized in that socially the acceptable time is constantly It cannot fall asleep and awaken (more than 6 months).Once falling asleep, these patients are able to maintain their sleep, have and normally always sleep It sleeps the time.(conversely, because being difficult to start or keep sleep, the patient with insomnia has more less than normal total sleep time Sleeping time).ASPS is characterized in that lasting dusk sleep morbidity (in 6:00 between 9:00pm), when awakening with early morning Between, usually in 3:00 between 5:00am.The frequency much less that ASPS ratio DSPS occurs is most commonly in of the elderly and depression Body.

The neural basal of circadian rhythm, suprachiasmatic nucleus (SCN) have been identified as producing positioned at the preceding veutro of hypothalamus The matrix of raw circadian activity.SCN lesion causes sleep-wake cycle, activity-quiescent period, skin temperature and cortex class The circadian rhythm rhythmicity of steroid production is lost.In the presence of the other rhythm of the heart adjusters (pacemakers) not being located in SCN.Example Such as, although bilateral cuts off SCN, the core temperature rhythm and pace of moving things is still had.Further, the research of free-running operation provides multiple saves round the clock Restrain the evidence of oscillator.Under conditions of free-running operation, circadian rhythm is segmented into several independent sectors.

SCN is the main circadian clock position of mammal.SCN clock mainly has light-dark cycle.Optical information is by view Film is by direct retinohypothalamic (retinohypothalamic) fiber conveying to SCN.SCN also receives other projections, Such as the cholinergic fiber from basal forebrain.Cholinergic is incoming and transmitting has been proved to the section round the clock for participating in reconciling photoinduction It restrains (Erhardt et al.2004The Neuroanantomy of the Circadian Rhythm.).

In the U.S., DSPS is very universal.Complain that the patient of the about 7-10% of insomnia is diagnosed with circadian disorders, it is most logical It is often DSPS.The illness rate of DSPS may be higher, because the total sleep time of the patient with DSPS is usually normal, and Because the patient with DSPS adjusts their life style to adapt to their sleep work and rest, without seeking therapeutic treatment. In puberty, illness rate is about 7%.On the contrary, genuine ASPS may quite lack.However, age-dependent phase is common in advance In the elderly, tend to go to bed early and get up early.

The diagnosis of circadian disorders is mainly based upon comprehensive social, body and neurology history.Temporary sexual dysfunction with The discrimination of long-term obstacle and primary sexual dysfunction and secondary sexual dysfunction affects the direction of evaluation and treatment plan.Such as all doctors History and psychiatry history are treated, naturally complains it is first thing.In the situation of insomnia, difference be difficult to starting sleep individual with It is difficult to keep the individual of sleep, there is the obvious individual for damaging (daytime impairment) in the daytime and complain non-restorative (nonrestorative) individual of sleep is critically important.

Obstacle relevant to various sleep disturbance includes narcolepsy, damping off, restless leg syndrome and sleep property are exhaled Inhale pause.Anxiety disorder does not include that normal emotional reactions, normal stress reaction or organic reason such as body illness are secondary Reaction or drug exposure.

E.CNS obstacle

Present invention is alternatively directed to be used by percutaneous injection or any administration route disclosed herein based on clostridium botulinum poison The drug of element induces method of the central nervous system impression effect to treat various CNS obstacles.The inventors discovered that clostridium botulinum Toxin plays CNS inhibiting effect in the rat that percutaneous injection enters scalp.Injection is not encephalic or is directly entered brain, but can be wrapped Include or particularly exclude intrathecal and intraspinal injection or administration.It is assumed that botulin toxin penetration rate of blood/brain barrier of percutaneous dosing. The present invention is provided to be hindered using the drug therapy breaking-out disclosed herein based on botulin toxin, anxiety, excitement, mania, two-phase Hinder, popularity breaking-out, mental retardation, delirium, excessively dynamic syndrome, attention deficit disorder (ADD), dementia, Heng Tingdunshi Disease, Alzheimer disease, Parkinson's disease, mental disease, schizophrenia, insomnia and other CNS obstacles.

In certain embodiments, disclosed herein to be used to lure with various dosage levels based on the drug of botulin toxin Send out the popularity atrophy effect of CNS.The effect is for treating various CNS obstacles.The inventors discovered that injection high dose meat poisoning bar Verticillium toxin is (that is, dosage is LD₅₀Or in its vicinity) rat show their intracerebral telocoeles expansion or expand.Control display does not have There is such effect, but the animal through treating shows obvious action.Popularity encephalatrophy is percutaneous dosing clostridium botulinum The performance of the bioactivity for the neurotransmitter levels that toxin induces.Evidence and the inhibiting effect one in the hypothalamus through treating animal It causes.This can cause the direct effect for releases such as hormones such as thyrotropin releasing factor, gonadotropin-releasing hormone (GRH).

The full content of all books, paper, patent or other publications and bibliography is incorporated herein by quoting. Any compound for referring to this paper all includes racemate and single enantiomter.

From the other cards for wearing cranium movement of the btulinum toxin injection of the Lu Wai injection of soft tissue and neck area of head zone According to (referring to zooscopy)

Based on the morphological change that head is injected outside high dose cranium in animal, it is direct to have shown that botulin toxin passes through It diffuses into brain and generates encephalatrophy.Neurotransmission and important neurotransmitter such as glutamic acid, norepinephrine and acetyl gallbladder The variation of alkali significantly changes under the dosage close to mortality levels.Grind about neurotransmission using a variety of important neurotransmitters Study carefully the scientific basic of the aspect effect.GABA receptor has been monitored (referring to Fig. 1).As the glutamate receptor on neuron subtracts It is few, also it is surprising to note that relative to right in the brain structure that will be injected into 20 to 30 grams of mouse outside botulin toxin cranium According to GABA acceptor intensity and expression reduction.These receptors are considered the balance of neurotransmission and its expression in to(for) glutamic acid Aspect is critically important.It was found that GABA receptor be also blocked it is meaningful in terms of the CNS effect for understanding botulin toxin.It has infused It anticipates to some GABA receptor blocking pharmacons such as benzene phenodiazineClass is active in treating many diseases, the disease include anxiety, The relevant anorexia of generalized anxiety disorder, anxiety, mandatory mandatory personal traits, mandatory pressure sexual behaviour, autotomy And it stress after wound.General anesthesiologist treated using such drug pain and pain medicine impression before excitement with Relieve pain impression.They are also used for mood and the disturbance of emotion as mentioned above.With blocked glutamic acid neurotransmission receptor It compares, blocks GABA transmitting that there is opposite effect.It seems that botulin toxin not only influences glutamic acid neurotransmission, but also right Have an impact in GABA transmitting.Whole summations are for injecting adjusting and stabilization of the botulin toxin to mood and the disturbance of emotion outside cranium Important role.

Botulin toxin is for treating maincenter hypertension (Central Hypertension)

The pathogenesis of excessive glutamic acid expression and the excessive norepinephrine transmitting of intracerebral and maincenter hypertension has It closes.Maincenter hypertension be it is a kind of due to central nervous system nerve mediator extremely caused by form of hypertension, cause from brain Increase with the sympathetic activities of brain stem structure.The norepinephrine release of glutamic acid initiation is described in document.It is past Research adjusts maincenter hypertension using the antagonist of N- methyl-D-Asp (NMDA) receptor and glutamate receptor.By force The strong other forms for showing nmda receptor and glutamate receptor and glutamate receptor are for central sympathetic tone and hypertension There is adjustment effect.

For maincenter hypertension, botulin toxin is moved into brain and blocks opposite glutamic acid metabolism (metabiotrophic) receptor and/or nmda receptor are derived from a variety of effects of the botulin toxin for central nervous system Principle.Mechanism is related to

1. the direct effect for anxiety

2. for the direct effect of sympathetic nerve central nervous system outflow

3. for promoting the direct effect of sleep and relieving insomnia

4. the direct effect for circadian rhythm period, such as regulation and control angiotensin-renine aldosterone system.

We have seen that with the example of the patient around btulinum toxin injection to face and eyes, with mood with Emotion improves, depression and improving and anxiety are reduced, also related with blood pressure reduction.It is photosensitive in certain patients to sexually revise instruction influence blood vessel The circadian rhythm effect of Angiotensin Converting Enzyme feritin (angiotension rennin) circulation.Such observation result can be used for passing through Following step treatment suffers from the predicament patient of hypertension:

1. identifying with maincenter hypertension or using the patient of drug technique, that is, drug drug resistance hypertension.

2. being spread in the soft tissue outside btulinum toxin injection to brainpan to enhance botulin toxin in method Into in the central nervous system areas in the region for including basal ganglion and locus coeruleus, pons, midbrain and thalamus.Caudate putamen It is the target spot of botulin toxin diffusion, is also possible to the target spot for injecting outside cranium.The target spot central nervous system it In, more particularly, in the brain stem area of control autonomic nerve outflow.

Occur to block by it very heavy in precise mechanism hypertension that pivot mediates in the treatment of at least one neurotransmitter It wants.The hypertension that such maincenter mediates may occur with the variation of cerebral disease or it can be special sending out and is primary The component part of hypertension.Essential hypertension is the target treated with botulin toxin.It is not that nephrosis, encephalopathy are secondary that it, which refers to, The hypertension of property or the hypertension of other ondary forms.

Up-regulation nmda receptor activity may also have an impact to hypothalamus.The sleeping with circadian clock exception instructed before Dormancy obstacle is also a kind of form of regulation hypertension.Think that botulin toxin has been used to treatment circadian disorders before, And targeting hypothalamus, cause the improvement of hypertension.

These observation results are consistent with the centurion effect concept of (Centurion Effect) is known as before, which represent The effect that inventor passes through following discoveries: 30 years experience of botulin toxin are injected using him and are noticed in the U.S. in 2007 The age apparently lives more higher than the U.S. patient for receiving botulin toxin for 61 years old repeatedly than the ordinary people of follow-up in census Long.

Emotion, mood, the relationship of anxiety and hypertension

Instructing as before, botulin toxin is for including that (major depression, anxiety disorder include mandatory pressure to depression Property personal traits, after wound stress and popularity free floating sexual anxiety and various forms of anxiety neurosises, and packet Include the sleep disturbance of various forms of insomnias) mood and the disturbance of emotion it is effective.This document describes using including following various aspects And multi-method technology treatment hypertension method:

1. the problem for the treatment of mood and emotion, especially anxiety, anxiety neurosis or the sleep disturbance after hypertension.

2. by the soft tissue outside btulinum toxin injection to brainpan, so that botulin toxin diffuses into central nervous system System brain parenchym, influences at least one neurotransmitter of brain.

3. identifying the patient for suffering from maincenter hypertension.

4. evaluation result is that systolic pressure and diastolic pressure improve.

It is also described herein and includes the steps that diagnosing maincenter hypertension.Maincenter hypertension can be by identifying at least one nerve Mediator diagnoses extremely.The neurotransmitter can be norepinephrine, glutamic acid, glutamate receptor, nmda receptor, remove first kidney Upper parathyrine receptor and norepinephrine neurotransmitter and acetylcholinergic receptor and acetylcholine neurotransmitter.More particularly, Glutamic acid neurotransmitter or glutamate receptor include nmda receptor.

In view of these observations as a result, scanning may include that spectrum MRI scan, PET scan or detection neurotransmitter are abnormal Other scanning forms image scanning.The method will is that

1. office hypertension

2. whether office hypertension is that routine treatment is intractable, the routine treatment such as use Beta receptor blockers, Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, ACE acceptor inhibitor, calcium channel blocking agent or diuretics.If these drugs are not enough or ineffective, it can be assumed that deposit Maincenter hypertension in situ.Further, and particularly, brain, brain stem (including diencephalon, midbrain), pons or medullary substance can be diagnosed Whether horizontal neurotransmitter abnormality is abnormal.Such abnormality may include to glutamate receptor, glutamic acid neurotransmission, Or the neurotransmitter of any other form transmits imaging.Once the diagnosis of maincenter hypertension is determined, then can with single stove or The Botox of LD50 unit of the multifocal injection strategy administration between 2.0 to 3,000, to be injected into brainpan External soft tissue, and it is highly preferred that injection site should be corresponding to distance closer to brain key abnormal area, to make Botulin toxin has enough chances to diffuse into the region under using relatively low-dose, so that defect mitigates.These agent Amount range is most preferably the A type toxin for being lower than 800 units, is more preferably less than the A type toxin of 400 units, and optimal Selection of land is lower than the A type toxin of 200 units.Purpose is to generate diffuse through brainpan, enter central nervous system across blood-brain barrier System, to act on neurotransmitter generation, so as to treat hypertension.It must be understood that hypertension is maincenter hypertension, and it is not As including caused by the other forms hypertension of renovascular hypertension.Main primary essential hypertension can be maincenter The combination of hypertension and possible renal function exception.This is also the target for proposing invention.

Target glutamate receptor neurotransmitter related disease

Glutamic acid is a kind of important neurotransmitter；It accounts for about the 40% of the transmitting of whole cynapse present in human brain and spinal cord To 50%.It is a kind of important neurotransmitter for being registered as participating in cell death and neurotoxicity, especially at a high level. At a high level, glutamic acid neurotransmitter with into nerve cell cause dead nmda receptor and glutamate receptor related from Subflow is related.A large amount of effort that a variety of central nervous system diseases are treated using glutamate receptor blocking agent are carried out.Ketamine It is related with the treatment of depression, depression is alleviated by blocked glutamic acid receptor.Block using glutamate receptor big Measure a large amount of effort of central nervous system disease process.Have been carried out use after a stroke glutamate receptor blocking agent as The test of neuroprotective agent.Because there are a variety of side effects using the trial drug for largely serving as glutamate receptor blocking agent, so far This method all has failed until the present.A kind of safely and effectively glutamate receptor blocking agent with hypotoxicity is needed to treat in a large amount of Pivot nervous system disease.Botulin toxin can pass through blood-brain barrier and enter central nervous system and effective by other mechanism The peculiar property for lowering glutamate receptor and blocked glutamic acid neurotransmission is obviously treating a large amount of central nervous system diseases Aspect achieves progress.High security characteristic determined by botulin toxin is enhanced in the neuroprotection described herein that needs Applicability in many clinical scenarios.

These central nervous system diseases include the disease or obstacle of mood and emotion, including major depression, bipolar disease, Bipolar Depression, bipolar mania, mania, schizophrenia, mental disease, dementia, Alzheimer disease, Heng Tingdunshi disease, Parkinson's disease, mandatory mandatory personal traits, Recurrent epilepsy, diversified forms anorexia, be related to the autoimmunity of glutamic acid Sexual centre the nervous system disease such as systemic loupus erythematosus of central nervous system participation, craniocerebral injury, head trauma, brain are frustrated Wound, ruptured cerebral aneurysm, hydrocephalus are related to any other central nervous system disease of disorganization.

It is important that glutamic acid can be imaged with spectrum MRI, PET scan or any other method.It confirms in disease mistake Journey Glutamic Acid or any other neurotransmitter, which are in high-caliber various methods and techniques and all show, gives meat to be administered The good chance of bacillus venenosus toxin, to be protected from neurotransmitter associated neuronal toxicity.

This document describes a kind of methods for the treatment of and prevention central nervous system disease progress, including outside the cranium on head Give medicine botulin toxin.This may include scalp, face, periocular area, incidence, mandibular region, ear week region or Nasal sinus, nasal cavity inner cavity, nasal sinus, bone structure and pars oralis pharyngis, so that botulin toxin sufficiently diffuses into intracerebral.The present invention is solid Have plenty of botulin toxin and be diffused directly into intracerebral, and causes a kind of blocking of important neurotransmitter.It is taught before other Lead is that botulin toxin cannot penetrate blood-brain barrier.This document describes opposite New Observer as a result, botulin toxin enters Intracerebral, and can have directly effect to neurotransmitter.More particularly, neurotransmitter include glutamic acid, acetylcholine, glycine, GABA, and its expression that can influence suitable acceptor is to resist cell death caused by toxicity neurotransmitter.

The method includes:

1. identifying central nervous system disorders.

2. botulin toxin is administered to outside cranium in soft tissue, to diffuse into intracerebral, to block at least one in brain Kind of neurotransmitter, so as to improve central nervous system disease symptom or slow down its progress.

4. with neuroimaging and medical history and the result of physical examination evaluation injection.

5. repeated application botulin toxin, and monitoring acts on, so that not occurring the progress of central nervous system disease.

In addition, central nervous system disease can be natural neurodegenerative disease, natural cranial vascular disease, natural Injury.Protection can occur in cranial nerve level.Neuroprotection can rise relative to virus or bacterium infection or cerebral hemorrhage Effect.

In short, the present invention can be described as:

1. the neurotransmitter anomaly evaluation using imaging identifies central nervous system disease.

2. botulin toxin is applied to outside the cranium of incidence in soft tissue.

3. evaluating the improvement for the symptom that central nervous system disease generates or reducing central nervous system disease progression rates.

Dosage administration

Dosage administration is between 2.5 to 3000 units again.Dosage administration can be located at more stove positions.Selectivity is administered into Intracerebral can be by injecting on targeting brain area domain.For example, periocular injections will be preferred if brain stem and midbrain are target spots 's.For the region, nasal sinus injection can also be given, and the injection of nasal cavity inner cavity nasal sinus can be given.If target spot is in temporal lobe It is interior, then it can give and inject in temporal bone ear week region.It, can be under neck or in foramen magnum or occipital bone if target spot is located at occipital lobe On give and inject, complete diffusion so as to pass through the diploic veins venae of head portion.It should be noted that into the quiet of intracerebral Arteries and veins drainage is usually in the soft tissue of cranium outer circulation, but mechanism can be not limited to the route of entry.A small amount of toxin can be direct It is diffused into soft tissue, even in bone.Fig. 1 gives the guidance for the neural cranium exterior domain for confirming venous drainage to incidence Figure.

According to necessity relevant to progression of disease, the duplicate injection in 3 to 4 months sections is needed, for improving total disease Shape.Imaging can be synchronized to neurotransmitter.Particularly, neurotransmitter can be glutamic acid, acetylcholine, GABA, sweet ammonia The selection version of acid or norepinephrine.

The relative scale of neurotransmitter can be evaluated with different imaging techniques, and diagnostic matching botulin toxin is made With the pathogenesis with targeting disease.

Application of the invention should be considered particularly matching the diagnosis that can be done and relevant neurotransmitter is abnormal.Mood and Affective disease is the common name for including following diseases: major depression；Bipolar disease；Minor depressive；Reactive depression；Schizophrenia Disease；Seasonal Emotional Disorders, generalized anxiety disorder have the anxiety neurosis of subclass, irritability syndrome after wound.Other Anxiety correlation anorexia, anorexia nervosa, mental disease；Obsessive-compulsive Personality；The Recurrent epilepsy of whole forms, including popularity Breaking-out, complex partial seizures, the breaking-out of focal motility；It lacks of proper care with any toxic metabolic occurred in central nervous system, It can be the target spot of local nerve mediator exception.

Preferred injection strategy

The brain neurotransmitter because currently known clostridium botulinum penetrates and extends influence, thus it is possible to vary injection strategy is so as to brain Specific part can receive the botulin toxin of preferred dose administration.The preferred dose administration of different brain areas is included within Different zones in the outer soft tissue of brainpan are using the botulin toxin measured step by step, so that wherein nervous centralis transmitting becomes for optimization The diffusion gradient in the brain area domain of target spot.This refers to for example, periocular area is more likely to, eye orbit areas is almost impossible, diffuses into Region in brain, frontal lobe and thalamus, this is anatomy drainage mode based on the region medium sized vein structure and close closes on position It sets.The processing in temporal lobe region is included on temporal bone and injects.It is injected into the rear pillow that cerebellum is included within covering Posterior fossa and cerebellum It is injected on bone.It is injected into the prominent upper injection of backbone that upper cervical spinal cord should be included with apophysis by vertebra, cover spinal cord.

Selectivity injection be based on delivering from anatomically determine, and can also pass through dosage administration optimization.As above Described, the importance injected outside cranium makes it suitable for the treatment based on office, and side effect is limited and for central nervous system The limited damage of important feature such as cortex and brain structure.The present invention is not instructed to be injected directly by any such technology Intracerebral.In order to enhance injection, it may include the important area in brainpan using minor thread pipe for complementary therapy, can make to expand It dissipates more greatly, if necessary to if given area generates stronger effect.

The uniqueness instructed herein is observation is that can be by being injected into soft tissue for btulinum toxin injection to brainpan Outer control nervous centralis transmitting.As instructed in other patents before the present inventor, the diffusion of botulin toxin is a kind of Dose dependent phenomenon.By be injected into soft tissue outside brainpan enter diseased brain tissue indicate it is a kind of before incognizant entrance The new entrance of central nervous system.With the progress that neurotransmitter is imaged, form of the invention and injection strategy are a kind of dose The new paragon of amount administration, administration and targeting disease.These diseases may include neurodegenerative disease comprising Alzheimer Disease, Parkinson's disease, Heng Tingdunshi disease, breaking-out obstacle, the recurrent exerbation obstacle with damage and mood and the disturbance of emotion, with And cerebrovascular occlusion damage.The damage for limiting cerebrovascular occlusion includes limiting the discharge of important neurotransmitter.The neurotransmitter is more It particularly may include the glutamic acid or glutamic acid related activity of maincenter synaptic levels.In the embodiment of this invention, it teaches herein:

1. being identified by imaging research, there are the brain area domains of neurotransmitter disease and movable focal area.

2. by direct injection or as elsewhere herein introduction other forms transdermal delivery system by botulin toxin It is applied to more close to the region.

3. measuring the clinical benefit from this injection strategy.

4. multiple scanning structure or scanning are to see whether to inhibit neurotransmitter hyperaction in time, it is contemplated that duplicate injection is many Year.

Use botulin toxin and unique injection strategy targeting brain area domain.

Since botulin toxin can directly spread, across venous drainage system or other conduits and penetrate blood-brain barrier Into in brainpan, brain area domain can be targeted using the glutamic acid neurotransmission of unusual high levels.So far, do not have before the technology It was described, and provided the unique method of a kind of dosage administration and change local cerebral neurotransmission, can be applied to retouch herein The various central nervous system disorders stated.In the newest technological advance of Brian Imaging, PET scan (positron emission can be used Tomography) and the research of spectrum MRI (magnetic resonance imaging) complete the imaging of various neurotransmitters.Contemplate that other methods.In this way Progress for start evaluation characterizing and understanding many moods and the disturbance of emotion (major depression, bipolar disease, mania, essence After refreshing Split disease, Parkinson's disease, Alzheimer disease, anxiety, wound, apoplexy, cerebral hemorrhage, circadian disorders (sleep disturbance, Hypertension, insomnia, hypersomnia, sleep apnea), anxiety disorder, irritability syndrome, chronic anxiety, anorexia after wound Sexual dysfunction, bulimia nerovsa) mechanism in the influence that lacks of the various mediators that work.These imaging methods not only characterize nerve biography The exception passed；The method can be with the maincenter of local positioning (geographic localization) wherein neurotransmission exception Nervous system regions.Such localization method has been obtained about following structure blueprints: wherein can with drug administration by injection outside cranium so that Preparation maximization based on botulin toxin penetrates into brainpan, passes through blood-brain barrier, so that target area receives administrating Object minimizes the diffusion in the region far from muscle, peripheral nerve and nervous centralis, wherein the medicinal application in the region is It is undesirable and cause side effect, for example facial expression is impaired, ptosis, cannot be closed that eyelid, head movement be weak, head piece Water, eyebrow are sagging, paralytic ectropion, facial asymmetry, facioplegia, diplopia, slurred speech, swallow difficult, upper gas Road insufficiency is accidentally inhaled (aspiration), facial appearance sorrow or is administered excessively with the musculature dosage of head-neck region Relevant other side effects.

The characterization of neurotransmitter exception can be used for preceding diagnosis entity to further characterize obstacle property.

It should not only be characterized by neurotransmitter type, also by wherein there is the abnormal specific brain regions region of neurotransmitter activity Characterization.For example, if the activity in the region Y of brain discovery neurotransmitter X is abnormal, it will be outside btulinum toxin injection to brainpan Soft tissue may be adapted to be preferentially targeted and penetrate and diffuse into the region Y with block nerves mediator X.

The region Y can be following any or combinations thereof:

Diencephalon (front side brain stem (rostral brainstem), caudate nucleus, thalamus, lenticular nucleus), midbrain, pons, medullary substance, the right side or Any specific gyrus, hypothalamus, infracerebral gland, frontal lobe-top-temporal lobe, spinal cord and occipital lobe or central nervous system in left brain hemisphere Any other part.

Neurotransmitter X can be following any or combinations thereof: glutamic acid, acetylcholine, γ aminobenzoic acid (GABA), Norepinephrine, glycine, thrombocytin or dopamine.More particularly, glutamic acid, acetylcholine GABA or noradrenaline Element.

Injection can be located at any position outside brainpan, and by wearing cranium delivering, by penetrating, across venous drainage, (socket of the eye is quiet Arteries and veins, facial vein, diploic veins venae) or blood-brain barrier any other part, maximumlly diffusion and central nervous system delivering.Make Can easily the distance to injection site it be divided with the anatomy of MR imaging or CT imaging by imaging with computer determination Analysis is classified.

Central nervous system disease includes mood and affective disease or obstacle comprising major depression, bipolar disease, two-phase Depression, bipolar mania, mania, schizophrenia, mental disease, dementia, Alzheimer disease, Heng Tingdunshi disease, pa gold Gloomy disease, Recurrent epilepsy, is related to the autoimmune central nervous system disease ratio of glutamic acid at mandatory mandatory personal traits Systemic loupus erythematosus, craniocerebral injury, head trauma, cerebral contusion, ruptured cerebral aneurysm, the brain product participated in such as central nervous system Water is related to any other central nervous system disease of nerve tissue damage.

The present invention has plenty of following intention admittedly: with spectrum MRI, PET scan or can show glutamic acid or any other Neurotransmitter is in high-caliber any other mechanism and glutamic acid is imaged, and the toxicity in such neurotransmitter and neuron is made With related.

There is also described herein a kind for the treatment of, slow down or prevent the method that central nervous system disease is in progress, including to brainpan Botulin toxin is administered to be prevented, be prolonged by using Botulinum toxin blocks neurotoxin neurotransmitter outside cranium in outer portion Late, slow down or even prevent the progress of any central nervous system disease.

Injection areas may include scalp, face, periocular area, incidence, mandibular region, ear week region or nasal sinus, Nasal cavity inner cavity, nasal sinus, bone and pars oralis pharyngis, to realize that botulin toxin sufficiently diffuses into the brain area domain of selection.It is accurate fixed The method of position is determined by aforementioned techniques and confirms the analysis with the brain area domain of neurotransmission exception and allow maximum delivering The selection of incidence cranium exterior domain.It is straight via cranium channel (not being direct injection of brain) is worn that the present invention has plenty of botulin toxin admittedly It connects and diffuses into brain, a kind of important neurotransmitter is caused to block.Introduction is all to block meat poisoning bar before every other people Verticillium toxin penetrates blood-brain barrier.A kind of viewpoint opposite with universal idea is described herein, clostridium botulinum is malicious after injection for description The New Observer that element is entered in brain within a few hours by injection outside cranium is as a result, and can have directly effect to neurotransmitter.More Particularly, neurotransmitter includes glutamic acid, acetylcholine, glycine, GABA, and botulin toxin can influence suitable acceptor Expression is to resist cell death caused by toxicity neurotransmitter.

The method includes:

1. identifying central nervous system disorders by diagnosis (diagnosis entity).Identify wherein neurotransmitter and is confirmed as abnormal brain Region carries out selection diagnosis.

2. by botulin toxin to diffuse into the amount for targeting brain area domain or being diffused into entire intracerebral in some cases enough Applied to soft tissue outside cranium.

3. blocking at least one of brain neurotransmitter, so as to improve symptom or slow down progression of disease.

4. evaluating injection result using the clinical evaluation of neuroimaging and S&S.Neuroimaging can be used for before The property or hypotype for diagnosing entity for determining injection position or being treated.

5. repeated application botulin toxin, and monitoring acts on, so that not occurring the progress of central nervous system disease.

Representative table for cranial nerve transmitting:

It is following to represent access (access) table of injection clostridium botulinum, the clostridium botulinum pass through expected target administration into Enter the various brain area domains with diagnosis illness.The table is intended for approximation and citing.It before application, all should needs assessment The neuroimaging of each individual with Abnormal neurotransmission.

Injection particularly can be given wherein can be by injecting the individual gyrus or very specific brain treated outside cranium The region of focal zone.For example, if the breaking-out of focal motility is to rise in sinistrocerebral prefrontal cortex, the area Ze Gai Injection may be implemented to be directly administered on brainpan in domain, without causing the influence for close region.

Upper table is only an example, can be based on the Anatomy and Gray's Anatomy of such as Grant's atlas The conventional anatomy extension of and Functional Nervous System Anatomy textbook description.In clinical practice, positioning preferably by Progress, especially spectrum MRI and PET scan are studied using neuroimaging or are identified as any other form of illness in brain area domain Location technology.In popularity brain or spinal cord pathologic condition, diffusion injection strategy can be used for and customize (customized) in Generate the more wide application to brain.

Inject the further perfect of strategy

Because confirmed that clostridium botulinum penetrates into intracerebral and effect obtained for neurotransmitter, thus it is possible to vary injection Strategy receives the botulin toxin of preferred dose administration so that specific brain taps.Preferred dose is administered in the domain of Different brain region The different zones in the outer soft tissue of brainpan are included within using the botulin toxin measured step by step, to optimize nervous centralis transmitting The diffusion gradient in the brain area domain as target spot.This refer to for example, be injected into periocular area will be more likely to diffuse into midbrain, frontal lobe and In the region of thalamus region, this is anatomy drainage mode based on the region to brain medium sized vein structure and close closes on position It sets.Treating temporal lobe region will include that injection enters in the soft tissue on temporal bone.Be injected into cerebellum be included within covering Posterior fossa and It is injected on the occipital bone of cerebellum.The prominent upper injection of backbone that injection is included within apophysis by vertebra into upper cervical spinal, covers spinal cord.

Selectivity injection be based on delivering from dissection go to school it is determining, and can also pass through dosage administration optimization.As above Described, the importance injected outside cranium makes it suitable for the treatment based on office, and side effect is limited and for central nervous system The limited damage of important feature such as cortex and brain structure.The present invention is not instructed to be injected directly by any such technology Intracerebral.

It can include the important area in brainpan for adjuvant treatment using minor thread pipe to enhance injection, it can be with Keep diffusion bigger, if necessary to if given area generates stronger effect.

For enhancing the implantable catheter needle (Conduit Pins) for wearing cranium diffusion

It is to pass through botulin toxin necessary to bone and blood-brain barrier be delivered in brain structure due to wearing cranium diffusion, In the presence of the method that can be used for enhancing the process, it can make to invade minimum and not need any main neurosurgery method.This A little methods will include being implanted into a kind of device, and enhancing botulin toxin is directed through into neural skull arched roof, passes through three In layer meninges (dura mater, arachnoid and pia mater (pia)) and the brain substance of entrance target location or diffusion is applied.For example, tool Self-drilling screw can be molded by having the titanium needle (pin) of opening conduit (open canals), and be put into outside head and middle part with And it is put into head in some cases in lamella.Such implantation material enhances around vein visible native transistor in osteocranium Road, and allow more toxin to penetrate if being injected on these implantation materials.These devices can be with biocompatible any Biocompatible materials (titanium, ceramics, plastics, plastics) preparation.They can be placed in suitable position, even if future does not need to infuse It penetrates.

Central nervous system infiltration is helped to allow using relatively low-dose to obtain higher cranial nerve endotoxin level using conduit, Without causing the excessive weakness due to being diffused into its neuromuscular action outside central nervous system.

Local action in dull-witted and other forms neurodegeneration:

Instruct herein unique is observation is that can be by injection of soft tissue by btulinum toxin injection to brainpan External control axis neurotransmission.Being instructed in referring to patent as before, the diffusion of botulin toxin be a kind of dosage according to Rely property phenomenon, it is incognizant before reaching diseased brain tissue by the soft structure that is injected into outside brainpan and indicating a kind of or before not The new entrance for entering central nervous system in direct mode of practice.With the progress of imaging neurotransmitter, form of the invention It is the new method for the disease that dosage administration and targeting are instructed as before with injection strategy.These diseases may include neurodegeneration disease Disease comprising Alzheimer disease, Parkinson's disease, Heng Tingdunshi disease, breaking-out obstacle, the recurrent exerbation obstacle with damage, With the damage of mood and the disturbance of emotion and cerebrovascular occlusion.Limiting cerebrovascular occlusion damage includes that limitation participation neuron is thin The important neurotransmitter of cellular damage.The neurotransmitter more particularly may include the glutamic acid or glutamic acid phase of maincenter synaptic levels Close activity.In the embodiment of this invention, it teaches herein:

1. identifying, there are the brain area domains of neurotransmitter disease and movable focal area；

2 answer botulin toxin by direct injection or such as the transdermal delivery system of the other forms of elsewhere herein introduction With to more close to the region.

3. measuring the clinical benefit from such injection strategy.

4. multiple scanning structure or scanning are to see whether to inhibit neurotransmitter hyperaction in time.

Insomnia

Notice that insomnia was related to some problems of circadian rhythm function in the past.Sleep, blood pressure control, skin in body circulation The circadian rhythm function of matter alcohol secretion is all related to central nervous system circadian system to a certain extent.

From the point of view of the medical perspective, vigilance disorders are related with the difficulty of controlling of blood pressure.Certain with drug resistance hypertension In patient population, sleep disturbance can be related with hypertension.In these groups, the form that Lu Wai injection of soft tissue can be used is used Botulin toxin, can be alleviated therefore sleep disturbance alleviates hypertension in a manner of by neurotoxin influences central nervous system. For hypertension, the mechanism that botulin toxin can work is:

1. improving sleep disturbance.

2. improving anxiety.

3. improving major depression.

4. the transmitting of glutamic acid central nervous system nerve is influenced, to preferably keep circadian clock and circadian rhythm.

The set of above-mentioned effect needs botulin toxin injection position outside cranium to move through brainpan, and influences at least A kind of neurotransmitter.Neurotransmitter most probable can be glutamic acid, but can be norepinephrine, acetylcholine or other forms Neurotransmitter.In terms of how the present invention works, it is very crucial to diffuse into intracerebral.It cannot particularly feel by influence Nerve adapts to have an impact or limit that weak any type of neuromuscular action is caused to work to sensory nerve.In reality It applies in the present invention, is contemplated that following:

1. diagnosing the essential hypertension that do not treat for conventional using resistant hypertension or before.

2. diagnosing has adjoint problem of sleeping.

3. botulin toxin, which is administered, treats sleep disturbance, (reconciling) hypertension is thus adjusted.

4. using standard monitoring device and process monitoring hypertension.

Contribution of the above-mentioned cognition to central nervous system for essential hypertension and other forms hypertension.

Sleep disturbance is related with the high incidence of a few peoples.Sleep disturbance is more likely to occur in obesity, in Black people group Also with the ethnic form (racial configuration) of more easily ill in body.Such crowd is also easier in angiocarpy In the risk of disease, therefore race and ethnic origin are critically important in terms of aid forecasting is using invention described herein.This It in situation, should need to High risk group, such as the non-descendants with much higher sleep disturbance and cardiovascular disorder disease incidence American race's tendency (racial preference) is evaluated.It can use such difference to concentrate the present invention Implement in High risk group.Further, since the present invention is doctor-administration technology, any patient's compliance is not needed, this Invention can be used for the patient that the use of its traditional Chinese medicine compliance is limited.

In these cases, the regular dosage of doctor is in 2.5 units to the toxin of 3000 unit A types.Patient does not need In specific time, daily therefore drug it is limited to comply with sexual factor.Unique duration of botulin toxin effect is very It is long, reached for 12 to 16 weeks, can be helpful.

Administration in depression, unique characteristic

(irritability syndrome after major depression, Bipolar Depression, seasonal Emotional Disorders, wound)

It teaches herein and botulin toxin is used for depressive disorder, especially major depressive disorder (MDD).It can also For irritability syndrome after Bipolar Depression, wound and the depressed such as seasonal Emotional Disorders of various other forms.

This document describes a kind of method that botulin toxin is administered, advantage be do not need wherein daily basis patient it is suitable Ying Xing.Moreover, which limit the risks of suicide in depression, because administration is all based on doctor, it is close patient is not needed A large amount of oral drugs.

Substantially, the suicide risk that botulin toxin is administered is substantially absent.This has in terms for the treatment of depressive patient There is big advantage.This document describes one kind not only to treat major depression, but also treats the major depression with high suicide risk Method.In the embodiment of this invention, psychiatrist or doctor are attempted based on his past medical history, suicide before and are used before The suicide risk of the compliance evaluation patient of drug.If it is determined that risk, then recommends botulin toxin.Of the invention this One property rely on the fact that with regard to dosage administration or use for, botulin toxin be unilaterally given by doctor without Need patient compliance.In this case, this shows the significant advantage in terms of practicability, and new with innovation, because For the main problem in being practiced which solve psychiatry.

Hypertension, glutamic acid and circadian disorders:

Blood pressure control is that a kind of have the function of the main circadian rhythm of day-night change.

Hypertension can be generated extremely by central nervous system function, and by using CNS agent such as clostridium botulinum Its adjustable treatment of toxin prepared product.Excessive sympathetic activities from the autonomous center CNS by circadian rhythm mechanism control, It can have pathological consequences.Myocardial infarction most commonly occurs in the morning, in part because the rising in the daytime of morning blood pressure and the heart Vascular stimulation.The circadian clock mechanism that cranium diffuses into hypothalamus, which is worn, via botulin toxin slows down sympathetic nerve output It actually can help to adjust controlling of blood pressure.

In rat test model, the periventricular nucleus (PVN) of hypothalamus helps to create hypertension.Neuron pool is projected into Sympathetic neuron in spinal cord and rostral ventrolateral medulla, and adjust sympathetic activities and vascular tone and blood pressure.It improves Sympathetic activity is the reason of one kind causes essential hypertension, such as spontaneously hypertensive rat model.Glutamic acid is room Basic neurotransmitter in other core.Glutamic acid is the main neurotransmitter in nucleus paraventricularis, in rat model, increase glutamic acid into The input for entering former sympathetic neuron (pre sympathetic neurons), which has shown that, causes vascular tone raising and height Blood pressure.Nucleus paraventricularis is with circadian rhythm nerve node largely incoming from suprachiasmatic nucleus (suprachiasmic nucleus) The part of structure.

It is injected directly into cranium external structure, makes inflow hypothalamus (0074), basal ganglion and hypophysis vascular system most Bigization, to adjust the glutamic acid neurotransmission in these regions, this is adjusting and is inhibiting to come from these regions such as nucleus paraventricularis Interior sympathetic nerve output is to adjust blood pressure aspect effectively.Related (the Castanada of glutamic acid and circadian rhythm in these regions T R,Circadian Rhythms of dopamine,glutamate,and GABA in the striatum and nucleus accumbens in the awake rat,modulation by light J.Pineal Res.2004 36 (3),177-85)。

Therefore, it is targeted using single injection or multiple injection using botulin toxin to facial forehead and cranium exterior domain, It makes venous drainage and transhipment botulin toxin to the brain maximum area of control circadian rhythm, to treat maincenter hypertension, The hypertension more particularly controlled by the day-night change of circadian rhythm.The hypertension obstacle of the form is asserted relative to cardiac muscle The cardiovascular risk of infarct is more dangerous.In the hypertension of the form, the decline of blood pressure is usually eliminated during sleep.By controlling Circadian disorders are treated, botulin toxin has effectively repaired diurnal blood pressure variation and alleviated hypertension.Dosage can be As described herein.

Circadian disorders:

Circadian rhythm is subjected to the variation and expression of various neurotransmitters and associated receptor.Various circadian disorders can be by The Pathologic changes of neurotransmitter cause, and the Pathologic changes of the neurotransmitter are based on losing photosensitive (blindness), obtain nerve Mediator obstacle and enzyme, mechanism albumen, receptor and neurotransmission molecular basis other components in genetic abnormality.

The function of changing circadian rhythm can effectively treat a large amount of associated diseases, such as sleep disturbance, attention deficit Pressure cvd caused by obstacle, hypertension, sympathetic nerve central nervous system flow out, the food for adjusting weight and Fat distribution Desire and mood degeneration physiological dysfunctions.Mood degeneration sex dysfunction includes and anxiety and stress relevant diarrhea (convulsion Contraction colonic diseases), hyperventilation, diffusivity perspiration, heart rate-palpitaition, asthma, pain increase, are dizzy, chest is uncomfortable, not specially Note, amnesia and fatigue.

Improve sleep, sleep synchronizes and contributes effectively to many associated circadian rhythm functions, therefore helps to control Treat relevant dysfunction.For example, improving, sleep is synchronized and related blood pressure control can contribute to treatment hypertension, coronal dynamic Symptom, asthma, functional abdominal pain, spastic colon, ADD and the systemic non-interruptible fatigue syndrome of arteries and veins occlusion (generalized non disrupt fatigue syndromes)。

Major depression, mania, bipolar disease, anxiety disorder, migraine correlation barrier can be improved by improving sleep synchronization Hinder, chronic tension headache, backache or any other chronic pain disorder.Sleep improvement can effectively improve

1. pain syndrome

2. other moods and the disturbance of emotion, including major depression, the anxious syndrome as defined in DSM IV

3. whole body fatigue (Generalized fatigue)

4. organic brain symptom, dementia, memory and cognition

5. the energy and interest of daily life function are impaired

6. absent minded

7. the pathological change of appetite

8. excitability and pathological excitement

9. reappearing idea (Recurring thoughts)

10. the mood component of essential hypertension

Botulin toxin is used for the purposes of eating disorder

As previously mentioned, the botulin toxin of this paper can be used for treating some form of eating disorder.These eating disorders Including to following relevant eating disorder: after generalized anxiety disorder, phobia, wound irritability syndrome and with depression it is relevant each The anorexia of kind form.If related with the social mentality of suitable form and mood and emotion barrier, anorexia nervosa is also meat poisoning bar The expection indication of verticillium toxin, is also possible to therapy target.

Circadian rhythm not only includes the circadian rhythm function of blood pressure maintenance, sleep and other forms, but also they are also hidden Contain control food intake.The neurotransmitter of glutamic acid neurotransmitter and other forms can be very for generating appetite and anorexia It is important.The method of patient this document describes treatment with certain form anorexia, the anorexia can be different with central nervous system It is often related with neurotransmission.The application is also by injecting strategy outside cranium, and usually used dosage is such as 5 to 2000 units, More particularly 100 to 300 units, more specifically about 150 to 200 units.

These injections are given with single stove and more stove positions, and are under subcutaneous (subcutaneous), corium (subdermal), percutaneous, intraosseous injection.Injection can also be given in a manner of toxin described in local administration, expand to target It is scattered on the important area of control appetite and brain will include hypothalamus and thalamus, front area and brain stem and middle brain stem.This It can be used in conjunction with the anorexia therapy of other forms, and can be used for controlling anorexia and nausea and appetite.

The downward of receptor relative:

This document describes the effects of opposite neurotransmitter glutamate and GABA.Lower the expression of receptor based on axoneuron Double activity be very unique characteristic that how botulin toxin acts in central nervous system.Due to glutamic acid with Nervous activity is excessively related and GABA is as neuron inhibitor, and botulin toxin adjusts excited sexual function and neuron simultaneously The inhibition of bioactivity.This effect has unique property relative to mood and emotion, including but not limited in certain meaning Upper experience extreme anxiety excitement and another extreme depression.

Embodiment

Following embodiments play that the present invention is further explained, still, are not to be seen as limiting in any way Its range.

Embodiment 1

One is recorded as sleep disturbance and 78 years old male of anxiety is initially diagnosed with blepharospasm.Pass through drug administration by injection Botulin toxin, subject records sleep improvement and anxiety is reduced.

Embodiment 2

One 44 years old Bus driver is diagnosed with hemifacial spasm, and report has anxiety symptom.Pass through drug administration by injection meat poisoning Bacillus toxin.Subject's record muddle with one's work related pressure and ability that difficult case is dealt with lower pressure it is more preferable.

Embodiment 3

Hemifacial spasm is suffered from by the diagnosis that drug administration by injection botulin toxin treats a report sleep disturbance and anxiety 72 years old consultant.Subject reports sleep improvement and anxiety is reduced and excitement is reduced.

Embodiment 4

One 45 years old women treats makeup indication with botulin toxin.Initial diagnosis is makeup fine wrinkle (cosmetic rhytides).Depressive symptom is less during subject records two months, and anxiety is reduced.

Embodiment 5

44 years old woman that a diagnosis suffers from serious tension headache and sleep disturbance is treated by injection botulin toxin Female.After the treatment up to two months, sleep pattern improves and has a headache less subject's record.

Embodiment 6

One 73 years old male with essential eyelid spasm reports sleep disturbance and is characterized as the anxiety of " nervous ". Pass through drug administration by injection botulin toxin.Subject records anxiety reduction and sleep improvement after injection.Symptom, which is reduced, to be continued It is two months to three months, final to recur.

Embodiment 7

43 years old personnel for suffering from myofacial pain and sleeping problems are treated by injection botulin toxin.Subject Sleep pattern is more preferable after injection for record, continues three months.

Embodiment 8

One 42 years old personnel is diagnosed with myofacial pain, tension headache and depression, passes through drug administration by injection meat poisoning bar Bacterium extract for treating.Sleep pattern obtains some improvement after subject is recorded in toxin injection.

Embodiment 9

Subject is 54 years old personnel, and diagnosis suffers from essential eyelid spasm and depression.Clostridium botulinum poison is introduced by injection Element.Depressive symptom is less after subject is recorded in btulinum toxin injection.

Embodiment 10

Subject is 57 years old doctor, and diagnosis suffers from essential eyelid spasm.Botulin toxin is introduced by injection.It is tested Person has floaty euphoria, happiness and mood to improve after being recorded in btulinum toxin injection.

Embodiment 11

One 47 years old women, the medical history with cervical headache and frequent insomnia problem.The feature of insomnia is to be difficult to open It moves sleep, interval sexual arousal, early morning awakening and is not able to maintain sleep.In the region and edge commonly used in treatment accessory cramp Multiple positions of the front and rear of hairline give and inject.Dosage range between each subcutaneous infusion sites 5-20 unit, Accumulated dose 100U.Within 3-5 days, insomnia occur improves, and continues 10-14 weeks.She changes each part of sleep disturbance It is kind.Occurs sleep disturbance recurrence after 10-14 weeks.

Embodiment 12

One 52 years old women receives clostridium botulinum injection for glabella fine wrinkle of erasing (facial gauffer).Along the more of hairline Other injections are given in a position, she also suffers from the insomnia of starting sleep and prolonged sleep difficulty.Injection botulin toxin it Afterwards, sleep pattern improved, and for about 10-12 weeks.In multiple positions, the accumulated dose of administration is 30 units.

Embodiment 13

60U is separately injected to 71 years old male with essential eyelid spasm along periocular area and forehead.Every After secondary injection, it is that the sleep pattern more continuously slept improves that feature, which is recorded,.Benefit for about 3 months, had recorded through Cross three injection cycles.When causing patient to pay attention to, he associates the improvement with btulinum toxin injection.It is wanted when he experiences When the time of duplicate injection botulin toxin, insomnia recurrence.

Embodiment 14

By including one pack system neurotoxic molecule, auxilin or compound protein are free of, appointing containing human serum albumins What immunization type (A-G) and nanoemulsions with various charges prepare botulinum toxin composition.Nanoemulsions can contain By by following any number of polymer formed: polyethylene glycol, vegetable oil, vegetable oil derivatives or monounsaturated or how unsaturated Oil.PH be can change in preparation to enhance permeability.Optionally, by include one pack system neurotoxin immunization type A-G, Albumin prepares botulin toxin, and no nanoemulsions carrier, acid pH is between 1-6 unit.Using commonly used in nerve The animal model (20-30 grams of mouse) of the rodent of degenerative disease research confirms the effect of percutaneous injection Central nervous system. The injection of Botox is given in scalp region, dosage is close and is about the LD of the animal₅₀.The animal of survival into Row autopsy cuts brain with continuous, and carries out histological stain using standard Nissle formula.Basal ganglion and brain is recorded A large amount of atrophys of room pericyte.This variation is usually not visible in the case where systemic disease is without direct brain pathology.Neuropathy Neo-Confucianism evaluation is high dose (close to the LD of animal model₅₀) direct repression that occurs in central nervous system.It is expected that And more minor change is anticipated in the clinical observation based on insomnia, dysmenorrhea, depression and anxiety validity under lower therapeutic dose. Experiment described herein shows that usually blocking the neurotransmission of excitatory neurotransmitter to reach brain structure the journey of Pathologic changes occurs Degree.The major central system neurotransmitters of blocking include glutamic acid, norepinephrine, acetylcholine.Enhance GABA Effect.The SNAP-25 in entire target area is recorded to crack.

Embodiment 15

Percutaneous injection is confirmed using the rodent models (20-30 grams of mouse) commonly used in research neurodegenerative disease The effect of Central nervous system.Four btulinum toxin injection agent are given in scalp region (amounts to 0.8LD₅₀Unit). The animal of survival carries out autopsy and continuously cuts brain, and carries out histological stain using standard Nissle formula.Record substrate A large amount of atrophys of neuromere and ventricles of the brain pericyte.Record cholinergic neuron largely reduces.Record cholinacetyltranslase Amount is a large amount of to be reduced.Clinical observation based on insomnia, dysmenorrhea, depression and anxiety validity under lower therapeutic dose is anticipated more micro- Small variation.Experiment described herein shows that usually blocking the neurotransmission of excitatory neurotransmitter to reach brain structure pathology change occurs The degree of change.The major central system neurotransmitters of blocking include glutamic acid, norepinephrine and acetylcholine.Enhancing GABA effect.The SNAP-25 in entire target area is recorded to crack.

Embodiment 16

Percutaneous injection is confirmed using the rodent models (20-30 grams of mouse) commonly used in research neurodegenerative disease The effect of Central nervous system.Four btulinum toxin injection agent are given in scalp region (amounts to 0.8LD₅₀Unit). The animal of survival carries out autopsy and continuously cuts brain, and carries out histological stain using standard Nissle formula.Use cresols Purple carries out Nissle substance stain to the mouse tissue slice continuously cut, and immunostaining is used for glutamate receptor activity. Washing slice 1 hour in the buffered saline of Tris- containing polysorbas20 (TBS-T) comprising 10% Normal Goat Serum.Then, it will cut Piece overnight incubation in the TBS-T containing 0.1% sodium azide and anti-GluR4.Slice is washed three times in TBS-T, is then existed It is cultivated 2-3 hours in TBS-T comprising goat anti mouse peroxidase-conjugation secondary antibody, to detect glutamic acid.So Afterwards, slice is washed three times in TBS-T.Antibody complex is set to develop using diaminobenzidine.Use excessive target protein Pre-absorption (Preabsorbtion) or the omission (omission) of first antibody or secondary antibody confirm antibody specificity, and Background is generated by testing and analyzing to test.Use the Nikon Eclipse E800 microscope inspection with Spot RT digital camera Look into histotomy.In mouse (four injections, the total of untreated mice (vacation injection) and botulin toxin processing 0.8LD₅₀BOTOX.RTM., the intramuscular injection in scalp region) in the tissue slice images of neostriatum be shown in Fig. 1.

Embodiment 17

Wear that cranium moves into brain parenchym and whether brain structure generates increased section for a further understanding of botulin toxin Evidence is learned, using the fusions of Alexa dyestuff and botulin toxin, and is put into tentative rat model described herein.Melt Prepared product is closed from the identical bacterial strain and culture for being used to prepare A type Toxin Hall bacterial strain, the A type Toxin Hall bacterial strain Commonly used in treating human diseases, such as the Botox (trade mark) of Allergan Pharmaceuticals distribution.The 3rd, 6,12, It 24 hours and 2 weeks, studies the botulinum toxin type A neurotoxin of the fusion and Alexa dyestuff is injected outside cranium and is diffused into brain Interior possibility.Each period analyzes one group of 3 to 5 mouse.At 6 hours, via with immunofluorescence microscopy brain notch And brain section, Alexa dyestuff is recorded in the brain and immunohistochemical analysis of central nervous system structures.At 3 hours, do not have Such dyestuff is recorded, and behind, any dyestuff is not recorded.This is to show toxin and dyestuff together outside cranium Injection is moved to the pharmacokinetic studies of intracerebral.

The expression of receptor of the anatomy the atrophy change and crucial brain neurotransmitter close under lethal dose is combined in the discovery Variation, shows obviously to move into botulin toxin in brainpan, and has life at least one neurotransmitter Object effect.This document describes the purposes from the experimental model, facilitates the disease that treatment includes mood and emotion, that is, handle The central nervous system nerve transmitting for being related to neurotransmitter is critically important for mood as described herein and the disturbance of emotion.

Embodiment 18

For major depressive disorder, within basal ganglion and adjacent cerebral hemisphere, the data phase compared with normal control Than identifying the exception of glutamic acid neurotransmission.MDD symptom is evaluated according to the standard of DSM IV.Treatment plan is configured to meat poisoning Bacillus toxin is applied to close to front-side base neuromere (rostral basal ganglion), wherein being reflected using anatomical parameters Not Wei neurotransmitter abnormal movement, and calculate dose dependent Diffusion Strategy.

By anatomy scan covering matching abnormal neuron mediator activity (such as glutamic acid neurotransmission, content of glutamic acid or Expression of metabotropic glutamate receptor la), to study extrapolation minimum range from neuroimaging.Agent variable is administered in single or multiple Dose locations The botulin toxin of amount, so that from targeted delivery is injected outside cranium into central nervous system and brain.

Embodiment 19

One suffers from 44 years old women of major depression, anti-to thrombocytin cell reabsorption inhibitor (Cymbalta-TM) and tricyclic Depressant drug is not corresponding, and has been diagnosed as having the DSM IV of at least five kinds of major depressions to determine factor, uses PET to sweep it Imaging apparatus analyzes glutamic acid neurotransmission and content of glutamic acid, with suitable computer aided program and non-depressed normal subjects Control level be compared.By image technique measured deviation, the glutamic acid deviation in image is positioned, for example is provided in Fig. 2 's.Deviation is indicated by an arrow.

By Botox along left periocular area be injected into left nose transmucosal deeply and Middle face in.Meat poisoning bar Verticillium toxin dosage is in total between 4-3000 unit, however, based on being measured in advance in the test bin clinical research of the multi-dose of image The calculations list measurement of variation carry out regulating dosage, clinical research measurement is about anatomy relevant range, dosage, note outside cranium Penetrate number and the biological effect conspicuousness for the effect of glutamic acid neurotransmission.To mitigate to facial expression muscle meat ill-effect Mode administration dosage, therefore, non-face muscle region are preferred.Give higher dosage score to facial muscles, being conducive to Adornment benefit, therefore avoid craniofacial asymmetry or disfigurement.

After to major depression effect several weeks, is evaluated, gives duplicate injection with 6-14 weeks interval.It can be with note Penetrate the various bleeding agents of strategy use such as hyaluronidase (hylauronidase) or polycation albumen.

Embodiment 20

One 67 years old male suffers from memory and space orientation defect.He is clinically diagnosed with Alzheimer Disease.PET and spectrum MRI scan are shown in the glutamate activity spread in entire cerebral cortex and increase, but in volume and temporo region On it is more prominent.For the neurotoxicity for the glutamic acid that the progress limited by Alzheimer disease generates, given in volume temporo region Multiple injection.In Fig. 3, excessive glutamic acid is expressed in region (arrow instruction) display in volume cortex and temporo cortex.By meat poisoning Bacillus, which is injected at, to be surrounded in the bone structure on cerebral cortex, causes the inhibition of glutamate activity, to inhibit organic brain function The symptom of obstacle, and slow down the progress of progressive dementia.

Embodiment 21

It is studied based on neuroimaging, record patient has excessive GABA neurotransmission.Fig. 4 shows the excessive of partial analysis The brain area domain in GABA neurotransmission region, and target and inject strategy outside cranium to treat these regions.Based on the animal confirmed herein Research, botulin toxin are proved to inhibit GABA neurotransmission, give in the single or multiple positions of cranium exterior domain effective Amount range is 5-3000U.

Claims (20)

1. a kind of method for treating central nervous system disorder, the central nervous system disorder be defined as intracerebral at least one or Have at least one brain neurotransmitter abnormal in multiple regions, including following methods:

A. by the cranium exterior domain or neck of btulinum toxin injection to head,

B. the cranium exterior domain and neck for making the head close to a region of brain, the region have by use PET scan, The abnormal neuron neurotransmitter activity that functional magnetic resonance imaging or brain scanning determine,

C. wherein the Botulinum toxin blocks involve the neurotransmission of at least one neurotransmitter.

2. the method for claim 1 wherein the neurotransmitter is glutamic acid.

3. the method for claim 1 wherein the neurotransmitter is acetylcholine.

4. the method for claim 1 wherein the neurotransmitter is GABA.

5. the method for claim 1 wherein the neurotransmitter is noradrenaline.

6. the method for claim 1 wherein the abnormalities of brain is related with Major Depressive Disorder.

7. the method for claim 1 wherein the abnormalities of brain is related with bipolar disease.

8. it is related with irritability syndrome after generalized anxiety disorder and wound that the method for claim 1 wherein the abnormalitiess of brain.

9. the method for claim 1 wherein the obstacle is related with breaking-out.

10. method for claim 9, wherein breaking-out includes focal motility and complex partial.

11. being characterized as Alzheimer disease, Parkinson's disease or henry the method for claim 1 wherein the obstacle is neurodegeneration Court of a feudal ruler Dun Shi disease.

12. the method for claim 1 wherein the obstacle is cerebrovascular accident.

13. the method for claim 1 wherein the obstacle is the hypertension that maincenter mediates.

14. the method for claim 13, wherein the obstacle involves the maincenter component (acentral of essential hypertension component)。

15. the method for claim 1 wherein the obstacle is as the dysorexia for involving compulsive disorder.

16. the method for claim 1 wherein the obstacle is circadian disorders.

17. the method for claim 1 wherein the obstacle is sleep disturbance.

18. being characterized as migraine, tension headache, tonicity the method for claim 1 wherein the obstacle is pain disorder Headache merges migraine, trigeminal neuralgia, myofascial pain, cluster headache, post-operative wound pain.

19. the method for claim 1 wherein the obstacle is schizophrenia.

20. the method for claim 1 wherein the obstacle is seasonal Emotional Disorders.