CN101043890A - Delta-9-thc for treating symptoms associated with multiple sclerosis - Google Patents
Delta-9-thc for treating symptoms associated with multiple sclerosis Download PDFInfo
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Abstract
Methods are provided for, inter alia, treating and/or preventing symptoms associated with multiple sclerosis and MS relapse.
Description
The application requires the U.S. Provisional Application No.60/517 of submission on November 5th, 2003, the priority that U.S.'s non-provisional application of submitting on November 3rd, 479 and 2004 " is used for the treatment of the related indication δ of multiple sclerosis-9-TCH compositions and method ".
Invention field
The present invention relates to treat and/or prevent the method for the method of the symptom relevant and the experimenter MS recurrence that prevention suffers from MS with multiple sclerosis (MS).
Background of invention
Think that multiple sclerosis (MS) is the autoimmune disease that influences central nervous system (CNS).CNS is made up of brain, spinal cord and optic nerve.Surround and the nerve fiber of protection CNS be to be called myelinic fatty tissue, it helps the nerve fiber conduct electrical impulses.In MS, myelin lacks in a plurality of zones, leaves over to be called hardened scar tissue.These affected area are also referred to as speckle and determine or scab.In some cases, nerve fiber self is impaired or be damaged.When myelin or nerve fiber are damaged or are impaired, neural electric pulse is transmitted to brain and from brain the ability of conduct electrical impulses will be damaged, and this result produces the various symptoms of MS.
The patient who suffers from MS can predict one of four kinds of clinical course of disease: recurrence-mitigation; Former-carry out; Secondary-carry out; Or carry out-recur.People with recurrence-mitigation MS experiences the burst of obviously determining (being also referred to as recurrence, outbreak or deterioration).These belong to the outbreak of function of nervous system's rapid deterioration and follow the partially or completely convalescent period (mitigation) of no longer developing by disease.
Patient with former-carrying out property MS is taken place slowly, but begins to experience the process that almost continues deterioration from its seizure of disease, does not significantly recur or relaxes.Yet the speed of development changes in time, and accidental plateau and temporary improvement are by a small margin arranged.
Incunabulum with patient experience recurrence-mitigation disease of secondary-carrying out property MS is followed the process that constantly worsens by disease, with or without the burst of chance, recovery of less degree (mitigation) or platform phase.
At last, have carry out-patient experience of recurrent MS begins the process that constantly worsens from seizure of disease, and has tangible acute burst (outbreak or recurrence), has or do not exist recovery.MS is opposite with recurrence-retentivity, and the stage between the recurrence is characterised in that the disease sustainable development.
The patient who suffers from MS also experiences one or more symptoms relevant with MS usually, comprises bladder or bowel dysfunction; With memory, attention and the relevant problem of dealing with problems; Dizzy and dizzy; Depression; Tired; Equilibrium problem; Dysbasia; Pain; Sexual dysfunction; Visual problems; Anakusis; Headache; Pruritus; Epilepsy; Spasticity; Speech and dysphagia; And/or tremble.
Paramyotonia (because of the increase of cone tonicity cause tetanic) and spasm in up to 90% MS patient, take place.This symptom causes the very big misery because of pain, motoricity descend and the interference activities of daily living is brought usually.The invalid feature of other of this disease is included in up to the ataxia among 80% the patient and trembles and up to the sensory symptoms among 50% the MS patient, comprise pain.The lower urinary tract malfunction is present in the philtrum of the long-term multiple sclerosis of existence more than 90%, and wherein modal symptom is frequent micturition and urgent micturition.Although many symptoms can be resolved in that the mitigation of multiple sclerosis is interim, spasticity, weakness, ataxia and bladder symptom normally PD characteristic and tend to worsen in time.
In general, there be two types the spasm relevant: musculus flexor and extensor spasm with MS.The musculus flexor spasm is the unconscious bending of hip or lower limb (relating generally to the tendon flesh on the back of thighs); Hip and knee joint are to thoracic curve.On the other hand, the extensor rigidity state is the unconscious tetanic of lower limb.The extensor rigidity state relates to musculus quadriceps and adductor; The mode that hip and knee joint are very approaching each other with both legs or two ankle joint intersect keeps straight.Spasticity can also occur on the arm, but in MS, this situation is more uncommon.
The symptomatic treatment of MS is far from being enough.For example, present treatment provides inadequate remission usually and is subjected to the toxicity restriction.The treatment of the existing spasticity that is used for MS patient generally comprises baclofen, tizanidine, diazepam or clonazepam.Baclofen (Lioresal ) is a kind of muscle relaxant that works in spinal cord.Baclofen relaxes normally and the muscle of spasm, is common side effect but feel sick.
Tizanidine (Zanaflex ) specifies the medicine that is used for the treatment of paramyotonia.Except that sleepy, dry mouth also is common and normally of short duration side effect.Hypotension (blood pressure is low) is another kind of possible side effect, but more uncommon.In addition, the tizanidine causes the sedation stronger than other medicines usually.
Also use diazepam (Valium ) treatment spasticity, use low dose of usually.Sleepy and possible dependency prolonged application makes diazepam undesirable for many patients.
Regrettably, there is not the medicine of single approval can effectively treat the spasm relevant and not have side effect beastly with MS.There is the demand of safe and effective method of symptom of improvement being suffered from the patient experience of MS thus.
Dronabinol is to have chemistry (6aR-is trans)-6a by name, 7,8, and 10a-tetrahydrochysene-6,6,9-trimethyl-3-amyl group-6H-dibenzo＞b, The cannabinoid of pyrans-1-alcohol and be also referred to as delta-9-Tetrahydrocannabinol (δ-9-THC or A-9-THC).Its natural existence and extraction from Fructus Cannabis (Cannabissativa L.) (Fructus Cannabis (marijuana)).It also can chemosynthesis.Dronabinol is sold with Marinol trade mark at present, be used for the treatment of alleviate relevant anorexia with the weight in patients of suffering from AIDS and be used for the treatment of with the patient in the relevant nausea and vomiting of cancer chemotherapy, these patients can not produce enough reactions to Bendectin treatment commonly used.Yet dronabinol is not approved for the treatment side effect relevant with MS at present as yet.
Summary of the invention
Find unexpectedly at present that Δ-9-THC can improve the symptom of MS and can reduce the MS recurrence.Therefore, the present invention provides the method that treats and/or prevents the side effect relevant with MS in one embodiment.This method comprises the cannabinoid of the experimenter who suffers from MS being treated effective dose, for example Δ-9-tetrahydrocannabinol.
The present invention provides in another embodiment and has reduced the method for being in hospital relevant with recurrence among the patient who suffers from MS.
The present invention provides the method that is used to increase experimenter's activeness of suffering from MS in another embodiment.
According to method of the present invention, can be separately or effectively carrier or other pharmaceutically acceptable excipient or additive give cannabinoid on one or more medicines.
In addition, can be with cannabinoid, for example dronabinol and other medicines therapy, promptly symptomatic treatment is simultaneously or give successively.
The accompanying drawing summary
Accompanying drawing 1 shows the change from the scoring of the Ashworth between all follow-up period of baseline to 13 according to walking state and center effect adjustment.
Accompanying drawing 2 shows the influence of treatment group walking state to the Ashworth scoring.
Accompanying drawing 3 shows follows up a case by regular visits to group and the change of treatment group in the Ashworth scoring.
Accompanying drawing 4 shows the median of 10 meters walking times of following up a case by regular visits to group and treatment group.
Detailed Description Of The Invention
The present invention provides in one embodiment and has been used for the treatment of, limits, alleviates, reduces, delays and/or improvement and the related indication method of MS.The method of this embodiment comprises the cannabinoid of the experimenter that these needs are arranged being treated effective dose.
The term of this paper " cannabinoid " is particularly including δ-8-tetrahydrocannabinol, Δ-9-tetrahydrocannabinol, cannabidiol (cannabidol), olivetol, cannabinol, cannabigerol, nabilone and delta-9-Tetrahydrocannabinol acid (tetrahydro cannabinotic acid).Non-spirit is regulated medicine cannabinoid 3-dimethyl nepty 11 carboxylic acid homologues (homologine) 8, δ-the 8-tetrahydrocannabinol (for example, referring to " pharmaceutical chemistry magazine " (J.Med.Chem.35,3135,1992) and the prodrug of Cannabinoids and officinal salt also be suitable for the present invention and be included in the term " cannabinoid ".The suitable precursor medicine is a THC-hemisuccinic acid ester.
When using compositions, this means that the dosage of therapeutic agent (or multiple actives) makes the activating agent of treatment level be delivered in the blood flow in the process of using said composition with " treatment effective dose " of the present invention.This class is sent and is depended on many variablees, comprises that the time bar or the therapeutic agent that use each dosage unit enter the flux rate of experimenter's systemic circulation.Yet, the concrete dosage level that is to be understood that the therapeutic agent of the present invention that is used for any particular subject depends on various factors, comprises activity, the experimenter's of used particular compound the order of severity and the form of medication of age, body weight, general health situation, sex and meals, administration time, excretion rate, drug regimen and the specified disease for the treatment of.Therapeutic dose generally can progressively increase so that make safety and effect reach best.In general, the useful guideline of relevant experimenter's administration optimal dose can be provided at first from the dose-effect relationship of external and/or in vivo test.The research of carrying out in animal model generally can be used for relevant guidance for the treatment of the effective dose of disease according to the present invention.With regard to therapeutic scheme, should understand dosage and depend on Several Factors, comprise the particular active agent that gives, route of administration, the physical state of particular active agent, state of an illness of particular subject etc.For example, the term of this paper " treatment effective dose " refers to is enough to treat, limit, alleviate, prevent, reduce, delay and/or the amount of the cannabinoid of one or more symptoms that improvement is relevant with MS.This class consumption can have very big change and depend on the order of severity and type, the described variation of specific cannabinoid metabolism in experimenter self and the effect of expectation of body weight, side effect especially between experimenter and the experimenter.As explanation, consumption can be about 0.01-35mg/kg body weight, and every day, administration was 1-5 time.
Can measure the toxicity and the therapeutic efficiency (with dosage thus) of therapeutic agent in the present composition by the standard drug operating procedure, for example, measure LD
50(making the lethal dosage of 50% colony) and ED
50(the effective dosage of treatment in 50% colony).Dosage between toxicity and the therapeutical effect is than being therapeutic index and it can being expressed as LD
50/ ED
50Ratio.In one embodiment of the invention, use shows the exponential chemical compound of bigger treatment.Although can use the chemical compound that shows toxic side effects, but should careful consideration design make this compounds targeting to the delivery system that is subjected to the invaded tissue position, so that may reduce to bottom line to the potential damage of uninfection cell, alleviate side effect thus.
In the context of the present invention, to the experimenter, particularly human experimenter's dosage should be enough to reasonably causing therapeutic response in the time range.This dosage is by the intensity of used particular composition and individual's the state of an illness and the individual's that treated body weight decision.The dosage size is also by the existence that may follow any adverse side effect that gives particular composition, nature and extent decision.The suitable dose of vivo medicine-feeding is 0.01-100mg/kg/ days.Preferred dose is 0.01-35mg/kg/ days.More preferably dosage is 0.05-5mg/kg/ days.Dronabinol suitable concentration in the pharmaceutical composition that oral administration is used is 0.05-15% (by weight).Preferred concentration is 0.02-5%.Preferred concentration is 0.1-4%.More preferably per os gives the 0.03-0.06mg/kg body weight/day and most preferably the peroral dosage form of 2.5mg is administered twice every day.The most preferred dosage of treated in vitro is in the scope of about 0.1mg/kg-5mg/kg body weight/day.With regard to rectum, part (comprise and sucking and the Sublingual) or transdermal administration approach, its preferred dosage (estimating with the alkali form) is in the scope of 0.05mg/kg-20mg/kg body weight/day.Although can give dronabinol as required, preferably with dronabinol administration every day 1-5 time.
If dronabinol is the active medicine in the compositions of using according to the inventive method, the total amount that so preferred dronabinol is present in this based composition is about the about 20mg of 0.5mg-, the about 15mg of preferably about 1mg-, and the about 12mg of 2mg-more preferably from about.As explanation, this based composition comprises about 2mg, about 2.5mg, the dronabinol of about 5mg or about 10mg.
Cannabinoid can be mixed with the pharmaceutical composition that is suitable for the inventive method arbitrarily.That this based composition can be included as is oral, suck, the dosage form of Sublingual, subcutaneous, transdermal, intramuscular or intravenous, rectum, part or inhalation design.
The pharmaceutical composition that is applicable to the inventive method can comprise the pharmaceutically acceptable excipient of one or more avirulences commonly used as required, such as filler, binding agent, carrier, adjuvant and/or vehicle.Operable carrier mass is those excipient arbitrarily commonly used in the pharmacy and should be based on selecting with the compatibility of used cannabinoid and the release characteristics of required dosage form or compositions.The limiting examples of suitable pharmaceutically acceptable excipient comprises binding agent, disintegrating agent, filler, surfactant, pH correction agent, stabilizing agent, lubricant, diluent, antitack agent, fluidizer, carrier etc.
The limiting examples of suitable bonding comprises arabic gum, alginic acid and salt thereof, the cellulose derivative class, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, aluminium-magnesium silicate, Polyethylene Glycol, the natural gum class, the polysaccharide acids, the swelling great soil group, hydroxypropyl emthylcellulose, gelatin, polyvinylpyrrolidone, polyvinylpyrrolidone//vinyl acetate copolymers, crospovidone, polyvidone, polymethacrylate, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, starch, pregelatinized starch, ethyl cellulose, Tragacanth, dextrin, microcrystalline Cellulose, sucrose or glucose etc.
The limiting examples of suitable disintegrants comprises starch based, pregelatinization corn starch, pregelatinized starch, cellulose, cross-linked carboxymethyl cellulose, crospovidone, crospolyvinylpyrrolidone, calcium, sodium alginate complex, clay, alginic acid salt, gummy class or sodium starch glycollate and is used for any disintegrating agent of preparation tablets.
The limiting examples of suitable filler comprises lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline Cellulose, cellulose powder, glucose, dextrates class, glucosan, starch based, pregelatinized starch, sucrose, xylitol, lactose, mannitol, sorbitol, sodium chloride, Polyethylene Glycol etc.
The limiting examples of suitable surfactant comprises sodium lauryl sulphate, dehydrating sorbitol monooleate, Tween-81, polysorbate esters, poloxamer class, bile salt, glyceryl monostearate, Pluronic series (BASF) etc.
The limiting examples of suitable pH correction agent (buffer agent) comprises citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, 1,3-propanedicarboxylic acid, sodium bicarbonate and sodium carbonate etc.
The limiting examples of suitable stabilizers comprises antioxidant, buffer agent or acid etc. arbitrarily.
The limiting examples of examples of suitable lubricants comprises magnesium stearate, calcium hydroxide, Pulvis Talci, sodium stearyl fumarate, hydrogenated vegetable oil, stearic acid, Gan You behenic acid ester (glycerylbehapate), magnesium stearate, calcium stearate and sodium stearate, stearic acid, Pulvis Talci, wax, Stearowet, boric acid, sodium benzoate, sodium acetate, sodium chloride, DL-leucine, polyethylene glycols, enuatrol or sodium lauryl sulphate etc.
The limiting examples of suitable wetting agent comprises oleic acid, glyceryl monostearate, dehydrating sorbitol monooleate, sorbitan monolaurate, Emulphor FM, Tween-81, Tween-20, enuatrol or sodium lauryl sulphate etc.
The limiting examples of suitable diluent comprises frumentum solid, amylose, Powderd cellulose, calcium carbonate, glycine or the bentonite etc. of lactose, starch, mannitol, sorbitol, glucose, microcrystalline Cellulose, calcium hydrogen phosphate, the sugar based on the diluent of sucrose, confection, calcium bisulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, inositol, hydrolysis.
The suitable antitack agent or the limiting examples of fluidizer comprise Pulvis Talci, corn starch, DL-leucine, sodium lauryl sulphate and magnesium stearate, calcium stearate or sodium stearate etc.
The limiting examples of compatibility carrier comprises arabic gum, gelatin, colloidal silica, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soybean lecithin, sodium chloride, tricalcium phosphate, dipotassium hydrogen phosphate, sodiumstearoyl lactylate, carrageenan, monoglyceride, diglyceride or pregelatinized starch etc. on the suitable medicine.
In addition, pharmaceutical preparation is discussed in following document: for example Remington " pharmacy science with put into practice " (
The Science and Practice of Pharmacy) (2000); Lieberman, H.A. and Lachman, " pharmaceutical dosage form " of L., (
Pharmaceutical Dosage Forms), Marcel Decker, New York, N.Y., 1980; With Liebeman etc. " pharmaceutical dosage form " (
Pharmaceutical Dosage Forms) (Volumes1-3,1990).
When required excipient was used as diluent, it can be solid, semisolid or liquid substance, and it plays vehicle, carrier or the medium of active component.Therefore, the compositions that is applicable to the inventive method can be tablet, pill, powder, lozenge, sachet, cachet, tablet, suspension, Emulsion, aerosol (as solid or in liquid medium), capsule (for example soft glutoid or HPMC capsule), aseptic packaging powder, adjustable powder, granule or liquid form.
Tabules can comprise following one or more: compatible carrier on lactose, mannitol, corn starch, potato starch, microcrystalline Cellulose, arabic gum, gelatin, colloidal silica, cross-linking sodium carboxymethyl cellulose, Pulvis Talci, magnesium stearate, stearic acid and other excipient, coloring agent, diluent, buffer agent, wetting agent, antiseptic, correctives and the medicine for example.In one embodiment of the invention, preparation process can be used the following a kind of method or the combination of method: (1) dry mixed; (2) direct compression; (3) grind; (4) dry or non-water is granulated; (5) melt granulation; Or merge (6).Lachman etc., " industrialization pharmacy theory and practice " (
The Theory and Practice of Industrial Pharmacy) (1986).This class tablet can also comprise the film coating layer, its disintegrate when oral absorption or contact diluent.
Compressed tablet is the solid dosage forms of the preparaton preparation by compressing the medicament that contains acid labile and/or buffer agent and/or excipient, and selecting described buffer agent and/or excipient is in order to help to process and improve the characteristic of product.Term " compressed tablet " generally refers to the smooth uncoated tablets that is used for oral absorption, and it carries out final compacting preparation subsequently by the single compacting or by gently compressing in advance.
Can be applicable to the tablet of the inventive method or coating of pill or otherwise with its chemical combination with the operation that improvement is provided or the dosage form of storage characteristics advantage.For example, described tablet or pill can comprise internal dose and outside dose components, and the latter is the former shell form of parcel.
Because tablet can be used to form quickly disintegrating tablet, chewable tablet, lozenge, tablet and maybe can swallow sheet, so preparation semi-finished product and preparation method thereof provide other aspect of the present invention.
Effervescent tablet and powder also can be used for the present invention.Salia effervescentia has been used to medicine is scattered in the water so that oral administration.Salia effervescentia is for containing the granule or the coarse powder of pharmaceutically active agents in dry mixture, described dry mixture is made up of sodium bicarbonate, citric acid and tartaric acid usually.When described salt was added to the water, bronsted lowry acids and bases bronsted lowry reacted and carbon dioxide gas, produced thus " effervescence ".
Liquid dosage form also can be used for method of the present invention and comprise: non-aqueous solution; The suitably non-aqueous syrup agent of flavoring; Oil suspension; With the Emulsion with the edible oil flavoring, described edible oil such as Oleum Gossypii semen, Oleum sesami, Oleum Cocois or Oleum Arachidis hypogaeae semen; And elixir and similar drug media thing.
The release delivery system of many other types be purchased and for as well known to those skilled in the art.They comprise: based on the system of polymer, such as polylactic acid and polyglycolic acid, polyanhydrides and polycaprolactone; Non-polymer system for lipid comprises steroid, such as cholesterol, cholesterol esters and fatty acid, or neutral fat, such as monoglyceride class, diacylglycerol esters and triglyceride; The hydrogel delivery system; The silicone rubber system; System based on peptide; The wax coatings; Use typical binders (for example, referring to Lieberman etc., " pharmaceutical dosage form " (
Pharmaceutical Dosage Forms), second edition, the 1st volume, the compressed tablet of 209-214 page or leaf (1990) and excipient; The implant of partial fusion etc.Concrete example includes, but are not limited to: (a) in U.S. Pat 4,452,775; U.S. Pat 4,667,014; And the wherein polysaccharide of describing in U.S. Pat 4,748,034 and the U.S. Pat 5,239,660 is the erosion system of the form that is included in the substrate; (b) in U.S. Pat 3,832,253 and U.S. Pat 3,854,480 in the active component described see through the diffusion system of polymer with controllable rate.
The preparation that is suitable for parenterai administration comprises: water and non-aqueous solution, isotonic sterile injection solution, and they can contain antioxidant, such as acetate and this class buffer agent of phosphate, such as this class toxicity regulator of sodium chloride, all example hydrochloric acids and this class pH regulator agent of phosphoric acid, antibacterial with make preparation and the isoosmotic solute of receiver's blood of plan; With water that can comprise suspending agent, solubilizing agent, thickening agent, stabilizing agent and antiseptic and non-water sterile suspension.These preparations may reside in unit dose or multiple dose sealed container, in ampoule and bottle, and can store under lyophilization (lyophilizing) condition, only need to add at once before use Injectable sterile liquid-carrier, for example water.Can be by the interim injection solution of sterilized powder, granule and preparation tablets and the suspension of the above-mentioned type.
In preferred embodiments, give dronabinol according to method of the present invention as aerosolized dosage form.The limiting examples of aerosolized dronabinol formulations is disclosed in the U.S. Pat 6,509,005 of Peart etc., and the full content of the document is incorporated herein by reference.
In another preferred embodiment, with dronabinol as the oral capsule compositions administration that contains 2.5mg, 5mg or 10mg dronabinol, Oleum sesami, gelatin, glycerol, methyl parahydroxybenzoate, propyl p-hydroxybenzoate and titanium dioxide.
Can be with dronabinol and one or more other medication combined administrations, described other medicine for example is symptom that is used for the treatment of MS or the medicine (improving the activating agent of disease) for the treatment of MS self.Can comprise amantadine with the limiting examples of the medicine of dronabinol administering drug combinations, baclofen, mineral oil, papaverine, meclizine (Antivert ), hydroxyzine (Atarax ), interferon-D-1a (Avonex ), the sulfamethoxazolum azoles (Bactrim , Septra), ciprofloxacin (Cipro ), docusate sodium (Colace ), acetic acid glatiramer (Copaxone ), pemoline (Cylert ), dantrolene (Dantrium ), Desmopressin (DDAVP ), dexamethasone (Decadron ), prednisone (Deltasone ), tolterodine (Detrol ), phenytoin (Dilantin ), oxibutynin (Ditropan ), bisacodyl (Dulcolax ), venlafaxine (Effexor ), amitriptyline (Elavil ), many storehouses ester salt (Enemeez ), sodium phosphate, hexamethylenamine (Mandelamine ), Balcofen , clonazepam (Klonopin ), isoniazid (Laniazid ), Vardenafil (Levitra ), nitrofurantoin (Macrodantin ), PHM (Metamucil ), Alprostadil, gabapentin (Neurontin ), mitoxantrone (Novantrone ), oxibutynin (Oxytrol ), nortriptyline (nortiptyline) (Pamelor ), paroxetine (Paxil ), propantheline bromide (Pro-Banthine ), Alprostadil (Prostin VR), modafinil (Provigil ), fluoxetine (Prozac ), phenazopyridine (Pyridium ), interferon-D-1a (Rebif ), glycerol (Sani-Supp ), methylprednisolone (Solu-Medro ), carbamazepine (Tegretol ), imipramine (Tofranil ), diazepam (Valium ), sldenafil (Viagra ), bupropion (Wellbutrin ), tizanidine (Zanaflex ) and Sertraline (Zoloft ).
The following example is explained embodiment of the present invention, but it should be considered as limit by any way scope of the present invention.
Embodiment
Embodiment 1
Carry out the randomization placebo-controlled study to estimate Fructus Cannabis extract and the application of δ-9-THC in the treatment various symptoms relevant with MS.Comprise that in this test the age is the 18-64 patient in year, they have the multiple sclerosis of determining clinically or laboratory is supported, pro-showed stable disease in 6 months, had problematic spasticity (Ashworth score 〉=2 in two or more lower limb muscle groups).Get rid of the patient suffer from ischemic heart desease, have those patients of the activeness source of infection and take those patients (may influence spasticity) such as this class medicine of interferon-.
Given patient is accepted one of two kinds of active component treatments or placebo at random.The active component treatment is by synthetic δ-9-THC (dronabinol, Solvay Pharmaceuticals, Atlanta, USA) or contain δ-9-THC and cannabidiol Fructus Cannabis extract (Cannador as main Cannabinoids, clinical research institute, IKF, Berlin, Germany) form.Prepare every capsule that contains 2.5mg δ-9-THC equivalent, 1.25mg cannabidiol and be lower than other Cannabinoids of 5%.With medicine twice one after each meal every day.As usual take all other medicines, but do not comprise that other requirement separates the capsule of taking separately based on oil with trial drug, so that avoid may be to the interference that absorbs.
This research is from 5-weekly dose titration phase.In this time limit process, the patient is by being that at interval every day, twice each 1 capsules (2.5mg Δ-9-THC equivalent) that increases increased its dosage with the week.If the generation side effect advises that so the patient does not increase this dosage, and if think that side effect can not tolerate, reduce this dosage so.Plateau, appear in 6-13 week, and in this stage, the participant keeps stable drug dose (following up a case by regular visits to 5,6 and 7).In the 14th week, the patient by twice of every day each 1 capsules that reduces reduce its medicine every day, stop taking the research medicine up to them.The patient is no longer taking trial drug the 15th week and finally estimating (following up a case by regular visits to 8) when finishes this week.
Use the Ashworth scoring of spasticity to find aspect the spasticity relevant with multiple sclerosis, the PRELIMINARY RESULTS of this research mensuration changed (for example, referring to Ashworth, B. " pre-stage test of carisoprodol in multiple sclerosis " (
Preliminary trial of Carisoprodol in multiple sclerosis.)-" working doctor " (Practitioner) 1964; 192:540-42.).Carrying out the Ashworth scoring when following up a case by regular visits to for 6 times estimates: (follow up a case by regular visits to 1 and 2) before the two treatments; (follow up a case by regular visits to 5,6 and 7) in three therapeutic processes; With behind stopped treatment (following up a case by regular visits to 8).Ashworth scoring is to the evaluation of biological damage and depends on clinicist's estimation.This score is made up of 5-point grade that (0=is normal; 1=is slightly stumbled when limb motion; The 2=severity surpasses is stumbled, but not constrained motion; The tonicity that 3=limits passive bending significantly increases; 4=limbs when crooked or stretching, extension are stiff).Estimate 10 muscle groups (elbow musculus flexor, extensor, pronator and supinators on the every side of health; Wrist and finger musculus flexor; Hip adductor, KF and extensor and plantar flexion of foot flesh).Make every patient lie on the back on the examining table or under the state that can tolerate as far as possible near this posture, rest and estimate after 15 minutes.Make the limbs of being estimated estimate rapid movement on the desired direction.Because spasticity can change with passive limb motion, makes the times of exercise in each joint remain on minimum.Exist more than 7 times clonic spasm to beat in the time of will checking the joint and be considered as at least 2 grades of spasm.
Hereinafter be right after the baseline characteristic that the participant is provided in the table 1 that provides.
The experimenter who comprises in the research of table 1.MS symptom distributes
| Fructus Cannabis extract | Δ-9-THC | Placebo | |
| The quantity meansigma methods | The quantity meansigma methods | The quantity meansigma methods | |
| The sex masculinity femininity | 76 -- 135 -- | 63 -- 143 -- | 78 -- 135 -- |
| Age (year) | 211 50.5 | 206 50.2 | 213 50.9 |
| Height (cm) | 209 167.5 | 205 167.9 | 210 168.0 |
| Body weight (kg) (n=630) | 211 71.7 | 206 71.2 | 213 71.6 |
| Body Mass Index (kg/m 2) | 209 25.6 | 205 25.2 | 210 25.4 |
| All muscle groups of average baselining Ashworth upper body mussels lower body muscle | 211 5.0 211 16.8 211 21.8 | 206 5.9 206 16.7 206 22.6 | 212 5.4 213 16.1 213 21.4 |
| The carrying out property of former carrying out property of form recurrence/mitigation secondary of MS | 6 3％ 53 25％ 152 72％ | 14 7％ 43 21％ 149 72％ | 13 3％ 49 23％ 151 71％ |
| The walking state can be walked and can not be walked | 103 49％ 108 51％ | 95 46％ 111 54％ | 105 49％ 108 51％ |
Among 630 patients that in the therapeutic interest analysis, comprise, obtained the follow up data of relevant PRELIMINARY RESULTS from 611 (97%) patients.The demanding perfection and repay totally also higherly of the data that second fruiting is measured, wherein the patient's data from 84-91% can be used for analyzing.
Aspect analysis Ashworth scoring, the patient of 81% (n=513) is from start to finish by identical estimator or different estimators (Fructus Cannabis extract 82% (n=173) only arranged when once following up a case by regular visits to, Δ-9-THC 82% (n=168), placebo 81% (n=172)) assessment.PRELIMINARY RESULTS is defined as from baseline (meansigma methods of following up a case by regular visits to before the treatment of twice baseline) change of (following up a case by regular visits to 7) when finishing to 13 all treatments phases.According to this scheme,, then must assign to substitute by the Ashworth that changes obtainable the last time in the therapeutic process over to if lack the Ashworth score of following up a case by regular visits at 7 o'clock.39 scores have been changed on the total over to; Be distributed in the treatment 28 from following up a case by regular visits to 6 and 11 from following up a case by regular visits to 5 (Fructus Cannabis extracts: 12; Δ-9-THC:17; Placebo: 10).To original randomized 46 patient's (Fructus Cannabis extracts: 12; Δ-9-THC:19; Placebo: 15) do not obtain the PRELIMINARY RESULTS data.
Treatment does not have the significance,statistical evidence to the influence that changes total Ashworth score of following up a case by regular visits to 13 weeks from baseline (p=0.29 has the adjustment to walking state and maincenter; P=0.40 does not adjust).Meansigma methods (SD) in total Ashworth score changes (baseline deducts and follows up a case by regular visits to) to Fructus Cannabis extract, and δ-9-THC and placebo are respectively 1.24 (6.60), and 1.86 (7.95) and 0.92 (6.56).Analog value to the upper body muscle group is-0.05 (4.11), 0.48 (4.70) and-0.11 (4.04), and be 1.29 (4.37) to the analog value of lower body muscle group, 1.39 (5.21) and 1.04 (4.20).With regard to the treatment of two kinds of active component, when maincenter and walking state are adjusted, observed improve (referring to the accompanying drawing 1) of therapeutical effect with respect to placebo.
Treatment (was carried out adjustment p=0.71 according to maincenter and walking state to the lower body in the Ashworth score, do not adjust p=0.74) or the influence that changes of upper body (p=0.20 and p=0.31) component do not have the significance,statistical evidence, and do not have maincenter with treatment, walking state and treatment or baseline Ashworth score and the evidence that influences of any interaction between treating.
Variation all has appreciable impact (accompanying drawing 2) to the Ashworth score for maincenter (p＜0.0001) and walking state (p=0.002).The walking patient is 1.78 with respect to the decreased average value of the estimation of total Ashworth score that can't the walking patient after according to treatment and maincenter adjustment.In all treatment groups, comprise that the average of the treatment of placebo group all makes moderate progress (accompanying drawing 3).
Also in above-mentioned research, measured second fruiting.This class second fruiting comprise Rivermead mobility index (for example, referring to Collen, F.M. etc., " Rivermead mobility index: the evaluation of Rivermead motor further develop " (
The Rivermead mobility Index:a further development of the Rivermead motor Assessment.)-Int.Disanil.Stud.1991; 13:50 54), application form-Britain's ND scoring of periodic 10 meters walkings, 4 self-fulfillments (for example, referring to Sharrack, B., Hughes R.A., " Guy ND grade: the new residue of multiple sclerosis settles the standard " (
The Guy ' s neurological disability scale (GNDS): a new disability measure for multiple sclerosis.-Mult.Sder.1999; 5:223-33)) and a series of 9 classes-equal interval scale.With regard to classification-classification standard evaluation, require symptom that the patient estimates them in last week, just to begin how and with this research before their symptom how to compare.Classification comprises irritability, depression, fatigue, myotonia, trembles, pain, sleep, muscular spasm and vigor amount.Data are as described below.
Aspect second fruiting determined, 322 patients provided the walking time of at least one baseline.In them, 7 patient's (Fructus Cannabis extracts: 1; Δ-9-THC:3; Placebo: 3) withdrawed from this test.278 patients the when walking time follows up a case by regular visits to available from the 7th time.Add up to 20 patients (Fructus Cannabis extract: 8 of can not walking; Δ-9-THC:5; 7) and individual placebo:, replace more travel time for these.
In a word, observe between following up a case by regular visits to for 7 times from baseline to the to the significance therapeutical effect (p=0.015) of travel time.The median of 10 meters required times of walking has descended 12% from baseline to following up a case by regular visits to when using δ-9-THC, by comparison, uses Fructus Cannabis extract to descend 4%, and uses placebo also to descend 4%.Accompanying drawing 4 expression is for the patient that walking time information is provided when all 6 estimators follow up a case by regular visits to, and follows up a case by regular visits to and the walking time median of treatment group.
Classification grade evaluation is used for evaluate patient whether feels that their symptom improves before than begin treatment when the treatment.Data are as shown in table 2 and 3.In a word, the patient has experienced when treating with active component, and the symptom of pain, sleep quality, spasm and spasticity is improved.Not to be noted irritability, depression, fatigue, tremble or vigor aspect influence.
Table 2. patient's second fruiting report
| Improve | Identical | Worsen | |||||||
| Fructus Cannabis extract | Δ-9-THC | Placebo | Fructus Cannabis extract | Δ-9-THC | Placebo | Fructus Cannabis extract | Δ-9-THC | Placebo | |
| Irritability | 46 (39％) | 37 (33％) | 31 (26％) | 42 (36％) | 42 (38％) | 63 (54％) | 30 (25％) | 32 (29％) | 23 (20％) |
| Depression | 43 (36％) | 36 (29％) | 38 (28％) | 44 (37％) | 47 (38％) | 64 (47％) | 33 (28％) | 42 (34％) | 35 (26％) |
| Tired | 46 (28％) | 35 (22％) | 37 (22％) | 51 (31％) | 46 (29％) | 79 (47％) | 68 (41％) | 76 (48％) | 52 (31％) |
| Spasticity | 95 (52％) | 89 (51％) | 67 (37％) | 43 (23％) | 40 (23％) | 52 (28％) | 46 (25％) | 47 (27％) | 64 (35％) |
| Shake/tremble | 49 (38％) | 52 (41％) | 45 (33％) | 48 (38％) | 44 (34％) | 53 (39％) | 31 (24％) | 32 (25％) | 37 (27％) |
| Pain | 68 (46％) | 64 (50％) | 42 (30％) | 48 (32％) | 43 (33％) | 58 (41％) | 32 (22％) | 22 (17％) | 42 (30％) |
| Sleep | 82 (50％) | 71 (47％) | 59 (36％) | 62 (38％) | 57 (38％) | 79 (48％) | 20 (12％) | 24 (16％) | 25 (15％) |
| Spasm | 96 (53％) | 81 (49％) | 67 (39％) | 50 (28％) | 49 (29％) | 68 (39％) | 34 (19％) | 37 (22％) | 38 (22％) |
| Vigor | 61 (33％) | 61 (35％) | 45 (24％) | 73 (40％) | 63 (36％) | 78 (42％) | 49 (27％) | 49 (28％) | 61 (33％) |
Embodiment 3
When the following up a case by regular visits to for the 8th time of research described in embodiment 1 and 2, to the patient propose to treat whether improved pain, trembled, the particular problem of spasticity or bladder symptom.Table 3 has been represented the reaction of patient to those problems.In a word, the multidigit patient felt when time, ratio was accepted placebo that in the described active component treatment of acceptance spasticity and pain have improvement.Sensuously do not have significant difference and do not identify therapeutical effect what tremble and improve the bladder symptom.Although these the concrete symptoms between group are not formed level, extensively compared these groups for these symptoms except that the bladder symptom, wherein in taking the group of Δ-9-THC, there is urethral symptom in less patient.
Whether there is significant correlation (p＜0.001) between the evaluation with the active component treatment the treatment of reality and the relevant patient of treatment doctor.According to treatment doctor's evaluation, the placebo group of the Δ of the Fructus Cannabis extract group, 66% (n=119) of 71% (n=140)-9-THC group and 43% (n=85) is treated with active component.Similarly, between the treatment of reality and patient are about the viewpoint of taking which kind of treatment, there is dependency (p＜0.001).According to patient's report, the Fructus Cannabis extract, Δ-9-THC and the placebo group that are respectively 77% (n=151), 77% (n=139) and 50% (n=98) think that they are in the active component treatment.
Between estimator's treatment viewpoint and actual treatment, there is not dependency (p=0.72).Think that with estimator's viewpoint using the ratio of active medicine in three groups is 44% (n=90) Fructus Cannabis extract, 39% (n=73) Δ-9-THC and 42% (n=86) placebo.
Table 3. patient is to the evaluation of the 8th week back treatment beneficial effect
| Doing well,improving | Fructus Cannabis extract | Δ-9-THC | Placebo |
| (n＝197) | (n＝181) | (n＝198) | |
| Bladder | |||
| Have | 68(44％) | 67(40％) | 51(33％) |
| Not | 87(56％) | 97(59％) | 102(67％) |
| Pain | |||
| Have | 83(57％) | 64(50％) | 51(37％) |
| Not | 63(43％) | 64(50％) | 86(63％) |
| Tremble | |||
| Have | 58(48％) | 44(40％) | 43(33％) |
| Not | 64(52％) | 67(60％) | 89(67％) |
| Spasticity | |||
| Have | 121(61％) | 108(60％) | 91(46％) |
| Not | 76(39％) | 73(40％) | 107(54％) |
Beat allly be that as can be observed in the table 4, the incidence rate of MS recurrence be organized than the remarkable decline of placebo group at Fructus Cannabis extract and Δ-9-THC.
The untoward reaction of table 4. patient report
| Untoward reaction | Fructus Cannabis extract | Δ-9-THC | Placebo |
| The MS recurrence maybe may be recurred | 1 | 1 | 7 |
| Urinary tract infection | 1 | 3 | 4 |
| Pneumonia | 1 | 2 | 1 |
| Catheter obstruction/insertion on the pubic arch | 1 | 0 | 3 |
| Constipation | 1 | 0 | 3 |
| Epilepsy grand mal | 1 | 0 | 1 |
| Other | 6 | 11 | 2 |
Claims (17)
1. the experimenter of needs is treated and/or prevented the method for the symptom relevant with MS, this method comprises the pharmaceutical composition that comprises Δ-9-tetrahydrocannabinol of this experimenter being treated effective dose.
2. the described method of claim 1, wherein said dosing step comprises oral administration.
3. the described method of claim 1 wherein gives described Δ-9-tetrahydrocannabinol with one or more capsular forms that comprise the delta-9-Tetrahydrocannabinol in the Oleum sesami.
4. the described method of claim 1, wherein said compositions comprises the dosage form that is selected from intranasal solution or suspension, suction solution or suspension, non-intestinal solution or suspension, transdermal patch, transdermal gel and transdermal cream.
5. the described method of claim 1, wherein said compositions is to be selected from the dosage form administration of tablet, capsule, inhalant, injection, preparation capable of permeating skin, sublingual formulation and suppository.
6. the described method of claim 5, wherein said compositions is the inhalant form.
7. the described method of claim 6 wherein gives described inhalant by the oral cavity.
8. the described method of claim 5, wherein said capsule is Perle or HPMC capsule.
9. the described method of claim 1 is wherein united with one or more MS therapies and is given described compositions.
10. the described method of claim 1, wherein said delta-9-Tetrahydrocannabinol is a dronabinol.
11. the described method of claim 1, wherein by be selected from oral cavity, intranasal, suction, injection, transdermal and Sublingual by way of giving described compositions.
12. the described method of claim 11, wherein said suction comprise that the oral cavity sucks.
13. the described method of claim 1 is wherein to be enough to the providing amount in about 2.5mg Δ-9-tetrahydrocannabinol-Yue 20mg Δ-9-tetrahydrocannabinol/sky to give described compositions.
14. the described method of claim 1 is wherein to be enough to the providing amount in about 2.5mg Δ-9-tetrahydrocannabinol/sky to give described compositions.
15. the described method of claim 1 is wherein with about 4 times of the about 1-of described compositions administration every day.
16. the described method of claim 1 wherein gives described compositions with single dose.
17. to the method that the experimenter of needs prevents the MS recurrence, this method comprises the pharmaceutical composition that comprises Δ-9-tetrahydrocannabinol of this experimenter being treated effective dose.
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