CN1326522C - Methods of using and compositions comprising immunomodulatory compounds for treatment, modification and management of pain - Google Patents

Abstract

Methods of treating, preventing, modifying and managing various types of pain are disclosed. Specific methods comprise the administration of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent and/or surgery, psychological or physical therapy. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

Be used for the treatment of, the compositions that comprises immunomodulatory compounds of change and pain management

1. technical field

The present invention relates to treat, prevent, the method for change and pain management, its comprise use separately or with the co-administered immunomodulatory compounds of known treatment agent.The invention still further relates to pharmaceutical composition and dosage regimen.The present invention comprises that particularly immunomodulatory compounds and antipsychotic drugs and/or other standard care unite the application that is used for the pain syndrome.

2. technical background

Pain is the leading symptom of many different syndromes and is defined as unhappy sensation and the emotional experience relevant with real or potential tissue injury, or such infringement is described.Merskey?H，Bogduk?N，eds.，Classification?of?Chronic?Pain，International?Association?for?the?Study?of?Pain(IASP)Task?Force?onTaxonomy，IASP?Press：Seattle，209-214，1994。Since very strong to the existing property of the master of the sensation of pain, so it is one of pathology that is difficult to most efficient diagnosis and treatment.The pain grievous injury functional capabilities, it has endangered patient's work, social activity and family life.According to estimates, about 5% people suffers from the pain that serious being enough to causes remarkable permanent disability in the adult colony.Choinowska E, Stannard C.Epidemiology of Chronic Pain, the 2nd chapter, 15-26 page or leaf: T.S.Jensen, P.R.Wilson, A.S.C.Rice eds., Clinical PainManagement Chronic Pain, Arnold, London, 2003.

In most of pain situations, the neural input signal that derives from periphery increases.The sensory nerve impulsion propagates into cornu dorsale medullae spinalis by the aixs cylinder of elementary afferent neuron, and it is there by propagating into the dorsal horn neuron at synapse place release excitatory amino acid and neuropeptide with neural impulse.The dorsal horn projection neuron pair information relevant with peripheral stimulation is handled and by up vertebra approach it is transplanted on brain.Mannion，R.J.and?Woolf，C.J.，Clin.J.of?Pain?16：S144-S156(2000)。

The excited input signal of its acceptance is not only depended in the startup of dorsal horn projection neuron, but also depends on the inhibition input signal that derives from spinal cord and higher nervous center.Some brain zones help descending inhibition approach.Discharging inhibitory substance from the neural fine young of these approach with other neuron that is arranged in this dorsal horn or elementary afferent neuron synapse place, as endogenous opiate-like sub stance, γ-An Jidingsuan (" GABA ") and serotonin, and suppress nociceptive propagation.Peripheral nerve injury can come producing change aspect the dorsal horn irritability by reduced inhibitory control on the dorsal horn neuron by various mechanism.

The neuronic repetition of dorsal horn or the long-time stimulus that produce owing to C-infringement sensor activation or injured nerve can cause the long dorsal horn neuronal excitability of a few hours of comparable this stimulus duration and continuing to increase of response.Thereby the neuronic sensitization of this dorsal horn has increased its irritability makes it produce response in mode excessive and that prolong to normal signal input.As everyone knows, this continuous activity in the elementary input C-fiber makes that having produced may be that morphology and the biochemistry that is difficult to reverse changes in said dorsal horn.In this dorsal horn, have been noted that some variations that aspect central sensitization, take place, comprising: (i) size of dorsal horn receptive field enlarges, thereby makes spinal neuron response to be arranged to the outer destructive stimulus of this neuron normal operation region; (ii) intensity and the persistent period to the response of given destructive stimulus increases (hyperpathia); (iii) to normal non noxious stimulation, for example, the normal non noxious stimulation that derives from the elementary A of importing into the beta fibers of mechanoreception produces pain sensation response (allodynia); (iv) pain expands to the tissue (referred pain) that does not come to harm.Koltzenburg, M.Clin.J.of Pain 16:S131-S138 (2000); And Mannion, R.J.and Woolf, C.J., Clin.J.of Pain 16:S144-S156 (2000).

Central sensitization can partly be explained constant pain and the hyperpathia that takes place after damage, and can be by promoting in the healing stage adaptability effect to be played in the protection of infringement.But central sensitization still can last long after this damage has been healed, thereby has kept chronic pain.Sensibilization also plays pivotal role in chronic pain, this helps that what is interpreted as, and it has usually surpassed the described stimulation that excites on time and space, and helps to be interpreted as the pain what has formed and be difficult to more suppress than acute pain.Koltzenburg，M.Clin.J.of?Pain?16：S131-S138(2000)。

2.1 The type of pain

2.1.1 Nociceptive pain

After tissue injury, generation disease or inflammation, when being released also as the inflammatory chemical mediator, harmful stimulation injured the normally functioning sensory receptor in position (nociceptor) when detecting, nociceptive pain is brought out .Koltzenburg, M.Clin.J.of Pain 16:S131-S138 (2000).The clinical example of nociceptive pain includes but not limited to incised wound and the relevant pain of contusion, osteoarthritis, rheumatoid arthritis, tendinitis and myofascial pain with chemistry or thermal burn, skin.

The distribution of nociceptor (sensory receptor) spreads all over peripheral tissues.They are to destructive stimulus (for example, heat, machinery or chemical stimulation) sensitivity, if its continuity, with damaging tissue.Such stimulation is discharged at following two kinds of dissimilar elementary afferent neuron moderate stimulations to the activation of periphery nociceptor: fine young bird of the unmyelinated C-that slowly conducts and A δ fiber rapider conduction, that thin myelin is arranged.The C-fiber is relevant with causalgia, and A δ fiber is relevant with twinge.Koltzenburg, M.Clin.J.Of Pain 16:S131-S138 (2000); Besson, J.M.Lancet 353:1610-15 (1999); And Johnson, B.W.PainMechanisms:Anatomy, Physiology and Neurochemistry, Chapter 11, Practical Management of Pain, chief editor P.Prithvi Raj. (the 3rd edition, Mosby, Inc.St Louis, 2000).Most of nociceptive pains relate to the signal from A δ type and the elementary afferent nerve fiber of C-type.

The periphery nociceptor is by inflammatory mediator such as prostaglandin, P material, Kallidin I, histamine and serotonin, and strong, repeat or destructive stimulus institute sensitization for a long time.In addition, also can affect the nerves first phenotype and function of cytokine and somatomedin (for example, nerve growth factor).Besson，J.M.Lancet?353：1610-15(1999)。When by sensitization, nociceptor shows the activation threshold value and reduces and start the speed increase, this means that they are rapider and produces neural impulse more continually.The peripheral sensitization of nociceptor acts in cornu dorsale medullae spinalis central sensitization and clinical pain status such as hyperpathia and the allodynia and plays an important role.

Inflammation may have another kind of important function to the nociceptor of periphery.Number of C-nociceptor all can not normal response to the machinery of any level or thermostimulation, and just can be activated when only responding under having the situation of inflammation or to tissue injury.Such nociceptor is called as " silence " nociceptor, and has obtained affirmation in internal organs and skin histology.Besson，J.M.Lancet353：1610-15(1999)；Koltzenburg，M.Clin.J.of?Pain?16：S131-S138(2000)。

The difference of the processing mode of destructive stimulus in different tissues has caused the different qualities of nociceptive pain.For example, the pain on the skin usually is described to locate clear and definite sharp pain, twinge or burning sensation, and the somatalgia of depths is described to diffusibility, sensation blunt or pain.Generally speaking, universal experience has influenced the pain perception because central nervous system is unified, so the relation between pain perception and the stimulus intensity varies.

2.1.2 Neuropathic pain

Neuropathic pain has reflected neural infringement or damage, and is defined as by IASP " by primary lesion in the nervous system or pain that malfunction caused or caused.”Merskey?H，Bogduk?N，eds.，Lassification?of?Chronic?Pain，International?Association?for?the?Study?of?Pain(IASP)Task?Force?onTaxonomy，IASP?Press：Seattle，209-214，1994。Some neuropathic pains are to be caused by the damage of peripheral nervous system or malfunction.Because damage, the expression of crucial sensor molecule, mediator and ion channel changes, thereby has changed the irritability of peripheral neurons.Johnson，B.W.Pain?Mechanisms：Anatomy，Physiology?andNeurochemistry，Chapter?11?in?Practical.Management?of?Pain?ed.P.Prithvi?Raj.(3 ^rd?Ed.，Mosby，Inc.St?Louis，2000)。The clinical example of neuropathic pain include but not limited to diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia and apoplexy after the relevant pain of pain.

The common characteristic different with some of neuropathic pain is relevant, as being seriality or intermittent pain, and can be described in many ways, as causalgia, tingling, twinge, penetrate pain, galvanic shock sample, Piercing Pain, crushing pain, degree of depth pain or spasmic pain.Usually there is strange anesthesia partially or completely in the patient who suffers from neuropathic pain, and these patients descend to the sensualness of heat and mechanical stimulus.Also may have unusual or unfamiliar sensation beastly (insensitive), and it has also aggravated patient's misery.Further feature has: to the original harmless algesiogenic ability of stimulation (allodynia), perhaps stimulate the out-of-proportion pain sensation perception (hyperpathia) when responding more than to threshold value.Johnson, B.W.PainMechanisms:Anatomy, Physiology and Neurochemistry, Chapter 11in Practical Management of PainEd.P.Prithvi Raj. (3 ^RdEd., Mosby, Inc.St Louis, 2000); And Attal, N.Clin.J.of Pain 16:S118-S130 (2000).

Complicated local pain syndrome (CRPS) is that a class does not exist (I type CPRS) or having the neuropathic pain that influences limbs under the situation of (II type CPRS) nerve injury usually.I type CPRS comprises the patient's condition that is called as sympathetic reflex dystrophy (RSD), and II type CPRS comprises the patient's condition that is called as causalgia, and two types CPRS has the consistent hypotype of keeping with sympathetic nerve of pain syndrome.In 1993, the diagnosis and the term of this disease were discussed in the special common recognition meeting (consensus conference) of IASP, and had approved term CRPS and two kinds of hypotypes thereof.Research subsequently and meeting are revised this definition, thereby make present guilding principle provide very high specificity (0.95) and higher sensitivity (0.70).Bruehl waits the people, Pain 81:147-154 (1999). still, and still not to the reason that causes this disease or how it is treated best and reach general unanimity.Paice，E.，British?Medical?Journal?310：1645-1648(1995)。

CRPS is the many nerves of a kind of influence, bone and the many symptoms of soft tissue (comprising one or more limbs) and the syndrome of multisystem, it is characterized by intensive pain.Though before 130 years, for the first time it was described, still very insufficient to the understanding of CRPS.For example, proposed periphery and maincenter somesthesia, the advocate peace variation and the pathologic sympathetic and that import system into of motion process interacts as its pathogeny certainly.Early stage with the CRPS that recovers of people such as Wasner proof, sympathetic neural blood vessel shrinks active function and completely loses on the skin.Wasner?G.，Heckmann?K.，Maier?C.，Arch?Neurol?56(5)：613-20(1999)。People such as Kurvers have proposed in the unusual relevant vertebra component of CPRS I phase and microcirculation, and it may show self by a kind of neuropathic inflammatory mechanism.Kurvers?H.A.，Jacobs?M.J.，Beuk?R.J.，Pain?60(3)：333-40(1995)。The reason of aberrant angiogenesis is unknown, and relevant the generation on the problem that whether relates to sympathetic nervous system (SNS) when these change arguement is arranged still.

CPRS remains unknown in the actual incidence rate of US, and also only can obtain finite information aspect the epidemiology of this disease.Masculinity and femininity is all influenced, but this syndromic sickness rate is higher in the women.This syndrome can betide any age group, comprises children population.Schwartzman?R.J.，Curr?Opin?Neurol?Neurosurg?6(4)：531-6(1993)。Cause a variety of causes of CPRS include but not limited to head injury, apoplexy, poliomyelitis, tumor, wound, amyotrophic lateral sclerosis (ALS), myocardial infarction, polymyalgia rheumatica, operation visit do, the arm nerve from sick (brachial plexopathy), cast (cast)/clamping plate fix, less limb injury and malignant tumor.

The symptom of CRPS includes but not limited to pain, autonomy malfunction, edema, motion disease, malnutrition and atrophy.Schwartzman?R.J.，N?Engl?J?Med?343(9)：654-6(2000)。This pain is described to very serious and continuous pain, usually has the calcination characteristic.90% complaint has spontaneous causalgia and allodynia among all CRPS patients, and it relates to the pain of touching.The clinicist is that pain may be much more serious than desired pain on the physical examination basis in the main difficulty that runs on this syndrome.Pain also with swelling and joint touch a tender spot, perspire increase, to temperature with light is tactiosensible and skin color changes.In fact, can not only on the basis of report pain, make the diagnosis of CRPS.The patient must have paraesthesia and the sign and the symptom of the vascular function obstacle that changes with excessively perspiration, edema or skin-nourishing.

As mentioned above, IASP is divided into CRPS two types, that is, and and I type CPRS (being also referred to as RSD) and II type CPRS (being also referred to as causalgia).These two types mainly according to whether comprising in its inducement that definable nerve injury distinguishes.After I type CPRS occurs in the harmful incident of constitutional except that nerve injury.After II type CPRS occurs in nerve injury.Aspect its development and performance, CRPS further is divided into three kinds of different stages.But the process of this disease seemingly very is difficult to predict between each patient, thereby it is always not clear and helpful to make that this stage is divided in the treatment.Schwartzman?R.J.，N?Engl?JMed?343(9)：654(2000).

In I stage or " early stage RSD ", pain is more serious than the desired pain that is caused by said damage, and it has and burns or the pain characteristic.It may increase owing to extremity, Body contact or emotion are irritated.The affected zone edema that generally becomes may occur too high or too low for temperaturely, and may show fingernail and natural on-off cycles of hair growth increases.Radiograph may show early stage sclerotin change.

In II stage or " RSD that determines ", the hardening of edema sex organization.The skin nice and cool hyperhidrosis that generally becomes has livedo reticularis or cyanosis simultaneously.Possible alopecia, and fingernail become crest line, crack and easily crisp is arranged.Hands is dried to become outstanding, and skin and the remarkable atrophy of subcutaneous tissue.Pain remains principal character.It usually is constant and all can makes its increase to any stimulation of involved area.Form stiff in this stage.Radiograph may show the diffusibility osteoporosis.

In III stage or " RSD in late period ", near pain expands to.Though its intensity may reduce, pain remains a kind of marked feature.May break out automatically.Irreversible histologic lesion takes place, and the general attenuation of skin and shinny.There is not edema, but contracture may take place.X-ray film generally shows significant bone demineralization.

In all stages of CPRS, the patient is standing serious chronic pain, and Most patients can not be slept.CRPS has quite high sickness rate, and therefore the consciousness that improves this disease is very important.Early stage and effective treatment can reduce the influence of CPRS in some individualities.People such as William D.Dzwierzynski, Hand Clinics Vol 10 (1): 29-44 (1994).

2.1.3 The pain of other type

Encelialgia is counted as the modification of somatalgia usually, but their mechanism on the neurological has difference.Think that also Encelialgia relates to reticent nociceptor--the visceral afferent fiber that only just is activated when having inflammation.Cervero，F.and?Laird?J.M.A.，Lancet353：2145-48(1999)。

Some Clinical symptoms is that Encelialgia is distinctive: (i) be not can both cause Encelialgia and always not relevant with visceral injury at all internal organs; (ii) since among central nervous system (CNS) the organizational structure of the approach of visceral sensation injury, particularly do not exist the ratio of independently visceral sense approach and the fine young bird of internal organs nervus centripetalis low, so Encelialgia usually is diffusible and polarization is poor; (iii) it relates to other non-internal organs structure sometimes; (iv) it is with motor reflex and autonomic reflex, as feeling sick.Johnson, B.W., Pain Mechanisms:Anatomy, Physiology and Neurochemistry, and Chapter 11 in Practical Managementof Pain ed.P.Prithvi Raj. (the 3rd edition, Mosby, Inc.St Louis, 2000); And Cervero, F. and Laird J.M.A., Lancet 353:2145-48 (1999).

Headache can be divided into constitutional and Secondary cases headache disease.Two kinds of modal constitutional diseases, promptly the pathophysiology of migraine and tension headache is very complicated, is not also fully understood.Nearest studies show that, because the activation and the sensitization of periphery nociceptor, the nociceptive input signal that is input among the CNS may increase, and the intensive attack of nociceptive impulsion makes the second level and third level neuronal activation and sensitization among the CNS.Therefore, central sensitization is played a role in may and keeping in the beginning of migraine and tension headache.Johnson, B.W.Pain Mechanisms:Pain Mechanisms:Anatomy, Physiology and Neurochemistry, Chapter 11 in Practical Managementof Pain ed.P.Prithvi Raj. (the 3rd edition, Mosby, Inc.St Louis, 2000).

Postoperative pain, the postoperative pain that causes as the tissue injury that is caused by intra-operative have produced intensive nociceptive input signal.After operation, the inflammatory reaction that relates to cytokine, neuropeptide and other inflammatory mediator is arranged at damage location.These chemical substances cause sensitization and make that thereby feasible, for example, threshold value reduces and the response that stimulates more than the threshold value is increased to the responding ability increase of outside stimulus.These processes have produced periphery and central sensitization together.Johnson, B.W.Pain Mechanisms:Anatomy, Physiology andNeurochemistry, Chapter 11 in Practical Management of Pain ed.P.Prithvi Raj. (the 3rd edition, Mosby, Inc.St Louis, 2000).

Mixing pain is a kind of chronic pain that not only has the nociception component but also have the neuropathic component.For example, can cause a kind of specific pain and keep this pain by a kind of pain pathways by a kind of different approach.The example that mixes pain status includes but not limited to cancer pain and back pain.

2.2 Pain therapy

The treatment that the pain relevant with CRPS is carried out at present comprises pain management and naturopathy widely, and it has and helps prevent edema and arthrogryposis and help pain minimization.Usually assist to treat serious pain with medicine and nerve block.Block with the Bier that uses many materials and to carry out the local nerve blocking-up, said material comprises local anesthetic, bretylium tosylate, steroid, calcitonin, reserpine and guanethidine.Perez R. S. waits the people, J PainSymptom Manage 2001 Jun; 21 (6): 511-26. carries out the nerve block of special selectivity sympathetic ganglion for diagnosis and therapeutic purposes.The principle of selectivity nerve block is to have blocked sympathetic nervous system and reduced sensorineural activation.The patient of failure may have and not rely on orthosympathetic CRPS. when nerve block is resisted in the treatment of the good nerve block of control, and pain generally will be that lifelong and serious may being enough to makes the people weak.

The medicine that uses in the treatment of chronic pain at present generally includes non-narcotic analgesics, opioid analgesic, calcium channel blocker, muscle relaxant and whole body cortical steroid material.But the patient seldom can obtain the alleviation fully of pain.In addition, because understand also very insufficiently, so this treatment is fully rule of thumb carried out to the mechanism of pain and autonomy malfunction.The CRPS patient of 5-10% forms a kind of chronic pain form, and it is usually with serious permanent disability, and widely-used pain medication.Therefore, still need to treat safely and effectively method with pain management.

2.3 Immunomodulatory compounds

One group of chemical compound is studied, selected this group chemical compound to be because it may suppress the generation of TNF-α by the PBMC that LPS stimulates.L.G.Corral waits the people, Ann.Rheum.Dis.58:(supplementary issue I) 1107-1113 (1999).These are called as IMiDs ^TMThe chemical compound of (Celgene Corporation) or immunomodulator not only can effectively suppress TNF-α, but also has significantly suppressed the generation of LPS inductive mononuclear cell IL1 β and IL12.Immunomodulatory compounds has also suppressed the inductive IL6 of LPS, though be partly to suppress.These chemical compounds are effective stimulus agent of the inductive IL10 of LPS.

3. General introduction of the present invention

The present invention includes treatment, prevention, change or the method for control (for example prolonging the time of alleviating) pain, it comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or the prodrug that uses treatment or prevention effective dose to its patient of needs.

Another embodiment of the invention comprises one or more immunomodulatory compounds and is used for the treatment of at present or the use in conjunction of other therapeutic agent of prevent irritation that said other therapeutic agent includes but not limited to antidepressant, antihypertensive, antianxiety drug, calcium channel blocker, muscle relaxant, non-narcotic analgesics, opioid analgesic, alpha adrenergic receptor agonists or antagonist, antiinflammatory, cox-2 inhibitor, immunomodulator, immunosuppressant, hyperbaric oxygen, jnk inhibitor and cortical steroid material.

Another embodiment of the invention comprises one or more immunomodulatory compounds and is used for the treatment of, the use in conjunction of the conventional therapy of prevention or pain management, said conventional therapy includes but not limited to, operation, intervention are visited and are done (for example, nerve block), naturopathy and psychotherapy.

The present invention also comprises pharmaceutical composition, monomer dosage form (single unit dosage form) and the test kit that is applicable to treatment, prevention, change and/or pain management, and it comprises a kind of immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug.

4. Detailed description of the present invention

The present invention is partly based on following viewpoint: thus chemical compound disclosed herein can be united the pain that works and effectively treat, prevent, change and/or control dissimilar and the order of severity separately or with other medicines.Under situation about not being bound by any theory, chemical compound of the present invention can (rather than essential) as analgesics.Specifically, because but some chemical compound appreciable impact cytokine (for example, TNF-α, IL-1 β, IL12 and IL-4) generation, so it is believed that the animal or human's that these chemical compounds can recover to sustain damage benchmark or normal pain threshold, thereby they can be used as " anti-hyperalgesic " and/or " neuroregulator " plays a role.Therefore, chemical compound of the present invention is different with the effect of analgesics, it has generally reduced the response brought out by stimulating, and as an alternative, it has changed the resistance of patient to described response by the responding ability that suppresses the misery relevant with pain or directly reduce nociceptor.For this reason, it is believed that chemical compound disclosed herein not only can be used for treatment, prevention, changes and control nocuity (norciceptive) pain, but also can be used for the pain (for example, neuropathic pain) of visibly different other type of nosetiology.In addition, because the unique mechanism that some chemical compound of the present invention who is assert works, it is believed that its can, even pain can be alleviated or reduce to the whole body administration also under the situation that does not produce the typical detrimental effect (for example anesthetic action) of some anesthetis (for example opioid).

First embodiment of the present invention comprises the method for treatment, prevention, change or pain management, and it comprises immunomodulatory compounds or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or the prodrug of taking treatment or prevention effective dose to its patient of needs.The invention still further relates to particular type treatment of pain, prevention, change or control, the pain of said particular type includes but not limited to mixing pain, Encelialgia, migraine, headache and the postoperative pain of nociceptive pain, neuropathic pain, nociceptive pain and neuropathic pain.

Unless stated otherwise, otherwise term " nociceptive pain " include but not limited to and chemistry or thermal burn, the incised wound of skin, the relevant pain of contusion, osteoarthritis, rheumatoid arthritis, tendinitis and myofascial pain of skin.

Unless stated otherwise, otherwise term " neuropathic pain " includes but not limited to I type CRPS, II type CRPS, reflex sympathetic dystrophy (RSD), reflection neural blood vessel malnutrition, reflex dystrophy, the pain syndrome that sympathetic nerve is kept, causalgia, (Sudeck) osteanabrosis after the wound, algoneurodystrophy, shoulder-hand syndrome, wound dystrophy, trigeminal neuralgia, postherpetic neuralgia, pain with related to cancer, phantom pain, fibromyalgia, chronic tired syndrome, the spinal cord injury pain, pain after the maincenter apoplexy, radiculopathy, diabetic neuropathy, pain after the apoplexy, the syphilis neuropathy, with the neuropathic condition of other pain, as those by medicine such as vincristine, the inductive patient's condition of veleade and Thalidomide.

Terminology used here " complicated regional pain syndrome ", " CRPS " and " CRPS and related syndromes " refer to the chronic pain disorders that is characterized as the situation below one or more: pain (no matter being spontaneity or arousing property pain) comprises allodynia (to the pain sensation response of not painful usually stimulation) and hyperpathia (to only being the slightly excessive response of the stimulation of misery usually); With the out-of-proportion pain of activating event (for example, the serious pain of several years behind the ankle sprain); Be not limited to the local pain that single peripheral nervous distributes; With relevant with the trophism skin change (ulcer on the unusual and skin of hair and nail growth) relevant autonomy imbalance (for example, edema, blood flow change and hyperhidrosis).

Another embodiment of the invention comprises the method that changes or regulate threshold value, development and/or the persistent period of pain, and it comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug to patient's administering therapeutic of such change of needs or adjusting or prevention effective dose.

Another embodiment of the invention comprises the pharmaceutical composition that comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug and optional carrier.

The present invention also comprises the monomer dosage form of immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug and optional carrier.

Another embodiment of the invention comprises the test kit that comprises a kind of pharmaceutical composition, and said pharmaceutical composition comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug.The present invention also comprises the test kit that comprises the monomer dosage form.The test kit that the present invention comprised can further comprise other active substance or its combination.

Bound by theory not, think some immunomodulatory compounds and can be used for treat the other medicines of pain symptom can be in treatment of pain, change or control to replenish or collaborative mode work.Therefore, one embodiment of the invention comprise the method for a kind of treatment, prevention, change and/or pain management, it comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or the prodrug of taking treatment or prevention effective dose to its patient of needs, and second kind of active substance of treatment or prevention effective dose.

The example of second kind of active substance includes but not limited to be used for the treatment of or the conventional therapy agent such as the antidepressant of prevent irritation, anticonvulsant, antihypertensive, antianxiety drug, calcium channel blocker, muscle relaxant, the non-narcotic analgesics, opioid analgesic, antiinflammatory, the cox-2 inhibitor, immunomodulator, alpha adrenergic receptor agonists or antagonist, immunosuppressant, the cortical steroid material, hyperbaric oxygen, ketamine, other anesthetis, nmda antagonist, other therapeutic agent that in Physician ' s Desk Reference 2003, can find for example.

The present invention also comprises the pharmaceutical composition that comprises one or more immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug and second kind of active substance.For example, test kit can comprise one or more chemical compounds of the present invention and antidepressant, calcium channel blocker, non-narcotic analgesics, opioid analgesic, antiinflammatory, cox-2 inhibitor, alpha adrenergic receptor agonists or antagonist, immunomodulator, immunosuppressant, anticonvulsant, maybe can alleviate or the other medicines of alleviating pain symptom.

Believing also that specific immunomodulatory compounds can reduce or eliminate with using is used for the treatment of the relevant detrimental effect of treatment of pain agent, thereby makes and can use the said therapeutic agent of bigger quantity and/or increase patient's adaptability to the patient.Therefore, another embodiment of the invention comprises a kind of reverse, reduces or avoids and the method for using the relevant detrimental effect of second kind of active substance for the patient suffer from pain, it comprise to needs its patient's administering therapeutic or immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or the prodrug of prevention effective dose.The example of detrimental effect includes but not limited to feel sick, epigastrium misery, vomiting, bleeding time prolongation, respiration inhibition, metabolic acidosis, hyperpyrexia, uriticaria, bronchoconstriction, vasodilation and Reye syndrome.

As other places here are described, can use the operation of naturopathy, psychotherapy and some type, such as but not limited to, selectivity body or sympathetic ganglion nerve block are treated the symptom of pain.Not bound by theory, thus think that the use in conjunction of such conventional therapy and immunomodulatory compounds can provide unique having reduced and the conventional therapy complications associated with arterial system with unexpected synergism.Therefore, the present invention includes the method for a kind of treatment, prevention, change and/or pain management, it (for example is included in operation, nerve block), naturopathy, psychotherapy or other routine be not before the treatment based on medicine, during or use immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug for afterwards patient (for example, people).

4.1 Immunomodulatory compounds

The used chemical compound of the present invention comprise the pure immunomodulatory compounds of raceme, stereoisomerism enrichment and stereoisomerism, with and pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate and prodrug.The chemical compound that the present invention preferably uses is the organic molecule of molecular weight less than about 1000g/mol, and is not albumen, peptide, oligonucleotide, oligosaccharide or other macromole.

As used herein and unless stated otherwise, otherwise term " stereoisomerism is pure " refers to a kind of stereoisomer that comprises a kind of chemical compound and the compositions that does not contain other stereoisomer of this chemical compound substantially.For example, the pure compositions of stereoisomerism with chemical compound of a chiral centre is incited somebody to action the another kind of enantiomer that will not contain this chemical compound substantially.The pure compositions of stereoisomerism with two neutral chemical compounds of chirality will not contain other diastereomer of this chemical compound substantially.The pure chemical compound of a kind of typical stereoisomerism comprises a kind of stereoisomer of this chemical compound that is higher than about 80% weight and less than other stereoisomer of this chemical compound of about 20% weight, more preferably be higher than about 90% weight this chemical compound a kind of stereoisomer and less than other stereoisomer of this chemical compound of about 10% weight, more preferably be higher than about 95% weight this chemical compound a kind of stereoisomer and less than other stereoisomer of this chemical compound of about 5% weight, and most preferably be higher than about 97% weight this chemical compound a kind of stereoisomer and less than other stereoisomer of this chemical compound of about 3% weight.As used herein like this and unless stated otherwise, otherwise term " the stereoisomerism enrichment " refers to a kind of a kind of stereoisomer that comprises a kind of chemical compound that is higher than about 60% weight, preferably be higher than about 70% weight, more preferably be higher than a kind of compositions of stereoisomer of a kind of chemical compound of about 80% weight.

As used herein like this and unless stated otherwise, otherwise term " enantiomer-pure " refers to the pure compositions of stereoisomerism of the chemical compound with a chiral centre.Similarly, term " the enantiomerism enrichment " refers to the compositions of the stereoisomerism enrichment of the chemical compound with a chiral centre.

As used herein like this and unless stated otherwise, otherwise terminology used here " immunomodulatory compounds " or " IMiDs ^TM" (Celgene Corporation) comprise that remarkable inhibition TNF-α, LPS inductive mononuclear cell IL1 β and IL12 and part suppress the little organic molecule that IL6 produces.

Be not subjected to the constraint of particular theory, a kind of in the biological action that immunomodulatory compounds is brought into play is reduce TNF-α synthetic.Immunomodulatory compounds has strengthened the degraded of TNF-α mRNA.When preferential use, immunomodulatory compounds can reduce allodynia and the hyperpathia that is processed into chronic narrow injured nerve pain model rat.Except that reducing endoneurial TNF-α, these chemical compounds also make cornu dorsale medullae spinalis met-enkephalin (a kind of important anti-nociceptive neurotransmitter) increase for a long time.

In addition, be not subjected to the constraint of particular theory, the used immunomodulatory compounds of the present invention is effective T cell costimulator and significantly increased cell proliferation in dose-dependent mode still.Immunomodulatory compounds may be higher than effect to the CD4+T cell subtype to the secondary stimulus effect of CD8+T cell subtype.In addition, this chemical compound preferably has antiinflammatory property, and can stimulate the T cell effectively altogether.

The particular instance of immunomodulatory compounds includes but not limited to, the cyano group of substituted phenylethylene material and carboxy derivatives, and as US 5,929, disclosed material in 117; 1-oxo-2-(2,6-dioxo-3-fluorine piperidines-3-yl) isoindoline and 1,3-dioxo-2-(2,6-dioxo-3-fluorine piperidines-3-yl) isoindoline class material such as US 5,874,448 and 5,955, the material described in 476; US 5,798, the quaternary 2-described in 368 (2,6-dioxopiperidine (piperdin)-3-yl)-I-oxoisoindoline diindyl class material; 1-oxo and 1,3-dioxo-2-(2,6-dioxopiperidine-3-yl) isoindoline class (for example, the 4-methyl-derivatives and the EM-12 of Thalidomide) includes but not limited to US 5,635, disclosed these materials in 517 and 6,403,613; At US 6,380, the 1-oxo and 1 that on the 4-of this indoline ring or 5-position, replaces described in 239,3-dioxo isoindoline class material (for example, 4-(4-amino-1,3-dioxo isoindoline-2-yl)-4-carbamoyl butanoic acid); US 6,458, described in 810 on the 2-position by 2, isoindoline-1-ketone and isoindoline-1 that 6-dioxo-3-hydroxy piperidine-the 5-base replaces, 3-diketone (for example, the amino isoindoline of 2-(2,6-dioxo-3-hydroxyl-5-fluorine piperidines-5-yl)-4--1-ketone); US 5,698, and 579 and 5,877, the class described in 200 is non--the cyclic amide material of polypeptide; The analog of Thalidomide and derivant comprise hydrolyzate, metabolite, derivant and the precursor of Thalidomide, as D ' Amato at US 5,593,990,5,629,327 and 6,071, the material described in 948; Analog, hydrolyzate, metabolite, derivant and the precursor of amino Thalidomide and amino Thalidomide, and substituted 2-(2,6-dioxopiperidine-3-yl) phthalimide and substituted 2-(2,6-dioxopiperidine-3-yl)-1-oxo isoindole class material such as US 6,281,230 and 6,316, the material described in 471; Iso-indoles-imine compound is 09/972 as the application serial of submitting to October 5 calendar year 2001,487 US patent application, in calendar year 2001 the application serial submitted to of December 21 days be 10/032,286 U.S. Patent application and the material described in International Application PCT/US01/50401 (international publication number WO 02/059106).Here each the given patent and the full content of patent application here all are introduced into as a reference.Immunomodulatory compounds of the present invention does not comprise Thalidomide (thalidomide).

Other specific immunomodulatory compounds includes but not limited to as being introduced into US 5 as a reference here, 635, the 1-oxo that on the benzo ring, is replaced described in 517 by amino-and 1,3 dioxo-2-(2,6-dioxopiperidine-3-yl) isoindoline class material.These chemical compounds have structure I:

Wherein among X and the Y is C=O, and another among X and the Y is C=O or CH ₂, and R ²Be hydrogen or low alkyl group, particularly methyl.Specific immunomodulatory compounds includes but not limited to:

The amino isoindoline of 1-oxo-2-(2,6-dioxopiperidine-3-yl)-4-;

The amino isoindoline of 1-oxo-2-(2,6-dioxopiperidine-3-yl)-5-;

The amino isoindoline of 1-oxo-2-(2,6-dioxopiperidine-3-yl)-6-;

The amino isoindoline of 1-oxo-2-(2,6-dioxopiperidine-3-yl)-7-;

1, the amino isoindoline of 3-dioxo-2-(2,6-dioxopiperidine-3-yl)-4-; With

1, the amino isoindoline of 3-dioxo-2-(2,6-dioxopiperidine-3-yl)-5-.

Other specific immunomodulatory compounds belongs to substituted 2-(2,6-dioxopiperidine-3-yl) phthalimide class material and substituted 2-(2,6-dioxopiperidine-3-yl)-1-oxo isoindole class material, as in US 6,281,230; 6,316,471; 6,335,349; With 6,476,052, and these materials described in International Patent Application PCT/US97/13375 (international publication number WO98/03502), said file here is introduced into.This apoplexy due to endogenous wind exemplary compounds is the chemical compound of following formula:

R wherein ¹Be hydrogen or methyl.At one independently in the embodiment, the present invention includes the application of these chemical compound enantiomer-pure forms (for example optically pure (R) or (S) enantiomer).

It is 10/032 that other other specific immunomodulatory compounds belongs to application serial, 286 and 09/972, iso-indoles imines class described in 487 US patent application and the International Application PCT/US01/50401 (international publication number is WO 02/059106), said each file here is introduced into as a reference.Exemplary compounds be formula II chemical compound with and pharmaceutically useful salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemic modification with and the mixture of stereoisomer:

Wherein:

Among X and the Y one is that C=O and another are CH ₂Or C=O;

R ¹Be H, (C ₁-C ₈) alkyl, (C ₃-C ₇) cycloalkyl, (C ₂-C ₈) alkenyl, (C ₂-C ₈) alkynyl, benzyl, aryl, (C ₀-C ₄) alkyl-(C ₁-C ₆) Heterocyclylalkyl, (C ₀-C ₄) alkyl-(C ₂-C ₅) heteroaryl, C (O) R ³, C (S) R ³, C (O) OR ⁴, (C ₁-C ₈) alkyl-N (R ⁶) ₂, (C ₁-C ₈) alkyl-OR ⁵, (C ₁-C ₈) alkyl-C (O) OR ⁵, C (O) NHR ³, C (S) NHR ³, C (O) NR ³R ³', C (S) NR ³R ³' or (C ₁-C ₈) alkyl-O (CO) R ⁵

R ²Be H, F, benzyl, (C ₁-C ₈) alkyl, (C ₂-C ₈) alkenyl or (C ₂-C ₈) alkynyl;

R ³And R ³' be (C independently ₁-C ₈) alkyl, (C ₃-C ₇) cycloalkyl, (C ₂-C ₈) alkenyl, (C ₂-C ₈) alkynyl, benzyl, aryl, (C ₀-C ₄) alkyl-(C ₁-C ₆) Heterocyclylalkyl, (C ₀-C ₄) alkyl-(C ₂-C ₅) heteroaryl, (C ₀-C ₈) alkyl-N (R ⁶) ₂, (C ₁-C ₈) alkyl-OR ⁵, (C ₁-C ₈) alkyl-C (O) OR ⁵, (Cl-C ₈) alkyl-O (CO) R ⁵, or C (O) OR ⁵

R ⁴Be (C ₁-C ₈) alkyl, (C ₂-C ₈) alkenyl, (C ₂-C ₈) alkynyl, (C ₁-C ₄) alkyl-OR ⁵, benzyl, aryl, (C ₀-C ₄) alkyl-(C ₁-C ₆) Heterocyclylalkyl or (C ₀-C ₄) alkyl-(C ₂-C ₅) heteroaryl;

R ⁵Be (Cl-C ₈) alkyl, (C ₂-C ₈) alkenyl, (C ₂-C ₈) alkynyl, benzyl, aryl or (C ₂-C ₅) heteroaryl;

R ⁶Be H, (C independently when occurring at every turn ₁-C ₈) alkyl, (C ₂-C ₈) alkenyl, (C ₂-C ₈) alkynyl, benzyl, aryl, (C ₂-C ₅) heteroaryl or (C ₀-C ₈) alkyl-C (O) O-R ⁵Or R ⁶Base can be connected to form a kind of Heterocyclylalkyl;

N is 0 or 1; With

^*Expression chiral carbon center.

In the specific compound of formula II, when n is 0, R then ¹Be (C ₃-C ₇) cycloalkyl, (C ₂-C ₈) alkenyl, (C ₂-C ₈) alkynyl, benzyl, aryl, (C ₀-C ₄) alkyl-(C ₁-C ₆) Heterocyclylalkyl, (C ₀-C ₄) alkyl-(C ₂-C ₅) heteroaryl, C (O) R ³, C (O) OR ⁴, (C ₁-C ₈) alkyl-N (R ⁶) ₂, (C ₁-C ₈) alkyl-OR ⁵, (C ₁-C ₈) alkyl-C (O) OR ⁵, C (S) NHR ³, or (C ₁-C ₈) alkyl-O (CO) R ⁵

R ²Be H or (C ₁-C ₈) alkyl; With

R ³Be (C ₁-C ₈) alkyl, (C ₃-C ₇) cycloalkyl, (C ₂-C ₈) alkenyl, (C ₂-C ₈) alkynyl, benzyl, aryl, (C ₀-C ₄) alkyl-(C ₁-C ₆) Heterocyclylalkyl, (C ₀-C ₄) alkyl-(C ₂-C ₅) heteroaryl, (C ₅-C ₈) alkyl-N (R ⁶) ₂(C ₀-C ₈) alkyl-NH-C (O) O-R ⁵(C ₁-C ₈) alkyl-OR ⁵, (C ₁-C ₈) alkyl-C (O) OR ⁵, (C ₁-C ₈) alkyl-O (CO) R ⁵, or C (O) OR ⁵Other variable has identical definition.

In other specific compound of formula II, R ²Be H or (C ₁-C ₄) alkyl.

In other specific compound of formula II, R ¹Be (C ₁-C ₈) alkyl or benzyl.

In other specific compound of formula II, R ¹Be H, (C ₁-C ₈) alkyl, benzyl, CH ₂OCH ₃, CH ₂CH ₂OCH ₃, or

In another embodiment of formula II chemical compound, R ¹Be

Or

Wherein Q is O or S, and R ⁷Be H, (C independently when occurring at every turn ₁-C ₈) alkyl, benzyl, CH ₂OCH ₃, or CH ₂CH ₂OCH ₃

In other specific compound of formula II, R ¹Be C (O) R ³

In other specific compound of formula II, R ³Be (C ₀-C ₄) alkyl-(C ₂-C ⁵) heteroaryl, (C ₁-C ₈) alkyl, aryl or (C ₀-C ₄) alkyl-OR ⁵

In other specific compound of formula II, heteroaryl is pyridine radicals, furyl or thienyl.

In other specific compound of formula II, R ¹Be C (O) OR ⁴

In other specific compound of formula II, the H of C (O) NHC (O) can be by (C ₁-C ₄) alkyl, aryl or benzyl replace.

It is disclosed iso-indoles-imines class among 09/781,179 U.S. Patent application and international publication number WO98/54170 and the US 6,395,754 that the specific immunomodulatory compounds of in addition other belongs to sequence number, and said each file here is introduced into.Exemplary compounds be formula III chemical compound with and pharmaceutically useful salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemic modification, with and the mixture of stereoisomer:

Wherein:

Among X and the Y one is that C=O and another are CH ₂Or C=O;

R is H or CH ₂OCOR ';

(i) R ¹, R ², R ³, or R ⁴Be the alkoxyl of the alkyl of halogen, 1 to 4 carbon atom or 1 to 4 carbon atom or (ii) R separately independently of one another ¹, R ², R ³, or R ⁴In one be nitro or-NHR ⁵And R ¹, R ², R ³, or R ⁴In remaining be hydrogen;

R ⁵It is the alkyl of hydrogen or 1 to 8 carbon

R ⁶Be alkyl, benzo, chlorine or the fluorine of hydrogen, 1 to 8 carbon atom;

R ' is R ⁷-CHR ¹⁰-N (R ⁸R ⁹);

R ⁷Between being-phenylene or right-phenylene or-(C _nH _2n)-, wherein n has 0 to 4 value; R ⁸And R ⁹Be the alkyl of hydrogen or 1 to 8 carbon atom separately independently of one another, or R ⁸And R ⁹Be together tetramethylene, pentamethylene, hexa-methylene or-CH ₂CH ₂[X] X ₁CH ₂CH ₂-[X] X wherein ₁Be-O-,-S-or-NH-;

R ¹⁰Be hydrogen, to the alkyl or the phenyl of 8 carbon atoms; With

^*Expression chiral carbon center.

Most preferred immunomodulatory compounds is 4-(amino)-2-(2,6-dioxo (3-piperidyl))-isoindoline-1,3-diketone and 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone.This chemical compound can obtain (for example see, be introduced into US 5,635,517 as a reference here) by the synthetic method of standard.4-(amino)-2-(2,6-dioxo (3-piperidyl))-isoindoline-1,3-diketone (ACTIMID ^TM) have a following chemical constitution:

3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone (REVIMID ^TM) have a following chemical constitution:

Chemical compound of the present invention can be prepared according to the method described in patent disclosed herein or the patent application.In addition, can come asymmetric synthesis or disassemble optically pure chemical compound with the organic chemistry synthetic technology of known resolving agent or chiral column and other standard.

As used herein like this and unless stated otherwise, otherwise term " pharmaceutically useful salt " comprises the nontoxic bronsted lowry acids and bases bronsted lowry addition salts of the chemical compound that this term is related.Acceptable nontoxic acid-addition salts comprises the salt that derives from organic and mineral acid well known in the prior art or alkali, it comprises, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, equisetic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid or the like.

In nature is that tart chemical compound can form salt with various pharmaceutically useful alkali.The alkali that can be used for preparing the pharmaceutically acceptable base addition salts of such acid compound is to form nontoxic base addition salts, promptly comprise pharmaceutically useful cationic salt (including but not limited to) as alkali metal or alkali salt and particularly calcium, magnesium, sodium or potassium salt, these alkali.Suitable organic base includes but not limited to N, N-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (meglumaine) (N-methylglucosamine), lysine and procaine.

As used herein like this and unless stated otherwise, otherwise term " prodrug " refer to can be under the biology condition (external or body in) provide the derivant of this chemical compound of said chemical compound by hydrolysis, oxidation or other reaction.But the example of prodrug includes but not limited to comprise the derivant of the immunomodulatory compounds of biological hydrolysis part, but but but but but but but the part of said biological hydrolysis as the uride of the carbonic ester biological hydrolysis of the carbamate biological hydrolysis of the ester biological hydrolysis of the amide biological hydrolysis of biological hydrolysis and the phosphate ester analog of biological hydrolysis.Other example of prodrug comprises and comprising-NO ,-NO ₂,-ONO or-ONO ₂The derivant of the immunomodulatory compounds of part.Prodrug generally can prepare with well-known method, as those at 1 Burger ' s Medicinal Chemistry andDrug Discovery, 172-178,949-982 (Manfred E.Wolff ed., 5th ed.1995), with the method described in the design (Design of Prodrugs) (H.Bundgaard ed., Elselvier, New York 1985) of prodrug.

As used herein like this and unless stated otherwise, otherwise term " but amide of biological hydrolysis " " but ester of biological hydrolysis ", " but the carbamate of biological hydrolysis ", " but the carbonic ester of biological hydrolysis ", " but the uride of biological hydrolysis ", " but the phosphate ester of biological hydrolysis " refers to a kind of amide of chemical compound respectively, ester, carbamate, carbonic ester, uride, or phosphate ester, its: 1) do not disturb the biologic activity of this chemical compound but can be this chemical compound provides character in the favourable body, as absorbing, the persistent period of effect, or the initiation of effect; Or 2) be non-activity biology, but can change into bioactive compound in vivo.But the example of the ester of biological hydrolysis includes but not limited to lower alkyl esters, the low-grade acyloxy Arrcostab is (as acetoxy-methyl, the acetoxyl group ethyl, amino carbonyl oxy-methyl, oxy acid methyl neopentyl, with the new pentane acyloxy ethyl ester), lactonyl ester (as phthalidyl and sulfo-phthalidyl ester), lower alkoxy acyloxy Arrcostab is (as the methoxyl group carbonyl oxy-methyl, ethyoxyl carbonyl oxygen base ethyl and isopropoxy carbonyl oxy ethyl ester), alkoxy alkyl, cholinester, with amidoalkyl ester (as the acetylamino methyl ester)., the example of the amide of biological hydrolysis includes but not limited to low-grade alkylamine, substituted ethylenediamine, aminoacid, hydroxy alkyl amine, heterocycle and heteroaromatic amine and polyetheramine but but including but not limited to the example of the carbamate of low alkyl group amide, alpha-amino acid amides, alkoxyl acyl group amide and alkyl amino alkyl-carbonyl amide biological hydrolysis.

Should be noted in the discussion above that then given reliability of structure is higher if the title of described structure and given this structure is not inconsistent.In addition, if for example runic of no use or broken broken line are indicated the spatial chemistry of the part of this structure or structure, then the part of this structure or this structure is understood that to comprise its all stereoisomers.

4.2 Second kind of active substance

In method and composition of the present invention, can use second kind of active component or material with immunomodulatory compounds.In a preferred embodiment, said second kind of active matter mass-energy alleviating pain, inflammation-inhibiting, sedation or neuralgia effect are provided or guarantee that the patient is comfortable.

The example of second kind of active substance includes but not limited to opioid analgesic, the non-narcotic analgesics, antiinflammatory, the cox-2 inhibitor, alpha adrenergic receptor agonists or antagonist, ketamine, anesthetis, nmda antagonist, immunomodulator, immunosuppressant, antidepressant, anticonvulsant, antihypertensive, antianxiety drug, calcium channel blocker, muscle relaxant, the cortical steroid material, hyperbaric oxygen, jnk inhibitor, known can lenitive other therapeutic agent, with and pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate, prodrug, and pharmacological activity metabolite.

Can treat serious pain with opioid.The example of opioid analgesic includes but not limited to, oxycodone (OxyContin ^), morphine sulfate (MS Contin ^, Duramorph ^, Astramorph ^), Pethidine (Demerol ^) and fentanyl percutaneous patch (Duragesic ^) and other known conventional medicines; See, for example, Physicians ' DeskReference, 594-595,2851 and 2991 (the 57th editions, 2003).Oxycodone (OxyContin ^) be a kind of long term form of opium and be normally used for the initial stage and late period CRPS.Because reliable and predictable effect, safety and can easily cancel with naloxone, morphine sulfate can be used for analgesia.Morphine sulfate in the U.S. with MS Contin ^, Duramorph ^, or Astramorph ^Trade name sell.See, for example, Physicians ' DeskReference, 594-595 (the 57th edition, 2003).Fentanyl percutaneous patch (Duragesic ^) be the effective opioid analgesics of a kind of half-life than morphine sulfate much shorter.Pethidine (Demero1 ^) and hydromorphone (Dilaudid ^) also can be used for pain management.See, for example, Physicians ' Desk Reference, 2991 (the 57th editions, 2003).

During conceived and breast feeding, preferably treat pain with non-narcotic analgesics and antiinflammatory.Antiinflammatory suppresses inflammatory reaction and pain by reducing the responsible synthetic cyclooxygenase-2 activity of prostaglandin as NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) and cox-2 inhibitor.NSAIDs can be in the graduated release pain early of pain syndrome.The example of antiinflammatory includes but not limited to aspirin (Aspirin ^), ibuprofen (Motrin ^, Advil ^), ketoprofen (Oruvail ^), rofecoxib (Vioxx ^), naproxen sodium (Anaprox ^, Naprelan ^, Naprosyn ^), ketorolac (Acular ^) and other known conventional medicine.A kind of specific cox-2 inhibitor is celecoxib (Celebrex ^).See, for example, Playsicians ' DeskReference, 1990,1910-1914 and 2891 (the 57th edition, 2003); Physicians ' DeskReference for Nonprescription Drugs and Dietary Supplements, 511,667 and 773 (the 23rd editions, 2002).

Antidepressant has increased the synapse concentration of serotonin among the CNS and/or norepinephrine by suppressing the presynaptic neuron film to its reuptake.Thereby some antidepressant also have the startup speed that the sodium channel blocking activity has reduced impaired periphery centripetal fiber.The example of antidepressant includes but not limited to nortriptyline (Pamelor ^), amitriptyline (Elavil ^), imipramine (Tofranil ^), doxepin (Sinequan ^), Clomipramine (Anafranil ^), fluoxetine (Prozac ^), Sertraline (Zoloft ^), nefazodone (Serzone ^), venlafaxine (Effexor ^), trazodone (Desyrel ^), BUP (Wellbutrin ^) and other known conventional medicine.See, for example, Physicians ' Desk Reference, 329,1417,1831 and 3270 (the 57th edition, 2003).

Also can use anticonvulsant in embodiments of the invention.The example of anticonvulsant includes but not limited to carbamazepine, oxcarbazepine, gabapentin (Neurontin ^), phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide and Tiagabine.See, for example, Physicians ' Desk Reference, 2563 (57 ^ThEd., 2003).

Also can be (for example with the cortical steroid material, prednisone, dexamethasone or hydrocortisone), orally active Ib class anti-arrhythmic agents (for example, every west rule), calcium channel blocker (for example, nifedipine), beta-Blocking agent (for example, Propranolol), α-Zu Zhiji (for example, phenoxybenzamine) and α 2-2-adrenergic agonist components (for example, clonidine) and immunomodulatory compounds coupling.See, for example, Physicians ' Desk Reference, 1979,2006 and 2190 (the 57th editions, 2003).

The used second kind of specific active substance of the present invention includes but not limited to aspirin (Aspirin ^), celecoxib (Celebrex ^), Enbrel ^, ketamine, gabapentin (Neurontin ^), phenytoin (Dilantin ^), carbamazepine (Tegretol ^), oxcarbazepine (Trileptal ^), valproic acid (Depakene ^), morphine sulfate, hydromorphone, prednisone, griseofulvin, C5, alendronate, dyphenhydramide, guanethidine, ketorolac (Acular ^), thyrocalcitonin, dimethyl sulfoxide (DMSO), clonidine (Catapress ^), bretylium tosylate, ketanserin, reserpine, droperidol, atropine, phenol want Lamine, bupivacaine, lignocaine, pounce on hot former times pain, nortriptyline (Pamelor ^), amitriptyline (Elavil ^), imipramine (Tofranil ^), doxepin (Sinequan ^), Clomipramine (Anafranil ^), fluoxetine (Prozac ^), Sertraline (Zoloft ^), nefazodone (Serzone ^), venlafaxine (Effexor ^), trazodone (Desyrel ^), BUP (Wellbutrin ^), mexiletine, nifedipine, Propranolol, tramadol, lamotrigine, ziconotide, ketamine, Levomethorphan, diazepam, baclofen, tizanidine and phenoxybenzamine.

4.3 The method of treatment and control

Method of the present invention comprises prevention, treats, changes and/or controls the method for various types of pain.So as used herein, unless stated otherwise, otherwise term " prevent irritation " includes but not limited to suppress or the order of severity of one or more symptoms that reduction is relevant with pain.The symptom relevant with pain includes but not limited to the autonomy malfunction, can not come into play, weak, tremble, muscle spasm, myodystonia (dytonia), malnutrition, atrophy, edema, stiff, touch a tender spot in the joint, perspiring increases, to temperature, touch sensitivity (allodynia), skin color changes, hyperpyrexia or hypothermia, fingernail and natural on-off cycles of hair growth increase, early stage bone changes, hyperhidrosis with livedo reticularis or cyanosis, alopecia, fingernail has crest line, crack or frangible is arranged, hands is done, diffuse osteoporosis, irreversible histologic lesion, skin is thin and glossy, arthrogryposis, and significant bone demineraliting.

So as used herein, unless stated otherwise, after pain symptom begins, use chemical compound of the present invention or other other active substance otherwise term " treatment pain " refers to, and " prevention " refer to before symptom begins, particularly had the patient of pain risk to carry out administration.There is the patient's of pain risk example to include but not limited to that those have the patient of wound, nervous disorders, myocardial infarction, flesh and bone disorders and malignant tumor situation.The patient that family's pain syndrome medical history is arranged also is the preferred candidate of prevention scheme.

As used herein like this and unless stated otherwise, otherwise term " change pain " comprises threshold value, development and the persistent period of regulating pain, perhaps changes the response mode of patient to pain.Bound by theory does not think that immunomodulatory compounds can be used as anti-hyperpathia and/or neuroregulator.In one embodiment, " change pain " comprise remove the excessive painful response of patient (that is, for particular stimulation, the pain level that is higher than normal pain of patient experience) and with system's band of human or animal to normal pain threshold.In another embodiment, " change pain " comprises the painful response of reduction patient to the stimulation of certain strength.In another embodiment, " change pain " comprises the pain threshold that improves the patient for the pain threshold of patient before using the effective dose immunomodulatory compounds.

As used herein like this and unless stated otherwise, otherwise term " pain management " comprises prevention has suffered from patient's pain recurrence of pain and/or prolonged the time that patient's pain of suffering from pain is alleviated.

The present invention includes treatment, prevention, change and control has the patient's of various stages and the said disease of particular type the method for pain syndrome, said pain syndrome includes but not limited to that those are called as mixing pain, Encelialgia, migraine and the postoperative pain of nociceptive pain, neuropathic pain, nocuity disease and neuropathic pain.The pain of particular type includes but not limited to and chemistry or thermal burn, the incised wound of skin, contusion, osteoarthritis, rheumatoid arthritis or the tendinitis of skin, the relevant pain of myofascial pain; I type CRPS, II type CPRS, reflex sympathetic dystrophy (RSD), reflection neural blood vessel malnutrition, reflex dystrophy, the pain syndrome that sympathetic nerve is kept, causalgia, sudeck atrophy, algoneurodystrophy, shoulder-hand syndrome, wound dystrophy, trigeminal neuralgia, postherpetic neuralgia, pain with related to cancer, phantom pain, fibromyalgia, chronic tired syndrome, the spinal cord injury pain, pain after the maincenter apoplexy, radiculopathy, diabetic neuropathy, pain after the apoplexy, the syphilis neuropathy, the neuropathy patient's condition with other pain, for example, by medicine such as vincristine, the neuropathy patient's condition of velcade and the iatrogenic inductive pain of Thalidomide.

The present invention also comprises treatment, change or control before pain had been carried out treatment but method not enough to the standard care response or that not have the patient of response and pain was not carried out the patient's that treats pain before.Because pain patients has multiple different clinical manifestation and different clinical therapeutic efficacies, so treatment, change or control that the patient is carried out can change according to his/her prognosis.Skilled clinicist can be under the situation of not carrying out undo experimentation easily determines the type of specific second kind of material, type of surgery and naturopathy of can be effectively particular patient being treated.

The method that the present invention comprised comprises to suffering from the patient (for example, people) that maybe may suffer from pain uses one or more immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug.

In one embodiment of the invention, carry out administration with the immunomodulatory compounds oral administration and with form single or that cut apart daily dose with about 0.10 to about 150mg/ day quantity.In a specific embodiment, with 4-(amino)-2-(2,6-dioxo (3-piperidyl))-isoindoline-1,3-diketone (Actimid ^TM) with about 0.1 to 10mg/ day amount administration, perhaps, perhaps adopt other reduction procedure every other day with about 0.1 to about 10mg quantity administration.In a preferred embodiment, with 3-(4-amino-l-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone (Revimid ^TM) with about 5 to 25mg/ days, perhaps every other day or other omission scheme with about 5 to about 50mg quantity administration.

In one embodiment, the present invention relates to a kind of treatment, prevention, control and/or change the method for nociceptive pain, it comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or the prodrug of using effective dose to its patient of needs.In certain embodiments, this nociceptive pain is by physical trauma (for example, the incised wound of skin or contusion; Or chemistry or thermal burn), osteoarthritis, rheumatoid arthritis or tendinitis produced.In another embodiment, this nociceptive pain is a myofascial pain.

In another embodiment, the present invention relates to a kind of treatment, prevention, control and/or change the method for neuropathic pain, it comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or the prodrug that uses effective dose to its patient of needs.In certain embodiments, this neuropathic pain and apoplexy, diabetic neuropathy, syphilis neuropathy, postherpetic neuralgia, trigeminal neuralgia or relevant by the neuropathy of medicine such as vincristine, velcade or the iatrogenic inductive pain of Thalidomide.

In other embodiments, the present invention relates to a kind of treatment, prevention, control and/or change mix pain (promptly, not only with nociception component but also the pain relevant with the neuropathic component), it comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or the prodrug of using effective dose to its patient of needs.

Another embodiment of the invention comprises to the patient uses one or more immunomodulatory compounds, or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate, or prodrug is with treatment, prevention, control and/or change Encelialgia, headache (for example, migraine), I type CPRS, II type CRPS, RSD, reflection neural blood vessel malnutrition, reflex dystrophy, the pain syndrome that the sympathetic nerve young bird is held, causalgia, sudeck atrophy, algoneurodystrophy, shoulder-hand syndrome, wound dystrophy, the autonomy malfunction, pain with related to cancer, phantom pain, fibromyalgia, chronic tired syndrome, postoperative pain, the spinal cord injury pain, pain after the maincenter apoplexy, or radiculopathy.

In another embodiment, the present invention relates to the method for a kind of treatment, prevention, control and/or the change pain relevant with cytokine, it comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or the prodrug of using effective dose to its patient of needs.In one embodiment, suppressing the generation of cytokine activity or cytokine makes and can treat, prevent, control and/or change pain.In another embodiment, said cytokine is TNF-α.In another embodiment, relevant with cytokine pain is nociceptive pain.In another embodiment, relevant with cytokine pain is neuropathic pain.

In another embodiment, the present invention relates to the method for the pain of a kind of treatment, prevention, control and/or change and inflammation-related, it comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or the prodrug of using effective dose to its patient of needs.

In another embodiment, the present invention relates to a kind of treatment, prevention, control and/or change and the relevant method of mitogen-activated protein kinase (MAPK), it comprises the immunomodulatory compounds of using effective dose to its patient of needs.In one embodiment, this MAPK is JNK (for example, JNK1, JNK2 or JNK3).In another embodiment, this MAPK is the kinases (ERK) (for example, ERK1 or ERK2) of extracellular signals-modulating.

In another embodiment, the present invention relates to the method for a kind of treatment, prevention, control and/or the change pain relevant with operation, described in one embodiment operation be planned operation (promptly, planned wound), described method comprises the immunomodulatory compounds of using effective dose to its patient of needs.In this embodiment, this immunomodulatory compounds can be before carrying out said planned operation, during and/or carry out administration afterwards.In a specific embodiment, before carrying out said planned operation, with immunomodulatory compounds the patient is carried out administration with about 5 to about 25mg/ days quantity in about 1-21 days, and/or with immunomodulatory compounds the patient was carried out administration with about 5 to about 25mg/ days quantity carrying out said planned operation back about 1-21 days.In another embodiment, before carrying out said planned operation, used this immunomodulatory compounds to the patient with about 10mg/ days quantity in about 1-21 days and/or carrying out after the said planned operation using immunomodulatory compounds with about 10mg/ days quantity to the patient in about 1-21 days.

4.3.1 Therapeutic alliance with second kind of active substance

Ad hoc approach of the present invention comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug and second kind of active substance or active component administering drug combinations.Disclosed herein is the example (seeing that for example, the 4.1st saves) of immunomodulatory compounds; And the example (seeing that for example, the 4.2nd saves) of second kind of active substance is here also disclosed.

Immunomodulatory compounds and second kind of active substance can carry out simultaneously or can carry out in succession by identical or different route of administration to patient's administration.For specific active substance, the fitness of used specific administration approach will be depended on this active substance itself (for example, its whether can be before entering blood under situation about not being decomposed oral administration) and the disease of being treated.The preferred route of administering of immunomodulatory compounds is oral.The preferred route of administering of second kind of active substance of the present invention or composition is known for those of ordinary skills.See, for example, Physicians ' Desk Reference, 594-597 (the 57th edition, 2003).

In one embodiment, said second kind of active substance is by oral, intravenous, intramuscular, subcutaneous, mucosa or percutaneous dosing and with about 1 to about 3,500mg, about 5 is to about 2, and 500mg, about 10 to about 500mg or about 25 to about 250mg quantity are administered once or twice every day.

The specific quantity of this second kind of active substance will depend on the type of the pain that used predetermined substance, institute treat or control, the order of severity and the amount of stage and immunomodulatory compounds and the quantity that is delivered medicine to patient's any optional other active substance together of pain.In a specific embodiment, said second kind of active substance is acetyl salicylic acid (Aspirin ^), celecoxib (Celebrex ^), Enbrel ^, Remicade ^, Humira ^, Kineret ^, ketamine, gabapentin (Neurontin ^), phenytoin (Dilantin ^), carbamazepine (Tegretol ^), oxcarbazepine (Trileptal ^), valproic acid (Depakene ^), morphine sulfate, hydromorphone, prednisone, griseofulvin, C5, alendronate, dyphenhydramide, guanethidine, ketorolac (Acular ^), thyrocalcitonin, dimethyl sulfoxide (DMSO), clonidine (Catapress ^), bretylium tosylate, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lignocaine, pounce on hot former times pain, nortriptyline (Pamelor ^), amitriptyline (Elavil ^), imipramine (Tofranil ^), doxepin (Sinequan ^), Clomipramine (Anafranil ^), fluoxetine (Prozac ^), serkaline (Zoloft ^), nefazodone (Serzone ^), venlafaxine (Effexor ^), trazodone (Desyrel ^), BUP (Wellbutrin ^), mexiletine, nifedipine, Propranolol, tramadol, lamotrigine, ziconotide, ketamine, Levomethorphan, diazepam, baclofen, tizanidine, phenoxybenzamine or its combination or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate, prodrug or pharmacological activity metabolite.

Hydromorphone (Dilaudid ^) preferably with the predose oral administration of about 2mg, perhaps with the predose intravenous administration of about 1mg with the control moderate to serious pain, see, for example, Physicians ' Desk Reference, 2991 (the 57th editions, 2003).Opioid analgesics, morphine sulfate (Duramorph whether have been taken according to the patient ^, Astramorph ^, MS Contin ^) preferably with the predose IV/SC/IM administration of about 2mg.See, for example, Physicians ' Desk Reference, 594-595 (the 57th edition, 2003).As long as the patient is carried out the observation of detrimental effect, respiration inhibition especially, then the dosage to institute's administration does not just have strict restriction.Can use various IV dosage, progressively increase dosage usually until obtaining required effect.For the patient who does not use the long term material, few just enough to the IV/SC dosage of 2mg.The common higher dosage of use that needs for the patient who uses long-acting opioid analgesics.Morphine sulfate can also with discharge immediately and the oral form of time release formulation obtained.This long-acting oral form can be administered twice every day.For the patient of pain burst period, may need the application before depending on of the form that discharges immediately, dosage.Oxycodone (OxyContin ^) be a kind of long-acting form of opium and initial stage and the late period that can be used for pain syndrome.Oxycodone (OxyContin ^) preferably with every day twice about 10-160mg quantity by administration.See, for example, Physicians ' Desk Reference, 2851 (the 57th editions, 2003).Pethidine (Demerol ^) preferably with the quantity of every 3-4 hour about 50-150mgPO/IV/IM/SC by administration.Pethidine (Demerol ^) typical paediatric dose be every 3-4 hour 1-1.8mg/kg (0.5-0.8mg/lb) PO/IV/IM/SC.See, for example, Physicians ' Desk Reference, 2991 (the 57th editions, 2003).Fentanyl percutaneous patch (Duragesic ^) can be obtained with the transdermal dosage form.Most patients is carried out administration with 72 hours dosing interval; But some patients may need about 48 hours dosing interval.Typical adult's dosage is about 25mcg/h (10cm ²), 50mcg/h (20cm ²), 75mcg/h (75cm ²), or 100mcg/h (100cm ²).See, for example, Physicians ' DeskReference, 1775 (the 57th editions, 2003).

Can treat the patient who suffers from slightly to moderate pain with non-narcotic analgesics and antiinflammatory such as NSAIDs and cox-2 inhibitor.With ibuprofen (Motrin ^, Advil ^) with the quantity oral administration of one day three 400-800mg.See, for example, Physicians ' DeskReference, 1900-1904 (the 57th edition, 2003); Physicians ' Desk ReferenceforNonprescription Drugs and Dietary Supplements, 511,667 and 773 (the 23rd editions, 2002).Also preferably with the quantity of one day three about 275mg or the quantity naproxen sodium (Anaprox of one day twice about 550mg ^, Naprelan ^, Naprosyn ^) alleviate slightly to moderate pain.See, for example, Pllysicians ' Desk Reference, 1417,2193 and 2891 (the 57th editions, 2003).

Can also use antidepressant in embodiments of the invention, for example, nortriptyline (Pamelor ^) patient who suffers from chronic and/or neuropathic pain is treated.Adult's oral dose is generally about 25-100mg, and preferably is no more than 200mg/d.Typical paediatric dose is as predose, if tolerance rises to high to about 0.5-2mg/d then with about 0.1mg/kg PO.Amitriptyline (Etrafon ^) preferably the adult's dosage with about 25-100mg PO be used for neuropathic pain.See, for example, Physician ' s Desk Reference, 1417 and 2193 (the 57th edition, 2003).

Can also use anticonvulsant such as gabapentin (Neurontin ^) come suffering from chronic and patient neuropathic pain treats.Gabapentin is preferably with one day three times about 100-1, the quantity oral administration of 200mg.See, for example, Physicians ' Desk Reference, 2563 (the 57th editions, 2003).With carbamazepine (Tegretol ^) treat the pain relevant with pure trigeminal neuralgia.Adult's oral dose typically with every day twice about 100mg quantity as predose, if tolerance, increase to high extremely about 2,400mg/ days.See, for example, Pllysicians ' Desk Reference, 2323-25 (the 57th edition, 2003).

In one embodiment, in order and in certain time interval immunomodulatory compounds and second kind of active substance are delivered medicine to the patient, preferred mammal, more preferably the people makes the benefit that is provided that the benefit that is provided when it adopts other administering mode administration is provided thereby make said immunomodulatory compounds to work with said other material.For example, can simultaneously or carry out the administration of second kind of active substance at different time points with any order; But, if not administration simultaneously, thus it should enough closely can provide required treatment or preventive effect on administration time.In one embodiment, said immunomodulatory compounds and second kind of active substance are brought into play its effect in the eclipsed time.Each material in said second kind of active substance can be with any suitable form with by any suitable approach independence administration.In other embodiments, said immunomodulatory compounds before said second kind of active substance administration, simultaneously or carry out administration after the administration.Also can adopting undergos surgery comes alleviating pain as preventive measure or with it.

In various embodiments, this immunomodulatory compounds and second kind of active substance are with less than about 1 hour interval, with about 1 hour interval, with about 1 hour to about 2 hours interval, with about 2 hours to about 3 hours interval, with about 3 hours to about 4 hours interval, with about 4 hours to about 5 hours interval, with about 5 hours to about 6 hours interval, with about 6 hours to about 7 hours interval, with about 7 hours to about 8 hours interval, with about 8 hours to about 9 hours interval, with about 9 hours to about 10 hours interval, with about 10 hours to about 11 hours interval, with about 11 hours to about 12 hours interval, be not more than 24 hours interval or be not more than 48 hours interval administration.In other embodiments, this immunomodulatory compounds and second kind of active substance are administrations simultaneously.

In other embodiments, this immunomodulatory compounds and second kind of active substance are with about 2 to 4 days interval, with about 4 to 6 days interval, with the interval in about 1 week, with the interval in about 1 to 2 week or greater than the interval administration in 2 weeks.

In certain embodiments, this immunomodulatory compounds and second kind of optional active substance are recycled and deliver medicine to the patient.Circulation treatment related to first kind of material administration a period of time, then with second kind of material and/or the third material administration a period of time and repeat this administration in succession.Circulation treatment can reduce one or more treatments are formed resistance, avoids or has reduced a kind of side effect in these treatments, and/or improved the effect of this treatment.

In certain embodiments, this immunomodulatory compounds and optional second kind of active substance one less than the cycle in about 3 weeks in by administration, approximately whenever biweekly, per approximately 10 days once or approximately once in a week.Circulation can comprise by carrying out administration at the about 45 minutes immunomodulatory compounds of each about 90 minutes of circulation input, each about 1 hour of circulation input, each circulation input and second kind of optional active substance.Each circulation can comprise the rest period at least one week, at least two weeks, at least three weeks.The number in administration cycle is about 1 to about 12 cycles, is more typically about 2 to about 10 cycles, and is more typically about 2 to about 8 cycles.

In another embodiment, said immunomodulatory compounds is with the beat dosage regimen, by continuous input or under the situation of the rest period that does not have to prolong frequent drug administration carry out administration.Such beat administration can comprise with constant interval is not having to carry out administration under the situation of rest period.This immunomodulatory compounds is used with lower dosage typically.Such dosage regimen is included in the long-term interior low relatively dosage of use every day that continues.In preferred embodiments, use lower dosage toxic and side effects can be minimized and eliminates the rest period.In certain embodiments, about 24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3 thoughtful about 1 month to about 2 months, to about 3 months, to about 4 months, to about 5 months, to about 6 months in by long-term low dose or continuous this immunomodulatory compounds of importing.Those of ordinary skills can be with such dosage regimen timetable optimization.

In other embodiments, can carry out some therapeutic processes to the patient simultaneously, promptly can still make said immunomodulatory compounds in the interval that second kind of active substance works, each dosage of second kind of active substance independently be carried out administration.For example, can once in a week a kind of component be carried out administration, simultaneously whenever biweekly or per three weeks once with other component administration.That is, though therapeutic agent be not administration simultaneously or be not on the same day by administration, in fact this dosage regimen also carries out simultaneously.

Said second kind of active substance can add with this immunomodulatory compounds and or more preferably collaborative onset.In one embodiment, with immunomodulatory compounds and one or more second kind of active substance administrations simultaneously in identical pharmaceutical composition.In another embodiment, with immunomodulatory compounds and one or more the second kind of active substance administrations simultaneously in other pharmaceutical composition.In another embodiment, before second kind of active substance administration or after the administration, give immunomodulatory compounds.The present invention considers to give immunomodulatory compounds and second kind of active substance by identical or different route of administration as oral and parenteral.In certain embodiments, when with immunomodulatory compounds during with second kind of active substance that may produce adverse side effect (including but not limited to toxicity) administration simultaneously, this second kind of active substance can be advantageously be lower than excite said adverse side effect threshold value dosage by administration.

4.3.2 Use with pain control intervention techniques

In another embodiment, the present invention includes the method for a kind of treatment, prevention, change and/or pain management, it comprise with the associating of pain control intervention techniques (for example before it, during or afterwards), give immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug.The example that pain is controlled intervention techniques includes but not limited to use sympathetic nerve blocking-up, the local blocking-up of intravenous, placement dorsal funciculus stimulant or placement to be used to transmit the interior input equipment of film of analgesic.Preferred pain control intervention techniques provides interrupts being subjected to the active selectivity nerve block of sympathetic nervous system of pain influence area.

The use in conjunction of immunomodulatory compounds and pain control intervention techniques can provide a kind of to the effective unexpectedly unique therapeutic scheme of some patient.Not bound by theory, think that when carrying out simultaneously with pain control intervention techniques, immunomodulatory compounds can provide and add and or synergism.The example of pain control intervention techniques is to use the local retardance of intravenous of the Bier retardance with various materials, said various material without limitation as local anesthetic as, bupivacaine and lignocaine, guanethidine, ketamine, bretylium tosylate, steroid, ketorolac and reserpine.People such as Perez R.S., J Pain Symptom Manage June calendar year 2001; 21 (6): 511-26.For the CRPS case that relates to upper limb, can use starlike (neck breast) ganglionoplegic.The present invention also comprises and uses the corporality retardance, and it comprises with the different modification of brachial plexus block and carries out the epidural input together continuously.Method also is useful on the axillary fossa of corporality retardance, the clavicle or under the clavicle.

4.3.3 Use naturopathy or psychotherapy

In another embodiment, the present invention includes the method for a kind of treatment, prevention, change and/or pain management, it comprises and naturopathy or psychotherapy's associating, gives immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug.

Such as mentioned above, the symptom of pain comprises vasomotion malfunction and motion disease.For the patient who suffers from pain syndrome, be crucial from gentle load-bearing to the stable of gradual active load-bearing.Desensitization gradually to enhanced sensory stimuli also may be helpful.Standardization sensation increase gradually trends towards reformed process among the CNS is resetted.Therefore, naturopathy may play an important role in the recovery of function.The purpose of naturopathy is to gain in strength gradually and motility.

Think that the use in conjunction of immunomodulatory compounds and naturopathy can provide a kind of therapeutic scheme effectively unique unexpectedly for some patients.Not bound by theory, think that when using simultaneously immunomodulatory compounds can provide and add and or synergism with naturopathy.

Many pain works have all write down the behavior of companion's row and the patient's condition on the psychiatry, as depression and anxiety.Think that immunomodulatory compounds and psychotherapy can provide a kind of therapeutic scheme effectively unique unexpectedly for some patients.Not bound by theory, think when using simultaneously with the psychotherapy, immunomodulatory compounds can provide add and or synergism, said psychotherapy includes but not limited to biofeedback, relaxation training, understanding-behavior therapy and individuality or family's psychotherapy.

Can be before naturopathy or psychotherapy, during the treatment or immunomodulatory compounds is used in the treatment back, in some concrete grammars, second kind of active substance also is applied to patient or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug.

4.4 Pharmaceutical composition and monomer dosage form

Pharmaceutical composition can with independently, the form of monomer dosage form is used.Pharmaceutical composition of the present invention and dosage form comprise immunomodulatory compounds, or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug.Pharmaceutical composition of the present invention and dosage form also can further comprise one or more excipient.

Pharmaceutical composition of the present invention and dosage form also can comprise one or more other active component.So, pharmaceutical composition of the present invention and dosage form comprise active substance disclosed herein (for example, immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug and second kind of active substance).Disclosed herein is the example (seeing that for example, the 4.2nd saves) of optional other active substance.

That monomer dosage form of the present invention is suitable for is oral, mucosa (for example, nose, Sublingual, vagina, cheek or rectum) or parenteral (for example, subcutaneous, intravenous, inject, intramuscular or intra-arterial), percutaneous (transdermal or transcutaneous) delivers medicine to the patient.The example of dosage form includes but not limited to: tablet; Caplet; Capsule is as the elasticity Perle; Cachet; Lozenge; Lozenge; Dispersion; Suppository; Powder; Aerosol (for example, nose spraying or inhalant); Gel; Be suitable for oral or mucosa delivery in patient's liquid dosage form, comprise suspension (for example, aqueous or non-aqueous liquid suspension, oil in water emulsion or Water-In-Oil liquid emulsion), solution and elixir; Be suitable for the liquid dosage form of parenteral in the patient; Thereby be suitable for the aseptic solid (for example, crystallization or unbodied solid) of parenteral in patient's liquid dosage form with being provided by recombinating.

The composition of dosage form of the present invention, shape and type generally will change according to its application.For example, the quantity of one or more active substances that used dosage form can comprise in the acute treatment of disease in can chronic treatment than same disease the used quantity that dosage form comprised bigger.Equally, the quantity of one or more active substances of comprising of parenteral dosage form can be lower than the quantity that is comprised in the peroral dosage form that is used for the treatment of same disease.These and other aspect of the particular dosage form that those skilled in the art will easily recognize the present invention and be comprised will differ from one another.See, for example, Remington ' s Pharmaceutical Sciences, the 18th edition, Mack Publishing, Easton PA (1990).

Typical pharmaceutical composition and dosage form comprise one or more excipient.Suitable excipient is well-known for the pharmaceutical field technical staff, and has provided the limiting examples of proper excipient here.Whether a kind of specific excipient is suitable for being blended into depends on many factors well-known in the art in a kind of pharmaceutical composition or the dosage form, include but not limited to that this dosage form will deliver medicine to patient's method.For example, peroral dosage form such as tablet may comprise the excipient that is not suitable for parenteral dosage form.The suitability of particular excipient may also depend on specific active ingredient in this dosage form.For example, some excipient such as lactose or when contacting, may quicken the decomposition of some active component with water.The active component that comprises primary amine or secondary amine is easy to be subjected to the influence of such accelerated decomposition especially.Therefore, comprise the lactose that also comprises seldom, other monosaccharide or the pharmaceutical composition and the dosage form of disaccharide if the present invention includes.So as used herein, term " does not contain lactose " and refers to if present, and the lactose lazy weight of existence is to enlarge markedly the degradation speed of active component.

The lactose-free compositions of the present invention can comprise well-known excipient in the prior art, for example listed excipient in US pharmacopeia (USP) 25-NF20 (2002).Generally speaking, compatible and pharmaceutically useful quantity comprises active component, binding agent/filler and lubricant to lactose-free compositions with pharmacy.Preferred lactose-free dosage form comprises active component, the fine young element of crystallite, pregelatinized Starch and magnesium stearate.

Because water can promote the degraded of some chemical compounds, so the present invention also comprises anhydrous pharmaceutical composition and the dosage form that comprises active component.For example, to determine some characteristics such as pot-life or the preparation method along with the stability of time lapse, adding entry (for example, 5%) is widely accepted in pharmaceutical field as the simulate long storage situation.See, for example, Jens T.Carstensen, Drug Stability:Principles ﹠amp; Practice, the 2nd edition., Marcel Dekker, NY, NY, 1995, the 379-80 pages or leaves.In fact, water and heat have been quickened the decomposition of some chemical compounds.Therefore, because in manufacturing, processing, the packing of preparation, store, transport and often run into moisture and/or dampness between the operating period, so water may be crucial to a kind of effect of preparation.

Anhydrous pharmaceutical composition of the present invention and dosage form can and be prepared under the condition of low moisture or low humidity with the composition of anhydrous or low moisture content.Can contact with moisture and/or dampness in a large number between manufacturing, packing and/or storage life if be expected at, the pharmaceutical composition and the dosage form that then comprise lactose and at least a active component that comprises primary amine or secondary amine are preferably anhydrous.

Should prepare and store anhydrous pharmaceutical composition in the mode of keeping its no aqueous.Therefore, thus preferably prevent that the material that contacts with water from coming this anhydrous composition packed and make it can be contained in the test kit of suitable form with known.The example of proper packing includes but not limited to bubble-tight paper tinsel, plastics, unit-dose container (for example, bottle), blister pack and strip packing.

The present invention also comprises the pharmaceutical composition and the dosage form of the chemical compound that comprises one or more reduction active component degradation rates.This compounds that is called as " stabilizing agent " here includes but not limited to antioxidant such as ascorbic acid, pH buffer agent or salt buffer agent.

The same with the quantity and the type of excipient, the quantity of active component and particular type can change along with many factors in a kind of dosage form, and said factor is delivered medicine to patient's approach without limitation as it.But exemplary dosage form of the present invention comprises immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug with about quantity of 0.10 to about 150mg.Representative dosage forms with about 0.1,1,2,5,7.5,10,12.5,15,17.5,20,25,50,100,150 or the quantity of 200mg comprise immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In a specific embodiment, preferred dosage form with about 1,2,5,10,25 or the quantity of 50mg comprise 4-(amino)-2-(2,6-dioxo (3-piperidyl))-isoindoline-1,3-diketone (Actimid ^TM).In a specific embodiment, preferred dosage form with about 5,10,25 or the quantity of 50mg comprise 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone (Revimid ^TM).Representative dosage forms is with about 1 to about 3, and 500mg, about 5 is to about 2,500mg, about 10 to about 500mg or about quantity of 25 to about 250mg comprise second kind of active substance.Certainly, the specific quantity of said second kind of active substance will depend on the quantity of used predetermined substance, institute's types of pain for the treatment of or controlling and the immunomodulatory compounds that is delivered medicine to the patient simultaneously and optional other active substance.

4.4.1 Peroral dosage form

The pharmaceutical composition of the present invention that is suitable for oral administration can exist with the form of discrete dosage form, without limitation as, tablet (for example, chewable tablet), Caplet, capsule and liquid (for example, tasteable syrup).Such dosage form comprises the active substance of predetermined quantity, and can be prepared with the well-known method of pharmacy of those skilled in the art.Generally can be referring to Remington ' s Pharmaceutical Sciences, the 18th edition, MackPublishing, Easton PA (1990).

Exemplary oral dosage form of the present invention can be mixed active component closely with at least a excipient by the pharmacy complex technique according to routine and is prepared.The dosage form required according to administration can use various forms of excipient.For example, the excipient that is applicable to liquid oral or aerosol dosage forms includes but not limited to water, ethylene glycol, oils, alcohols, correctives, antiseptic and coloring agent.The example that is applicable to the excipient of solid oral dosage form (for example powder, tablet, capsule and Caplet) includes but not limited to starch, sugar, microcrystalline Cellulose, diluent, granulation agent, lubricant, binding agent and disintegrating agent.

Because it is easy to administration,, in this kind situation, use solid excipient so tablet and capsule have been represented best oral dosage unit form.If necessary, can carry out coating to tablet with the aqueous or the non-aqueous technology of standard.Can prepare such dosage form with any method of pharmacy.Generally speaking, these pharmaceutical compositions and dosage form can be processed into required shape then if necessary by with active component and liquid-carrier, the very thin solid carrier of cutting apart or liquid-carrier and being prepared all even the mixing nearly of very thin solid carrier of cutting apart.

For example, tablet can be prepared by compression or molding.Compressed tablet can be prepared by in suitable machine the active component of the free-flowing form that randomly is mixed with excipient such as powder or particle form being compressed.The molding sheet can be by will being prepared with the powder compound molding that inert liquid diluent has wet in suitable machine.

The example that can be used for the excipient of peroral dosage form of the present invention includes but not limited to binding agent, filler, disintegrating agent and lubricant.The binding agent that is applicable to these pharmaceutical compositions and dosage form includes but not limited to corn starch, potato starch, or other starch, gelatin, natural and paragutta such as arabic gum, sodium alginate, alginic acid, other alginate, powdered tragacanth, guar gum, fine young plain with and derivant (for example, ethyl is fine young plain, acetic acid is fine young plain, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized Starch, hydroxypropyl emthylcellulose (for example, sequence number 2208,2906,2910), microcrystalline Cellulose, with and composition thereof.

The suitable form of microcrystalline Cellulose includes but not limited to (derive from FMCCorporation with AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105, American Viscose Division, Avicel Sales, Marcus Hook, the material that PA) form is sold, with and composition thereof.A kind of specific binding agent is with the form of AVICEL RC-581 microcrystalline Cellulose of selling and the mixture of counting sodium carboxymethylcellulose pyce.Suitable anhydrous or low-moisture excipient or additive comprise AVICEL-PH-103 ^TMWith Starch 1500 LM.

The example that is applicable to the filler of pharmaceutical composition disclosed herein and dosage form include but not limited to Pulvis Talci, calcium carbonate (for example, granule or Powdered), the fine young element of crystallite, Powderd cellulose, glucosan (dextrates), Kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized Starch, with and composition thereof.In the pharmaceutical composition of the present invention the amount of binding agent or filler be generally this pharmaceutical composition or dosage form about 50% to about 99% weight.

Using disintegrating agent in compositions of the present invention is in order to make disintegration of tablet when contacting with aqueous environments.The tablet that comprises too much disintegrating agent may disintegrate when storing, may not be with required speed disintegrate or can not disintegrate under required condition and comprise the tablet of seldom measuring disintegrating agent.Therefore, should form solid oral dosage form of the present invention with the disintegrating agent of sufficient amount, its quantity can not be too much can not be very little, in order to avoid change the release of active component undeservedly.The quantity of used disintegrating agent changes according to the type of preparation, and can easily be distinguished by those skilled in the art.Typical pharmaceutical composition comprises about 0.5% disintegrating agent to about 15% weight, preferably comprises about 1% disintegrating agent to about 5% weight.

The disintegrating agent that can be used for pharmaceutical composition of the present invention and dosage form include but not limited to agar, alginic acid, calcium carbonate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, poly-gram force woods potassium (polacrilin potassium), sodium starch glycolate, Rhizoma Solani tuber osi or tapioca, other starch, pregelatinized Starch, other starch, clay, other algin, other cellulose, natural gum, with and composition thereof.

The lubricant that can be used for pharmaceutical composition of the present invention and dosage form include but not limited to calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, Polyethylene Glycol, other glycol, stearic acid, sodium lauryl sulfate, Pulvis Talci, hydrogenated vegetable oil (for example, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum helianthi, Oleum sesami, olive oil, Semen Maydis oil and Oleum Glycines), zinc stearate, ethyl oleate, ethyl laurate (ethyl laureate), agar, with and composition thereof.Other lubricant for example comprises, syloid silica gel (AEROSIL200, by W.R.Grace Co.of Baltimore, the MD manufacturing), the solidified gas colloidal sol of synthetic silica is (by Degussa Co.of Plano, TX sells), CAB-O-SIL (a kind of by Cabot Co.ofBoston, the pyrogenic silica that MA sells), with and composition thereof.If you are using, the typical amounts of lubricant less than its be blended into wherein pharmaceutical composition or about 1% weight of dosage form.

A kind of preferred solid oral dosage form of the present invention comprises immunomodulatory compounds, Lactis Anhydrous, microcrystalline Cellulose, polyvinylpyrrolidone, stearic acid, colloidal silica anhydrous and gelatin.

4.4.2 Delayed release dosage forms

Active substance of the present invention can carry out administration with well-known controlled release method of those of ordinary skills or transfer device.The example includes but not limited at US:3 845,770; 3,916,899; 3,536,809; 3,598,123; With 4,008,719,5,674,533,5,059,595,5,591,767,5,120,548,5,073,543,5,639,476,5,354,556 and 5,733, these materials described in 566, said each file here is introduced into as a reference.This type of dosage form can use hydroxypropyl emthylcellulose for example, other polymeric matrix, gel, permeable film, osmotic pump system, multiple coatings, microgranule, liposome, microsphere or its to make up to provide one or more active component slowly or controlled release thereby the expection release property of different proportion is provided.The known to a person of ordinary skill in the art suitable controlled release preparation that can easily select to comprise these preparations as described herein is used for using with active component of the present invention.Therefore, the present invention comprises and is suitable for oral monomer dosage form, includes but not limited to tablet, capsule, gelcaps and Caplet as being suitable for controlled release.

All controlled release medicines all have and improve Drug therapy and make it be better than the common objective of the treatment that obtains with the homologue of non-controlled release.The desired characteristics of using the optimal controlled release preparation of design in Drug therapy is for curing with minimum medicine in the minimum time or controlling said situation.The advantage of controlled release preparation comprises and has prolonged pharmaceutically active, reduced medicine frequency and increased patient's compliance.Therefore in addition, time or other characteristic of influence onset can be come,, and the generation of side effect (for example detrimental effect) can be influenced as the blood levels of medicine with controlled release preparation.

Most of controlled release preparations are designed to can produce rapidly in initial release medicine (active component) quantity of required therapeutical effect, and can be gradually and the medicine that discharges other quantity continuously in long-term, to keep the level of this treatment or preventive effect.In order to keep medicine this constant level in vivo, medicine must discharge from this dosage form can substitute those quantity by body institute's metabolism and excretory medication amount.Can come the controlled release of stimulating activity composition by various situations, said situation includes but not limited to pH, temperature, enzyme, water or other physiological conditions or chemical compound.

4.4.3 Parenteral dosage form

Parenteral dosage form can be applied to the patient by number of ways, and that said approach includes but not limited to is subcutaneous, intravenous (comprise and injecting), intramuscular and intra-arterial administration.Because the natural defence that the patient resists pollutant has generally been walked around in its administration, thus parenteral dosage form preferably aseptic or can before being applied to the patient, be sterilized.The example of parenteral dosage form includes but not limited to injection solution, is easy to dissolve or be suspended in the dryed product in injection pharmaceutically suitable carrier, the suspension that is used to inject and Emulsion.

Being used to the suitable carrier of parenteral dosage form of the present invention is provided is well-known to those skilled in the art.The example includes but not limited to: water for injection USP; Aqueous matrix for example, but is not limited to, chloride injection agent, woods Ge Shi injection, glucose injection agent, glucose and chloride injection agent and lactic acid salinization woods Ge Shi injection; The mixable substrate of water, without limitation as, ethanol, Polyethylene Glycol and polypropylene glycol; With non-aqueous substrate, without limitation as, Semen Maydis oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum sesami, ethyl oleate, isopropyl myristate and benzyl benzoate.

Can also in parenteral dosage form of the present invention, sneak into the chemical compound that can increase one or more dissolubility in the active component disclosed herein.For example, can with cyclodextrin with and derivant increase immunomodulatory compounds with and the dissolubility of derivant.See that for example, US 5,134,127, it here is introduced into as a reference.

4.4.4 Part and mucosa dosage form

Part of the present invention and mucosa dosage form include but not limited to spray, aerosol, solution, Emulsion, suspension, or other form well known by persons skilled in the art.See, for example, Remington ' s Pharmaceutical Sciences, the 16th and the 18th edition, MackPublishing, Easton PA (1980 ﹠amp; 1990); And Introduction toPharmaceutical Dosage Forms, the 4th edition, Lea ﹠amp; Febiger, Philadelphia (1985).The dosage form that is suitable for handling intraoral mucosal tissue can be prepared to collutory or oral area gel.

The proper excipient that can be used for providing included part of the present invention and mucosa dosage form (for example, carrier and diluent) and other material be well-known for the pharmaceutical field technical staff, and depend on that given pharmaceutical composition or dosage form are with the particular organization that is employed.The typical excipient that is used to form solution, Emulsion or gel includes but not limited to water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-glycol, isopropyl myristate, isopropyl palmitate, mineral oil, with and composition thereof, it is nontoxic and pharmaceutically useful.If necessary, can also in these pharmaceutical compositions and dosage form, add humidizer or wetting agent.The example of the composition that such is other is well known in the prior art.See, for example, Remington ' sPharmaceutical Sciences, the 16th and the 18th edition, Mack Publishing, EastonPA (1980 ﹠amp; 1990).

The pH that can also regulate this pharmaceutical composition or dosage form is to improve sending of one or more active component.Equally, polarity, its ionic strength or the isotonia that can also regulate solvent carrier sent with improvement.Thereby can also add chemical compound such as stearate in pharmaceutical composition or dosage form advantageously changes the plain aqueous of one or more active component or lipophile and improves and send.Thus, stearate can be used as the lipid carrier of preparation, as emulsifying agent or surfactant and can be used as to send and strengthen or penetration enhancers.Can come with different salt, hydrate or the solvate of active component the character of resulting composition is further adjusted.

4.4.5 Test kit

Active component of the present invention does not generally preferably deliver medicine to the patient in the identical time or with identical route of administration.Therefore, the present invention comprises when being used by the medical science practitioner and can simplify the test kit of suitable number active component to patient's administration.

The typical test kit of the present invention comprises the dosage form of immunomodulatory compounds or its pharmaceutically useful salt, solvate, hydrate, stereoisomer, prodrug or clathrate.The test kit that the present invention comprised can further comprise other active component or its combination.The example of other active component includes but not limited to that antidepressant, anticonvulsant, antihypertensive, antianxiety drug, calcium channel blocker, muscle relaxant, non-narcotic analgesics, opioid analgesic, antiinflammatory, cox-2 inhibitor, immunomodulator, immunosuppressant, cortical steroid material, hyperbaric oxygen or other therapeutic agent discussed herein (see, for example, the 4.2nd joint).

Test kit of the present invention can further comprise the device that is used to give active component.The example of such device includes but not limited to syringe, bag, paster and inhaler instil.

Test kit of the present invention can further comprise the pharmaceutically useful carrier that can be used for giving one or more active component.For example, if active component is to provide with solid form, must can comprise the sealed container that appropriate carrier is housed in this test kit so to its reconstruct to be used for parenteral, described active component dissolves in the carrier, is suitable for the agranular sterile solution of parenteral with formation.The example of pharmaceutically suitable carrier includes but not limited to: water for injection USP; Aqueous matrix is without limitation as chloride injection agent, woods Ge Shi injection, glucose injection agent, glucose and chloride injection agent and lactic acid salinization woods Ge Shi injection; The mixable substrate of water is without limitation as ethanol, Polyethylene Glycol and polypropylene glycol; With non-aqueous substrate, without limitation as Semen Maydis oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum sesami, ethyl oleate, isopropyl myristate and benzyl benzoate.

5. Embodiment

The following examples are said some aspect of the present invention, but its scope are not construed as limiting.

5.1 Pharmaceutical research

Pain be begin by inflammatory reaction and continue because of the existence of inflammatory cytokine such as TNF-α.TNF-α may play certain pathology effect in nociceptive pain and neuropathic pain.A kind of biological action that immunomodulatory compounds is brought into play is reduce TNF-α synthetic.Immunomodulatory compounds has increased the degraded of TNF-α mRNA.In people's painful neuropathy, show it and in Schwann cell, express increase.Compare with the neuralgia patient who does not report allodynia, suffer from that soluble TNF-α receptor increases in patient's the serum of allodynia.This cytokine can be induced the abnormal activity in the elementary afferent nociceptor, and therefore, it is a hyperalgesic potential cause in the neuropathic pain.A kind of possible mechanism is that TNF-α can form active sodium-ion channel in cell.The sodium flow increase that enters into nociceptor will make it be easy to paradoxical discharge.If its nervous lesion in malfunction partly enlivens, then this cytokine may play a kind of pathology effect.

Not bound by theory, when preferential use, immunomodulatory compounds can reduce mechanical allodynia and the thermal hyperalgesia in the chronic narrow damage model rat of neuropathic pain.Except that reducing endoneurial TNF-α, this chemical compound also can cause the long-term increase of cornu dorsale medullae spinalis met-enkephalin (a kind of important anti-nociceptive neurotransmitter).Immunomodulatory compounds can also suppress inflammatory hyperpathia and the nociceptive response of mouse writhing of rat.

In in vitro study 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone, 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-and isoindoline-1,3-diketone and Thalidomide stimulate the inhibitory action of back TNF-α generation to human PBMC and people's whole blood LPS-.Stimulate back 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-isoindoline-1 at the LPS-of human PBMC and people's whole blood, the 3-diketone suppresses the IC that TNF-α produces ₅₀Be respectively～24nM (6.55ng/mL) and～25nM (6.83ng/mL).Stimulate back 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2 at the LPS-of human PBMC and people's whole blood, the 6-diketone suppresses the IC that TNF-α produces ₅₀Be respectively～100nM (25.9ng/mL) and～480nM (103.6ng/mL).On the contrary, stimulate the back Thalidomide to suppress the IC that TNF-α produces at the LPS of PBMC ₅₀Be～194 μ M (50.1 μ g/mL).

In vitro study shows 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone or 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-isoindoline-1, the pharmacological activity of 3-diketone is similar to Thalidomide, but it is stronger 50 to 2,000 times than Thalidomide.3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone or 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-isoindoline-1, the pharmacotoxicological effect of 3-diketone derives from it as to the trophic signals of receptor-startup (for example, IGF-1, VEGF, COX-2) effect and other activity of cellular response inhibitor.Therefore, 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone or 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-isoindoline-1, the 3-diketone suppressed releasing and activity of inflammatory cytokines, reduced adhesion molecule and apoptosis inhibitor albumen (for example, cFLIP, cIAP), promoted the sensitivity of programmed cell death that death receptor is started and suppressed to generate the response of blood vessel.

In addition, having shown stimulates aspect the T-cell proliferation after being induced by former of T-cell receptors (TCR) activation generation, 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone or 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-and isoindoline-1, powerful about 50 to 100 times of the effectiveness of 3-diketone than Thalidomide.The effectiveness of these chemical compounds aspect the TCR of PBMC (IL2) or T-cell (IFN-γ) activation back increase IL2 and IFN-γ generation is also than high about 50 to 100 times of Thalidomide.In addition, preceding inflammatory cytokine TNF-α, IL1 β that these chemical compounds stimulate the LPS-of PBMC and the generation of IL6 show the inhibitory action of dose dependent, and it has increased the generation of anti-inflammatory cytokines IL10 simultaneously.

5.2 Toxicologic study

With anesthesia Canis familiaris L. to 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone and 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-isoindoline-1, the 3-diketone is studied the inhibitory action of cardiovascular and respiratory function.Use two groups than lattice (Beagle) Canis familiaris L. (2/ sex/group).One group of three kinds of dosage only accepting carrier, another winding is subjected to 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone or 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-and isoindoline-1, three kinds of rising dosage of 3-diketone (2,10 and 20mg/kg).In all situations, pass through to import with 3-(4-amino-1-oxo-1 with at least 30 minutes intervals by jugular vein, 3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone, 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-isoindoline-1,3-diketone or carrier continuous administration.

When comparing with the vehicle Control group, in all dosage groups, 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone or 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-and isoindoline-1, inductive cardiovascular of 3-diketone and respiratory change all are minimized.Giving the 3-of low dosage (4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2,6-diketone or 4-(amino)-2-(2,6-dioxo-(3-piperidyl))-isoindoline-1, behind the 3-diketone, unique significant significant difference is that arteriotony increases slightly between carrier and the matched group.This effect was kept about 15 minutes and was not observed in this effect under higher dosage.The femur blood flow of matched group and treatment group, respiration parameter and Qtc deviation at interval is identical, does not think that therefore it is that treatment is relevant.

5.3 The research of carrying out with the animal pain model

Can test the ability of immunomodulatory compounds treatment, prevention, control and/or change pain with well-known any pain model in the prior art.At Hogan, Q., local anesthesia and pain medical science (Regional Anesthesia and Pain Medicine) 27 (4): among the 385-401 (2002) many animal pain models are described, its here its full content be introduced into as a reference.

The example of nociceptive pain model comprises gate-Papacostas' tests, hot plate test and tail-flick test.Be described below the illustrative example of gate-Papacostas' tests, hot plate test and tail-flick test.

The most frequently used neuropathic pain model is Bennett, Selzer and Chung model.Siddall, P.J. and Munglani, R., the animal model of pain (Animal Models ofPain), 377-384 page or leaf, Bountra, C., Munglani, R., Schmidt, W.K., editor, (Pain:Current Understanding, Emerging Therapies and NovelApproaches to Drug Discovery), Marcel Dekker, Inc., New York, 2003.This Bennett and Selzer model are well-known and can finish rapidly.The Chung model all is effectively to the unusual pain of mechanicalness of most of animals, though complicated, it has been carried out good description.These models have been represented a series of trials and have been simulated infringement in some clinical settings and the method for malfunction.For the some diseases relevant, some animal models are also arranged, as diabetic neuropathy or new osteocarcinoma and Encelialgia model with pain.

5.3.1 Be used to measure the gate-Papacostas' tests of rat constant pain

Regulate chemical compound or carrier (contrast) for the animal injecting immune, then with the back side of formalin injection to pawl.This animal observed to measure it shrink back in 60 minutes time that it has accepted the number of times of the claw of injection.This model makes and can assess anti-nociceptive medicine in the pain therapy.Abbott, people Pain 60:91-102 (1995) such as F..

During Therapy lasted, animal is placed in the footwear box cage.Pin (28.5G) is put into above the toe and ankle joint below, and be inserted into below the skin, thus with formalin (50 μ l; 0.5%) is expelled to the back side of right back pawl.After injection, open timer immediately with the labelling beginning in the 1st stage.After injection, animal was observed 10 minutes and its its number of times that has carried out the claw of injection of shrinking back is counted.After first time injection of formalin 30 minutes, the 2nd stage began.In ensuing 20 minutes, count shrinking back with the method identical with the 1st stage.Before gate-Papacostas' tests, reach 24 hours by oral route with about 0.10 to about 150mg/ day quantity with the immunomodulatory compounds administration.Carry out reprocessing with its treatment time ordered pair animal.After experimental period finishes, pass through CO according to the IACUC guilding principle immediately ₂Suffocate these animal euthanasias.

At any time of this research point, intervene the animal of the incident that any experience is not expected to by the veterinary and assess.Pass through CO immediately according to the IACUC guilding principle ₂Suffocating will be with the irreclaimable any animal euthanasia of standard veterinary care.

5.3.2 Be used to measure the hot plate test of rat acute pain

Regulate chemical compound or carrier (contrast) for the animal injecting immune, each then ground places it on the hot plate.Lick the time that its claw spends by animal and measure the incubation period that this thermostimulation is taken place in response.Malmberg, A. and Yaksh, T., Pain 60:83-90 (1995).Come anti-nociceptive medicine in the pain therapy is assessed with this model.People such as Langerman, Pharmacol.Toxicol.Methods 34:23-27 (1995).

Determine best hot plate temperature with the morphine treatment.8 to 10mg/kg morphine (i.p.) dosage provides the anti-nociceptive response of intimate maximum in the acute pain test.This device is set in these dose of morphine observes under the temperature of such anti-nociception response (about 55 ℃).Before hot plate test, grow to 24 hours, with the dosed administration of immunomodulatory compounds by oral route with about 0.10 to about 150mg/ day.When the treatment after go by the time, begin each animal is tested.Be placed on an independent animal on the hot plate and start code table or timer immediately.To this animal observe until its show nociceptive response (for example, licking its claw) or until reach 30 seconds deadline (with will be when contacting for a long time with hot surface contingent histologic lesion minimize).Animal is taken off and writes down its preclinical time from hot plate.For for the animal that did not have response before deadline, should remember deadline and make its response time.With its inferior ordered pair animal repeated treatments of being treated.Guilding principle according to IACUC after experiment is passed through CO immediately ₂Suffocate animal euthanasia.

At any time of this research point, intervene the animal of the incident that any experience is not expected to by the veterinary and assess.Pass through CO immediately according to the IACUC guilding principle ₂Suffocating will be with the irreclaimable any animal euthanasia of standard veterinary care.

5.3.3 Be used to measure the tail-flick test of rat acute pain

Regulate chemical compound or substrate (contrast) for the animal injecting immune, then light beam is focused on its afterbody.Flick the time of its tail by animal and measure the incubation period that this stimulation is taken place in response.With this model anti-nociceptive medicine in the pain therapy is assessed.See people such as Langerman, Pharmacol.Toxicol.Methods34:23-27 (1995).

According to the IACUC guilding principle, carry out growing to 24 hours before the tail-flick test, with of the quantity administration of immunomodulatory compounds by oral route with about 0.10 to about 150mg/ day.When the treatment after go by the time, begin each animal is tested.An independent animal is placed on light beam is accumulated on its tail ventral surface.Responding incubation period is the time of getting rid of its tail to it from using up.To this animal observe until its show nociceptive response (for example, whipping) or until reach 10 seconds deadline (with will be when contacting for a long time with hot surface contingent histologic lesion minimize).Animal is taken off from light source, write down the incubation period of its response, pass through CO according to the guilding principle of IACUC then ₂Suffocate animal euthanasia.Adjust beam intensity to produce the 2.5-4 benchmark incubation period of second.For for the animal that response did not take place before deadline, its response time will be recorded as this deadline.With its inferior ordered pair animal repeated treatments of being treated.

At any time of this research point, intervene the animal of the incident that any experience is not expected to by the veterinary and assess.Pass through CO immediately according to the IACUC guilding principle ₂Suffocating will be with the irreclaimable any animal euthanasia of standard veterinary care.

5.3.4 The model that is used for local capsaicin-inductive heat anomaly pain

The model that is specially adapted to heat anomaly pain is local capsaicin-inductive heat anomaly pain model.Butelman, people J.of Pharmacol.Exp.Therap.306:1106-1114 (2003) such as E.R..This model is the modification that hot water is removed the tail model.Ko, people such as M.C., J.of Pharmacol.Exp.Therap.289:378-385 (1999).Briefly, monkey is sitting on a kind of chair of customization of the room (20-22 ℃) that is arranged in controlled temperature.With the standard pruning tool hair on its tail is shaved off and in the water of 38 ℃ and 42 ℃ stimulates with 0.1 second increment will remove the preclinical time of tail be decided to be high extremely the highest 20 seconds so that a kind of benchmark to be provided.After benchmark is measured, with its tail leniently dry and with the isopropyl alcohol pad with its defat.About before use 15 minutes, capsaicin is dissolved in the substrate of forming by 70% ethanol and 30% sterilized water to 0.0013 or the capsaicin final concentration of 0.004M.(0.3mL) slowly is expelled in the Gauze with this solution, makes this sheet saturated and avoid its overflow.In that this capsaicin solution is joined said thin slice in last 30 second, the capsaicin pad is fixed on its tail with belt.After 15 minutes, this sheet taken off and in the water of 38 ℃ and 42 ℃ stimulates, remove tail like that as mentioned above and test.Compare with reference measurement, detect allodynia with the form of removing tail reduction incubation period.In order to determine that immunomodulatory compounds reduces the ability of allodynia, (for example 15 minutes, 30 minutes, 60 minutes or 90 minutes before) give the single dose of this chemical compound before using said capsaicin sheet.Perhaps, also can be after using this capsaicin sheet (for example after 30 minutes, 60 minutes or 90 minutes immediately) single dose of giving this chemical compound allodynia of measuring immunomodulatory compounds reverse property.

This capsaicin model is applicable to the material that is used for treating hyperpathia and allodynia (for example vanilloid receptor 1 (VR1) antagonist and AMPA antagonist), and the UV skin burn may be applicable to bradykinin b 1 receptor antagonist, cannabinoid agonists and VR1 antagonist.The anti-hyperpathia effect of medicine such as opioid, local anesthetic, ketamine and the gabapentin of some clinical uses has been supported in the clinical practice of capsaicin model.The internal organs model is may be so far still unknown and need confirm as the hyperpathia model.

5.4 The clinical research of carrying out with pain patients

In three to six months with immunomodulatory compounds such as 4-(amino)-2-(2,6-dioxo (3-piperidyl))-isoindoline-1,3-diketone and 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-and piperidines-2, the 6-diketone delivers medicine to the patient who suffers from pain syndrome with 0.1 to 25mg/ day quantity.Drug therapy is carried out benchmarking exercise to effect, the pain of pain intensity to the influence of daily life and the consumption of other pain medication.

In a specific embodiment, with suffer from upper limb CRPS conventional naturopathy not have to respond and ill at least one year patient carries out clinical research.Early stage in its disease, in regular autonomy test (quantitative urge antiperspirant axon reflex test (QSART), have a rest and perspire and thermography), the patient has the clearly evidence of autonomy malfunction.If this can not obtain, the record of clinical indication shows with allodynia and swelling symptom and autonomy malfunction (change of hydration, temperature, skin, fingernail or natural on-off cycles of hair growth) occurred.The patient uses 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-piperidines-2 continuously, and the 6-diketone is treated with the oral dose of every day 10 to 25mg.With standard pain score for example, the digital score assessment (Numeric Pain Scale Assessment) of pain (VAS) is assessed these responses, quality of life is assessed as the reduction of swelling, perspiration, skin color variable color, temperature change, skin, hair and the nail growth variation of range estimation and trickle motor activity with the objective sign in the clinical examination of McGill exponential sum.Treating as successive oral daily dose with 10mg can be by well tolerable.This medicine that studies show that with the CPRS patient of immunomodulatory compounds treatment had the analgesia benefit to this disease.

Embodiment of the present invention described here only are that some the selectivity samplings in the scope of the invention are described.Should fully understand gamut of the present invention with reference to appended claim.

Claims (12)

1. immunomodulatory compounds 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-and piperidines-2,6-diketone or its pharmaceutically useful salt, solvate or stereoisomer are used for the treatment of in preparation, the purposes in the pharmaceutical composition of prevention, change or pain management.

2. immunomodulatory compounds 3-(4-amino-1-oxo-1,3-dihydro-iso-indoles-2-yl)-and piperidines-2,6-diketone or its pharmaceutically useful salt, solvate or stereoisomer and at least a second kind of active substance are used for the treatment of in preparation, the purposes in the pharmaceutical composition of prevention, change or pain management.

3. purposes as claimed in claim 2, pain is alleviated or reduced to wherein said second kind of active matter mass-energy.

4. purposes as claimed in claim 2, wherein said second kind of active substance is antidepressant, antihypertensive, antianxiety drug, calcium channel blocker, alpha adrenergic receptor agonists, alpha-adrenergic aceptor antagonist, ketamine, anesthetis, muscle relaxant, non-narcotic analgesics, opioid analgesic, antiinflammatory, immunomodulator, immunosuppressant, corticosteroid, anticonvulsant, cox-2 inhibitor, hyperbaric oxygen or its combination.

5. purposes as claimed in claim 2, wherein said second kind of active substance be aspirin, celecoxib, ketamine, gabapentin, carbamazepine, oxcarbazepine, phenytoin, sodium valproate, prednisone, nifedipine, clonidine, oxycodone, Pethidine, morphine sulfate, hydromorphone, fentanyl, pounce on hot former times pain, ibuprofen, naproxen sodium, griseofulvin, amitriptyline, imipramine or doxepin.

6. purposes as claimed in claim 1, wherein said pain is nociceptive pain or neuropathic pain.

7. purposes as claimed in claim 6, wherein said pain are and chemistry or thermal burn, skin incised wound, skin contusion, osteoarthritis, rheumatoid arthritis, tendinitis or the relevant pain of myofascial pain.

8. purposes as claimed in claim 6, wherein said pain is diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, pain after the apoplexy, complicated regional pain syndrome, the pain syndrome that sympathetic nerve is kept, reflex sympathetic dystrophy, reflection neural blood vessel malnutrition, reflex dystrophy, the spinal cord injury pain, sudeck atrophy, algoneurodystrophy, shoulder-hand syndrome, wound dystrophy, pain with related to cancer, phantom pain, fibromyalgia, chronic tired syndrome, radiculopathy, the syphilis neuropathy, or by the neuropathy patient's condition of drug-induced pain.

9. purposes as claimed in claim 8, wherein the regional pain syndrome of said complexity is I type or II type.

10. purposes as claimed in claim 8, wherein the neuropathy patient's condition of said pain is iatrogenic inductive by vincristine, velcade or Thalidomide.

11. purposes as claimed in claim 1, wherein said pain are the mixing pain of Encelialgia, migraine, tension-type headache, postoperative pain or nociceptive pain and neuropathic pain.

12. purposes as claimed in claim 1, wherein the stereoisomer of said immunomodulatory compounds is an enantiomer-pure.