CN104888199A - Application of calcitonin to preparation of new drug for treating Alzheimer's disease - Google Patents
Application of calcitonin to preparation of new drug for treating Alzheimer's disease Download PDFInfo
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- CN104888199A CN104888199A CN201510236702.4A CN201510236702A CN104888199A CN 104888199 A CN104888199 A CN 104888199A CN 201510236702 A CN201510236702 A CN 201510236702A CN 104888199 A CN104888199 A CN 104888199A
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- calcitonin
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Abstract
The invention relates to the medical field and particularly discloses novel application of calcitonin to preparation of a medicine which can be used for treating Alzheimer's disease.
Description
Technical field the present invention relates to medical domain, is specially calcitonin at the novelty teabag manufacturing treatment senile dementia.
Background technology senile dementia is also the brain aging that Alzheimer (AD) belongs to a kind of morbid state, namely the degeneration that brain is gradual, relative to common brain aging, more serious neuron degeneration death and brain atrophy can be there is at faster speed in senile dementia within the shorter time, understanding, memory and the phenomenon of thinking serious degradation, and increase the weight of rapidly so that occur cognitive and thought disturbance, until dull-witted.
For senile dementia, its pathogenesis not clear and definite at present, so its treatment means, one is the spiritual pathological symptom controlling to occur together, comprise anxiolytic drugs, antidepressant drug, antipsychotic drug, such as alprazolam, doxepin, risperidone etc., one is Fructus Alpiniae Oxyphyllae and improves cognitive function, comprising and intend choline for treating, promotion cerebral circulation, the nutrition of enhancing cranial nerve etc., is not specific treatment means.
Summary of the invention the present invention discloses a kind of calcitonin in the purposes manufacturing novel drugs, and this medicine is used for the treatment of senile dementia.
Applicant finds, calcitonin has clear and definite curative effect to treatment senile dementia.So the present invention relates to calcitonin and manufacturing the novelty teabag in medicine, this medicine is used for the treatment of or prevents senile dementia.
The present invention also relates to a kind of medicine for preventing or treat senile dementia, it comprises calcitonin, and a kind of medically acceptable carrier or diluent.As a kind of example, described carrier or diluent adopt water, i.e. H20.
Calcitonin (calcitonin, CT) is existing medicine, and be a kind of containing 32 amino acid whose linear type peptide hormones, be manufactured by parafollicular cell (parafollicular cells, also known as C cell) in human body.This hormone is all there is at Fish, reptile class, birds, mammal body.Calcitonin is white powder, soluble in water.The calcitonin of Clinical practice is from people, salmon, Anguillar japonica or pig, and conventional have: salmon calcitonin see calcimar, (molecular formula: C145H240N44O48S2, molecular weight: 3431.87, convenience goods name: Calcitonin Salmon); Eel calcitonin, (molecular formula: C148H244N42O47, molecular weight: 3363.82, convenience goods name: elcatonin).Current salmon calcitonin can synthetic, application more.Human calcitonin molecular weight is 3400, relatively few use.Certainly do not get rid of other manually to extract or the calcitonin belonging to peptide hormone with identical biological effect of synthetic yet, be appreciated that its effect biologically and therapeutic effect are similar.
Described medicine can adopt the form of tablet, injection, spray, patch, with the mode administration of oral, injection, nose spray, mucosa absorption, Transdermal absorption.Be more suitably adopt injection to carry out injecting (subcutaneous, muscle or intravenous injection) administration, or adopt spray to carry out the mode of nose spray by mucosa delivery, or adopt the mode of patch to carry out Transdermal absorption.
For the manufacture of when being used for the treatment of the medicine of senile dementia, contained by its medicine, the suitable amounts of calcitonin is: (for salmon calcitonin nasal spray), every day 40-400IU, point once or secondary administration.2-7 times weekly.More suitably: each 100-200IU, once a day.Or according to circumstances determined by doctor.For elcatonin or other calcitonins, or adopt drug administration by injection, its consumption adjusts accordingly.
Current calcitonin is in the application of medical science, and one is for hypercalcemia, and to reduce calcium level, two is be used for the treatment of senile osteoporosis, and by suppressing osteoclast and stimulating osteoblast to increase bone calcium, three is the pain relievings for osteodynia.And applicant finds, calcitonin may be used for treating senile dementia, and has remarkable result, so can be used for producing related drugs.For the biological mechanism accurately of its therapeutic effect, not yet completely clear and definite at present, applicant analyzes: the mechanism being first brain aging: old people is due to bone deterioration, osteoporosis, bone calcium is excessively discharged in blood by osteoclast, cause the calcium level of old people generally higher, thus calcium ion concentration outside brain cell membrane is higher, because concentration difference strengthens, interior stream strengthens calcium ion, exceed the outer row's ability of calcium of cell, calcium balance inside and outside cell membrane produces skew, causes intracellular free calcium level higher for a long time; And the long-term higher neural activity that can affect brain cell of intracellular free calcium level, and produce the material (such as free radical) with physiological-toxicity too much, (such as generating A amyloid beta matter pathological changes and neural senile plaque) is caused damage to brain cell; And decline for the ability of these physiological-toxicity materials clean in old people's body, degeneration is dead because damaging constantly accumulation to cause brain cell finally, brain cell death accumulates gradually and causes brain cell quantity to decline and brain atrophy, thus engendering the decline of memory and other brain functioies, this is also the nature process of brain aging.
And senile dementia is a kind of brain aging of morbid state of special processing; applicant analyzes: for some people; in the process of brain aging; be subject to bringing out of some factor; the such as expression of self aberrant gene; (i.e. heritability); or health other diseases, fracture, drug-induced blood calcium increase; or spirit causes neururgic ANOMALOUS VARIATIONS by greater impact; normal brain aging process can be made to occur abnormal change; cause ager process to accelerate rapidly to increase the weight of, in several years, just develop into cognition and thought disturbance, until dull-witted.In the process of brain aging and senile dementia, blood calcium concentration is higher and then to cause brain cell intracellular calcium concentration higher, thus causes damage to brain cell and cause cytopathy and apoptosis (death), is an important risk factor.And calcitonin can suppress the movable of osteoclast and stimulating osteoblast, by blood calcium transfer curing to bone calcium, thus reduce the level of blood calcium, so antagonism can be formed to the ager process of senile dementia brain cell, stop and slow down infringement and the death of brain cell, play the therapeutic effect stoping PD, mitigation symptoms.
According to its therapy mechanism, infer and seem also should have similar therapeutic effect by other medicines that can reduce blood calcium or reduce intracellular calcium concentration, but experiment finds that the therapeutic effect of other drug is not as calcitonin.Applicant analyzes its reason: higher intracellular free calcium level is long-term accumulated to the infringement that brain cell causes, and also needs the longer time slowly to recover.If adopt calcium channel blocker (calcium antagonist) or calbindin (comprising calmodulin) to reduce intracellular free calcium level, the effect of short time can only be played, because upper eye lid outer calcium ion concentration (blood calcium concentration) in source is still higher, calcium ion still can endlessly by diffusing in born of the same parents, so its effect is temporary transient, and its trend cannot be changed, limited efficiency.And if employing calcium chelating agent reduces calcium level, then medicine is when reduction blood calcium, blood calcium regulatory mechanism can be stimulated, bone calcium is caused to accelerate by osteoclast to blood calcium transfer release, so be also difficult to maintain lower calcium level for a long time, cause its therapeutic effect not remarkable, and can cause or increase the weight of senile osteoporosis.And calcitonin promotes that blood calcium is to bone calcium transfer curing, the calcium level that the maintenance that can continue is lower, removing burning wood away under the boiler, reduce the calcium ion concentration outside brain cell from source, thus intracellular free calcium level and the infringement that causes thereof are declined, gradually so can have more significant effect, and side effect is little, while reduction blood calcium, also improve bone calcium density, prevention senile osteoporosis is the method for killing two birds with one stone.
It should be noted that, brain cell belongs to the well differentiated cell no longer divided, the brain cell reduced because of degeneration and death generally can not regenerate, the infringement that senile dementia causes is irreversible, so impaired brain cell be cured and be recovered to calcitonin cannot, just impedance and alleviate this course of damage is also impedance and process and the development speed delaying senile dementia.And; calcitonin reduces calcium ion concentration higher inside and outside brain cell membrane by directly reducing blood calcium; the neural activity of brain cell particularly cholinergic nerve is improved; so can play a role in improving to the memory of patient and thinking activities, these are all have very positive medical significance.
The present invention use calcitonin before be used for the treatment of osteoporosis, and both consumptions and usage close, its side effect and taboo can with reference to related data.Because calcitonin is polypeptide, groups of people may be irritated, so must carry out skin test before injection.
To use and enforcement is described of the present invention below detailed description of the invention.
One, the medicine containing calcitonin produced by employing calcitonin.The present invention relates to the novelty teabag of calcitonin, its medicine produced is for delaying brain aging or treatment senile dementia.And the preparation of the acquisition of calcitonin, injection, spray or patch, can directly adopt or the correlation technique of the osteoporotic calcitonin drug of reference treatment, or with reference to the preparation technique of medicament like other form classes.
Pharmaceutical pack of the present invention is containing calcitonin, and a kind of medically acceptable carrier or diluent, and as a kind of example, because calcitonin is soluble in water, described carrier or diluent adopt water, i.e. H20, or normal saline.
The acquisition of material: be usually used in before calcitonin treating osteoporosis, there is the finished product of the marketization.The calcitonin of current Clinical practice is from people, salmon, Anguillar japonica or pig, and conventional is: salmon calcitonin see calcimar, (molecular formula: C145H240N44O48S2, molecular weight: 3431.87, convenience goods name: Calcitonin Salmon); Eel calcitonin, (molecular formula: C148H244N42O47, molecular weight: 3363.82, convenience goods name: elcatonin).The salmon calcitonin of what current application was maximum is synthetic.Human calcitonin molecular weight is 3400, and physiologic effect, not as salmon calcitonin and elcatonin, is used relatively less.Certainly artificial extraction or the synthetic calcitonin of other types is not got rid of yet.The calcitonin of these separate sources, its biological action and therapeutic effect are similar, and just its equivalent consumption is different.
The mode of administration: described medicine can adopt the form of tablet, injection, spray, patch, with the mode administration of oral, injection, nose spray, Transdermal absorption.But in fact because calcitonin is polypeptide, can be degraded in digestive tract, therefore oral absorption efficiency is very low, more suitably adopt injection to carry out injecting (subcutaneous, muscle or intravenous injection) administration clinically, or adopt spray to carry out the mode of nose spray by mucosa delivery, or the mode of patch is adopted to carry out Transdermal absorption.
The consumption of medicine: the consumption of calcitonin is substantially similar with treatment senile osteoporosis when treating senile dementia, such as contained by its medicine, the suitable amounts of calcitonin is: (for salmon calcitonin nasal spray), 40-400IU every day (iu), divide once or secondary administration.2-7 times weekly.Suitable consumption is: each 100-200IU, once a day.Or according to circumstances determined by doctor.
Above-mentioned consumption adopts salmon calcitonin nasal spray to be example, and for eel calcitonin or other calcitonins, or adopting other administering modes such as injection, its consumption can adjust accordingly.Calcitonin is commonly used in treatment senile osteoporosis, is general knowledge to the adjustment of different calcitonin consumption, no longer describes here.The consumption of description of test calcitonin one in a big way in (100-400IU/ days) change time can have approximate effect, this may because calcitonin is had an effect with the mutual antagonism of parathyroid hormone PTH, PTH can be caused antagonism is increased when the large usage quantity of calcitonin, when calcitonin is a small amount of, PTH antagonism declines, so its effect has larger elasticity.
In general, even slightly excessively use calcitonin also can not cause low blood calcium, this is because when calcitonin causes blood calcium to drop to concentration on the low side, can the generation of intense stimulus parathyroid hormone PTH, the effect of PTH is well beyond the effect of calcitonin, thus raising blood calcium concentration, maintain the level of blood calcium.But for the purpose of careful, over the course for the treatment of, should monitor whether there will be low blood calcium and related symptoms, if there is low blood calcium symptom, or blood calcium is lower than 2.2mmol/L, or blood ionized calcium is lower than 1.1mmol/L, then answer brief interruption administration, give parathyroid hormone PTH if desired and treat.
Two, the medicine adopting calcitonin to make is at the application and result for the treatment of senile dementia.The major pathologic features of senile dementia AD comprises neurocyte is deposited as core formation senile plaque (SP) with amyloid-beta (β-amyloid protein, A β).More research is verified, in cerebrospinal fluid, A β 42 protein content is the important biomolecule mark of AD diagnosis, due to the deposition of A β 42 albumen on brain cell, Cerebrospinal Fluid in Patients A β 42 protein content can be caused significantly to reduce, this index has significant specificity, and reasonable dismissal can be carried out, so can be used as the index for the treatment of senile dementia effect.
Experimental establishment: the AD patient of 72-78 years old 20, each 10 of men and women, the AD disease time that can obviously discover is about 2 years, and (early stage AD), is divided into two groups, i.e. experimental group and matched group, often organizes 10, each 5 of men and women.Give calcitonin treatment and expectant treatment respectively, wherein experimental group adopts salmon calcitonin nasal spray, each 0.1 milliliter of 100IU, once a day, matched group is traditional treatment, (for humanity, also should not interrupt its normal therapeutic), based on common promotion cerebral circulation, improves brain cell nutrition.The treatment phase is three months.Detect A β 42 protein content of the cerebrospinal fluid of two groups of patients before and after treatment respectively, and calculate the meansigma methods of two groups of patients, its data are as table 2.And by its family members, overall merit is carried out to its memory, ability of thinking, the mental status, operational capacity, ADL, be obviously deteriorated as-2 points, be a little deteriorated as-1 point, be not changed to 0 point, be improved as a little+1 point, be obviously improved as+2 points.Its result is as table 3.
Table 2: the cerebrospinal fluid A β 42 protein content meansigma methods of experimental group and matched group: (unit: pg/ml).
Table 3: calcitonin is used for the treatment of the effect assessment table of AD.(unit: people).
As can be seen from Table 2, experimental group significantly improves Cerebrospinal Fluid in Patients A β 42 protein content, (although not reaching the value of normal person), illustrates that the current deposition of A β 42 albumen on brain cell decreases, and also namely the impedance development speed of AD is described.
As can be seen from Table 3, compare matched group, experimental group " is obviously deteriorated " and significantly reduces with " being a little deteriorated ", and " a little improving " significantly increases with " obviously improving " number, experimental group brings good subjective assessment, illustrate on brain function, calcitonin drug has clear and definite effect in treatment senile dementia.
Applicant also appeals that medical circle will be paid close attention to current old people and to replenish the calcium mistake that is theoretical and way, and the way of replenishing the calcium of this mistake is likely brought out or increases the weight of brain aging and senile dementia.Below this is sketched.
Clinical data shows, the calcium level of human body presents child and old people two head height, young and middle-aged middle low feature.For child, because whole body is in vigorous trophophase, skeleton is growing fast and is upgrading, the activity of osteoblast and osteoclast is all vigorous and skeletonization is greater than brokenly bone, so, keep higher calcium level, be equivalent to the transfer house that maintenance one has sufficient calcium raw material, to meet the needs of bone growth, this is understandable.And in the growth course that this is vigorous, the ability of child's body scavenging free radicals and other toxin is also strong, so higher calcium level can't cause anything to damage to child's body.Arrived young and middle-aged period, skeleton not regrowth only has renewal, and osteoblast and osteoclast activity are in poised state, and calcium level reduces, and this is also normal and rational.The skeleton of old people only has degenerates and does not grow, and bone upgrades and also slow down, so old people's body is also few to the demand of calcium, blood calcium also should maintain lower level normally.; after 50 years old (climacteric); the calcium level of human body is abnormal generally to be increased; and the top level in all one's life how old is reached 70, and meanwhile, the calcium content of bone of human body reduces year by year; the TC in body is caused also to reduce year by year; and easily there is osteoporosis, obviously, this just belongs to abnormal and un-reasonable phenomenon.
For this abnormal phenomena, current a kind of very popular medical science viewpoint is thought: old people is deteriorated due to digestive and absorptive functions, calcium absorption is not enough, cause blood calcium not enough, so in order to maintain enough blood calcium, body can pass through blood calcium regulatory mechanism, absorbs bone calcium and is discharged in blood calcium, cause blood calcium higher and therefore cause osteoporosis.According to its viewpoint, old people's blood calcium is higher can not illustrate old people's not calcium deficiency, and hypocalcia in your body is exactly described, so bone calcium just can be discharged into blood calcium by blood calcium regulatory mechanism, so more should replenish the calcium, and be want heavy dose to replenish the calcium, and vitamin D strengthen calcium absorption simultaneously.Such theory is full of various medical article and magazine, and the lecture of various medical treatment and health care.This is theoretical just, and Many researchers is thought habitually, and old people is calcium deficiency, and ignores old people's blood calcium fact higher for a long time, and does not note the chronic neurotoxicity that old people's blood calcium is higher and the fall out effect to brain aging and senile dementia thereof.
Applicant thinks, above-mentioned this theory exist concept displacement and logical error: (1), concept displacement, " bone calcium deficiency " (osteoporosis) and " blood calcium deficiency " (blood calcium is not enough) is two diverse concepts, and old people is bone calcium deficiency instead of blood calcium deficiency.Blood calcium deficiency may cause bone calcium deficiency, and this is just contingent when serious calcium pickup is not enough, and it is low at this moment should to show as obvious blood calcium.And bone calcium deficiency to be not equal to completely be exactly blood calcium deficiency, and be more that osteoclast activity increases and caused because the osteoblast activity of skeleton weakens, or go wrong due to blood calcium regulatory mechanism.(2), logical error, if because blood calcium deficiency just causes body, by blood calcium regulatory mechanism, bone calcium is discharged into blood calcium, so, when blood calcium rises to normal level, this adjustment process of blood calcium regulatory mechanism just should stop, particularly when occurring that blood calcium is higher, just by regulatory mechanism blood calcium should be fixed in bone calcium and go, and recover normal calcium level, disconnected can not should not occur that blood calcium concentration is higher for a long time and osteoporosis proceeds, bone calcium continues to be released to situation in blood calcium on one side yet.In addition, according to clinical data, from the young and the middle aged to old age, do not have one from start to finish generally occur the stage that blood calcium trend is lower how old human blood calcium deficiency being just described?
Applicant thinks, the osteoporosis of old people, and not calcium absorption picked-up not enough and blood calcium is on the low side brings out, and most importantly because old people's hormone secretion change caused by.First be climacteric sex hormones secretion minimizing (it is aging that this belongs to reproduction, applicant think reproduction aging be the root of whole organism aging process), and then have impact on the balance of parathyroid hormone PTH and calcitonin PC secretion, PTH increases relative to PC secretion, osteoblast activity is caused to weaken and osteoclast activity increases, more bone calcium is released to due to the activity of osteoclast in blood calcium, causes bone deterioration to be also osteoporosis, also causes blood calcium to raise simultaneously.In addition, old people reduces due to the activity of limb activity especially high strength, reduces and weakens, also can cause bone deterioration, accelerate this change process the stimulus intensity of skeleton and muscle.Applicant infers: when muscular movement, the activity of myocyte may cause the change of the physicochemical environment of surrounding, the such as change of certain material or ion concentration, this change may be delivered to osseous tissue, affect the activity change of osteoblast and osteoclast, thus old people's activity minimizing affects skeletonization or broken bone phenomenon, so also can cause and accelerate bone deterioration.So the change of hormone secretion and movablely to reduce, just result in old people and occur it being osteoporosis, while be the higher contradictory phenomena of blood calcium.Certainly, this just causes old people to occur higher within normal range of blood calcium, or just exceed normal range a little, mostly also be not enough to the hypercalcemia occurring morbid state, therefore also cause this phenomenon and concern is not caused for a long time to the brain aging even fall out effect of senile dementia.
So applicant thinks: if bone calcium will be increased by taking in calcium, preferably coming to carry out what enter into the climacteric period, at this moment may also have certain effect.And once enter into the climacteric period, body has entered the stage of bone deterioration, then replenish the calcium and just only can raise blood calcium, and be difficult to blood calcium to supplement to be fixed in bone calcium go.Especially, if its blood calcium concentration of old people with osteoporosis is higher, also attempt to treat osteoporosis by replenishing the calcium, then this way is just obviously incorrect, although this can by improving calcium level, carry out antagonism bone calcium to a certain extent to discharge to the transfer of blood calcium, but effect is very low, (in fact current old people treats the certain limited efficiency of osteoporosis by replenishing the calcium, so some " experts " just think need replenishing the calcium of larger dose), and may bring out and accelerate the process of brain aging or senile dementia, even, based on similar primary cellular defect mechanism, too high blood calcium also may cause the infringement to other gut cell, just because brain aging and other primary cellular defects are all processes slowly, this infringement is not easy to be noted.
Applicant thinks, senile osteoporosis and the higher phenomenon of blood calcium, the phenomenon that the body progressive emaciation caused with diabetes and blood glucose raise is similar: if not to the announcement of diabetes, we can think that body is become thin by mistake is that alimentation is bad, and adopt the measure had additional nutrients, and owing to there being correct understanding to diabetes, we can know that it is wrong for having additional nutrients in this case, at this moment it not is that alimentation is not enough that body is become thin, but mechanism of blood glucose regulation goes wrong, correct way is intervened mechanism of blood glucose regulation.Same, the osteoporosis (being equivalent to becoming thin of bone) of a lot of old people, and the absorption of non-calcium picked-up is not enough, but bone deterioration and blood calcium regulatory mechanism go wrong, in this case, it is wrong for being undertaken replenishing the calcium by increase absorption, but should intervene for bone deterioration and blood calcium regulatory mechanism.Comprise: (1), keep the body movement of some strength, to strengthen the stimulation to muscle and skeleton, promote osteoblastic activity, prevent or slow down bone deterioration; (2), at climacteric suitable complementarity hormone, delay bone deterioration from root, but the various physiological functions of complementarity hormone meeting overall effect body, need careful carrying out; (3), suppress the secretion of parathyroid hormone, or supplementary calcitonin, carries out direct intervention to blood calcium regulatory mechanism, calcitonin can suppress osteoclast activity and promote that osteoblast is movable, thus the calcium transfer in blood plasma is consolidated in skeleton, strengthen bone calcium density.In fact, calcitonin has been used to treatment osteoporosis clinically and has obtained good result.Certainly, calcitonin is as a kind of hormone, and the side effect of its life-time service needs to be observed further.
Claims (8)
1. calcitonin is manufacturing the novelty teabag in medicine, senile dementia that this medicine is used for the treatment of (or prevention).
2. be used for the treatment of the medicine of (or prevention) senile dementia, it comprises calcitonin, and a kind of medically acceptable carrier or diluent, such as: water.
3. calcitonin according to claim 1 is manufacturing the novelty teabag in medicine, or medicine according to claim 2, and it is characterized in that: described calcitonin (CT) is peptide hormone, it is manufactured by parafollicular cell at human body.
4. calcitonin according to claim 1 is manufacturing the novelty teabag in medicine, or medicine according to claim 2, it is characterized in that: described calcitonin can be salmon calcitonin see calcimar, eel calcitonin, human calcitonin, pig calcitonin or other there is the calcitonin belonging to peptide hormone of identical biological effect.
5. calcitonin according to claim 1 is manufacturing the novelty teabag in medicine, or medicine according to claim 2, it is characterized in that: described medicine produces therapeutical effect by regulating reduction blood calcium concentration.
6. calcitonin according to claim 1 is manufacturing the novelty teabag in medicine, or medicine according to claim 2, it is characterized in that: described medicine is by promoting that blood calcium is to the transfer of bone calcium, maintains lower calcium level, calcium ion concentration in brain cell is declined, produces therapeutical effect.
7. calcitonin according to claim 1 is manufacturing the novelty teabag in medicine, or medicine according to claim 2, it is characterized in that: described medicine adopts the form of tablet or injection or spray or patch.
8. calcitonin according to claim 1 is manufacturing the novelty teabag in medicine, or medicine according to claim 2, it is characterized in that: described medicine is with the mode administration of injection or nose spray or mucosa absorption or Transdermal absorption.
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| CN102834095A (en) * | 2009-11-03 | 2012-12-19 | 法奈科斯公司 | New therapeutic approaches for treating alzheimer disease |
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