CN108904486A - PT2385 is used to prepare the purposes of prevention and treatment altitude erythrocytosis drug - Google Patents
PT2385 is used to prepare the purposes of prevention and treatment altitude erythrocytosis drug Download PDFInfo
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- CN108904486A CN108904486A CN201810861075.7A CN201810861075A CN108904486A CN 108904486 A CN108904486 A CN 108904486A CN 201810861075 A CN201810861075 A CN 201810861075A CN 108904486 A CN108904486 A CN 108904486A
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- drug
- altitude erythrocytosis
- treatment
- prevention
- erythrocytosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Abstract
The present invention provides a kind of new applications of PT2385, more particularly to application of the PT2385 in the prevention and treatment drug of preparation altitude erythrocytosis, the present invention passes through further investigation altitude erythrocytosis and organism physiology and the relationship of pathologic process, confirm that PT2385 can obviously inhibit the expression of HIF-2 α by serial experiment, inhibit the generation of hematopoietin (EPO), reduce hemoglobin level, and the symptom for significantly mitigating altitude erythrocytosis and the disease are to the degree of injury of the vitals such as lungs, to achieve the purpose that prevent and treat altitude erythrocytosis；PT2385 can be used for preparing the prevention and treatment drug of altitude erythrocytosis, provides new medicament sources for the prevention and treatment of altitude erythrocytosis, has broad application prospects and huge market value.
Description
Technical field
The present invention relates to biomedicine technical fields, and in particular to PT2385 is used to prepare prevention and treatment altitude erythrocytosis
The purposes of drug.
Background technique
Altitude erythrocytosis (referred to as " high red disease ") is the red blood cell over compensation due to caused by environment of low oxygen plateau
A kind of chronic plateau sickness of property hyperplasia (i.e. red blood cell proliferation is excessive).Compared with the Healthy People with height above sea level, high red disease patient
Red blood cell, hemoglobin, red cell volume significantly increase, arterial oxygen saturation reduces, and with plethoric clinical condition
Shape and sign.The clinical manifestation of altitude erythrocytosis includes that red blood cell, hemoglobin, hematocrit increase, multi viscera
And tissue hyperemia, stasis of blood stream and hypoxic disease, while also with the symptoms such as cyanosis, headache, giddy, out of strength, expiratory dyspnea.
The area more than height above sea level 3000m occurs for most high red disease cases, is more common in and migrates Male resident.Red blood cell proliferation excessively,
Blood viscosity increases and hypoxic disease can not only aggravate the anoxic conditions of whole body, forms cause and effect and alternately recycles, can also develop into
The various complication such as bleeding, thrombosis or local tissue necrosis.
When human body anoxia, histocyte can by up-regulation hypoxia inducible factor (Hypoxia inducible factors,
HIFs expression) adapts to anaerobic environment.HIF family is the transcription factor family of heterodimer, by hypoxia-inducible expression
The HIF-1 β subunit composition of HIF- α subunit (HIF-1 α, HIF-2 α and HIF-3 α) and constitutive character expression.Under normal oxygen condition, HIF- α
The oxygen dependence degrading texture domain (The oxygen-dependent-degradation domain, ODD domain) of subunit
402nd and 564 proline can be in the work of proline hydroxylase (Prolyl hydroxylase-domain protein, PHD)
With lower hydroxylation, VHL albumen (Von Hippel-Lindau protein) can identify the HIF- α of hydroxylation and in combination, in turn
It degrades through ubiquitination pathway, is kept low the HIF- α in cytoplasm.When anoxic, PHD miopragia, the ODD of HIF- α
The proline hydroxylation rate of structural domain is low, and the HIF- α without hydroxylation cannot be identified by VHL, and HIF- α is caused sharply to accumulate in cytoplasm
And enter in core, heterodimer is formed with HIF-1 β, becomes active transcription factor, the hypoxia response member with downstream gene
Part (Hypoxia-responsive element, HRE) combines, and mediates the expression of hundreds of gene of the downstream HIF, and then adjust more
Kind biological function.
HIF-1 α and HIF-2 α are the members that function is mostly important in HIF family, and the amino acid sequence of the two has very high
Homology, but function is not quite similar.The study found that HIF-1 α is expressed in almost all of cell type, and HIF-2
The expression of α has more cell-specific, mainly in endothelial cell, macrophage, spongiocyte, II type alveolar epithelial cells, the heart
Myocyte, kidney fibroblast and pancreas duodenum, liver interstitial cell in express.HIF-1 α is usually in severe depletion of oxygen
It playing a role in the short time (2-24 hours) when (~1%), the expression of HIF-1 α can degrade rapidly when body reoxidizes, and
HIF-2 α is just active and continue the relatively longer time at modest hypoxia (~5%).It is worth noting that, intravascular
Skin growth factor (vascular endothelial growth factor, VEGF) is the common downstream base of HIF-1 α and HIF-2 α
Cause, compared with HIF-1 α, HIF-2 α has stronger transcriptional activation function to the promoter of VEGF.PT2385 is that a kind of take orally has
The HIF-2 alpha specific inhibitor of effect, PT2385 has been tested by clinical I phase as clear cell carcinoma of kidney medication at present, and is shown
Good safety and curative effect, but it has not been reported in the application of altitude erythrocytosis prevention and control field.
CN101244047A is related to application of the n-octacosanol in preparation prevention and treatment altitude erythrocytosis drug, will mention
The purity taken is mixed in 98% or more n-octacosanol with disintegrating agent-carboxymethyl starch, is packed into capsule, is contained in every capsule
N-octacosanol 10mg, disintegrating agent 0.3mg, the invention can effectively prevent erythremia caused by long-term chronic anoxic, have and change
The effect of kind microcirculation.CN104013622A discloses methazolamide answering in preparation treatment altitude erythrocytosis drug
With by establishing decompression hypoxemia induction altitude erythrocytosis Wistar rat model, observation methazolamide and acetazolamide diamox
To the curative effect of altitude erythrocytosis rat, it is found that it is red methazolamide and acetazolamide diamox administration can effectively treat plateau in 4 weeks
Cytosis, and there is dose dependent, methazolamide reduces mean constant of red blood cell, hemoglobin concentration and hematocrit,
Whole blood viscosity is reduced, drug effect is better than acetazolamide diamox.
But the prior art does not disclose purposes of the PT2385 in terms of preventing and treating altitude erythrocytosis, at present PT2385
It has been tested by clinical I phase as clear cell carcinoma of kidney medication, and has shown good safety and curative effect, but it is red on plateau
The application of cytosis prevention and control field has not been reported.
Summary of the invention
In view of the deficiencies of the prior art and actual demand, the present invention provide PT2385 and are used to prepare the high pronormoblast of prevention and treatment
Increase the purposes of disease drug, provide new medicament sources for the prevention and treatment of altitude erythrocytosis, before wide application
Scape and huge market value.
For this purpose, the present invention uses following technical scheme：
In a first aspect, the present invention provides the purposes of PT2385 a kind of, the purposes is preparation prevention and treatment plateau erythremia
The drug of disease.
In the present invention, relationship of the inventor by further investigation altitude erythrocytosis and organism physiology process, design
Complex experiment test confirm PT238 can effectively be inhibited by potent and selective inhibition HIF-2 α the expression of HIF-2 α with
Function inhibits the generation of hematopoietin (EPO), reduces hemoglobin level and significantly mitigates plateau erythremia
The symptom of disease and the disease are to the degree of injury of the vitals such as lungs, to reach prevention and treatment altitude erythrocytosis
Purpose, and slow down red blood cell and hemoglobin increases, multi viscera and tissue are congested, stasis of blood stream that chronic reaction under high pressure causes
Etc. symptoms, that is, provide T2385 be used to prepare prevention and treatment altitude erythrocytosis drug new application.
PT2385 is a kind of orally active HIF-2 alpha specific inhibitor, and structural formula is as shown in formula I；PT2385 can be special
The opposite sex inhibits the combination of HIF-2 α and HIF-1 β, inhibits the functional transcription of HIF-2, to inhibit downstream important gene EPO, VEGF
Deng expression, the present invention provides the new application of PT2385 a kind of, that is, prepares the medicinal application of prevention and treatment altitude erythrocytosis, is
The prevention and treatment of altitude erythrocytosis provides new medicament sources, has broad application prospects and huge market value.
Second aspect, the present invention provide a kind of drug for preventing and treating altitude erythrocytosis, and the drug includes PT2385.
Preferably, the purity of the PT2385 is 98-100%, such as can be 98%, 98.5%, 99% or 100%；
The drug contains the PT2385 for the treatment of effective dose, and the treatment effective dose is 50-200mg every or each capsule.
Preferably, the dosage form of the drug includes any one in tablet, capsule, electuary, pill or granule
Or at least two combination.
Preferably, the drug further includes pharmacologically acceptable excipient, and the excipient is inertia and nontoxic.
Preferably, the excipient include carrier, solvent, emulsifier, dispersing agent, wetting agent, adhesive, stabilizer or
In toner any one or at least two combination.
The third aspect, the present invention provide a kind of drug as described in second aspect and are used to prepare prevention and treatment plateau erythremia
The application of the drug of disease.
Compared with prior art, the present invention has the advantages that：
PT2385 provided by the invention is used to prepare the drug of prevention and treatment altitude erythrocytosis, can obviously inhibit HIF-2 α
Expression, inhibit hematopoietin (EPO) generation, reduce hemoglobin level and significantly mitigate the increasing of high pronormoblast
The symptom of more diseases and the disease prevent and treat plateau erythremia to reach to the degree of injury of the vitals such as lungs
The purpose of disease；Results of animal shows that PT2385 is preventing and treating altitude erythrocytosis, slowing down chronic mountain reaction and plateau
There is good curative effect in terms of polycythemia clinical symptoms；In addition, PT2385 and the drug containing PT2385 have safety
Good, the advantages such as Small side effects of property, have a good application prospect, provide new drug for the prevention and treatment of altitude erythrocytosis
Source.
Detailed description of the invention
Fig. 1 is the pretherapy and post-treatment outside drawing of altitude erythrocytosis group rat；Wherein, Fig. 1 (A) is the increasing of high pronormoblast
More disease group rats；And Fig. 1 (B) is PT2385 treatment group rat；
Fig. 2 is the variation diagram of pretherapy and post-treatment rat blood serum hematopoietin (EPO) level of PT2385；
Fig. 3 is the variation diagram of the pretherapy and post-treatment rat hemoglobin of PT2385 (HB) level；
Fig. 4 is the variation diagram of red blood cell (RBC) in the pretherapy and post-treatment rat serum of PT2385；
Fig. 5 is the variation of altitude erythrocytosis model group and PT2385 treatment group lungs tissue pathological slice
Figure；Wherein, Fig. 5 (A) is altitude erythrocytosis；Fig. 5 (B) is PT2385 administration group；
Fig. 6 is the variation diagram of the pretherapy and post-treatment rat kidney tissue pathological slice of PT2385, wherein Fig. 6 (A) is that plateau is red thin
Born of the same parents' increase disease group；Fig. 6 (B) is PT2385 administration group.
Specific embodiment
Further to illustrate technological means and its effect adopted by the present invention, below in conjunction with attached drawing and by specific real
Mode to further illustrate the technical scheme of the present invention is applied, but the present invention is not limited in scope of embodiments.
Embodiment 1：The preparation of altitude erythrocytosis therapeutic agent PT2385 piece
It accurately weighs 50 grams of PT2385 monomers (purity is greater than 98.5%), medical starch 250g is added, the two is sufficiently mixed
After be made 1000,0.3 gram of every slice weight, 50mg containing PT2385.
Embodiment 2：The preparation of altitude erythrocytosis therapeutic agent PT2385 capsule
50 grams of PT2385 monomers (purity is greater than 98.5%) is accurately weighed, medical starch 250g is added, the two is sufficiently mixed
It is pelletized afterwards with 20 meshes, 60 DEG C of dryings dispense later and insert Capsules and can dispense 1000 capsules, every weight is made
0.3 gram, 50mg containing PT2385.
The preparation of 3 altitude erythrocytosis therapeutic agent PT2385 piece of embodiment
It accurately weighs 50 grams of PT2385 monomers (purity is greater than 98%), medical starch 250g is added, after the two is sufficiently mixed
It is made 1000,0.3 gram of every slice weight, 50mg containing PT2385.
Embodiment 4：PT2385 alleviates the studies on some in dications of of altitude erythrocytosis rat
1) model construction：20 healthy SD rats (SPF grades, male, weight 240-270g) adaptive feeding 1 week first, 1
Zhou Houyi is extremely《Altitude environment simulates animal model of human disease feeding system, DOSSY-H3》(height above sea level 4500m, atmospheric pressure
54kPa, oxygen content 11%) under the conditions of raise, raising to after 6 weeks, 8 weeks, 10 weeks to the progress blood routine detection of modeling animal, according to
The discrimination standard of altitude erythrocytosis according to the literature, rat hemoglobin content (Hb)>200g/L is considered as modeling success,
All modeling animal hematoglobin contents reach 200g/L or more after detection raising 10 weeks, it was demonstrated that altitude erythrocytosis
Animal model modeling success.
2) experimental group and administration：Modeling successful subsequent continues《Altitude environment simulates animal model of human disease》Raising,
10 rats are randomly selected as altitude erythrocytosis model group (A group, A1-A10), residue 10 is only used as treatment group (B
Group, B1-B10), PT2385 drug administration dosage is 8mg/kg/ days, and the drug is that embodiment 1 or 2 is prepared, in two times
Stomach-filling；Environment temperature is set as 15 DEG C -20 DEG C, relative humidity：40%-70%, 12h/12h light and shade alternate illumination, therapeutic process
Middle difference takes blood to carry out blood routine, EPO detection, the important target organ damage Histopathology inspection of rat after 2 weeks after the treatment, 3 weeks
Survey etc..
3) Germicidal efficacy detects：
It is high in Fig. 1 (A) shown in the pretherapy and post-treatment outside drawing of altitude erythrocytosis group rat such as Fig. 1 (A)-Fig. 1 (B)
The words purple of erythremia group rat is dim, ear color is dim, red pawl and the tail portion colour of skin are dim red obvious, changes in obvious extravasated blood；
And pawl, tail skin, lip, tongue and the ear color of rat are without obvious dark violet, dark red color table after Fig. 1 (B) PT2385 treatment 3 weeks
It is existing, it is in cerise, gradually restores rat normal color appearance.
As shown in Figure 2, as shown in Figure 2, the EPO level of PT2385 administration group rat is higher after treatment 3 weeks for EPO testing result
The decline of erythremia rat control group, there is significant difference (P<0.01)；Altitude erythrocytosis group EPO level with
The extended variation tendency of hypoxic exposure, as can be seen from Figure 2 EPO still has and increases trend after three weeks for model group raising；
Significant change occurs for PT2385 treatment group EPO level, from Fig. 2 this it appears that PT2385 treatment is under EPO is horizontal after three weeks
Drop, the generation of EPO receive obvious inhibition.
Blood routine testing result as shown in figure 3 and figure 4, as can be seen from figs. 3 and 4, treatment 2 weeks after PT2385 administration group it is red
Cell (RBC) counts, hemoglobin (Hb) value is decreased obviously compared with altitude erythrocytosis rat control group, there is significant difference
(P<0.01)；Red blood cell (RBC) counting of PT2385 administration group rat, hemoglobin (Hb) value are red compared with plateau thin after treating 3 weeks
Born of the same parents' increase disease rat control group further declines, and has significant difference (P<0.001)；
Fig. 3 is the variation diagram of the pretherapy and post-treatment rat hemoglobin of PT2385 (HB) level, and left side is plateau erythremia
Disease group HB level with hypoxic exposure variation tendency, it can be seen that model group with hypoxic exposure extend (0 day, 2 weeks, 3
Week) HB level has and obviously increases trend in blood；And right side is the variation tendency of PT2385 treatment group HB level, it can be seen that
As the HB level in extension (0 day, 2 weeks, 3 weeks) rat serum of PT2385 treatment time gradually declines, the generation of HB is by bright
It is aobvious to inhibit.
Fig. 4 is the variation diagram of red blood cell (RBC) in the pretherapy and post-treatment rat serum of PT2385, and left side is altitude erythrocytosis
Group RBC level with hypoxic exposure variation tendency, it can be seen that model group with hypoxic exposure extend (0 day, 2 weeks, 3
Week), RBC level has the tendency that further increasing in blood after especially 3 weeks；And right side is the change of PT2385 treatment group RBC level
Change trend, as can be seen from the figure with RBC in blood after the extension of PT2385 treatment time (0 day, 2 weeks, 3 weeks) especially 3 weeks
Level has further downward trend, and PT2385 is prompted to have certain inhibiting effect to the generation of RBC.
In addition, histopathological study result is shown in that this is as the result is shown shown in Fig. 5 (A)-Fig. 5 (B) and Fig. 6 (A)-Fig. 6 (B)
The degree of injury of the internal organs of the liver and lungs of PT2385 administration group has obviously compared with control group (altitude erythrocytosis rat)
Alleviation, wherein Fig. 5 (A) is altitude erythrocytosis group, and pulmonary artery tube wall obviously thickens, congested, around blood vessel and ramuscule
A large amount of cell infiltrations around tracheae；Fig. 5 (B) is PT2385 administration group, only has a small amount of cell infiltration around blood vessel, other knots
Structure is normal；Fig. 6 (A) is altitude erythrocytosis group, the therefrom obvious enlargement of visible glomerulus, extravasated blood, the change of capsula glomeruli blister cavities
It is small, visible a large amount of red blood cell depositions in glomus；Also visible a large amount of red blood cells deposit interstitial；Fig. 6 (B) is PT2385 administration
Group, structure is normally clear in this group of glomerulus, and red blood cell deposits in interstitial occasional vessel.
The above results show that PT2385 can slow down by the expression of inhibition HIF-2 α and adjust back hematopoietin in blood
(EPO), the ascendant trend of red blood cell and hemoglobin, while rat hemoglobin is horizontal and organ damage degree has significantly
Alleviate.
In conclusion the present invention provides the purposes of PT2385 a kind of, and in particular to PT2385 is preparing high pronormoblast
The application of increase disease prevented and treated in drug, experiments prove that PT2385 can obviously inhibit the expression of HIF-2 α, suppression
The generation of hematopoietin (EPO) processed, the symptom for reducing hemoglobin level and significantly mitigating altitude erythrocytosis
And the disease is to the degree of injury of the vitals such as lungs, thus achieve the purpose that prevent and treat altitude erythrocytosis,
New medicament sources are provided for the prevention and treatment of altitude erythrocytosis, are had broad application prospects and huge market price
Value.
The Applicant declares that the present invention is explained by the above embodiments method detailed of the invention, but the present invention not office
Be limited to above-mentioned method detailed, that is, do not mean that the invention must rely on the above detailed methods to implement.Technical field
Technical staff it will be clearly understood that any improvement in the present invention, equivalence replacement and auxiliary element to each raw material of product of the present invention
Addition, selection of concrete mode etc., all of which fall within the scope of protection and disclosure of the present invention.
Claims (7)
1. a kind of purposes of PT2385, which is characterized in that the purposes is the drug of preparation prevention and treatment altitude erythrocytosis.
2. a kind of drug for preventing and treating altitude erythrocytosis, which is characterized in that the drug includes PT2385.
3. drug according to claim 2, which is characterized in that the purity of the PT2385 is 98-100%.
4. the drug according to any one of claim 2-3, which is characterized in that the dosage form of the drug includes tablet, glue
In wafer, electuary, pill or granule any one or at least two combination.
5. the drug according to any one of claim 2-3, which is characterized in that the drug further includes that can pharmacologically connect
The excipient received.
6. drug according to claim 5, which is characterized in that the excipient includes carrier, solvent, emulsifier, dispersion
In agent, wetting agent, adhesive, stabilizer or colorant any one or at least two combination.
7. the drug that a kind of drug as described in any one of claim 2-6 is used to prepare prevention and treatment altitude erythrocytosis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810861075.7A CN108904486A (en) | 2018-08-01 | 2018-08-01 | PT2385 is used to prepare the purposes of prevention and treatment altitude erythrocytosis drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810861075.7A CN108904486A (en) | 2018-08-01 | 2018-08-01 | PT2385 is used to prepare the purposes of prevention and treatment altitude erythrocytosis drug |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112755015A (en) * | 2021-02-01 | 2021-05-07 | 中国人民解放军陆军军医大学 | Application of PT2385 in preparation of medicine for preventing and treating pulmonary hypertension |
| CN114209834A (en) * | 2021-05-07 | 2022-03-22 | 中国人民解放军军事科学院军事医学研究院 | Application of MCUR1 as biomarker of altitude erythrocytosis and method for screening medicine |
-
2018
- 2018-08-01 CN CN201810861075.7A patent/CN108904486A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112755015A (en) * | 2021-02-01 | 2021-05-07 | 中国人民解放军陆军军医大学 | Application of PT2385 in preparation of medicine for preventing and treating pulmonary hypertension |
| CN114209834A (en) * | 2021-05-07 | 2022-03-22 | 中国人民解放军军事科学院军事医学研究院 | Application of MCUR1 as biomarker of altitude erythrocytosis and method for screening medicine |
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Application publication date: 20181130 |