CN110354131A - Alfuzosin is treating or preventing the purposes in Parkinson's disease and related disease - Google Patents
Alfuzosin is treating or preventing the purposes in Parkinson's disease and related disease Download PDFInfo
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Abstract
The present invention relates to Alfuzosins to treat or prevent the purposes in Parkinson's disease and related disease.The invention belongs to pharmaceutical technology fields, are related to the pharmaceutic usage of Alfuzosin, and the purposes of parkinsonism and related disease is treated more particularly to Alfuzosin.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to the pharmaceutic usage of Alfuzosin, control more particularly to Alfuzosin
Treat the purposes of parkinsonism and related disease.
Background technique
Usually with its hydrochloride for clinic, the specification for having listed tablet or capsule has Alfuzosin (Alfuzosin)
1mg, 2mg and 5mg etc..Alfuzosin hydrochloride can be used for treating benign prostate hyperplasia, it can also be used to hypertension is treated, it can be single
It solely uses or is shared with other drugs for hypertension such as diuretics or Alpha 1 adrenergic blocking agent.For existing clinical suitable
Disease is answered, Alfuzosin is 1~20mg for adult daily dose usual range.Alfuzosin is for treating benign prostatic hyperplasis
(BPH), benign prostate hyperplasia shape mitigates after medication and urine flow speed improves and the α 1- adrenaline in neck of urinary bladder and prostate
Smooth muscle relaxation caused by energy receptor blocking is related.Because there is relatively little of alpha 1 adrenergic receptor in body of urinary bladder, because
This Alfuzosin can reduce contraction of the obstruction of bladder outlet without influencing bladder.In addition, Alfuzosin is total outer by reducing
All vascular resistences are to make blood pressure reduce.Vasodilation, the blood pressure reduction effect of Alfuzosin seem mainly by α 1- adrenal gland
Caused by plain energy receptor blocking.
Alfuzosin chemical name are as follows:
N-(3-((4-amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino)propyl)
Tetrahydrofuran-2-carboxamide or N- [3- [(4- amino -6,7- dimethoxy -2- quinazolyl) methylamino]
Propyl]) tetrahydro -2- furoyl amine hydrochlorate.Molecular formula is C19H27N50CHL, chemical structural formula are following formula:
The chemical name of TZ-md are as follows:
(4-(1-amino-6,7-dimethoxyisoquinolin-3-yl)piperazin-1-yl)
(tetrahydrofuran-2-yl) metha none or [4- (1- amino -6,7- dimethoxy-isoquinoline -3- base) piperazine -1-
Base] (tetrahydrofuran -2- base) ketone.Chemical structural formula is a following formula:
The chemical name of AZ-md are as follows:
N-(3-((1-amino-6,7-dimethoxyisoquinolin-3-yl)(methyl)amino)propyl)
Tetrahydrofuran-2-carboxamide or N- (3- ((1- amino -6,7- dimethoxy-isoquinoline -3- base) (methyl) ammonia
Base) propyl) 2-TETRAHYDROFUROYL amine.Chemical structural formula is a following formula:
Alfuzosin (Alfuzosin can be replaced herein with AZ) has listed usually with its hydrochloride for clinic
The specification of tablet or capsule has 1mg, 2mg and 5mg.Alfuzosin hydrochloride can be used for treating benign prostatic hyperplasis, it is also possible to
In treatment hypertension, it can be used alone or combine with other drugs for hypertension such as diuretics or Alpha 1 adrenergic blocking agent
Use [Roehrborn CG (2001) Alfuzosin:overview of pharmacokinetics, safety, and
Efficacy of a clinically uroselective alpha-blocker.Urology 58:55-63；McVary
KT(2006)Alfuzosin for symptomatic benign prostatic hyperplasia:long-term
experience.Journal of Urology 175:35-42；Elhilali MM(2006)Alfuzosin:an alpha1-
receptor blocker for the treatment of lower urinary tract symptoms associated
with benign prostatic hyperplasia.Expert Opinion in Pharmacothrapy 7:583-96]。
Alfuzosin is for treating benign prostatic hyperplasis (BPH), and benign prostate hyperplasia shape mitigates after medication and urine flow speed improves
Block caused smooth muscle relaxation related with the alpha 1 adrenergic receptor in neck of urinary bladder and prostate.Because in body of urinary bladder
In have a relatively little of alpha 1 adrenergic receptor, therefore Alfuzosin can reduce the obstruction of bladder outlet without influencing bladder
Contraction [MacDonald R, Wilt TJ (2005) Alfuzosin for treatment of lower urinary
tract symptoms compatible with benign prostatic hyperplasia:a systematic
review of efficacy and adverse effects.Urology 66:780-8].In addition, Alfuzosin is by subtracting
Few Total peripheral vascular resistance is to make blood pressure reduce.Vasodilation, the blood pressure reduction effect of Alfuzosin are mainly by α 1- kidney
Caused by noradrenergic receptor blockade.#
Parkinsonism is divided into two classes: one kind is Familial Occurrence, accounts for 5% of number of the infected or so；One kind is sporadic
, account for 95% of number of the infected or so.In the genetic parkinsonism patient of family, there are two the mutation of gene to be ground extensively
Study carefully, is Pink1 and Parkin respectively.The major function of the two genes is update and the metabolism [Vives- for participating in mitochondria
Bauza C,Zhou C,Huang Y,Cui M,de Vries RL,et al.(2010)PINK1-dependent
recruitment of Parkin to mitochondria in mitophagy.Proc Natl Acad Sci U S A
107:378-383；Matsuda N,Sato S,Shiba K,Okatsu K,Saisho K,et al.(2010)PINK1
stabilized by mitochondrial depolarization recruits Parkin to damaged
mitochondria and activates latent Parkin for mitophagy.J Cell Biol 189:211-
221]。
It is well known that the neuron of brain is the extremely active cell of a kind of physiological activity, their normal operation needs
Big energy, therefore, the metabolic function of mitochondria are particularly important.But meanwhile the over-activity of mitochondria also results in largely
Mitochondrial oxidation stress, the side effects such as the damage of mitochondrial DNA.At this moment, mitochondria is passed through impaired mitochondria by fracture
Autophagy system excludes [Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial
fission and fusion balance:a new mechanism of neurodegeneration.Ann N Y Acad
Sci 1147:283-292].When the film potential of mitochondria lowers, Parkin is enrolled on mitochondria from cytoplasm, this
One process is that Pink1 is relied on.Therefore, Pink1 and Parkin is the key protein of detection of run-out mitochondria.Then, Pink1 is logical
Recruitment Parkin is crossed, and Parkin recruits autophagy system, reaches phagocytosis (mitophagy) [Vives-Bauza to mitochondria
C,Zhou C,Huang Y,Cui M,de Vries RL,et al.(2010)PINK1-dependent recruitment of
Parkin to mitochondria in mitophagy.Proc Natl Acad Sci U S A 107:378-383；
Matsuda N,Sato S,Shiba K,Okatsu K,Saisho K,et al.(2010)PINK1 stabilized by
mitochondrial depolarization recruits Parkin to damaged mitochondria and
activates latent Parkin for mitophagy.J Cell Biol 189:211-221].As Pink1 or
When Parkin mutates, the autophagy system of mitochondria is unable to complete, and causes the mitochondria being largely damaged that can not be metabolized, from
And hinder the autonomous update of mitochondria.This process results in the decline of mitochondrial function.Because cell energy supply not
Foot, eventually led to neuron function reduction and cell death [Narendra DP, Jin SM, Tanaka A, Suen DF,
Gautier CA,et al.(2010)PINK1 is selectively stabilized on impaired
mitochondria to activate Parkin.PLoS Biol 8:e1000298]。
Similar to the mutation of Pink1 and Parkin, sporadic parkinsonism is also that mitochondrial function obstacle occurs and leads
It causes.A large amount of document report discloses, and the toxicity of sporadic parkinsonism and pesticide, chemical pollutant has substantial connection.This
The respiratory chain of a little harmful compounds mainly damage mitochondria, and such as common MPTP (1- methyl 4-phenyl -1,2,3,6- tetra-
Pyridinium hydroxide), Rotanone (rotenone, a kind of insecticide), they are the inhibitor of mitochondrial respiratory chain complex
[Greenamyre JT,Betarbet R,Sherer TB(2003)The rotenone model of Parkinson's
disease:genes,environment and mitochondria.Parkinsonism Relat Disord 9Suppl
2:S59-64；Luo Y,Hoffer A,Hoffer B,Qi X(2015)Mitochondria:A Therapeutic Target
For Parkinson's Disease? Int J Mol Sci 16:20704-20730].(such as drosophila, small in animal model
Mouse and rat), the MPTP or rotenone of low dosage can lead to the dopamine neuron death and classical parkinsonism of specificity
Shape (muscular rigidity, limbs tremble) [Liao J, Morin LW, Ahmad ST (2014) Methods to characterize
spontaneous and startle-induced locomotion in a rotenone-induced Parkinson's
disease model of Drosophila.J Vis Exp；Liu Y,Sun JD,Song LK,Li J,Chu SF,et al.
(2015)Environment-contact administration of rotenone:A new rodent model of
Parkinson's disease.Behav Brain Res 294:149-161；Puchades M,Sogn CJ,Maehlen J,
Bergersen LH,Gundersen V(2013)Unaltered lactate and glucose transporter
levels in the MPTP mouse model of Parkinson's disease.J Parkinsons Dis 3:371-
385]。
There is only the damages of dopamine neuron for Parkinson's disease, and there is also functions for the multiple types neuron of Different brain region
Variation, leads to a variety of disease phenotypes.Motor symptoms and non-motor symptoms are generally divided into, motor symptoms include bradykinesia, rest
When tremble, stiff and posture is unstable, gait is difficult, fall etc..Non-motor symptoms include fatigue, vision and dysosmia, pain
Bitterly, depression and anxiety, postural hypotension, sleep disturbance, hypomnesia, brain blood flow reduction, cardiovascular stomodaeal nervous system obstacle
Deng [Fabbrini G, Latorre A, Suppa A, Bloise M, Frontoni M, Berardelli A (2013) Fatigue
In Parkinson's disease:motor or non-motor symptom? Parkinsonism Related
Disorders 19:148-52；Visanji N, Marras C (2015) The relevance of pre-motor
symptoms in Parkinson's disease.Expert Review of Neurotherapy 15:1205-17；
Maier F, Prigatano GP (2017) Impaired Self-Awareness of Motor Disturbances in
Parkinson's Disease.Archives in Clinical Neuropsychology 32:802-9]。#
In the treatment, in the world without inhibition injury of mitochondria and the clinical medicine of neuronal death.Patient mainly mentions
For L-DOPA donor, reduce absorption, the nerous sedative etc. of dopamine, mitigate the phenotype of patient in symptom.However, long-term
Medication (patient is often used 10-20) can generate very strong drug resistance.During medication, need a period of time drug withdrawal, to
The rotation of medicine.Because that can not eradicate, the state of an illness gradually aggravates [Jenner P (2015) Treatment of the later stages
of Parkinson's disease-pharmacological approaches now and in the
future.Translational Neurodegeneration 4:3]。
Therefore, this field urgently expects to be clinically to provide have the function of to slow down, terminate even reverses neuronal forfeiture
Drug, to change Parkinson's disease process.
Summary of the invention
It is an object of the invention to clinically to provide a kind of drug with anti-Parkinson disease function.The present inventor uses
One common medicine Alfuzosin clinically declines this critical issue for energy caused by injury of mitochondria and is visited
Rope, and then know that Alfuzosin is beneficial in terms for the treatment of parkinsonism.It is a discovery of the invention that Alfuzosin can be valuably right
Anti-Parkinson disease and related complication.This discovery provides important scheme to treat or prevent parkinsonism.Meanwhile I
Obtain two new chemical derivatives (TZ-md and AZ-md), it may have pharmaceutical activity similar with AZ.The present invention is based on
This finds and is accomplished.
For this purpose, the present invention provides Alfuzosin or its pharmaceutical salts or its solvate in preparation for treating or preventing pa
Purposes in the drug of the gloomy disease of gold.
Pharmaceutical applications according to the present invention, wherein the pharmaceutical salts are, for example, Alfuzosin (and derivative TZ-md and AZ-
Md hydrochloride, phosphate, benzene sulfonate, mesylate, sulfate, nitrate).
Pharmaceutical applications according to the present invention, wherein the solvate is the compounds alfuzosin (and derivative TZ-
Md and AZ-md) or the hydrate, such as monohydrate, dihydrate of its pharmaceutical salts etc..
In specific test herein, when using Alfuzosin, does not in addition particularly illustrate such as, use its hydrochloride
What dihydrate was tested.
Pharmaceutical applications according to the present invention, be used for human body dosage can according to the weight of many factors such as people, the age,
Condition etc. and adjust, it is common be can daily 0.001~1mg/kg weight dosage administration, such as with daily 0.003
The dosage of~0.5mg/kg weight is administered, such as is administered with the dosage of daily 0.003~0.1mg/kg weight.These dosage are under
It is comparable that text, which tests dosage used, and suitable with the conventional dosage of Alfuzosin currently clinically.In addition, at this
In invention, Alfuzosin can be administered with various administration routes, such as the approach such as oral, injection, percutaneous, as treatment or prevention
The drug of parkinsonism, oral administration are beneficial, and identical as its existing administration route.Administration route is being determined
In the case of, the dosage form selection of drug is easy.
It has been found by the present inventors that Alfuzosin (and derivative TZ-md and AZ-md) can be beneficial be used for Parkinson
Disease.
Detailed description of the invention
Fig. 1 presents the effect of Alfuzosin and TZ-md in mouse MPTP parkinsonism model.
Fig. 2 presents the effect of Alfuzosin and AZ-md in drosophila rotenone Parkinson disease model.
Fig. 3 and Fig. 4 presents Alfuzosin to the effect in Parkinsonian.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention carries out the material and test method arrived used in test general
And/or specific description.Although to realize the present invention many materials and operating method used in purpose be it is known in the art that
But the present invention is still described in this detail as much as possible.Following embodiment further illustrates the present invention, rather than limits this hair
It is bright.The made only formal but not substantive equivalent transformation of any design according to the present invention is regarded as the present invention
Technical solution scope.
Below in test, if not otherwise indicated, the Alfuzosin used is its hydrochloride dihydrate.It is well-known
It is that various forms of salt and/or its solvate usually only influence the physicochemical property such as dissolubility etc. of drug, without will affect
The biological activity of drug, therefore it is desired that Alfuzosin free alkali and its salt of other forms such as sulfate, phosphate
Deng, they test below in biological property the result worked as with alfuzosin hydrochloride dihydrate etc. will be presented.
It tests (Fig. 1): the effect in the parkinsonism model of mouse MPTP
A, mouse black substance brain area protein immunoblot experiment is as a result, detect mouse black substance brain area tyrosine hydroxylase (TH)
Protein level, give within the 0th day 8 week old 4 intraperitoneal injection neurotoxin MPTP of C57BL/6N male mice (20mg/kg, every time
Interval 2 hours), mouse peritoneal injection Alfuzosin (AZ, 10 μ g/kg) or Terazosin modification are then given since the 0th day
The physiological saline of object (TZ-md, 10 μ g/kg) or isodose continues one week once a day, carries out materials detection, β-within the 7th day
Actin is loading internal reference, N=6；B, mouse was placed at the 7th day and ramps up fortune by mouse transfer rod Behaviors survey test result
On the round bar turned, record mouse is maintained at the time moved on round bar, and ordinate indicates that mouse maintains movement in transfer rod instrument
Relative time, N=10.Administration group and non-administered group comparison have statistical difference (One-way ANOVA, * * represent P <
0.01；* * represents p < 0.001).
It tests (Fig. 2): the effect in drosophila Parkinson disease model
A, the protein immunoblot experiment of drosophila head tyrosine hydroxylase (TH) is as a result, collect the W in birth 3 days1118
Drosophila, the neurotoxin rotenone (rotenone) of 250 μM of independent feeding or with Alfuzosin (AZ, 10 μM)/Terazosin
Modifier (AZ-md, 10 μM) while feeding take head protein to be tested after one week, and β-actin is loading internal reference, N=6；
B、W1118Drosophila apogeotropism after feeding rotenone (or with AZ/TZ-md simultaneously feeding) is one week climbs pipe Behavior test
Drosophila is put into a height of 40cm by statistical result, and diameter is then to touch drosophila to bottom of the tube, record in the transparent pipe of 1.5cm
Height of creeping within 20s is more than the drosophila number of elements of 25cm, and retest 3 times as an experimental result, N=10, every time test
(One-way ANOVA, * represent p < 0.05 to every group of 100 drosophilas；* represents P < 0.01；* * represents p < 0.001).
It tests (Fig. 3): retrospective analysis effect of the Alfuzosin to Parkinson's disease
A figure is in the U.S. Parkinson ' s Progression Markers Initiative (PPMI) database
[Marek,K(2011)The Parkinson Progression Marker Initiative(PPMI).Progressive
Neurobiology:95:629-35] amount of Parkinsonian's dyskinesia divides table, and which divides table to be by international movement obstacle
Association unifies the of Parkinson's disease measuring scale (Unified Parkinson ' s Disease Rating Scale, UPDRS)
Three parts (motion parts) are evaluated motor function in patients with Parkinson ' got comprehensive score.This is analyzed,
Only medicine group is included into using the participant of AZ or Tamsulosin in baseline PPMI interview.PPMI agreement provides the 4th visit
Depending on that should be carried out in or so baseline Visit latter year；Therefore, including any interview between baseline Visit and the 4th PPMI interview.
Participant must also repeatedly be accessed.AZ and the patient of Tamsulosin group must take medicine incessantly over the course for the treatment of
Object.The AZ of all patients and the indication of Tamsulosin are benign prostatauxe or urinary system problem not yet explicitly.Only
When subject not yet take PD drug or in actual definition closed state (at least taking for the last time levodopa or appoint
What 6 hours after his anti-PD drug) when obtain UPDRS reading just for this analyze.We are returned using linear hybrid effect
(LMER) analyze assess take the patient of AZ and do not take AZ patient between opposite updrs score slope difference.Mould
Covariant in type includes the age that baseline age, symptom occur and the PD drug that uses when medical every time.Maximum likelihood method
For testing the difference of the gradient between intercept and group.R is used for all analyses.Ordinate is the comprehensive score of patient motion obstacle, horizontal
Coordinate is this time to analyze the tracked time, and that red represents is the Parkinsonian (N=for taking Alfuzosin (AZ)
200) that, green represents is the Parkinsonian (N=306) for taking Tamsulosin (tamsulosin), and what blue represented is
It neither takes Alfuzosin nor takes the Parkinsonian (N=812) of Tamsulosin.We have checked individually take AZ or
Parkinson's prognostic markers object of the patient of Tamsulosin proposes (PPMI) database.Pass through maximal possibility estimation, Alfuzosin group
There is significant difference (p=0.011) with Tamsulosin group
It tests (Fig. 4): effect of the Alfuzosin to the epidemiological analysis of Parkinson's disease
Define the coding of Parkinson's disease and related disease
Data come from Truven Health Markets (Truven health insurance company, the U.S.).From 2011 to 2016
The male participant of at least one Parkinson's Disease Clinic diagnosis (ICD-9 332.0, ICD-10G20) during year, they are clothes
With Alfuzosin (AZ) or tamsulosin (control).Analysis is only limitted to initial when subject takes one of 4 kinds of drugs
The uninterrupted time.The coding and coding relevant to PD of PD patient are determined, we determined that most common first 500 in queue
ICD-9 coding, no matter whether subject takes AZ or Tamsulosin.Most common 497 ICD-9 coding is also by two nerves
Section doctor examines that this leaves one group of 79 code relevant to PD to us.These codes are further classified as movement, non-
Movement or complication.
Define medication number of days
We are initially coated with the compliance measurement of number of days ratio (pdc).Pdc is the number of days provided in dispensing event and should
Drug the ratio between the number of days before dispensing event next time.For the drug for treating diabetes and cardiovascular disease, 80%
Threshold value is typically considered " adhering to treating ", this is the threshold value that we select herein.80% pdc, which is equivalent to, is no more than supply
It is filled again in the case where the 125% of number of days.We determined that each dispensing event, and by following 125% supply day
Number encoder is " taking drugs ".After may being discontinued including drug and then restart the data after medication, because drug changes
The reason of it is unknown, may result in and obscure.First medication cycle is defined as the week of all medications after first time medication by us
Phase, the in this way interval time twice between medication do not exceed (125% medication number of days)+90 days.
Analysis method
According to quasi- Poisson distribution (quasi-Poisson distribution), estimated using generalized linear model (GLM)
The effect of AZ and Tamsulosin.Model is as follows:
ni=β0+β1di+log(ti)+εi
Wherein niIt is the number of days of i-th subject's outpatient clinic and the diagnostic code of Parkinson's disease related disease occurs.di=
1 is that subject takes AZ or diIf=0 that take is tamsulosin；tiIt is total number of days of subject's medication；εiIt is one flat
The term of equal zero error.log(ti) value be it is a kind of offset different subject's observing times, link letter with expected from quasi- Poisson distribution
Number is corresponding.We select the quasi- Poisson GLM used on classical Poisson GLM, allow excessively dispersion.Poisson distribution assumed average
It is equal with variance.This quasi- Poisson GLM is by assuming that variance can be written as the product of a scalar multiplier and average.This makes
Data have the bigger variance allowed under classical Poisson frame.We estimate 497 test code relative risks, 166
(33.4%) there were significant differences.Group intercurrent disease rate p=0.05.Wherein 43 (25.9%) may be related with Parkinson's disease.Upper
Face description by code model, we consider the incidence of each code respectively.
Result is analyzed to summarize
The patient of AZ or Tamsulosin (tamsulosin) are taken in comparison, in the relevant diagnostic code of 79 kinds of Parkinson's diseases
In, AZ reduces the occurrence risk of a variety of diseases than Tamsulosin, and yellow flag has statistical difference (P < 0.05)
Various diseases, including multi-motion symptom (including bradykinesia, tremble, gait is difficult, falls etc.) and non-motor symptoms it is (tired
Labor, vision and dysosmia, pain, depression and anxiety, postural hypotension, sleep disturbance, hypomnesia, vascular sclerosis and narrow
It is narrow etc.).
Industrial applicability
The present invention provides a kind of Alfuzosin or the new pharmaceutical applications of its analog, this new pharmaceutical applications can be with
New selection scheme is provided for the treatment of clinically relevant disease.
Claims (10)
1. Alfuzosin or derivatives thereof and their pharmaceutical salts or its solvate are in preparation for treating or preventing pa gold
Purposes in the drug of gloomy disease and related disease.
2. purposes according to claim 1, wherein the pharmaceutical salts be selected from the hydrochloride of Alfuzosin, phosphate, benzene sulfonate,
Mesylate, sulfate, nitrate.
3. purposes according to claim 1, wherein the solvate is the compounds alfuzosin or the water of its pharmaceutical salts
Close object.
4. purposes according to claim 3, wherein the hydrate is monohydrate or dihydrate.
5. purposes according to claim 1, wherein the Alfuzosin is alfuzosin hydrochloride dihydrate.
6. purposes according to claim 1, wherein the Alfuzosin is administered with the dosage of daily 0.001~1mg/kg weight.
7. purposes according to claim 1, wherein the Alfuzosin is given with the dosage of daily 0.003~0.5mg/kg weight
Medicine.
8. purposes according to claim 1, wherein the Alfuzosin is given with the dosage of daily 0.003~0.1mg/kg weight
Medicine.
9. purposes according to claim 1, wherein the Alfuzosin is administered with various administration routes, such as oral, injection, warp
The approach such as skin.
10. -9 purposes according to claim 1, the derivative is TZ-md or AZ-md.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102869775A (en) * | 2009-09-30 | 2013-01-09 | 哈佛大学校长及研究员协会 | Methods for modulation of autophagy through the modulation of autophagy-inhibiting gene products |
| CN105616417A (en) * | 2015-12-26 | 2016-06-01 | 刘磊 | Application of terazosin in treatment of Parkinsonism |
-
2019
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102869775A (en) * | 2009-09-30 | 2013-01-09 | 哈佛大学校长及研究员协会 | Methods for modulation of autophagy through the modulation of autophagy-inhibiting gene products |
| CN105616417A (en) * | 2015-12-26 | 2016-06-01 | 刘磊 | Application of terazosin in treatment of Parkinsonism |
Non-Patent Citations (1)
| Title |
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| BORDNER J等: "1,3-Diamino-6,7-dimethoxyisoquinoline derivatives as potential alpha 1-adrenoceptor antagonists", 《J MED CHEM》 * |
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