CN103059043A - Clavatine A-C and preparation method as well as pharmaceutical composition and application thereof - Google Patents

Clavatine A-C and preparation method as well as pharmaceutical composition and application thereof Download PDF

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CN103059043A
CN103059043A CN2011103254504A CN201110325450A CN103059043A CN 103059043 A CN103059043 A CN 103059043A CN 2011103254504 A CN2011103254504 A CN 2011103254504A CN 201110325450 A CN201110325450 A CN 201110325450A CN 103059043 A CN103059043 A CN 103059043A
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herba lycopodii
alkali
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庾石山
陈乃宏
王晓婧
苑玉和
屈晶
马双刚
李勇
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Abstract

The invention discloses clavatine A-C and a preparation method as well as a pharmaceutical composition and application thereof. The invention relates to 3 alkaloids (clavatine A-C) separated from Lycopodium japonicum Thunb. as well as pharmaceutically acceptable salts and preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds in preparation of an acetylcholin esterase inhibitor medicament, a medicament for treating Alzheimer disease and a medicament for resisting fade of memory and cognitive competence of middle-aged and old persons.

Description

Herba Lycopodii alkali A-C, its method for making and its pharmaceutical composition and purposes
Technical field
The invention belongs to technical field of pharmaceuticals, particularly, the present invention relates to a class lycopodium alkaloid compound: Herba Lycopodii alkali A-C (1-3), acceptable salt on its pharmacodynamics, its preparation method, the pharmaceutical composition that contains this compounds, and this compounds is in the preparation acetylcholine esterase inhibitor medication, in preparation treatment presenile dementia disease drug and prepare go down the application in the disease medicament of anti-person in middle and old age's memory and cognition ability.
Background technology
Year by year increase along with the world population mean lifetime, the sickness rate of senile dementia is also along with rapid rising, it is alzheimer's disease (AD) that 50%-70% is arranged in the senile dementia, claim again degenerative brain disorder, patient's brain function fails gradually, occurs that memory, abstract thinking ability and ability of language expression go down, handicapped and other functional disorders, and system function affects the nerves, not only bring misery to the patient, and bring many problems for family and society.AD is that a kind of cognitive and memory injury is main central nervous system degenerative disease take carrying out property, becomes the principal disease that causes death after cardiovascular diseases and tumour in developed country.The medicine for the treatment of AD mainly contains choline drugs thing, neurocyte metabolism Reinforcing agent, antioxidant, calcium ion antagonist, nerve growth factor, oestrogenic hormon, antiphlogiston, anti-beta amyloid medicine etc.Treating clinically at present the most successful method of this disease is exactly by improving the level of central nervous system Cholinergic neurotransmitter-vagusstoff, improving patient's AD symptom.Acetylcholinesterase depressant (AChEI) improves levels of acetylcholine in the brain by acetylcholine esterase inhibition (AChE) pointedly to the hydrolytic action of vagusstoff, becomes the first-line drug for the treatment of AD.Effectively medicine such as tacrine, aricept, Exelon, lycoremine and selagine are acetylcholinesterase depressant clinically.And famous natural product selagine is from Chinese endemic fern plant Herba Lycopodii serrati (Herba Lycopodii serrati, Huperzia serrata (Thunb) Trev., Huperziaceae (Huperziaceae)) a kind of alkaloid that extracts in, be reversibility Pseudocholinesterase specific inhibitor, acetylcholinesterase had selective inhibitory, and toxicity is low, long action time, be developed at present the most safely and effectively one of medicine for the treatment of benign memory deficits and presenile dementia, also be the pioneering a kind of world-class new drug of China, its develop also makes us see and seeks the novel active composition and carry out the hope of new drug development from natural product.
Herba Lycopodii (lycopod, Lycopodium japonicum Thunb.) is Lycopodiaceae (Lycopodiaceae) Lycopodium plant, is China's traditional Chinese medicine commonly used, and main effect is used for joint pain, joint stuffiness for dispelling rheumatism, stimulating the circulation of the blood and cause the muscles and joints to relax.Use among the people and clinical finds that hint wherein may contain the effective chemical ingredients of cholinergic system with strengthening myocardial contraction, excited unstriated muscle, causing the cholinergic side reaction such as Muscle contraction tic.Technical solution of the present invention attempts the Alkaloid constituents in the Herba Lycopodii is furtherd investigate, and novel structure is found in expectation, has the active skull cap components of acetylcholinesteraseinhibition inhibition.
Summary of the invention
The technical problem to be solved in the present invention is that the compound of a class new texture type is provided: acceptable salt on Herba Lycopodii alkali A-C (1-3) and the pharmacodynamics thereof.
Figure BDA0000101499930000031
Another aspect of the present invention relates to the preparation method of compound Herba Lycopodii alkali A-C (1-3).
Another aspect of the present invention relates to again a kind of pharmaceutical composition, it comprise medicine effective dose, as carrier commonly used in the compound Herba Lycopodii alkali A-C (1-3) of activeconstituents and the pharmacy field.
Another aspect of the present invention relates to compound Herba Lycopodii alkali A-C (1-3) and composition thereof in the preparation acetylcholine esterase inhibitor medication, in preparation treatment presenile dementia disease drug and prepares go down the application in the disease medicament of anti-person in middle and old age's memory and cognition ability.
The pharmaceutical composition of the compounds of this invention can be according to method preparation well known in the art.When being used for this purpose, if necessary, the compounds of this invention and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make the suitable administration form or the dosage form that can be used as drug use.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, abdominal injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc., preferred oral administration.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be widely used various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, poly-second two propyl alcohol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For pill is made in the administration unit, can be widely used various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are such as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire 44/14, kaolin, talcum powder etc.; Tackiness agent is such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent is such as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.
For suppository is made in the administration unit, can be widely used various carrier well known in the art.Example about carrier is, such as the ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.
For capsule is made in the administration unit, effective constituent the compounds of this invention Herba Lycopodii alkali A-C (1-3) is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also the effective constituent the compounds of this invention can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.
For example, the compounds of this invention Herba Lycopodii alkali A-C (1-3) is made injection preparation, such as solution, suspensoid solution, emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can contain acceptable carrier, thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent on a kind of and/or multiple pharmacodynamics.Can be selected from isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters of isooctadecanol, the polyoxy of water, ethanol, polyoxyethylene glycol, 1,3-PD, ethoxylation etc. such as thinner.In addition, to ooze injection liquid in order preparing etc., can in injection preparation, to add an amount of sodium-chlor, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH adjusting agent etc.These auxiliary materials are that this area is commonly used.
In addition, such as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
For reaching the medication purpose, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition depends on many factors, for example to prevent or treat character and the severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times, therapeutic purpose, therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.Can be according to actual drug quantity contained in the preparation last in the compounds of this invention composition, in addition suitable adjustment to reach the requirement of its treatment significant quantity, is finished prevention of the present invention or therapeutic purpose.The appropriate dose scope of the every day of the compounds of this invention is 0.001～10mg/Kg body weight, divides and takes for 2-4 time.Compound of the present invention or composition can be taken separately, or merge use and adjust dosage with other treatment medicine or symptomatic drugs.
Term and abbreviation
The AChE acetylcholinesterase
The ESI-MS electrospray ionization mass spectrum
HMBC heteronuclear multikey relevant (a kind of two dimensional NMR spectrum of measuring molecule medium-long range hydrogen carbon annexation)
The HPLC high performance liquid chromatography
HRESI-MS high resolution electrospray ionization mass spectrum
The single quantum of HSQC heteronuclear relevant (a kind of measure that hydrogen carbon in the molecule directly links to each other the two dimensional NMR spectrum of relation)
IC 5050 3nhibitory dose
The IR infrared spectra
The NMR nucleus magnetic resonance
ROESY rotating frame Ou Wohaosi gain spectral (a kind of measure the two dimensional NMR spectrum that relation is closed in hydrogen atom locus in the molecule)
The UV UV spectrum
Description of drawings
The extraction separation of Fig. 1 Herba Lycopodii and the preparation flow figure of Herba Lycopodii alkali A-C (1-3)
The X-ray single crystal diffraction result of Fig. 2 Herba Lycopodii alkali A-C (1-3) (molecule ellipsoid figure)
Embodiment
According to the literature, lycopsid mainly contains the compositions such as lycopodium alkaloid, terpene, organic acid, flavones and anthraquinone, and Herba Lycopodii is as a kind of common lycopsid, and its alkaloids composition not go deep into because content is lower studying thoroughly.The inventor is by strengthening the medicinal material consumption, alkaloid position for this medicinal substances extract, obtain having three active compounds of inhibiting activity of acetylcholinesterase, by separation means such as positive and negative phase chromatograms, and prove conclusively three lycopodium alkaloid compounds with novel skeleton that its chemical structure was not reported for forefathers through multiple spectral data and X-ray single crystal diffraction.The experiment of the following examples and pharmaceutical activity is used for further specifying the present invention, but this and do not mean that any limitation of the invention.
Separation and the structural characterization of embodiment 1 Herba Lycopodii alkali A-C (1-3)
The about 100Kg of Herba Lycopodii herb is cut into segment, and (ethanol, 1200L) refluxing extraction is 3 times, 3 hours first time, rear twice each 2 hours with 95%EtOH.The extracting solution concentrating under reduced pressure obtains medicinal extract 18Kg (being denoted as A), and medicinal extract is dissolved in 3% aqueous tartaric acid solution (pH=2,150L), uses ethyl acetate (3 times, each 150L) extraction behind the elimination insolubles (being denoted as E, 5Kg) again.Sour water after the extraction is transferred pH to 10 with saturated sodium bicarbonate solution (18L), chloroform extraction (4 times, each 150L) till the chloroform layer lifeless matter alkali reaction, the concentrated total alkaloids 135g (being denoted as B) that to get of chloroform layer.Total alkaloids is used sherwood oil: acetone=20: 1 through alkaline silica gel post (200-300 order, pH 8-9) chromatogram, 10: 1,5: 1,1: 1,0: 1, acetone: methyl alcohol=20: 1,5: 1,0: 1 wash-out, each gradient elution 18000ml, every 1000ml receive 1 stream part, and each stream part decompression and solvent recovery is by TLC (sherwood oil: acetone: diethylamine=1: 1: 0.1) inspection knowledge, merged according to principal spot, obtained nine components of B1～B9.B component 3 (8.7g) is through silicagel column (200-300 order, pH 6-7) chromatogram, adopt sherwood oil: ethyl acetate: diethylamine=10: 1: 0.1,8: 1: 0.1,6: 1: 0.1,4: 1: 0.1,2: 1: 0.1,1: 1: 0.1 gradient elution, each gradient elution 1500ml, every 100ml receives 1 stream part, (sherwood oil: ethyl acetate: diethylamine=1: 1: 0.1) inspection knowledge merging obtains nine components of B3-1～B3-9 by TLC respectively to flow part recovery solvent, (methylene dichloride: methyl alcohol=1: 1) (Shimadzu LC-6AD type prepares the liquid phase instrument to B3-3 component (2.65g) for purifying and preparation HPLC through gel Sephadex LH-20 again, YMC-packODS-A chromatographic column (250 * 20mm, 5 μ m), elution requirement: acetonitrile/ammonium acetate buffer (0.04mol/L ammonium acetate+0.1% acetic acid)=15/85,5ml/min, t R=27min) separation obtains compound 3 (33mg); B component 7 (34.0g) is through silicagel column (200-300 order, pH 6-7) chromatogram, adopt sherwood oil: ethyl acetate: diethylamine=8: 1: 0.1,5: 1: 0.1,3: 1: 0.1,1: 1: 0.1,1: 2: 0.2 gradient elution, each gradient elution 6000ml, every 500ml receives 1 stream part, (sherwood oil: ethyl acetate: diethylamine=1: 2: 0.1) inspection knowledge merging obtains 13 components of B7-1～B7-13 by TLC respectively to flow part recovery solvent, B7-9 (2.10g) component adopts methylene dichloride: methyl alcohol=60: 1 again through silicagel column (200-300 order, pH 6-7) chromatogram, 40: 1,20: 1,10: 1,5: 1 gradient elutions, (methylene dichloride: methyl alcohol=10: 1) inspection knowledge merging obtains seven components of B7-9a～B7-9g, and B7-9c (0.21g) is by preparation type TLC (methylene dichloride: methyl alcohol=20: 1) obtain compound 2 (30mg) through TLC; B7-10 (1.34g) component is through silicagel column (200-300 order, pH 6-7) chromatogram, adopt methylene dichloride: methyl alcohol=1: 0,40: 1,30: 1,20: 1 gradient elutions, (methylene dichloride: methyl alcohol=10: 1) inspection knowledge merging obtains five components of B7-10a～B7-10e through TLC, have needle crystal to separate out in the B7-10a component put procedure, getting white crystals with washing with acetone is compound 1 (40mg).Extract the schema of separation as shown in Figure 1.
Structural formula and the authentication method of Herba Lycopodii alkali A-C (1-3)
Figure BDA0000101499930000091
Spectral data and the physico-chemical property of Herba Lycopodii alkali A-C (1-3)
1. Herba Lycopodii alkali A (1)
The water white transparency crystallization, mp.223-225 ℃;
Figure BDA0000101499930000092
UV (MeOH): λ Max=203,300nm; IR:v Max=3371,2967,2928,1736,1697,1488,1454,1415,1378,1257,1138,910,856,612,587,544cm -1(+) ESI-MS:m/z=292.1[M+H] +HR-ESI-MS:m/z=292.1545[M+H] +(be calculated as C 16H 21NO 4); 1H NMR and 13C NMR data see Table 1.
2. Herba Lycopodii alkali B (2)
The water white transparency crystallization, mp.175-177 ℃; UV (MeOH): λ Max=202,259,300nm; IR:v Max=3460,3319,2921,2850,1700,1646,1465,1416,1279,1095,1080,848,787,581,547cm -1(+) ESI-MS:m/z=294.2[M+H] +HR-ESI-MS:m/z=294.1703[M+H] +(be calculated as C 16H 23NO 4); 1H NMR and 13C NMR data see Table 1.
3. Herba Lycopodii alkali C (3)
The water white transparency crystallization, mp.147-149 ℃;
Figure BDA0000101499930000094
UV (CHCl 3): λ Max=241nm; IR:v Max=2981,2956,2938,2773,1726,1657,1442,1384,1262,1203,1159,1121,1069,885cm -1(+) ESI-MS:m/z=274.2[M+H] +HR-ESI-MS:m/z=274.1809[M+H] +(be calculated as C 17H 23NO 2); 1H NMR and 13C NMR data see Table 1.
Table 1. compound 1-3's 1HNMR (500MHz) and 13CNMR (125MHz) data (δ in ppm, J in Hz)
Figure BDA0000101499930000101
A deuterated pyridine b deuterochloroform
Pharmacological evaluation
The AChE of test example 1 Herba Lycopodii alkali A-C (1-3) suppresses determination of activity
Experimental principle:
Acetylcholinesterase (acetylcholinesterase, AChE) the hydrolysis vagusstoff generates choline and acetic acid, choline can generate TNB (symmetrical trinitrobenzene with the reaction of sulfydryl developer, Sym-Trinitrobenzene) yellow compound, carry out colorimetric assay according to shade, the quantity of hydrolysate choline can reflect the cholinesterase enzyme activity.
Experiment material and required instrument:
Microplate reader, water bath, micropipet, acetylcholinesterase is measured test kit (bio-engineering research institute is built up in Nanjing), and reagent forms and comprises: one: 1 μ mol/L of reagent Standard Applying Solution; Reagent two: substrate; Reagent three: developer storing solution; Reagent four: inhibitor; Reagent five: transparent base; Reagent six: stablizer; Reagent seven: physiological saline.
Operation steps:
Figure BDA0000101499930000111
Mixing was placed 15 minutes, and microplate reader is measured absorbancy under the 412nm.
Inhibiting rate=[1-(measuring pipe OD value-control tube OD value)/(standard pipe OD value-blank tube OD value)] * 100%
Select the positive contrast of selagine, its concentration is its IC 50Concentration 8.2 * 10 -8Mol/L, the final concentration of compound is respectively 10 in the mixed solution of compound and Standard Applying Solution -5, 10 -6, 10 -7Mol/L.
Measurement result:
Figure BDA0000101499930000121
From above-mentioned pharmacology activity research result, Herba Lycopodii A-C (1-3) all has significant inhibiting activity of acetylcholinesterase,, and its active and positive control drug selagine (HupA) are of great value novel structure compounds quite or stronger.

Claims (7)

1. as shown in the formula acceptable salt on the Herba Lycopodii alkali (A-C) shown in formula 2 and the formula 3 and the pharmacodynamics thereof
2. a pharmaceutical composition is characterized in that, contains acceptable salt on the Herba Lycopodii alkali A-C (1-3) of effective dose or its pharmacodynamics, and acceptable carrier on the pharmacodynamics.
3. according to claim 2 pharmaceutical composition is characterized in that described pharmaceutical composition can be tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or particulate delivery system.
4. the preparation method of claim 1 compound Herba Lycopodii alkali A-C, it is mainly derived from the herb of pteridophyte Herba Lycopodii (Lycopodium japonicum Thunb.).
5. the application of acceptable salt in the preparation acetylcholine esterase inhibitor medication on claim 1 compound Herba Lycopodii alkali A-C and the pharmacodynamics thereof.
6. the application of acceptable salt in preparation treatment presenile dementia disease drug on claim 1 compound Herba Lycopodii alkali A-C and the pharmacodynamics thereof.
7. the application of acceptable salt in the anti-person in middle and old age's memory and cognition ability of preparation goes down disease medicament on claim 1 compound Herba Lycopodii alkali A-C and the pharmacodynamics thereof.
CN2011103254504A 2011-10-24 2011-10-24 Clavatine A-C and preparation method as well as pharmaceutical composition and application thereof Pending CN103059043A (en)

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CN103446136B (en) * 2013-09-23 2015-12-02 温州成桥科技有限公司 The application of Lycojaponicumin A in the anti-lung cancer metastasis medicine of preparation
CN103463069B (en) * 2013-09-23 2015-12-02 温州成桥科技有限公司 The application of Lycojaponicumin C in preparation treatment medicine for nasopharyngeal
CN103463024B (en) * 2013-09-23 2015-12-02 温州成桥科技有限公司 The application of Lycojaponicumin B in preparation treatment renal carcinoma medicine
CN103446128B (en) * 2013-09-23 2015-12-02 温州成桥科技有限公司 The application of Lycojaponicumin B in preparation treatment skin carcinoma medicine
CN103446133B (en) * 2013-09-23 2015-12-02 李淑兰 The application of Lycojaponicumin B in preparation treatment tongue cancer drug
CN103479637B (en) * 2013-09-23 2015-12-02 温州成桥科技有限公司 The application of Lycojaponicumin C in the medicine preparing anti-herpesvirus
CN103479630B (en) * 2013-09-23 2015-12-02 温州成桥科技有限公司 The application of Lycojaponicumin A in preparation treatment breast cancer medicines
CN103463034B (en) * 2013-09-23 2015-12-02 温州成桥科技有限公司 The application of Lycojaponicumin B in preparation treatment ovarian cancer
CN103463053B (en) * 2013-09-23 2015-12-02 温州成桥科技有限公司 Lycojaponicumin A is preparing the application in Hepatoma therapy medicine
CN103463044B (en) * 2013-09-23 2015-12-09 李淑兰 The application of Lycojaponicumin A in preparation treatment skin carcinoma medicine
CN103479628B (en) * 2013-09-23 2015-12-09 温州成桥科技有限公司 The application of Lycojaponicumin A in the medicine preparing anti-herpesvirus
CN103479633B (en) * 2013-09-23 2015-12-09 温州成桥科技有限公司 The application of Lycojaponicumin B in preparation treatment medicine for nasopharyngeal
CN103463064B (en) * 2013-09-23 2015-12-09 温州成桥科技有限公司 The application of Lycojaponicumin C in preparation treatment leukemia medicament
CN103463067B (en) * 2013-09-23 2015-12-09 温州成桥科技有限公司 The application of Lycojaponicumin C in preparation treatment flavivirus infections medicine
CN103446143B (en) * 2013-09-23 2015-12-09 李彦良 The application of Lycojaponicumin C in preparation treatment gastric cancer medicament
CN103463078B (en) * 2013-09-23 2015-12-23 温州成桥科技有限公司 The application of Lycojaponicumin C in preparation treatment renal carcinoma medicine
CN103446146B (en) * 2013-09-23 2016-01-06 隋安奎 The application of Lycojaponicumin C in preparation treatment blindgut cancer
CN103463040B (en) * 2013-09-23 2016-03-02 吕洪生 The application of Lycojaponicumin A in preparation treatment hemorrhagic fever with renal syndrome medicine

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