CN112047988A - Paederoside monomer compound, preparation method and application thereof - Google Patents

Paederoside monomer compound, preparation method and application thereof Download PDF

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CN112047988A
CN112047988A CN201910486995.XA CN201910486995A CN112047988A CN 112047988 A CN112047988 A CN 112047988A CN 201910486995 A CN201910486995 A CN 201910486995A CN 112047988 A CN112047988 A CN 112047988A
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ethanol
paederoside
water
methanol
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吴彤
沈幸光
周海凤
吴立峰
乐心逸
沈龙海
李睿
李默影
张蓓
徐柳
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NINGBO DACHANG PHARMACEUTICAL CO Ltd
Shanghai Institute of Pharmaceutical Industry
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Abstract

The invention provides a paederoside monomer compound, a preparation method thereof and application thereof in preparing a medicament for reducing uric acid, wherein the paederoside monomer compound is prepared by the following steps: a) extracting herba Paederiae with ethanol to obtain extractive solution; b) concentrating the extracting solution until no alcohol smell exists, performing macroporous adsorption resin chromatography, sequentially eluting with water and 80-90% ethanol, collecting eluent, and drying under reduced pressure to obtain a fevervine herb extract; c) loading the paederia scandens extract to macroporous adsorption resin chromatography, eluting with water and 5% -30% ethanol in sequence, collecting 15% -20% ethanol elution part, concentrating and drying to obtain refined paederia scandens extract; and d) carrying out fast column chromatography on the refined extract of the paederia scandens, eluting by using methanol, water or acetonitrile, water as an elution solvent, collecting the elution part of 15-16% of methanol or 8-86% of acetonitrile, and drying under reduced pressure to obtain the paederia scandens glycoside monomeric compound.

Description

Paederoside monomer compound, preparation method and application thereof
Technical Field
The invention relates to a paederoside monomer compound, a preparation method and application thereof.
Background
Paederia scandens (Lour.) Merr is aerial part or whole plant of Paederia scandens of Rubiaceae, also called herba Paederiae and caulis Kadsurae Longipedunculatae. The paederia scandens is sweet and sour in taste and neutral in nature, enters liver, stomach and large intestine channels, has the effects of promoting digestion, removing food retention, dispelling wind, activating blood circulation, relieving pain and diminishing swelling, is mainly distributed in the southeast coastal areas of China, Yangtze river watershed regions and the like, and is a traditional Chinese medicinal material. Modern pharmacological research proves that the Chinese fevervine herb has a plurality of remarkable effects of resisting inflammation, easing pain, calming, treating digestive system diseases and the like. The paederia scandens comprises iridoid glycosides, flavones, triterpenes, steroids, phenylpropanoids, volatile oil and other natural products.
The applicant's previous chinese patent publication specifications CN104398619A, CN104435226A and CN104474068A disclose fevervine extract and its use in reducing uric acid, anti-inflammatory and anti-gouty arthritis. However, the above patent publication does not disclose the obtention of a monomeric compound of paederoside.
Disclosure of Invention
The invention further separates and identifies a monomer compound from the Chinese fevervine herb extract on the basis of the patent publication specification: a paederoside monomer compound. The monomeric compound of paederoside separated according to the method of the invention has purity of more than 90% and proves to have better in vitro uric acid reducing activity compared with the paederoside extract.
Paederoside is a known compound with CAS number 20547-45-9, having the following chemical structure:
Figure BDA0002085734360000021
accordingly, in one aspect, the present invention provides a paederoside monomeric compound prepared by the following method:
a) extracting herba Paederiae with ethanol to obtain extractive solution;
b) concentrating the extract until no alcohol smell exists, performing macroporous adsorption resin chromatography, sequentially eluting with water and 80-90% ethanol, collecting eluate, and drying under reduced pressure to obtain herba Paederiae extract;
c) loading the paederia scandens extract to macroporous adsorption resin chromatography, eluting with water and 5% -30% ethanol in sequence, collecting 15% -20% ethanol elution part, concentrating and drying to obtain refined paederia scandens extract; and
d) and (2) carrying out flash column chromatography on the paederia scandens refined extract, eluting by using methanol, water or acetonitrile, water as an elution solvent, collecting 15-16% of methanol elution part or 8-86% of acetonitrile elution part, and drying under reduced pressure to obtain the paederia scandens glycoside monomer compound.
According to a preferred embodiment of the invention, the amount ratio of the Chinese fevervine herb to the resin is 1kg of herb, and 300ml of macroporous resin after swelling pretreatment by absolute ethyl alcohol is needed.
According to a preferred embodiment of the invention, the elution in step b) is carried out with water and 85% ethanol in sequence, and the 85% ethanol eluate is collected.
According to a preferred embodiment of the invention, the elution in step c) is carried out with water, 5% ethanol, 10% ethanol, 15% ethanol, 20% ethanol, 25% ethanol and 30% ethanol in sequence.
According to a preferred embodiment of the present invention, the elution procedure in step d) with methanol to water as elution solvent is 15% methanol 5BV → 15% -16% methanol 3BV → 16% -100% methanol 0.01BV → 100% methanol 5 BV.
According to a preferred embodiment of the present invention, the elution procedure in step d) with acetonitrile to water as elution solvent is 8% acetonitrile 3BV → 8% -86% acetonitrile 5BV → 100% acetonitrile 3 BV.
According to a preferred embodiment of the invention, the residue obtained after the reduced pressure drying in the step d) is added with methanol for redissolving, filtered, and the subsequent filtrate is collected, and the solvent is recovered under reduced pressure until the solvent is dried, so that the paederoside monomer compound is obtained. According to a particularly preferred embodiment of the invention, the methanol concentration is greater than or equal to 95%, most preferably pure methanol.
According to a preferred embodiment of the present invention, the macroporous adsorbent resin in steps b) and c) is a neat grade resin with model number D101, manufactured by cangzhou baien adsorbent materials technologies ltd.
According to a preferred embodiment of the invention, the residue obtained after the concentration and drying in the step c) is dissolved in water, and then the residue is subjected to macroporous adsorption resin column chromatography again, and then eluted by deionized water, 10% ethanol, 15% ethanol and 20% ethanol in sequence, the eluted part of the 15% ethanol is collected, and the extract is concentrated under reduced pressure, and the solvent is recovered to be dry, so that the refined paederia scandens extract is obtained.
According to a preferred embodiment of the invention, the residue obtained after the concentration and drying in the step c) is dissolved in water, and then the residue is subjected to macroporous adsorption resin column chromatography again, and then eluted by deionized water, 10% ethanol, 15% ethanol and 20% ethanol in sequence, the eluted part of 20% ethanol is collected, the pressure is reduced and the concentration is carried out, and the solvent is recovered to be dry, so that the refined extract of the paederia scandens is obtained.
According to a preferred embodiment of the present invention, the column diameter height ratio of the macroporous adsorbent resin in step b) is 1:8-1: 12.
According to a preferred embodiment of the invention, the flow rate of the sample in step b) is between 1.0 and 2.0BV/h and the elution flow rate is between 4 and 6 BV/h.
The second aspect of the present invention provides a method for preparing a paederoside monomer compound, comprising the steps of:
a) extracting herba Paederiae with ethanol to obtain extractive solution;
b) concentrating the extract until no alcohol smell exists, performing macroporous adsorption resin chromatography, sequentially eluting with water and 80-90% ethanol, collecting eluate, and drying under reduced pressure to obtain herba Paederiae extract;
c) loading the paederia scandens extract to macroporous adsorption resin chromatography, eluting with water and 5% -30% ethanol in sequence, collecting 15% -20% ethanol elution part, concentrating and drying to obtain refined paederia scandens extract; and
d) and (2) carrying out flash column chromatography on the paederia scandens refined extract, eluting by using methanol, water or acetonitrile, water as an elution solvent, collecting 15-16% of methanol elution part or 8-86% of acetonitrile elution part, and drying under reduced pressure to obtain the paederia scandens glycoside monomer compound.
The third aspect of the invention provides the application of the paederoside monomer compound in preparing a medicament for reducing uric acid.
The fourth aspect of the invention provides the application of the paederoside monomer compound in preparing a medicament for treating gouty arthritis.
The fifth aspect of the invention provides the application of the paederoside monomer compound in preparing a medicament for treating hyperuricemia.
The preparation method of the paederoside monomer compound has the advantages of simple process, reasonable design and small environmental pollution. The method has no pollution to environment, less ethanol and methanol consumption, lower cost and higher yield, and is suitable for industrial production.
Because the purity of the paederoside monomer compound is up to more than 90%, compared with the paederoside extract, the paederoside monomer compound has more remarkable uric acid reducing effect on acute hyperuricemia rats and presents a certain dose dependence relationship.
Drawings
FIG. 1 is a high performance liquid chromatogram of a Paederia scandens extract used in example 1 of the present invention;
FIG. 2 is a high performance liquid chromatogram of a paederoside monomer compound obtained in example 1 of the invention;
FIG. 3 is a high performance liquid chromatogram of a Paederia scandens extract used in example 2 of the present invention;
FIG. 4 is a high performance liquid chromatogram of the monomeric compound of paederoside obtained in example 2 of the present invention.
Detailed Description
The conditions for HPLC analysis of the monomeric compounds of paederoside in the following examples are as follows:
a chromatographic column: wates Atlantis C184.6 × 250mm, 5um
Fluidity: acetonitrile as mobile phase A (%) 0.1% phosphoric acid water as mobile phase (B),
the elution procedure was as follows:
0-25min 15→25 85→75
flow rate: 1 ml/min; column temperature: 30 ℃; detection wavelength: 235 nm.
Comparative example (Paederia scandens extract obtained in example 1 of CN104435226A was further refined):
719kg of Yunnan Paederia scandens (batch number: 150830) is taken, 8 times of 95% ethanol is added for reflux extraction for 3 hours, extraction is carried out for 3 times, the extract is filtered and combined, the reduced pressure concentration is carried out at 60 ℃ until no alcohol smell exists, deionized water is added to 4L for dissolution and centrifugation, the supernatant is taken, D101 macroporous adsorption resin (D101 resin after swelling pretreatment of the medicinal material by the absolute ethanol is needed for 300ml of the medicinal material and the resin amount ratio is 1 kg), the height ratio of the resin column is 1:8, the sampling flow rate is 1.0BV/h, after sampling is finished, the elution flow rate is 5BV/h, the deionized water is firstly used for eluting the resin column for 2BV, the flow-through liquid and the water eluent are discarded, the resin column is then eluted by 85% ethanol for 6BV, the eluent of the ethanol with the concentration is carried out at 60 ℃ under reduced pressure, the thick extract is concentrated to be added with a proper amount (about 1/7 times of the medicinal material amount), D101 macroporous adsorption, the flow rate of sample loading is 1.0BV/h, after sample loading is finished, the flow rate of elution is 5BV/h, the resin column is eluted by deionized water until the eluent is clear (about to 1/3 column volumes), 30% ethanol is replaced to continue elution for 8BV, all the eluent is collected, the eluent is decompressed and concentrated at 60 ℃, and drying is carried out, so that 11.2kg of the refined extract of the paederia scandens is obtained, the yield is 1.58%, the content of the paederia scandens acid is 31.19%, the content of the paederia scandens glycoside is 5.16% and the content of the methyl ester of the paederia scandens acid is 10.27% calculated by taking the paederia scandens acid.
Example 1:
201.96g of the Paederia scandens extract (liquid phase chromatogram is shown in figure 1) obtained in the above comparative example is taken, 2000ml of deionized water is added for dissolution, macroporous adsorption resin column chromatography (column volume 7000ml, diameter-height ratio 1: 10) is carried out, the sample loading flow rate is 1BV/h, and 5BV of deionized water, 5% ethanol, 10% ethanol, 15% ethanol, 20% ethanol, 25% ethanol and 30% ethanol are eluted in turn. Collecting 15% -20% ethanol elution part, concentrating under reduced pressure, and recovering solvent to dry. Dissolving the residue in deionized water, purifying with macroporous adsorbent resin column chromatography (column volume 3500ml, column diameter 10cm diameter/height ratio 1: 12), loading at flow rate of 1BV/h, sequentially eluting with deionized water, 10% ethanol, 15% ethanol, and 20% ethanol for 3 BV. Collecting 15% ethanol eluate, concentrating under reduced pressure, and recovering solvent to dry to obtain herba Paederiae refined extract-1. Extract-1 was extracted from fevervine scandens, purified by flash preparative apparatus (Biotage Isolera One, Biotage, sweden) and purified by flash column chromatography (sepaflame semi-chromatographic C18, 50um,
Figure BDA0002085734360000061
100g, Santai Technologies, Inc.), the elution solvent is methanol, water; the elution procedure was: 15% methanol 5BV → 15% -16% methanol 3BV → 16% -100% methanol 0.01BV → 100% methanol 5 BV; monitoring the wavelength at 230nm and the flow rate at 50ml/min, and collecting the part with higher absorption value intensity of the 15-16% methanol elution peak. ReducingRecovering solvent under pressure to dry, adding methanol for redissolving, filtering, collecting filtrate, and recovering solvent under reduced pressure to dry to obtain paederoside monomer compound. The detection spectrum is shown in figure 2, and the purity is 96.92 percent by an area normalization method.
Example 2:
201.96g of the Paederia scandens extract (liquid chromatogram is shown in figure 3) obtained in the above comparative example is taken, 2000ml of deionized water is added for dissolution, macroporous adsorption resin column chromatography (column volume 7000ml, diameter-height ratio 1: 10) is carried out, the sample loading flow rate is 1BV/h, and 5BV of deionized water, 5% ethanol, 10% ethanol, 15% ethanol, 20% ethanol, 25% ethanol and 30% ethanol are eluted in turn. Collecting 15% -20% ethanol elution part, concentrating under reduced pressure, and recovering solvent to dry. Dissolving the residue in deionized water, purifying with macroporous adsorbent resin column chromatography (column volume 3500ml, diameter/height ratio 1: 10) at flow rate of 1BV/h, and eluting with deionized water, 10% ethanol, 15% ethanol, and 20% ethanol for 3 BV. Collecting the 20% ethanol eluate, concentrating under reduced pressure, and recovering solvent to dry to obtain herba Paederiae refined extract-2. Collecting herba Paederiae refined extract-2, purifying with flash preparative instrument (Biotage Isolera One, Biotage Co., Ltd.) by flash chromatography column (Biotage SNAP card KP-C18-HS 30g, Biotage Technologies, Inc.), and eluting with acetonitrile and water; the elution procedure was: 8% acetonitrile 3BV → 8% -86% acetonitrile 5BV → 100% acetonitrile 3 BV; monitoring the wavelength of 230nm and the flow rate of 50ml/min, and collecting the part with higher absorption value intensity of 8-86% acetonitrile elution peak. Recovering solvent under reduced pressure to dry, adding methanol for redissolving, filtering, collecting filtrate, and recovering solvent under reduced pressure to dry to obtain paederoside monomer compound. The detection pattern is shown in FIG. 4, and the purity by the area normalization method is 93.68%.
Example 3: uric acid reduction experiment of paederia scandens monomer compound for treating rat acute hyperuricemia model caused by potassium oxonate
Instrument and material
1.1 test drugs
1.1.1 samples
Name/abbreviated number: paederoside monomeric compound obtained in example 1
The source is as follows: shanghai institute of pharmaceutical industry
Lot number and specification: 181110, respectively;
traits and storage conditions: white powder with purity more than 90 percent is stored in a sealed way at low temperature and in dark place;
the preparation method of the medicine comprises the following steps: diluting with normal saline;
designing the dose: the low dose is 20mg/kg, and the high dose is 40 mg/kg;
route of administration and volume: and (4) intragastric administration, and dosing according to the weight conversion.
1.1.2 Positive control
Name/abbreviated number: allopurinol tablets;
the source is as follows: shanghai Xin Wanxiang pharmaceutical Co., Ltd;
lot number and specification: (110802), 100 mg;
traits and storage conditions: tablets are dried and stored at room temperature;
designing the dose: 50 mg/kg;
route of administration and volume: and (4) intragastric administration, and dosing according to the weight conversion.
1.2 instruments and reagents
1.2.1 Experimental instruments
(1) Electronic analytical balance, model: sartorius ALC-210.3, manufacturer: siderelis corporation;
(2) high-speed centrifuge, model: 5810R, manufacturer: eppendorf (germany);
(3) full-automatic serum biochemical analyzer, model: 7080, manufacturer: calendar (japan);
(4) mouse scale, manufacturer: nanjing, Ma Neuli pharmaceutical instruments, Inc.;
1.2.2 Experimental reagents
A molding agent: potassium Oxonate (Adamas Reagent Co., Ltd.; LOT: P1275208);
solvent: physiological saline.
1.3 animals
1.3.1 animal sources
Strains and species: SD rat
Animal quality certification number: 2015000550327
Providing a unit: shanghai Si Laike laboratory animal responsibility Co., Ltd
Production license: SCXK (Shanghai) 2015-0005-
The unit of use: shanghai institute of pharmaceutical industry
The use license: SYXK 2014-40018
1.3.2 animal Specifications
SPF grade SD rats, 6-8 weeks old, 180-.
1.3.3 gender and number
And 36 males.
1.3.4 animal feeding
SPF-grade environmental animal laboratory, laboratory animals use license numbers: SYXK (Shanghai) 2014-0018. Animals were fed standard SPF-grade complete rat feed purchased from the experimental animal center of shanghai seliaceae, chinese academy. Drinking water for animals is supplied by drinking bottles, and the animals can drink water freely. 10-15 animals are raised in each cage, the room temperature of the animals is set to be 20-22 ℃, the humidity is set to be 40-70%, and the animals are alternately illuminated in light and shade for 12 hours. The padding is replaced at least 2 times per week, the feeding box is replaced at the same time, and the feeding box is replaced at any time when abnormal conditions occur. The sterilized drinking bottle and the bottle stopper are replaced every day, and the cage is sterilized for 1 time every two weeks. All the replaced and washed cages are sterilized by high pressure after being washed.
Second, Experimental methods
2.1 pharmaceutical formulation
(1) Test agent configuration: the monomeric compound of paederoside obtained in example 1 is dissolved in 0.9% physiological saline, prepared into suspensions with corresponding concentration according to different dosages, and stored in a refrigerator at 4 ℃ for later use.
(2) Potassium oxonate suspension: potassium oxonate powder is prepared into suspension by 0.9 percent of physiological saline according to the dosage of 300mg/kg, and the suspension is prepared on the day of the experiment.
(3) Allopurinol suspension: preparing into suspension according to the dose of 50mg/kg, and the preparation method is the same as that in (1).
2.2 Molding and grouping
2.2.1 animal groups
Animals were randomly assigned to 6 groups of 6 animals each after 1 week of acclimatization. The groups are normal control group, model group, positive medicine group, and high and low dosage groups of the tested medicine.
2.2.2 Molding and administration
After grouping, except for the normal group, the rats in other groups are subjected to intraperitoneal administration of potassium oxonate suspension (1 ml/mouse), and are subjected to intragastric administration after 1h interval, and the rats in the normal and model groups are subjected to isovolumetric administration of normal saline.
2.2.3 index detection
Collecting blood from rat fundus venous plexus 1h after administration, centrifuging the obtained whole blood at 12000rpm for 5min to separate serum, inspecting with a Niri serum biochemical detector, and detecting the change of Uric Acid (UA) content in serum.
Third, experimental results
The influence of the paederoside monomer compound obtained in the embodiment 1 on the SUA (acute hyperuricemia) caused by potassium oxonate
Figure BDA0002085734360000091
Figure BDA0002085734360000092
Comparison with the normal group:#P<0.05,##P<0.01,###p is less than 0.001; comparison with model groups:*P<0.05,**P<0.01
the results are shown in the table, the blood uric acid concentration of the rat in the model group is very different from that of the normal control group (P is less than 0.001), and the modeling is successful; the allopurinol which is a positive drug has extremely obvious inhibition effect (P is less than 0.001) on the increase of the SUA caused by the increase of the endogenous uric acid, and the paederoside monomer compound has obvious uric acid reduction effect (P is less than 0.01) on low and high dose groups of rats with acute hyperuricemia and shows a certain dose dependence relationship.
The influence of the paederoside monomer compound obtained in the embodiment 2 on the SUA (acute hyperuricemia) caused by potassium oxonate
Figure BDA0002085734360000101
Figure BDA0002085734360000102
Comparison with the normal group:#P<0.05,##P<0.01,###P<0.001; comparison with model groups: p<0.05,**P<0.01
The results are shown in the table, the blood uric acid concentration of the rats in the model group is very significantly different from that of the rats in the normal control group (P <0.001), and the modeling is successful; the positive allopurinol has extremely obvious inhibition effect (P is less than 0.001) on the increase of SUA caused by the increase of endogenous uric acid, and the paederoside monomer compound has obvious uric acid reduction effect (P is less than 0.05) on a 20mg/kg dose group of rats with acute hyperuricemia.

Claims (12)

1. A paederoside monomer compound, which is prepared by the following method:
a) extracting herba Paederiae with ethanol to obtain extractive solution;
b) concentrating the extracting solution until no alcohol smell exists, performing macroporous adsorption resin chromatography, sequentially eluting with water and 80-90% ethanol, collecting ethanol eluate, and drying under reduced pressure to obtain herba Paederiae extract;
c) loading the paederia scandens extract to macroporous adsorption resin chromatography, eluting with water and 5% -30% ethanol in sequence, collecting 15% -20% ethanol elution part, concentrating and drying to obtain refined paederia scandens extract; and
d) and (2) carrying out flash column chromatography on the paederia scandens refined extract, eluting by using methanol, water or acetonitrile, water as an elution solvent, collecting 15-16% of methanol elution part or 8-86% of acetonitrile elution part, and drying under reduced pressure to obtain the paederia scandens glycoside monomer compound.
2. The monomeric compound of paederoside according to claim 1, wherein in step b) the elution with water and 85% ethanol is performed sequentially, and the 85% ethanol eluate is collected.
3. The monomeric compound of paederoside according to claim 1, wherein in step c) the elution is sequentially with water, 5% ethanol, 10% ethanol, 15% ethanol, 20% ethanol, 25% ethanol and 30% ethanol.
4. The paederoside monomeric compound according to claim 1, wherein the elution procedure in step d) using methanolic water as the elution solvent is 15% methanol 5BV → 15% -16% methanol 3BV → 16% -100% methanol 0.01BV → 100% methanol 5 BV.
5. The paederoside monomer compound according to claim 1, wherein the elution procedure in step d) using acetonitrile to water as an elution solvent is 8% acetonitrile 3BV → 8% -86% acetonitrile 5BV → 100% acetonitrile 3 BV.
6. The paederoside monomeric compound according to claim 1, wherein the residue obtained in step d) is dried under reduced pressure, methanol is added into the residue for redissolving, filtering is carried out, a secondary filtrate is collected, and the filtrate is evaporated to dryness under reduced pressure to obtain the paederoside monomeric compound.
7. The monomeric compound of paederoside according to claim 6, wherein the concentration of methanol is greater than or equal to 95%.
8. The monomeric compound of paederoside according to claim 1, wherein the macroporous adsorbent resin in steps b) and c) is type D101.
9. A method for preparing a paederoside monomer compound comprises the following steps:
a) extracting herba Paederiae with ethanol to obtain extractive solution;
b) concentrating the extracting solution until no alcohol smell exists, performing macroporous adsorption resin chromatography, sequentially eluting with water and 80-90% ethanol, collecting eluent, and drying under reduced pressure to obtain a fevervine herb extract;
c) loading the paederia scandens extract to macroporous adsorption resin chromatography, eluting with water and 5% -30% ethanol in sequence, collecting 15% -20% ethanol elution part, concentrating and drying to obtain refined paederia scandens extract; and
d) and (2) carrying out flash column chromatography on the paederia scandens refined extract, eluting by using methanol, water or acetonitrile, water as an elution solvent, collecting 15-16% of methanol elution part or 8-86% of acetonitrile elution part, and drying under reduced pressure to obtain the paederia scandens glycoside monomer compound.
10. Use of the monomeric compound of paederoside according to claims 1-8 or obtained by the method according to claim 9 in the preparation of a medicament for reducing uric acid.
11. Use of the monomeric compound of paederoside according to any one of claims 1-8 or obtained by the method according to claim 9 in the preparation of a medicament for the treatment of gouty arthritis.
12. Use of the paederoside monomer compound of any one of claims 1-8 or obtained by the method of claim 9 in the preparation of a medicament for the treatment of hyperuricemia.
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Citations (7)

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