What Is Cilostazol?

The chemical name of cilostazol is 6- [4- (1-cyclohexyl-5-tetrazole) butoxy] -1,2,3,4-tetrahydro-2-oxoquinoline, white Or off-white crystalline powder; odorless. Easily soluble in glacial acetic acid or chloroform, soluble in dimethylformamide, slightly soluble in methanol or anhydrous ethanol, almost in water, 0.1mol / L hydrochloric acid solution or 0.1mol / L sodium hydroxide solution Insoluble. The molecular formula is C20H27N5O2, the molecular weight is 369.46100, the density is 1.34 g / cm3, the melting point is 159-160ºC, and the boiling point is 664.7ºC at 760 mmHg.

The chemical name of cilostazol is 6- [4- (1-cyclohexyl-5-tetrazole) butoxy] -1,2,3,4-tetrahydro-2-oxoquinoline, white Or off-white crystalline powder; odorless. Easily soluble in glacial acetic acid or chloroform, soluble in dimethylformamide, slightly soluble in methanol or anhydrous ethanol, almost in water, 0.1mol / L hydrochloric acid solution or 0.1mol / L sodium hydroxide solution Insoluble. The molecular formula is C20H27N5O2, the molecular weight is 369.46100, the density is 1.34 g / cm3, the melting point is 159-160ºC, and the boiling point is 664.7ºC at 760 mmHg.
Chinese name
Cilostazol
Foreign name
Cilostazol
CAS number
73963-72-1
Molecular formula
C20H27N5O2
Molecular weight
369.46100
Melting point
159-160

Introduction to cilostazol compounds

Cilostazol Basic Information

Chinese name: cilostazol
Chinese alias: triptolide; triptolide;
English name: cilostazol
English alias: PLETAAL; RETAL; PLETAL; Cilostal; CILOSTAZOLE;
CAS number: 73963-72-1
MDL number: MFCD00866780
RTECS number: VC8277500
PubChem number: 24278291
Molecular formula: C 20 H 27 N 5 O 2
Chemical structure:
Molecular weight: 369.46100
Exact mass: 369.21600
PSA: 81.93000
LogP: 3.60270 [1]

Physiochemical properties of cilostazol

Appearance and properties: off-white solid
Density: 1.34 g / cm 3
Melting point: 159-160ºC
Boiling point: 664.7ºC at 760 mmHg
Flash point: 355.8ºC
Refractive index: 1.675
Storage conditions: Store in original container in a cool dark place. [1]

Cilostazol Toxicology Data

Mouse and rat LD50 (mg / kg):> 2000,> 2000 intraperitoneally;> 5000,> 5000 by mouth. [2]

Cilostazol molecular structure data

1. Molar refractive index: 129.78
2. Molar volume (cm3 / mol): 345.7
3. Isotonic specific volume (90.2K): 968.8
4. Surface tension (dyne / cm): 61.6
5. Polarizability (10-24cm3): 51.45 [2]

Cilostazol Computational Chemical Data

1. Hydrophobic parameter calculation reference value (XlogP): 3.1
2.Number of hydrogen-bonded donors: 1
3.Number of hydrogen bond acceptors: 5
4.Number of rotatable chemical bonds: 7
5.Number of tautomers: 3
6. Topological molecular polar surface area 81.9
7.Number of heavy atoms: 27
8.Surface charge: 0
9.Complexity: 485
10.Number of isotope atoms: 0
11. Determine the number of atomic stereocenters: 0
12. Uncertain number of atomic stereocenters: 0
13. Determine the number of chemical bond stereocenters: 0
14. Uncertain number of chemical bond stereocenters: 0
15. Number of covalent bond units: 1 [2]

Cilostazol synthesis method

Under ice-cooling, in a benzene solution of 5-chloro-N-cyclohexylvaleramide, phosphorus pentachloride was slowly added, and a benzene solution of ammonia was added at room temperature with stirring. After stirring the reaction, it was treated to obtain 5- (4-chlorobutyl) -1-cyclohexyltetrazole. 6-Hydroxy-3,4-dihydro-2 (1H) quinolinone and potassium hydroxide were dissolved in isopropanol, and 5- (4-chlorobutyl) -1-cyclohexyl was added dropwise under reflux. A solution of tetrazole in isopropanol. Continue stirring at reflux, and the resulting material is cilostazol after treatment. [2]

Cilostazol uses

It has vasodilatory and anti-platelet functions. By inhibiting the activity of phosphodiesterase in platelets and vascular smooth muscle, it can increase the concentration of cAMP in platelets and smooth muscle, exert antiplatelet effect and vasodilator effect. Inhibits ADP, epinephrine, collagen, and arachidonic acid-induced platelet initial and secondary aggregation and release responses. It has obvious models for cerebral circulation and peripheral circulation disorders caused by collagen, ADP, arachidonic acid, and sodium laurate Antithrombotic effect. It can be used to treat chronic arterial occlusive disease caused by atherosclerosis, arteritis, thrombo-occlusive vasculitis, and diabetes. [2]

Cilostazol Pharmacopoeia Standard

Source (name), content (potency) of cilostazol

This product is 6- [4- (1-cyclohexyl-5-tetrazole) butoxy] -1,2,3,4-tetrahydro-2-oxoquinoline. Calculated on dry basis, containing C20H27N5O2 should be 98.0% to 102.0%. [3]

Cilostazol traits

White or off-white crystalline powder; odorless.
Easily soluble in glacial acetic acid or chloroform, soluble in dimethylformamide, slightly soluble in methanol or anhydrous ethanol, almost in water, 0.1mol / L hydrochloric acid solution or 0.1mol / L sodium hydroxide solution Insoluble.
The melting point is 157 to 161 ° C. [3]

Cilostazol identification

(1) In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.
(2) The infrared absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Drugs", Figure 754).

Cilostazol check

relative substance
Take an appropriate amount of this product, add methanol-water (70:30) to dissolve and dilute it to make a solution containing about 0.25mg of cilostazol per 1ml as the test solution; take 1ml precisely and place it in a 100ml measuring bottle , Dilute to the mark with methanol-water (70:30), shake well, and use it as a control solution. According to the method under content determination, take 20l of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 10% of the full range, and then accurately measure each of the test solution and the control solution. 20l, respectively injected into the liquid chromatograph, record the chromatogram to 3 times the peak retention time of the main component. If there is an impurity peak in the chromatogram of the test solution, the sum of the area of each impurity peak must not be greater than the main peak area of the control solution (1.0%).
Residual solvents: toluene, dichloromethane, acetone and ethanol
Take an appropriate amount of this product, accurately weigh it, add dimethylformamide to dissolve and quantitatively dilute it to make a solution containing about 75mg per 1ml as the test solution; separately take appropriate amounts of toluene, dichloromethane, acetone and ethanol. , Weigh accurately, add dimethylformamide to quantitatively dilute to make a mixed solution containing about 66.8g, 45g, 375g and 375g per 1ml, as a reference solution. Precisely measure 4ml each of the reference solution and the test solution, and place them in 20ml headspace bottles. Then add 6.0ml of water, shake well, seal immediately, and test according to the residual solvent measurement method. A quartz capillary column with 5% phenyl-95% methyl polysiloxane (or similar polarity) as the fixed liquid is used as the chromatographic column; the initial temperature is 35 ° C, it is maintained for 7 minutes, and the temperature is increased at a rate of 25 ° C per minute Hold at 220 ° C for 5 minutes; inlet temperature is 130 ° C; detector temperature is 250 ° C; headspace bottle equilibrium temperature is 80 ° C and equilibration time is 60 minutes. Take the reference solution headspace sample, the resolution between the peaks of each component should meet the requirements; the number of theoretical plates calculated from the ethanol peak is not less than 7000. Take the test solution and the reference solution solution for headspace injection, record the chromatogram, and calculate the peak area according to the external standard method, which should meet the requirements.
chloride
Take 0.50g of this product, add 50ml of water, heat in a water bath for 10 minutes, shake from time to time, let it cool, filter, and take 25ml of the filtrate, check it according to law, and compare it with a control solution made of 7.0ml of standard sodium chloride solution. Must not be thicker (0.028%).
Loss on drying
Take this product and dry it at 105 to constant weight, and the weight loss shall not exceed 0.5%.
Residue on ignition
Take 1.0g of this product and inspect it according to law. The residual residue should not exceed 0.1%.
Heavy metal
Take the residue left under the item of burning residue and inspect it according to law. The content of heavy metals must not exceed 20 parts per million.

Determination of cilostazol

As determined by high performance liquid chromatography.
Chromatographic conditions and system suitability tests
Octadecylsilane-bonded silica gel was used as the filler; water was used as the mobile phase A and methanol was used as the mobile phase B. The gradient elution was performed according to the following table; the detection wavelength was 257 nm. The number of theoretical plates is not less than 5000 based on the cilostazol peak.
Time (minutes)
Mobile phase A (%)
Mobile phase B (%)
0
0
70
8
30
70
18
10
90
twenty one
10
90
Assay
Take about 20mg of this product, weigh it accurately, place it in a 200ml measuring bottle, add an appropriate amount of methanol water (70:30), dissolve it with ultrasound, and dilute to the mark with methanol-water (70:30), shake well, and accurately measure 20l Inject the liquid chromatograph and record the chromatogram; take another cilostazol reference substance and measure it in the same way. Calculate the peak area according to the external standard method. [3]

Overview of basic information about cilostazol

Cilostazol drug name:

[General name] cilostazol tablets
[English name] Cilostazol Tablets
[Chinese Pinyin] Xi Luo Ta Zuo Pian [4]

Cilostazol warning:

Angina pectoris may occur as a result of taking this medicine, which may increase the heart rhythm. Pay special attention to the observation and consultation of angina pectoris symptoms (chest pain). In a trial of prepaid recurrence after cerebral infarction completed in Japan, some patients experienced a significant increase in long-term blood pressure and arrhythmia (pressure rate product), and the incidence of angina pectoris in the test group was 1.16% (6/516), compared with the comfort group Nothing happened (0/518).

Cilostazol Ingredients:

The main ingredient of this product is cilostazol. Its chemical name is 6- [4- (1-cyclohexyl-1H-pentatetrazole (5 ') butoxy) 3,4-dihydro-1H-quinolone. (2')
Molecular formula: C20H27N5O2
Molecular weight: 369.46

Cilostazol belongs to the category:

Chemicals & Biological Products >> Blood System Drugs >> Antiplatelet Drugs >> Platelet Aggregation Inhibitors

Cilostazol indications:

  1. Improve ischemic symptoms such as ulcers, limb pain, cold sensation, and intermittent claudication caused by chronic arterial occlusive disease.
  2. Prevent recurrence of cerebral infarction (except cardiac infarction).

Cilostazol Usage and Dosage:

Normally, adults take 0.1 g (2 tablets) of cilostazol orally twice a day. In addition, it can be appropriately increased or decreased according to age and symptoms. [4]

Cilostazol adverse reactions:

1. Serious adverse reaction
(1) Sometimes congestive heart failure, myocardial infarction, angina pectoris, and ventricular tachycardia occur, and the incidence is unknown. When abnormalities are found, dosing should be stopped and treated appropriately.
(2) Bleeding: There may be intracranial hemorrhage such as cerebral hemorrhage (initial symptoms: headache, nausea, vomiting, disturbance of consciousness, and hemiplegia). The incidence is unknown. With these symptoms, dosing should be stopped and appropriately treated.
Pulmonary hemorrhage (incidence rate unknown), gastrointestinal bleeding, nosebleed, fundus bleeding (less than 0.1%), etc. may occur. With these symptoms, dosing should be stopped and appropriately treated.
(3) There is a possibility of pancytopenia, agranulocytosis (incidence rate unknown), and thrombocytopenia (less than 0.1%). Full attention should be paid to observations. When abnormalities are found, dosing should be stopped and treated appropriately.
(4) Interstitial pneumonia (incidence rate is unknown): Interstitial pneumonia accompanied by fever, cough, dyspnea, abnormal chest X-rays, and increased eosinophilia sometimes occur. If you have any of the above symptoms, you should stop administration and perform appropriate treatment such as adrenocortical hormone administration.
(5) Liver dysfunction (less than 0.1 to 5%), jaundice (incidence rate is unknown): due to the occurrence of elevated AST (GOT), ALT (GPT), Al-P, LDH, etc., and jaundice, etc., full attention should be paid to observation , When abnormalities are found, dosing should be stopped and treated appropriately.
2. General adverse reactions

Note 1) Dosing should be stopped at this time. Note 2) Appropriate treatment such as reduction or suspension should be given at this time.

Cilostazol Contraindications:

  1. Patients with bleeding (hemophilia, capillary fragility, intracranial bleeding, gastrointestinal bleeding, urinary tract bleeding, hemoptysis, vitreous hemorrhage, etc.) (may increase bleeding);
  2. Patients with congestive heart failure (may exacerbate symptoms) [This product is a drug with PDE3 inhibitory effect. It has been reported abroad that drugs that have PDE3 inhibitory effects (milinone, vesilinone) have a survival rate in placebo-controlled long-term comparative trials of patients with congestive heart failure (NYHA class III to IV). Lower than placebo. In addition, the prognosis when long-term administration of PDE3 inhibitors including this product to patients without congestive heart failure is unclear];
  3. Patients with a history of allergies to the ingredients of this product;
  4. Women who are pregnant or likely to become pregnant. [4]

Cilostazol Notes:

1. Cautious administration (the following patients are carefully administered)
(1) Patients during menstrual period (may increase bleeding);
(2) Patients with bleeding tendency (may increase bleeding);
(3) Anticoagulants (warfarin) or antiplatelet drugs (aspirin, ticlopidine, etc.), thrombolytic drugs (urokinase, alteplase), prostaglandin E1 preparations and derivatives (top Dil, Limatoprost acyclodextrin) (used with sufficient attention to coagulation);
(4) Patients with coronary stenosis (the increase in heart rate caused by the administration of this drug may induce angina);
(5) Patients with diabetes or impaired glucose tolerance (adverse bleeding reactions may occur);
(6) Patients with severe liver dysfunction (blood concentration of cilostazol may increase) and patients with severe renal dysfunction (blood concentration of cilostazol metabolites may increase);
(7) Hypertension patients with persistently elevated blood pressure (malignant hypertension, etc.).
2. Important note
(1) Patients with cerebral infarction should start administration after the symptoms of cerebral infarction are stable.
(2) In patients with coronary artery stenosis, when excessive heart rate increases during the administration of this product, there may be the possibility of inducing angina pectoris. At this time, appropriate measures such as reduction or termination of administration should be taken.
(3) For patients with cerebral infarction, pay attention to the interaction with other drugs that inhibit platelet aggregation, and give caution to patients with persistent hypertension, and fully control blood pressure during the administration.
3 Other considerations
(1) In SHR-SP rats (spontaneously hypertensive stroke rats) with inherited and persistently high blood pressure and stroke, compared with the control group, cilostazol was administered with 0.3% mixed bait The survival time was shortened in the group (mean life expectancy: 40.2 weeks in the cilostazol group and 43.5 weeks in the placebo group).
(2) According to foreign reports, when cilostazol 0.1g was co-administered with HMG-CoA reductase inhibitor lovastatin 80mg, compared with lovastatin alone, the AUC of lovastatin increased by 64%.

Cilostazol for pregnant and lactating women:

  1. Do not take medicine for pregnant women and women who may become pregnant (animal (rat) trials have reported abnormal fetal gain, low birth weight, and increased mortality);
  2. Breastfeeding women should avoid breastfeeding when taking medication (animal (rat) trials have reported milk penetration).

Cilostazol for children:

The safety of low birth weight infants, newborns, infants, young children, and children has not been established (less experience in use).

Cilostazol for the elderly:

In general, elderly patients have low physiological functions, so attention should be paid to reductions.

Cilostazol drug interactions:

Cilostazol is mainly metabolized by the liver metabolic enzyme CYP3A4, and part of it is metabolized by CYP2D6 and CYP2C19. Pay attention.

Cilostazol overdose:

Information on overdose of this product is limited. The acute symptoms of overdose are manifested as excessive pharmacological effects, including severe headache, diarrhea, hypotension, tachycardia, and possibly arrhythmia. Patients should be observed and given adjuvant treatment. Due to the high binding rate of cilostazol to protein, it is not easy to be effectively removed during hemodialysis and peritoneal dialysis. The LD50 of oral cilostazol was> 5.0g / kg in mice and rats, and> 2.0g / kg in dogs. [4]

Cilostazol pharmacology and toxicology:

I. Pharmacological effects
1. Antiplatelet effect
(1) In Vitro
For human platelets, platelet aggregation caused by ADP, collagen, arachidonic acid, epinephrine, and thrombin can be inhibited. In addition, it can inhibit platelet aggregation induced by shear stress.
For human platelets, it can inhibit the primary aggregation of platelets caused by ADP and epinephrine, as well as dissociate platelet aggregates caused by inducing factors.
· Inhibit the production of thromboxane A2 in human platelets.
· Inhibition of blood coagulation promoting activity in human platelets.
(2) In Vivo
· Beagle dogs and pigs are administered orally to suppress platelet aggregation caused by ADP and collagen.
· Continuous oral administration of rats does not reduce the inhibitory effect on ADP-induced platelet aggregation.
· Chronic arterial occlusive patients and patients with cerebral infarction can inhibit platelet aggregation caused by ADP, collagen, arachidonic acid, epinephrine, etc. after oral administration.
· Inhibition of platelet aggregation occurs quickly after administration in human body, and the effect can be maintained without diminishing after continuous administration.
· After stopping the product, the inhibited platelet aggregation can be restored to the pre-dose value with the decrease of the blood concentration of the product, and no rebound phenomenon (hyperaggregation) is found.
2. Antithrombotic effect
· Suppresses the death caused by pulmonary embolism induced by injection of ADP and collagen into mice.
· Suppresses the progression of thrombotic hind limb dysfunction induced by the injection of sodium laurate into the femoral artery of dogs.
· Suppresses local thromboembolism induced by replacement of femoral arteries in dogs with artificial blood vessels.
· It can inhibit the thrombosis induced by electrical stimulation of porcine carotid artery.
· It can reduce the cerebral infarction area caused by arachidonic acid injection in rabbit internal carotid artery.
Can reduce the number of attacks in patients with transient ischemic attack.
3 Vasodilation
Can relax KCl, prostaglandin F2 induced contraction of isolated femoral artery, middle cerebral artery and basilar artery in dogs.
Increase blood flow to the femoral, vertebral, common carotid, and internal carotid arteries of anesthetized dogs.
Increase blood flow to the cerebral cortex of anesthetized dogs and cats.
Increase blood flow to the cerebral cortex or lower thalamus in unanesthetized rats.
· In patients with chronic arterial occlusive disease, an increase in blood flow to the ankle and calf tissue can be observed by plethysmography. Furthermore, the thermal imaging method can be observed to increase the skin temperature of the extremities and increase the skin blood flow.
· Xenon inhalation method was found to increase cerebral blood flow in patients with ischemic cerebrovascular disorder.
4. Effect on vascular cells
-Inhibition of 3H-thymidine in human cultured vascular smooth muscle.
· Inhibition of lactate dehydrogenase leakage caused by stimulating human endothelial cells with homocysteine or lipopolysaccharide.
5. Mechanism
· This product can inhibit the release of serotonin in rabbit platelets, but does not affect the uptake of serotonin and adenosine by platelets. In addition, it can also inhibit platelet aggregation caused by thromboxane A2.
· This product exerts anti-platelet and vasodilation effects by selectively inhibiting the activity of phosphodiesterase III (PDE3, cGMP-inhibited phosphodiesterase) in platelets and vascular smooth muscle.
· In the presence of cultured human vascular endothelial cells or prostaglandin E1, this product enhances the inhibition of platelet aggregation in human platelets.
In the presence of prostacyclin or adenosine, this product enhances the inhibition of platelet aggregation in canine platelets.
2. Toxicology research
1. Acute toxicity
The LD50 value of cilostazol in mice and rats was greater than 5g / kg, and the LD50 value of cilostazol in dogs was greater than 2g / kg.
2. Subacute and chronic toxicity
Canine subacute toxicity test (oral 13 weeks) and chronic toxicity test (oral 52 weeks), using high doses can detect left ventricular endocardial hypertrophy and coronary artery disease, the safe doses are 30mg / kg / day and 12mg / kg / day. No cardiac changes were found in rats and monkeys. In a 1-week intravenous cardiotoxicity test, changes were found in the left ventricle endocardium, right atrium epicardium, and coronary arteries in dogs, while mild left ventricular hemorrhage changes were found in monkeys. Among other PDE inhibitors and vasodilators, it is also found to be cardiotoxic to animals. It is particularly reported that dogs are an animal that is prone to cardiotoxicity.
3 Reproductive toxicity test
Administration tests in rats during pregnancy and early pregnancy have no effect on mating and conception. The administration tests in rats during the organogenesis period slightly increased the number of abnormal fetuses at a dose of 1 g / kg / day. No effect was observed in rabbits. In the perinatal and lactation administration tests, rats at low doses above 0.15g / kg / day showed low birth weight and increased mortality, but they developed well after childbirth.
4 Antigenicity
No antigenicity was seen.
5. Mutagenicity
Tests using bacteria and mouse bone marrow cells did not reveal mutagenicity.
6. Carcinogenicity
Carcinogenicity was not found in mice and rats.
Third, general pharmacology
Except for circulatory system effects such as relaxation of vascular smooth muscle, increase of heart rate, and enhancement of myocardial contractility, there are almost no other effects.

Cilostazol pharmacokinetics:

1. Blood concentration
When a healthy adult man was orally administered 0.1 g once on an empty stomach, the blood concentration increased rapidly, and the highest concentration was 763.9 ng / mL 3 hours after the administration. In addition, the half-life of plasma concentration was in a two-compartment model, with an alpha phase of 2.2 hours and a beta phase of 18.0 hours. In addition, active metabolites such as OPC-13015 produced by dehydration of cilostazol and OPC-13213 produced by hydroxylation can be detected in plasma.
Cmax and AUCinf administered to a healthy adult man on an empty stomach and after a single oral administration of 50 mg cilostazol were 2.3 times and 1.4 times that of fasting.
2. Metabolic enzymes
Cilostazol is mainly metabolized by the cytochrome P450 isoenzyme CYP3A4 in liver microsomes, followed by CYP2D6 and CYP2C19 (in vitro).
3 Protein binding rate
Cilostazol: 95% or more (in vitro, equilibrium dialysis, 0.1 to 6 g / mL)
Active metabolite OPC-13015: 97.4% (in vitro, ultrafiltration, 1 g / mL)
Active metabolite OPC-13213: 53.7% (in vitro, ultrafiltration, 1 g / mL)
4. Metabolism in the body in patients with renal dysfunction
For patients with severe renal dysfunction, when cilostazol was administered orally at 0.1 g for 8 days, the Cmax and AUC of cilostazol were reduced by 29% and 39%, respectively, compared with healthy adults, and the active metabolite OPC- The Cmax and AUC of 13213 increased by 173% and 209%, respectively. No differences were found in mild and moderate patients.
5. In vivo metabolism in patients with liver dysfunction
When a single oral cilostazol dose of 0.1 g was given to patients with mild and moderate liver dysfunction, no difference was found in blood concentration compared with healthy adults. (Cmax of cilostazol decreased by 7% and AUC increased by 8%.)
6. distributed
When 14C-cilostazol was orally administered to male rats, the highest organs distributed within 1 hour after administration were the stomach, and the distribution in the liver and kidney was higher than the blood concentration, and the distribution in the central nervous system was extremely low.
7. excretion
When 14C-cilostazol was orally administered to male rats, the excretion rate up to 72 hours after administration was 42.7% in urine and 61.7% in feces.
8. Through the placenta and into the milk
Tests were performed in rats and found to enter the placenta and milk. [4]

Cilostazol Expert Reviews

The antiplatelet aggregation effect of this product is formed by aspirin, but it is expensive and has many adverse reactions. It is therefore unwise to completely replace aspirin with this product. This product can increase blood flow to the limbs, improve peripheral blood circulation, and inhibit thrombosis. This product is a quinoline derivative, which is a new drug for the treatment of intermittent intermittent claudication. It treats stable intermittent claudication by inhibiting cell phosphodiesterase (especially the inhibition of PDEIII). Cilostazol and its metabolites are cAMP-PDE III inhibitors. Inhibition of phosphodiesterase activity and cAMP degradation (and conversion) cause cAMP to rise in platelets and blood vessels, inhibit platelet aggregation and dilate blood vessels, prevent thrombosis and vascular obstruction, thereby effectively treating and alleviating "walk-pain- Rest-Relief "repetitive symptoms. [5]

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