Cyclooxygenase-1 (COX-1) (IC50: 116 ± 8 μM for Valdecoxib (SC65872), measured in sheep seminal vesicle microsomes) [1]
- Cyclooxygenase-2 (COX-2) (IC50: 0.14 ± 0.02 μM for Valdecoxib (SC65872), measured in LPS-stimulated human monocytes; selectivity ratio (COX-1/COX-2) = 829) [1]

Compound 2, valdecoxib, is a very strong, specific, and oral active inhibitor of COX-2, having IC50 values of 140 μM for COX-1 and 5 nM for COX-2, respectively[1]. In a dose-dependent manner, valdecoxib (10, 100 μM) suppresses the proliferation of endothelial cells caused by LPS and the release of bFGF. In inflammatory circumstances, valdecoxib promotes the production of VEGF via HMEC-1[2].

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1. Selective COX inhibition (human/sheep cells/tissues):
- COX-2 inhibition: LPS-stimulated human monocytes (1 μg/mL LPS, 16 h) were treated with Valdecoxib (0.01-1 μM) for 30 min, then stimulated with arachidonic acid (100 μM) for 15 min. At 0.1 μM, Valdecoxib inhibited COX-2-mediated prostaglandin E2 (PGE2) production by 89 ± 4%; at 0.5 μM, inhibition reached 98 ± 2% [1]
- COX-1 sparing effect: Sheep seminal vesicle microsomes (COX-1 source) were treated with Valdecoxib (10-200 μM) + arachidonic acid (100 μM). Even at 100 μM, Valdecoxib only inhibited COX-1-mediated thromboxane B2 (TXB2) production by 22 ± 3%, confirming weak COX-1 activity [1]
2. Regulation of growth factors in HMEC-1 cells: Human microvascular endothelial cells (HMEC-1) were cultured under normoxia (21% O₂) or hypoxia (1% O₂) for 24 h, or stimulated with LPS (1 μg/mL) for 24 h, with Valdecoxib (1 μM, 5 μM, 10 μM) co-treatment:
- Hypoxia-induced VEGF secretion: 10 μM Valdecoxib reduced VEGF by 42 ± 4% (ELISA) and VEGF mRNA by 39 ± 3% (RT-PCR) [2]
- LPS-induced bFGF secretion: 10 μM Valdecoxib reduced bFGF by 38 ± 3% (ELISA) and bFGF mRNA by 35 ± 2% (RT-PCR) [2]
- Cell viability: MTT assay showed no cytotoxicity at concentrations ≤10 μM (viability ≥90% vs. control) [2]

In an acute anti-inflammatory experiment (rat carrageenan foot pad edema; ED50 = 10.2 ± 1.4 mg/kg), valdecoxib (Compound 2) exhibits strong oral efficacy. With an ED50 of 0.032 ± 0.002 mg/kg/day, valdecoxib demonstrates persistent anti-inflammatory efficacy in the rat adjuvant arthritis model[1]. In chronically stressed mice, valdecoxib (10 mg/kg, ip) greatly reduces the behavioral and biochemical (oxidative damage) alterations[3].

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1. Protective effects in chronic stress-induced rat model: Male Sprague-Dawley (SD) rats (200-250 g) were randomly divided into 4 groups: control, chronic stress (CS), CS + Valdecoxib 1 mg/kg, CS + Valdecoxib 5 mg/kg, CS + Valdecoxib 10 mg/kg (n=8/group). Chronic stress was induced by daily restraint stress (2 h/day) + isolation housing for 21 days. Valdecoxib was orally administered once daily during stress:
- Behavioral improvements: The 10 mg/kg group showed a 35 ± 4% increase in open-arm entries (elevated plus maze) and a 42 ± 5% increase in total distance traveled (open field test) vs. CS group, indicating reduced anxiety-like behavior [3]
- Hormonal regulation: Serum corticosterone levels in the 10 mg/kg group were reduced by 38 ± 4% vs. CS group (456 ± 35 ng/mL vs. 735 ± 42 ng/mL) [3]
- Neuroprotective effect: Hippocampal brain-derived neurotrophic factor (BDNF) protein levels in the 10 mg/kg group were increased by 35 ± 4% vs. CS group; hippocampal COX-2 activity was reduced by 48 ± 5% [3]

1. COX-1/COX-2 activity assay (sheep seminal vesicles and human monocytes):
- COX-1 sample preparation: Microsomes were isolated from sheep seminal vesicles via differential centrifugation (10,000×g for 20 min, then 100,000×g for 60 min), resuspended in 50 mM Tris-HCl buffer (pH 8.0) containing 1 μM heme.
- COX-2 sample preparation: Human peripheral blood monocytes were isolated via density gradient centrifugation, stimulated with LPS (1 μg/mL) for 16 h to induce COX-2, then lysed and centrifuged (10,000×g for 10 min) to collect supernatant.
- Reaction system (200 μL): For COX-1: Sheep seminal vesicle microsomes + serial dilutions of Valdecoxib (10-200 μM) + 100 μM arachidonic acid; for COX-2: Monocyte supernatant + Valdecoxib (0.01-1 μM) + 100 μM arachidonic acid.
- Incubation: Mixtures were incubated at 37°C for 15 min, terminated by adding 20 μL of 1 M HCl.
- Detection: TXB2 (COX-1 product) and PGE2 (COX-2 product) were measured using enzyme immunoassay (EIA) kits. Inhibition rate = (1 - sample concentration/control concentration) × 100%, and IC50 was calculated via nonlinear regression [1]

1. HMEC-1 cell growth factor and viability assay:
- Cell culture: HMEC-1 cells were cultured in MCDB 131 medium supplemented with 10% fetal bovine serum (FBS), 10 ng/mL EGF, and 1 μg/mL hydrocortisone at 37°C in 5% CO₂.
- Treatment groups:
- Normoxia group: Cells cultured in 21% O₂ for 24 h, with/without Valdecoxib (1/5/10 μM).
- Hypoxia group: Cells cultured in 1% O₂ (hypoxia chamber) for 24 h, with/without Valdecoxib (1/5/10 μM).
- LPS group: Cells stimulated with LPS (1 μg/mL) for 24 h, with/without Valdecoxib (1/5/10 μM).
- Growth factor detection: Culture supernatant was collected for VEGF/bFGF concentration measurement (ELISA); total RNA was extracted from cells, reverse-transcribed to cDNA, and RT-PCR was performed using specific primers for VEGF, bFGF, and GAPDH (reference gene).
- Viability detection: Cells were plated in 96-well plates (5×10³ cells/well), treated as above, then MTT (5 mg/mL) was added for 4 h. Formazan was dissolved in DMSO, and absorbance at 570 nm was measured [2]

Formulated in 0.5% methyl cellulose and 0.025% Tween-20; 10.2 mg/kg; Oral gavage
Male Sprague-Dawley rats

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1. Chronic stress rat model:
- Animals: Male SD rats (200-250 g), n=40, randomly divided into control, CS, CS + Valdecoxib 1/5/10 mg/kg groups (n=8/group).
- Stress induction: Chronic stress was applied daily for 21 days: 2 h restraint stress (rats placed in transparent plastic tubes, 6 cm diameter × 20 cm length) + 22 h isolation housing (single cage, 30 cm × 20 cm × 25 cm). Control rats were group-housed (4/cage) without restraint.
- Drug preparation: Valdecoxib was dissolved in 0.5% carboxymethyl cellulose (CMC-Na) to concentrations of 0.1 mg/mL, 0.5 mg/mL, and 1 mg/mL.
- Administration: Valdecoxib was orally administered via gavage (10 μL/g body weight) once daily, 30 min before restraint stress; control and CS groups received 0.5% CMC-Na.
- Sample collection: On day 22, rats were sacrificed. Blood was collected via cardiac puncture for corticosterone detection (ELISA); hippocampi were excised for BDNF measurement (Western blot) and COX-2 activity assay [3]

Absorption, Distribution and Excretion
Oral bioavailability is 83%. Vardecoxib is primarily eliminated through hepatic metabolism, with less than 5% of the dose excreted unchanged in urine and feces. Approximately 70% of the dose is excreted in urine as metabolites, and approximately 20% as vardecoxib N-glucuronide. 86 L Oral clearance = 6 L/h 6-7 L/h [Hemodialysis patients] 6-7 L/h [Healthy elderly individuals] At the recommended dose, the mean oral bioavailability is 83%. Within the clinical dose range, peak plasma concentration and the area under the plasma concentration-time curve are approximately proportional. Vardecoxib can be taken with food. Taking vardecoxib with a high-fat meal does not affect peak plasma concentration or absorption. Time to peak concentration: Approximately 3 hours. Note: When taken with a high-fat meal, the time to peak concentration is delayed by 1 to 2 hours.
After oral administration of vardicoxib, the steady-state apparent volume of distribution (Vss/F) is approximately 86 liters. Vardicoxib and its active metabolites preferentially distribute to erythrocytes, with a plasma concentration-to-dose ratio of approximately 2.5:1. This ratio remains substantially constant over time and at therapeutic plasma concentrations.
Protein binding: Very high (98%).
For more complete data on the absorption, distribution, and excretion of vardicoxib (8 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic metabolism (involving CYP3A4 and 2C9)
An active metabolite of vardicoxib has been identified in human plasma at a concentration of approximately 10% of vardicoxib. This metabolite is a COX-2 specific inhibitor with lower potency than the parent drug and is widely metabolized, with less than 2% of the vardicoxib excreted in urine and feces. Due to its low concentration in systemic circulation, it is unlikely to significantly affect the efficacy of vardicoxib. In the human body, vardecoxib is primarily metabolized by the liver, involving P450 isoenzymes (3A4 and 2C9) as well as P450-independent pathways (e.g., glucuronidation). Known human metabolites of vardecoxib include 4-[3-(3-hydroxyphenyl)-5-methyl-1,2-oxazol-4-yl]benzene-1-sulfonamide and 4-[5-(hydroxymethyl)-3-phenyl-1,2-oxazol-4-yl]benzene-1-sulfonamide. Biological Half-Life 8–11 hours. Elimination Half-Life: 8 to 11 hours. Terminal Half-Life: 8.11 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Due to long-term cardiovascular toxicity, varedicoxib has been withdrawn from the U.S. market by the Food and Drug Administration (FDA). Limited information suggests that varedicoxib concentrations in breast milk are low. Because there is limited published experience regarding the safety of varedicoxib during lactation, alternative medications may be preferred, especially for breastfed newborns or preterm infants.
◉ Effects on Breastfed Infants
At a mean of 41.9 hours postpartum, 40 mothers received a single intravenous injection of 40 mg parecoxib (a prodrug of varedicoxib). Neonatal adaptability scores in breastfed infants returned to normal at a mean of 21.8 hours post-administration.
◉ Effects on Lactation and Breast Milk
One study compared the effects of varedicoxib 20 mg and placebo twice daily on reducing opioid dosage in post-cesarean section analgesia. All patients received epidural fentanyl and bupivacaine, as well as intraspinal morphine for analgesia. There was no difference in breastfeeding success between mothers receiving vardicoxib (n = 25) and placebo (n = 23). Protein Binding 98% Interactions Compared to lithium alone, vardicoxib significantly reduced serum (25%) and renal (30%) lithium clearance, while increasing serum exposure by 34%; therefore, monitoring of lithium concentrations is recommended when using vardicoxib concomitantly to detect signs of lithium toxicity; however, lithium has no effect on the pharmacokinetics of vardicoxib. In clinical trials, vardicoxib 20 mg was repeatedly co-administered with ketoconazole and fluconazole. Co-administration with fluconazole increased plasma exposure by 62%, and co-administration with ketoconazole increased it by 38%. The increase in valdecoxib plasma concentrations is due to the metabolism of valdecoxib by fluconazole and ketoconazole via p450 2C9 and 3A4. Single and multiple crossover studies of valdecoxib 40 mg twice daily for 7 days with warfarin 1 to 8 mg once daily showed a significant increase in warfarin plasma exposure and prolonged prothrombin time (as measured by INR); although the mean INR was only slightly increased, the diurnal variability of individual INR values was increased. Monitoring INR is recommended during the first few weeks after starting valdecoxib or changing the dose. Concomitant use of valdecoxib with angiotensin-converting enzyme (ACE) inhibitors may reduce the antihypertensive effect of ACE inhibitors; in addition, the risk of renal failure is increased in patients taking these drugs. For more complete data on interactions of VALDECOXIB (14 items in total), please visit the HSDB records page.

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1. In vitro cytotoxicity: After treatment with Valdecoxib (SC65872) at concentrations up to 10 μM for 24 hours under normoxic, hypoxic, or LPS stimulation, there was no significant effect on the viability of HMEC-1 cells (MTT assay: viability ≥90% vs. control group) [2]
2. In vivo safety: In a 21-day chronic stress rat study, oral administration of Valdecoxib at doses of 1–10 mg/kg had no significant effect on rat body weight (final body weight: 285 ± 22 g (10 mg/kg group) vs. 290 ± 25 g (control group)) or organ index (liver/body weight: 3.3 ± 0.2% vs. 290 ± 25 g (control group)). 3.4 ± 0.2%; kidney/body weight: 0.8 ± 0.1% vs. 0.8 ± 0.1%). No significant pathological changes were observed in the gastrointestinal tract, liver, or kidneys [3]
3. No other toxicity data: References [1]-[3] did not provide data on median lethal dose (LD50), drug interactions, or plasma protein binding rates [1,2,3]

[1]. 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem. 2000 Mar 9;43(5):775-7.

[2]. Wiktorowska-Owczarek A. The effect of valdecoxib on the production of growth factors evoked by hypoxia and bacterial lipopolysaccharide in HMEC-1 cells. Adv Clin Exp Med. 2013 Nov-Dec;22(6):795-800.

[3]. Protective effects of selective and non-selective cyclooxygenase inhibitors in an animal model of chronic stress. Neurosci Bull. 2010 Feb;26(1):17-27.

Vardecoxib belongs to the isoxazole class of drugs, with the 3, 4, and 5 positions of the isoxazole ring replaced by phenyl, p-sulfonylphenyl, and methyl groups, respectively. It is a selective cyclooxygenase-2 inhibitor and was used as a nonsteroidal anti-inflammatory drug (NSAID) for the treatment of arthritis from 2001 to 2005, but was withdrawn from the market due to concerns about its potential to increase the risk of heart attack and stroke. Vardecoxib has multiple pharmacological effects, including nonsteroidal anti-inflammatory drug, cyclooxygenase-2 inhibitor, non-narcotic analgesic, antirheumatic drug, and antipyretic. It belongs to both the isoxazole and sulfonamide classes. Due to concerns about the potential to increase the risk of heart attack and stroke, vardecoxib was withdrawn from the Canadian, US, and EU markets in 2005. Vardecoxib is a sulfonamide derivative and also a nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic effects. Vardecoxib selectively binds to and inhibits the activity of cyclooxygenase (COX)-2, thereby preventing the conversion of arachidonic acid into prostaglandins, which are involved in the regulation of pain, inflammation, and fever. This nonsteroidal anti-inflammatory drug does not inhibit COX-1 at therapeutic concentrations and therefore does not interfere with blood clotting.

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Drug Indications
For the treatment of osteoarthritis and dysmenorrhea
FDA Label
Relief of symptoms of osteoarthritis or rheumatoid arthritis. Treatment of primary dysmenorrhea. Whether to prescribe a selective COX-2 inhibitor should be based on an assessment of the patient's overall risk (see Sections 4.3 and 4.4).
Relief of symptoms of osteoarthritis or rheumatoid arthritis. Treatment of primary dysmenorrhea.
Relief of symptoms of osteoarthritis or rheumatoid arthritis. Treatment of primary dysmenorrhea.

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Mechanism of Action
Both COX-1 and COX-2 catalyze the conversion of arachidonic acid into prostaglandin (PG)H2, which is a precursor to prostaglandins and thromboxanes. Vardecoxib selectively inhibits cyclooxygenase-2 (COX-2), an enzyme that plays a crucial role in mediating inflammation and pain. Unlike non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), vardecoxib does not inhibit platelet aggregation. Vardecoxib is an NSAID with anti-inflammatory, analgesic, and antipyretic effects. Studies suggest that vardecoxib reduces the production of prostaglandin precursors by inhibiting cyclooxygenase-2 (COX-2) activity. However, unlike most NSAIDs, vardecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme in humans at therapeutic concentrations.

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Therapeutic Uses
Vardecoxib is indicated for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis in adults. /US Product Label Includes/
Vardecoxib is indicated for the treatment of primary dysmenorrhea. /US Product Label Contains/

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Drug Warnings
Serious, potentially life-threatening skin reactions, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (TEN), have been reported in post-marketing surveillance of vardicoxib. There have been reports of deaths due to Stevens-Johnson syndrome or toxic epidermal necrolysis. While serious adverse reactions can occur at any time during vardicoxib treatment, the risk appears to be highest during the first two weeks of treatment. Patients with a history of sulfonamide allergy may be at higher risk of skin reactions, but patients without such allergies are also at risk of serious skin reactions. These reactions are rare, but have been reported to occur more frequently with vardicoxib than with other selective COX-2 inhibitors (such as celecoxib). Vardicoxib should be discontinued immediately if a rash or any other allergic reaction occurs.
There is a risk of potentially fatal gastrointestinal ulcers, bleeding, and perforation. Most studies suggest that vardicoxib carries a lower risk of gastrointestinal ulceration compared to typical nonsteroidal anti-inflammatory drugs (NSAIDs); however, the relative risk remains to be determined. Caution should be exercised when using vardicoxib in patients at risk of gastrointestinal bleeding (e.g., those with a history of gastrointestinal bleeding or ulceration, those receiving oral corticosteroids or anticoagulants, those on long-term NSAID use, elderly patients, frail patients, smokers, or those with alcohol dependence). Alternative treatment options should be considered for patients at high risk of gastrointestinal bleeding. …
Severe (rarely fatal) anaphylactic reactions have occurred in patients receiving NSAIDs, and anaphylactic reactions (e.g., anaphylactic shock, angioedema) have also been reported in post-marketing surveillance of vardicoxib. Such reactions have occurred in patients with or without a history of sulfonamide allergy. …Cross-sensitivity reactions may occur between aspirin and other NSAIDs. Aspirin is contraindicated in patients with bronchospasm who are allergic to aspirin. Avoid use in patients with aspirin triad. Patients with a history of asthma should use this medication with caution, as bronchospasm may occur. Vardecoxib may cause increased fluid retention or edema in patients with conditions that predispose to and/or worsen fluid retention (congestive heart failure or edema, pre-existing hypertension); additionally, patients with congestive heart failure have an increased risk of renal failure; these patients should start with the lowest effective dose of vardecoxib. For more drug warnings (full version) (16 in total) on vardecoxib, please visit the HSDB record page.

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Pharmacodynamics
Vardecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor, belonging to the class of nonsteroidal anti-inflammatory drugs (NSAIDs). Vardecoxib is used to treat osteoarthritis (OA) and dysmenorrhea or acute pain due to its anti-inflammatory, analgesic, and antipyretic effects. Unlike celecoxib, vardecoxib does not contain a sulfonamide chain and its metabolism does not require the CYP450 enzyme.

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1. Vardecoxib (SC65872) is a highly selective cyclooxygenase-2 (COX-2) inhibitor (selectivity ratio to COX-1 >800) developed for anti-inflammatory and analgesic purposes. Its core structure is 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, which belongs to the isoxazolonamide class of nonsteroidal anti-inflammatory drugs (NSAIDs) [1]
2. In addition to inhibiting COX-2, vardecoxib can also regulate angiogenesis-related growth factors (VEGF, bFGF) in endothelial cells under hypoxia/LPS stimulation, suggesting its potential application value in inflammatory angiogenesis-related diseases (such as rheumatoid arthritis) [2]
3. Under chronic stress, vardecoxib exerts neuroprotective effects by reducing hippocampal COX-2 activity and increasing BDNF expression, thereby alleviating stress-induced anxiety and hormonal imbalance (elevated corticosterone). This indicates that it has potential application value in the treatment of stress-related neuropsychiatric disorders [3]

C16H14N2O3S

314.36

314.072

181695-72-7

Valdecoxib-d3;1219794-90-7

119607

White to off-white solid powder

1.3±0.1 g/cm3

481.2±55.0 °C at 760 mmHg

162-164ºC

244.8±31.5 °C

0.0±1.2 mmHg at 25°C

1.609

1.71

1

5

3

22

462

0

LNPDTQAFDNKSHK-UHFFFAOYSA-N

InChI=1S/C16H14N2O3S/c1-11-15(12-7-9-14(10-8-12)22(17,19)20)16(18-21-11)13-5-3-2-4-6-13/h2-10H,1H3,(H2,17,19,20)

4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)benzenesulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.95 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5% methylcellulose+0.2% Tween 80 : 19 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)