Nine- to ten-week-old female Zucker fatty rats were used.
Salsalate was administered orally by mixing it into the standard rodent diet at a dose of 300 mg per day, provided ad libitum.
Treatment was initiated 1 week prior to inducing vascular injury and continued for an additional 21 days post-injury.
Vascular injury was induced via balloon catheter injury of the left carotid artery under anesthesia. Briefly, a catheter was inserted via the femoral artery, advanced to the carotid artery, the balloon was inflated to denude the endothelium, and then the catheter was removed.
Rats were euthanized 22 days post-injury (3 weeks post-injury while on treatment). Blood was collected for serum analysis (e.g., IL-6), and tissues (injured/contralateral carotid arteries, aortic arch) were harvested for morphometric analysis (hematoxylin and eosin staining for I/M ratio), immunohistochemistry (for VEGF), and Western blot analysis (for eNOS, p-eNOS, NF-κB p65, MnSOD).[1]

Absorption, Distribution and Excretion
Salicylate is insoluble in acidic gastric juice (< 0.1 mg/ml at pH 1.0), but readily soluble in the small intestine, where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged. When administered at a salicylic acid molar equivalent (3.6 g salicylate/5 g aspirin), salicylate provides approximately 15% less salicylic acid than aspirin. Food slows the absorption of all salicylates, including salicylate. Metabolism/Metabolites Salicylate is readily soluble in the small intestine and is partially hydrolyzed to two molecules of salicylic acid. Most of the parent compound is absorbed unchanged and rapidly hydrolyzed by esterases in vivo. Biological Half-Life The elimination half-life of the parent compound is approximately 1 hour. At anti-inflammatory doses of salicylate, the biotransformation of salicylic acid (the active metabolite) is saturated. This limited biotransformation capacity results in the salicylic acid half-life being extended from 3.5 hours to 16 hours or longer.

Hepatotoxicity
Prospective studies have shown that some patients taking sodium salicylate experience at least transient increases in serum transaminases, especially at higher doses. These abnormalities may resolve with continued use or dose reduction. Significant increases in transaminases (more than 10-fold) are rare, except at higher doses (4 grams or more daily), and their mechanism of action is similar to that of aspirin. There are no reports of clinically significant liver damage and jaundice caused by sodium salicylate, and such cases should be very rare. Sodium salicylate may induce Reye's syndrome in susceptible children or adolescents, and therefore, as with aspirin, its use should be avoided in these age groups.
Probability rating: A [HD] (High doses are a known cause of liver damage).
Effects during pregnancy and lactation
◉ Overview of use during lactation
The use of sodium salicylate during lactation has not been studied, but sodium salicylate causes salicylic acid to appear in the blood. The use of salicylic acid and aspirin during lactation has been studied. With increasing maternal dosage, the excretion of salicylates in breast milk increases disproportionately. A breastfed infant may develop metabolic acidosis due to the mother's long-term use of high-dose aspirin. Reye's syndrome has been associated with aspirin administration to infants with viral infections, but the risk of salicylates in breast milk causing Reye's syndrome is unclear. Alternative medications are recommended to replace salicylates.
◉ Effects on breastfed infants
A 16-day-old breastfed infant developed metabolic acidosis with a serum salicylate level of 240 mg/L, and salicylate metabolites were also detected in the urine. The mother was taking 3.9 grams of aspirin daily for arthritis; salicylates in breast milk may have contributed to the infant's illness, but the possibility of direct ingestion of salicylates by the infant cannot be ruled out.
A 5-month-old breastfed infant developed thrombocytopenia, fever, anorexia, and petechiae 5 days after the mother began taking aspirin to reduce fever. One week after the infant recovered, a single dose of 125 mg aspirin caused a further drop in platelet count. The initial symptoms may have been caused by salicylates in breast milk. A mother of a 23-day-old infant with glucose-6-phosphate dehydrogenase (G6PD) deficiency experienced hemolysis after taking aspirin and phenacetin, possibly due to aspirin in breast milk. In a telephone follow-up study, 15 mothers of infants exposed to aspirin through breast milk (dosage and infant age not specified) reported no side effects. ◉ Effects on lactation and breast milk: As of the revision date, no relevant published information was found. Protein binding: Salicylate: Binding rate is 90-95% at plasma salicylate concentrations <100 mcg/mL; 70-85% at concentrations of 100-400 mcg/mL; and 25-60% at concentrations >400 mcg/mL.

[1]. Effects of salsalate therapy on recovery from vascular injury in female Zucker fatty rats. Diabetes. 2010;59(12):3240-3246.

[2]. Gastroduodenal mucosal damage with salsalate versus aspirin: results of experimental models and endoscopic studies in humans. Semin Arthritis Rheum. 1990;20(2):121-127.

[3]. Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome. Am J Physiol Endocrinol Metab. 2020;319(4):E744-E752.

Salicylate is a dibenzoic acid ester formed by the intermolecular condensation reaction of the carboxyl group of one salicylic acid molecule with the phenolic group of another salicylic acid molecule. It is a prodrug of salicylic acid used to treat rheumatoid arthritis and osteoarthritis, and is also effective for type II diabetes. It has various pharmacological effects, including nonsteroidal anti-inflammatory drug (NSAID), non-narcotic analgesic, antirheumatic drug, hypoglycemic agent, antitumor drug, EC 3.5.2.6 (β-lactamase) inhibitor, and prodrug. It is a benzoic acid ester belonging to the benzoic acid, phenolic, and salicylate classes of compounds. Its function is related to salicylic acid. Salicylate is an oral NSAID. The mechanism of action of sodium salicylate as an anti-inflammatory and antirheumatic drug may be related to its inhibition of prostaglandin synthesis and release. The efficacy of salicylic acid, the active metabolite of sodium salicylate, in treating arthritis has been demonstrated. Unlike aspirin, sodium salicylate does not cause more fecal or gastrointestinal bleeding than placebo. Sodium salicylate is readily soluble in the small intestine and partially hydrolyzes into two molecules of salicylic acid within the small intestine. A significant portion of the unchanged compound is absorbed and rapidly hydrolyzed by esterases in vivo. The elimination half-life of the unchanged compound is approximately 1 hour. At anti-inflammatory doses of sodium salicylate, the biotransformation of salicylic acid (the active metabolite) reaches saturation. This capacity-limited biotransformation leads to an extended half-life of salicylic acid from 3.5 hours to 16 hours or longer. Sodium salicylate is a non-acetylated dimer of salicylic acid used to treat chronic arthritis, possessing analgesic and antipyretic effects. High doses of sodium salicylate can cause a moderate increase in serum transaminases, with a mechanism of action similar to aspirin. Sodium salicylate is an orally effective nonsteroidal anti-inflammatory drug (NSAID) of salicylates with anti-inflammatory, analgesic, and antipyretic effects. As a prodrug, sodium salicylate hydrolyzes to salicylic acid, which inhibits the expression of cyclooxygenase (COX). This prevents the conversion of arachidonic acid into prostaglandin precursors, thereby reducing the production of prostaglandins involved in pain, fever, and inflammation. Furthermore, sodium salicylate appears to inhibit nuclear factor-κB (NF-κB), thereby preventing NF-κB-mediated pathway activation and the expression of inflammation-related genes.
See also: Sodium salicylate (its active ingredient).

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Drug Indications
For the relief of signs and symptoms of rheumatoid arthritis, osteoarthritis, and related rheumatic diseases.

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Mechanism of Action
The anti-inflammatory mechanism of sodium salicylate and other nonsteroidal anti-inflammatory drugs (NSAIDs) is not fully understood, but it appears to be primarily related to the inhibition of prostaglandin synthesis. This inhibition of prostaglandin synthesis is achieved by inactivating cyclooxygenase-1 (COX-1) and COX-2, which are responsible for catalyzing the production of prostaglandins in the arachidonic acid pathway. Although salicylic acid (the main metabolite of salicylates) has a weak inhibitory effect on prostaglandin synthesis in vitro, salicylates appear to selectively inhibit prostaglandin synthesis in vivo, thus exerting an anti-inflammatory effect comparable to aspirin and indomethacin. Unlike aspirin, salicylates do not inhibit platelet aggregation.

C14H10O5

28.23

258.052

552-94-3

Salsalate (Standard);552-94-3

5161

White to off-white solid powder

1.4±0.1 g/cm3

482.9±25.0 °C at 760 mmHg

139-151 °C

188.0±16.7 °C

0.0±1.3 mmHg at 25°C

1.646

3.05

2

5

4

19

341

0

O=C(OC1=CC=CC=C1C(O)=O)C2=CC=CC=C2O

WVYADZUPLLSGPU-UHFFFAOYSA-N

InChI=1S/C14H10O5/c15-11-7-3-1-5-9(11)14(18)19-12-8-4-2-6-10(12)13(16)17/h1-8,15H,(H,16,17)

2-(2-hydroxybenzoyl)oxybenzoic acid

Salsalate Salicylsalicylic acid Sasapyrine Disalicylic acid disalicylic acid Disalcid

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)

DMSO : ≥ 100 mg/mL (~387.25 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.68 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 (9.68 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 (9.68 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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 (Please use freshly prepared in vivo formulations for optimal results.)