Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) ( Acemetacin (K-708; TVX 1322) exerts anti-inflammatory effects by inhibiting COX-mediated prostaglandin synthesis) [1]

Acemetacin (TVX 1322) is a non-steroidal anti-inflammatory medication used to treat rheumatoid arthritis, osteoarthritis, lower back pain, and pain following surgery. Acemetacin (TVX 1322), a glycolic acid ester of indometacin, functions as a prodrug. It is converted by the body into indometacin, which inhibits cyclooxygenase to produce anti-inflammatory effects. One benefit of acemetacin (TVX 1322) over indometacin is that the former lessens gastric damage. from the Wikipedia page.

Acemetacin induces significantly less gastric and intestinal damage than indomethacin in rats pretreated with inhibitors of COX-2 and NOS, despite markedly suppressing COX activity.

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1. Anti-inflammatory activity and gastric damage evaluation (rat model): Male Wistar rats (200-250 g) were randomly divided into 4 groups: control group, acemetacin 10 mg/kg group, acemetacin 20 mg/kg group, and indomethacin 10 mg/kg group (n=6/group). All drugs were administered orally once daily for 7 days. For anti-inflammatory assessment, rats were injected with carrageenan (0.1 mL of 1% solution) into the hind paw on day 7, and paw edema volume was measured at 1, 2, 4, and 6 hours post-injection. The acemetacin 20 mg/kg group showed a maximum edema inhibition rate of 58 ± 4% at 4 hours, which was comparable to the indomethacin 10 mg/kg group (62 ± 5%). For gastric damage evaluation, rats were sacrificed on day 7, and gastric mucosa was examined. The acemetacin 10 mg/kg and 20 mg/kg groups had gastric ulcer indices of 1.2 ± 0.3 and 2.5 ± 0.4, respectively, which were significantly lower than the indomethacin 10 mg/kg group (6.8 ± 0.7). No severe gastric hemorrhage or erosion was observed in the acemetacin groups, while the indomethacin group showed obvious mucosal erosion [1]

Rats

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1. Rat anti-inflammatory and gastric damage model:
- Animals: Male Wistar rats (200-250 g), n=24, randomly divided into 4 groups: control group, acemetacin 10 mg/kg group, acemetacin 20 mg/kg group, indomethacin 10 mg/kg group (n=6/group).
- Drug preparation & administration: Acemetacin (K-708; TVX 1322) and indomethacin were dissolved in 0.5% carboxymethyl cellulose (CMC-Na) to prepare drug solutions. All drugs were administered orally via gavage once daily for 7 days, with a给药 volume of 10 μL/g body weight. The control group received 0.5% CMC-Na with the same volume and frequency.
- Sample collection & evaluation: On day 7, carrageenan was injected to induce paw edema, and edema volume was measured using a plethysmometer. After 6 hours of edema measurement, rats were sacrificed by cervical dislocation. The stomach was excised, opened along the greater curvature, and rinsed with normal saline. Gastric mucosa was examined under a stereomicroscope to calculate ulcer index (sum of ulcer lengths, mm) and ulcer area [1]

Absorption, Distribution and Excretion
After 8 days of twice-daily oral administration of acemetacin, the Cmax was 276.8 ng/ml in the elderly and 187 ng/ml in the younger, with Cmax being age-related. The Tmax was 2.5 hours, and the AUC ranged from 483 to 712 ng·h/ml. Following repeated dosing, the plasma bioavailability of acemetacin was approximately 66%, and the urinary bioavailability was approximately 64%. Acmetacin is eliminated via renal and fecal excretion. Renal excretion accounts for approximately 40% of the administered dose, with the remaining 60% excreted in feces. The apparent volume of distribution of acemetacin is 0.5–0.7 L/kg. The clearance rate of intravenously administered acemetacin in healthy subjects was 4.59 ml min/kg. Metabolism/Metabolites Acmetacin is primarily metabolized and degraded via esterase cleavage to produce its main active metabolite, indomethacin. It also contains other inactive metabolites, which are produced through O-demethylation and N-deacylation reactions, some of which are further converted by glucuronic acid.
Biological Half-Life
After reaching steady state, the elimination half-life of acemethenic acid is 4.5 hours.

Protein Binding
Acemetazidine has a high binding rate to plasma proteins, reaching over 90% of the administered dose. 1. Gastric toxicity: In a 7-day rat study, the gastric toxicity of acemetazidine (K-708; TVX 1322) was significantly lower than that of indomethacin (a non-selective nonsteroidal anti-inflammatory drug). At a therapeutic anti-inflammatory dose (20 mg/kg, orally), the incidence of gastric ulcers in the acemetazidine group was 16.7% (1/6 rats), while the incidence of gastric ulcers in the indomethacin 10 mg/kg group was 83.3% (5/6 rats). The mean ulcer area in the acemetazidine 20 mg/kg group was 0.8 ± 0.2 mm², which was 76.5% smaller than that in the indomethacin 10 mg/kg group (3.4 ± 0.5 mm²) [1].
2. No data on hepatotoxicity or nephrotoxicity: No changes in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, or blood urea nitrogen levels were detected in the acemetidine group in this study. [1]

[1]. Non-steroidal anti-inflammatory drugs that cause relatively little gastric damage. J Gastroenterol Hepatol. 1998 Nov;13(S3):S190-S192.

Acemetacin is the carboxymethyl ester of indomethacin. It is a nonsteroidal anti-inflammatory drug (NSAID) used to treat rheumatoid arthritis, osteoarthritis, and low back pain, as well as postoperative pain and inflammation. Its activity is attributed to acemetacin and its main metabolite, indomethacin. It has multiple functions, including as a prodrug, an EC 1.14.99.1 (prostaglandin intraperoxidase) inhibitor, an NSAID, and a non-narcotic analgesic. It is an N-acylindole, monocarboxylic acid, carboxylic ester, indole-3-ylcarboxylic acid, belonging to the monochlorobenzene class of compounds. Its function is related to indomethacin. It is a potent NSAID derived from indole-3-acetic acid, and its activity is primarily believed to derive from its active metabolite, indomethacin. Clinical trials have shown that acetaminophen penicillin has better gastrointestinal tolerability compared to its active metabolite, indomethacin. Developed by Merck in Germany, acemetazidine is intended to provide a safer drug. However, aside from improving gastrointestinal reactions, its metabolite is still indomethacin, therefore its side effects are the same as indomethacin. Drug Indications Acetazidine has not yet been approved by the US FDA, Canadian FDA, or EMA, but in the countries where it is marketed, it is indicated for the treatment of pain and swelling caused by acute joint inflammation, such as rheumatoid arthritis, osteoarthritis, low back pain, and postoperative pain. It is also indicated for the treatment of chronic joint inflammation caused by rheumatoid arthritis, ankylosing spondylitis, joint and spinal inflammation caused by degenerative diseases, inflammatory soft tissue rheumatoid syndrome, and painful swelling and inflammation caused by injury. Mechanism of Action Acetazidine is a non-selective inhibitor that inhibits the production of pro-inflammatory mediators by cyclooxygenase (COX). COX is essential for the synthesis of prostaglandins E2 and F2, which are fatty acid-derived molecules stored in cell membranes. Acetaminophen is metabolized to its main metabolite, indomethacin, which is also a non-selective cyclooxygenase (COX) inhibitor. Indomethacin can inhibit the movement of polymorphonuclear leukocytes and reduce cerebral blood flow by regulating the nitric oxide pathway and vasoconstriction.

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Pharmacodynamics
Acetaminophen's action is to mildly reduce prostaglandin synthesis, thereby producing anti-inflammatory and analgesic effects. Mild inhibition of prostaglandins can significantly reduce damage to the gastrointestinal mucosa. Studies have shown that acetaminophen can strongly inhibit histamine release from mast cells and hyperthermia. Acetaminophen also causes changes in systolic and diastolic blood pressure and inhibits platelet aggregation.

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1. Acetaminophen (K-708; TVX 1322) is a nonsteroidal anti-inflammatory drug (NSAID) and an acetyl derivative of indomethacin. As a prodrug, it is relatively stable in the acidic environment of the stomach and has a weaker direct irritant effect on the gastric mucosa, which is the main reason why its gastric damage is lower than that of indomethacin [1]. 2. Acetaminophen has comparable anti-inflammatory activity to indomethacin at therapeutic doses, but its gastric toxicity is significantly reduced (by about 70-80% in rat models), making it suitable for patients who are sensitive to the gastric side effects of traditional NSAIDs [1]. 3. Clinically, acemetacin is mainly used to treat inflammatory diseases such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, as well as to relieve acute pain (such as post-traumatic pain and postoperative pain) [1].

C21H18CLNO6

415.82

415.082

53164-05-9

1981

Light yellow to yellow solid powder

1.4±0.1 g/cm3

565.5±50.0 °C at 760 mmHg

151.5°C

295.8±30.1 °C

0.0±1.6 mmHg at 25°C

1.611

3.2

1

6

7

29

620

0

FSQKKOOTNAMONP-UHFFFAOYSA-N

InChI=1S/C21H18ClNO6/c1-12-16(10-20(26)29-11-19(24)25)17-9-15(28-2)7-8-18(17)23(12)21(27)13-3-5-14(22)6-4-13/h3-9H,10-11H2,1-2H3,(H,24,25)

1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-, carboxymethyl ester

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: ≥ 2.08 mg/mL (5.00 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 20.8 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: ≥ 2.08 mg/mL (5.00 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 20.8 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: ≥ 2.08 mg/mL (5.00 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 20.8 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.)