Cyclooxygenase (COX) (inhibits prostaglandin synthesis via inhibition of COX, but does not inhibit 5-lipoxygenase)
COX-1 and COX-2 (selectivity ratio of human COX-1:COX-2 inhibitory potency = 0.6, intermediate between tenidap or piroxicam (0.2) and tenoxicam (1.2) or ketorolac (1.3)) [1]

In vitro activity: Lornoxicam is as effective as the opioid analgesics morphine, pethidine (meperidine) and tramadol in relieving postoperative pain following gynaecological or orthopaedic surgery, and as effective as other NSAIDs after oral surgery. Lornoxicam is also as effective as other NSAIDs in relieving symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute sciatica and low back pain.
Cell Assay: Studies on intact human cells showed that lornoxicam intensively inhibit COX-1 and COX-2 with the lowest IC50 among a large panel of NSAIDs tested. Similar findings were obtained in the whole blood for COX-1/-2. In addition lornoxicam suppressed NO formation in a dose-dependently manner with an IC50 of 65 μM.

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In vitro: Lornoxicam inhibited PGD2 formation in rat polymorphonuclear leucocytes with IC50 = 0.02 μmol/L, showing 100-fold greater potency than tenoxicam (IC50 = 2.45 μmol/L). [1]
In vitro: Lornoxicam inhibited superoxide release from human polymorphs and platelet-derived growth factor (PDGF) release from human platelets. [1]
In vitro: Lornoxicam (0.1 to 1.0 mg/L) stimulated proteoglycan synthesis in cultures of porcine cartilage, suggesting a possible reparative effect in rheumatoid arthritis. [1]

Lornoxicam dose relatedly reduces the total number of c-Fos-LI neurons with the strongest effect corresponding to the 75% reduction for the highest dose of 9 mg/kg, and the 45% reduction for the low dose of 0.3 mg/kg. Lornoxicam (0.1, 0.3 mg/kg, 1 mg/kg, 3 mg/kg and 9 mg/kg, i.v.) significantly reduces the number of c-Fos-LI neurons in both superficial (24%, 33%, 53%, 54%, and 63% reduction, respectively) and deep (28%, 48%, 62%, 69% and 79% reduction, respectively) laminae of the dorsal horn of the spinal cord. Lornoxicam reduces hyperalgesia with an effective dose that provides 50% inhibition (ED50) of 0.083 mg/kg, 3.9 mg/kg and 4.3 mg/kg respectively in a chronic rat model of arthritis. Lornoxicam significantly reduces the PGE2 level in paw exudate and the cerebrospinal fluid in rats. Lornoxicam 0.16 mg/kg, celecoxib 4 mg/kg and loxoprofen 2.4 mg/kg significantly reduces hyperalgesia to a similar extent in acute oedematous rats.

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In vivo: In the acetylcholine-induced writhing test in mice, Lornoxicam showed approximately 10-fold greater analgesic activity than tenoxicam (ED50 = 0.1 mg/kg orally for lornoxicam). [1]
In vivo: In the carrageenin-induced oedema test in rats, Lornoxicam was 10-fold more active than tenoxicam (ED50 = 0.4 mg/kg orally for lornoxicam vs 4 mg/kg for tenoxicam). [1]
In vivo: In the adjuvant-induced polyarthritic rat model, Lornoxicam was 10-fold more active than tenoxicam in inhibiting paw swelling (ED50 = 0.03 mg/kg orally for lornoxicam vs 0.3 mg/kg for tenoxicam). At 0.1 mg/kg orally, it prevented degenerative bone loss, possibly by inhibiting polymorphonuclear leucocyte migration. [1]
In vivo: Lornoxicam demonstrated antipyretic effects at doses 10-fold above those required to produce anti-inflammatory effects. [1]
In vivo: In the arachidonic acid-induced lethality mouse model, Lornoxicam was more potent than indomethacin and piroxicam (ED50 = 0.012 mg/kg orally for lornoxicam vs 0.150 mg/kg for indomethacin and 0.870 mg/kg for piroxicam). [1]

Enzyme Assay: The inhibitory effect of Lornoxicam on prostaglandin synthesis was assessed by measuring PGD2 formation in rat polymorphonuclear leucocytes in vitro. The concentration producing 50% inhibition (IC50) was determined. Lornoxicam showed an IC50 of 0.02 μmol/L, while tenoxicam showed 2.45 μmol/L. [1]
Enzyme Assay: The selectivity of Lornoxicam for COX-1 versus COX-2 was determined based on the ratio of human COX-1:COX-2 inhibitory potency, which was reported as 0.6 (data on file). [1]

Cell Assay: Rat polymorphonuclear leucocytes were used to measure PGD2 formation as an indicator of cyclooxygenase activity. Cells were incubated with Lornoxicam and the IC50 for inhibition of PGD2 formation was calculated. [1]
Cell Assay: Human polymorphonuclear leucocytes were used to study superoxide release; Lornoxicam inhibited superoxide release. Human platelets were used to study platelet-derived growth factor (PDGF) release; Lornoxicam inhibited PDGF release. [1]
Cell Assay: Cultures of porcine cartilage were used to evaluate proteoglycan synthesis. Lornoxicam at concentrations of 0.1 to 1.0 mg/L stimulated proteoglycan synthesis. [1]

0.1, 0.3 mg/kg, 1 mg/kg, 3 mg/kg and 9 mg/kg, i.v. Rats

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Animal Protocol: Acetylcholine-induced writhing test in mice: Lornoxicam was administered orally at various doses to determine the ED50 for inhibition of writhing responses. [1]
Animal Protocol: Carrageenin-induced oedema test in rats: Lornoxicam was given orally, and paw oedema was measured to calculate ED50 for inhibition. [1]
Animal Protocol: Adjuvant-induced polyarthritis in rats: Lornoxicam was administered orally, and paw swelling and bone loss were assessed. ED50 values for inhibition of paw swelling were determined. [1]
Animal Protocol: Arachidonic acid-induced lethality in mice: Lornoxicam was given orally, and the effective dose protecting 50% of animals (ED50) was calculated. [1]
Animal Protocol: Endoscopic studies in healthy volunteers: Lornoxicam 16 mg/day was given for 7 days in a crossover design, and gastroduodenal injury was compared to naproxen 1000 mg/day. [1]
Animal Protocol: Faecal blood loss study in healthy volunteers: Lornoxicam 4 mg twice daily for 14 days was compared to indomethacin 50 mg twice daily. [1]

Absorption, Distribution and Excretion
Lonoxicon is rapidly and almost completely absorbed (90-100%) from the gastrointestinal tract. Metabolism/Metabolites Lonoxicon is completely metabolized by CYP 2C9, with the major metabolite being 5'-hydroxylonoxicon. Only a very small amount of intact lonoxicon is excreted unchanged in the urine. Approximately two-thirds of the drug is excreted in its active form via the liver, and one-third via the kidneys. Known metabolites of lonoxicon include 5'-hydroxylonoxicon. Biological Half-Life 3-5 hours

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ADME/Pharmacokinetics: Absorption: Lornoxicam is completely absorbed after oral administration, reaching peak plasma concentration (Cmax) of 270 μg/L within 2.5 hours (tmax) after a 4 mg dose. Absorption is delayed and marginally reduced (≈20%) in the presence of food. Bioavailability after intramuscular administration is estimated to be 87%. [1]
Distribution: Lornoxicam is highly bound (99%) to plasma proteins (almost exclusively serum albumin), with a low apparent volume of distribution (0.2 L/kg). It penetrates into perivascular interstitial spaces, including synovial fluid. Synovial fluid:plasma AUC ratio is approximately 0.5 after 4 mg twice daily for 5 days in rheumatoid arthritis patients. [1]
Metabolism: Lornoxicam is extensively metabolised in the liver, primarily via cytochrome P450 (CYP)2C subfamily (possibly CYP2C9), to the inactive metabolite 5'-hydroxy-lornoxicam. Negligible amounts of unchanged drug are detected in urine. [1]
Excretion: After a single oral dose of [14C]-Lornoxicam 4 mg, 42% of radiolabel was excreted in urine and 51% in faeces. Renal clearance of unchanged drug is negligible. [1]
Half-life: Lornoxicam has a relatively short terminal plasma elimination half-life (t½β) of 3 to 5 hours in healthy young volunteers, with considerable interindividual variability. The 5'-hydroxy metabolite has a half-life of approximately 11 hours. [1]
Clearance: Apparent oral clearance of Lornoxicam (4 to 8 mg twice daily) ranges from 1.5 to 3.4 L/h in healthy volunteers. [1]
Effects of age/disease: Pharmacokinetics not appreciably modified by advanced age or renal impairment, but accumulation of the inactive metabolite occurs in patients with impaired hepatic function. Enhanced enterohepatic elimination may compensate for reduced renal elimination in severe renal dysfunction. [1]

Protein Binding
Lonoxac has a 99% binding rate to plasma proteins (almost completely binding to serum albumin).

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Toxicity/Toxicokinetics: Gastrointestinal effects: In healthy volunteers, Lornoxicam 16 mg/day induced significantly less endoscopically verified gastroduodenal injury than naproxen 1000 mg/day. Lornoxicam 8 mg/day tended to cause less faecal blood loss than indomethacin 100 mg/day. Lornoxicam 4 mg twice daily for 2 weeks did not increase serum pepsinogen I levels in 17 of 18 patients. [1]
Renal effects: Short-term studies (≤3 weeks) with Lornoxicam up to 8 mg twice daily showed no evidence of nephrotoxicity in healthy volunteers or patients with mild-to-moderate renal impairment. [1]
Haematological effects: Lornoxicam 4 mg twice daily for 14 days did not affect haemostasis, coagulation or thrombolysis in healthy volunteers, except for prolonging the time until start of clot formation (from 489 to 567 seconds, p<0.01). [1]
Protein binding: Lornoxicam is 99% bound to plasma proteins. [1]
Drug interactions: Cimetidine inhibits elimination of Lornoxicam (increases Cmax by 28% and AUC by 9%, reduces plasma clearance by 12%). Ranitidine and antacids (aluminium, magnesium, calcium, bismuth) do not appreciably modify its pharmacokinetics. Lornoxicam increases warfarin plasma concentrations by ≈30% and enhances anticoagulant effect. It increases steady-state serum lithium Cmax by 20%. It attenuates diuretic and natriuretic effects of furosemide. It increases methotrexate AUC by >20%. It potentiates metabolic effects of glibenclamide (increase in 24-hour plasma insulin secretion by ≈45%) but does not affect its pharmacokinetics. No effect on phenazone (antipyrine) clearance, indicating lack of effect on hepatic drug metabolising enzymes. [1]

Drugs.1996 Apr;51(4):639-57;Inflammopharmacology.1997;5(4):331-41.

Lornoxicam is a thienoxicam monocarboxylic acid amide, formed by the condensation of the carboxyl group of 1,1-dioxide of 6-chloro-4-hydroxy-2-methylthieno[2,3-e][1,2]thiazine-3-carboxylic acid with the amino group of 2-aminopyridine. It is primarily used to treat joint inflammation, osteoarthritis, post-operative pain, sciatica, and other inflammatory pain. It is a nonsteroidal anti-inflammatory drug (NSAID), a non-narcotic analgesic, and an antipyretic. It belongs to the thienoxicam class, pyridine class, monocarboxylic acid amide class, organochlorine compounds, and heteroaryl hydroxy compounds. Lonoxac (clotenoxac) is a novel oxacin class NSAID with analgesic, anti-inflammatory, and antipyretic effects. Lonoxac differs from other oxacin compounds in its potent inhibition of prostaglandin biosynthesis, a characteristic that explains its significant therapeutic efficacy. Lonoxac has been approved for use in Japan.
Lonoxacin is a highly bioavailable oral nonsteroidal anti-inflammatory drug (NSAID) of the cyclooxygenase class, possessing analgesic, antipyretic, antithrombotic, and anti-inflammatory effects. After oral administration, lonoxicam binds to and inhibits the activity of cyclooxygenase (COX) type 1 (COX-1) and type 2 (COX-2). This drug blocks COX-mediated signaling pathways, thereby reducing the production of prostaglandins and thromboxanes, and alleviating pain, fever, and inflammation.
Indications

For the treatment of acute mild to moderate pain, and joint inflammation and pain caused by certain types of rheumatic diseases.
Mechanism of Action

Like other NSAIDs, the anti-inflammatory and analgesic effects of lonoxicam are related to its inhibition of prostaglandin and thromboxane synthesis by inhibiting COX-1 and COX-2. This reduces prostaglandin-mediated inflammation, pain, fever, and swelling. However, like other nonsteroidal anti-inflammatory drugs (NSAIDs), the exact mechanism of action of lonoxicam is not fully understood.

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Pharmacodynamics
Lonnoxicam is a nonsteroidal anti-inflammatory drug (NSAID) belonging to the oxacin class. Like other NSAIDs, lonoxicam is a potent inhibitor of cyclooxygenase, which catalyzes the conversion of arachidonic acid into prostaglandins (acting as messenger molecules in the inflammatory process) and thromboxanes. Unlike some NSAIDs, lonoxicam's inhibition of cyclooxygenase does not lead to increased leukotriene production, meaning that arachidonic acid does not enter the 5-lipoxygenase cascade, thus minimizing the risk of adverse reactions.

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Additional Info: Mechanism of action: In addition to COX inhibition, Lornoxicam may increase endogenous opioid release; in patients with acute lower back pain, intravenous lornoxicam 4 mg twice daily for 5 days significantly increased plasma levels of dynorphin (by 140%) and β-endorphin (by 33%). [1]
Therapeutic potential: Lornoxicam has been evaluated for acute pain (post-orthopaedic/gynaecological surgery, oral surgery, acute sciatica/low back pain) and chronic pain (osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, chronic low back pain, migraine prophylaxis). It is as effective as pethidine, tramadol, and morphine for postoperative pain, and as effective as diclofenac, naproxen, piroxicam, and indomethacin for arthritic conditions. [1]
Dosage: Common oral dosages are 4 mg twice or three times daily or 8 mg twice daily for arthritic conditions and low back pain; single or repeated doses of 4 or 8 mg (oral or intravenous) for postoperative pain. [1]
Caution: Recommended in patients with impaired renal function, and in those receiving warfarin, oral sulphonylureas, loop or thiazide diuretics, or digoxin. [1]

C13H10CLN3O4S2

371.82

370.98

70374-39-9

Lornoxicam-d4;1216527-48-8

54690031

Light yellow to yellow solid powder

1.7±0.1 g/cm3

225-230°C (dec.)

1.741

2.18

2

7

2

23

634

0

WLHQHAUOOXYABV-UHFFFAOYSA-N

InChI=1S/C13H10ClN3O4S2/c1-17-10(13(19)16-9-4-2-3-5-15-9)11(18)12-7(23(17,20)21)6-8(14)22-12/h2-6,18H,1H3,(H,15,16,19)

6-chloro-4-hydroxy-2-methyl-1,1-dioxo-N-pyridin-2-ylthieno[2,3-e]thiazine-3-carboxamide

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)