Novel Non-steroidal Anti-inflammatory Drug Research Articles

The non-steroidal anti-inflammatory drug tepoxalin inhibits interleukin-6 and alpha l-anti-chymotrypsin synthesis in astrocytes by preventing degradation of IκB-alpha

Tepoxalin is a structurally and functionally novel non-steroidal anti-inflammatory drug (NSAID) with potent anti-inflammatory and analgesic properties. Apart from its inhibitory effect on cyclooxygenase activity, tepoxalin is able to inhibit production of cytokines in peripheral cells outside the CNS. No data, however, are available concerning the effects of this drug in the CNS. Since cytokines such as interleukin-1 (IL-1) or interleukin-6 (IL-6) as well as acute-phase proteins such as α 1-anti-chymotrypsin (ACT) participate in the etiopathology of Alzheimer’s disease (AD), we were interested whether tepoxalin is able to inhibit the synthesis of these immunomodulators in primary rat microglia and astrocytes as well as in the human astrocytoma cell line U373 MG. We found that tepoxalin markedly inhibits IL-1β-induced IL-6 and ACT synthesis in astrocytes and the synthesis of IL-1β and IL-6 in lipopolysaccharide (LPS)-stimulated microglial cells. Electrophoretic mobility shift and reporter gene assays revealed that tepoxalin exerts its inhibitory effect through the inhibition of nuclear factor kappaB (NF-κB), a transcription factor involved in the induction of IL-1, IL-6 and ACT gene expression. We show that inhibition of NF-κB activation by tepoxalin is mediated by preventing IκB-α degradation. Based on this inhibitory effect of tepoxalin on cytokine and ACT synthesis and the documented therapeutic efficacy of NSAIDs in AD, we conclude that tepoxalin may be of therapeutic benefit for the treatment of AD patients and should therefore be tested in clinical trials.

Effects of a novel non-steroidal anti-inflammatory drug (M-5011) on bone metabolism in rats with collagen-induced arthritis

The effects of a novel non-steroidal anti-inflammatory drug (NSAID), d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid: M-5011, and other NSAIDs (indomethacin, zaltoprofen and tiaprofenic acid) on bone metabolism in Dark Agouti (DA) strain rats with collagen-induced arthritis were evaluated. M-5011 (1.5 and 4.5 mg/kg) and other NSAIDs (1.5 mg/kg) were administered orally once a day from day 14 to day 35 after collagen immunization. In arthritic rats, paw volume and serum levels of anti-type II collagen antibody were increased on day 21 compared to those in non-immunized rats. M-5011 (4.5 mg/kg), indomethacin and zaltoprofen tended to prevent this increase in paw volume. Elevated urinary pyridinoline and deoxypyridinoline levels were found on days 28 and 35 in arthritic rats. M-5011 (4.5 mg/kg) also tended to prevent the increase in urinary pyridinoline level on day 28, but none of the other NSAIDs affected urinary deoxypyridinoline levels. Bone mineral densities in the hindpaw and vertebrae were also decreased in arthritic rats. M-5011 and tiaprofenic acid prevented this decrease in vertebral bone mineral density. These findings indicate that M-5011 partially inhibits the generalized bone loss accompanying the development of collagen-induced arthritis in rats.

Evaluation of chronic oral toxicity and carcinogenic potential of lornoxicam in rats

As part of the preclinical development program for lornoxicam, a novel non-steroidal anti-inflammatory drug (NSAID), its chronic oral toxicity and carcinogenic potential was assessed in Sprague-Dawley rats. Male and female rats were administered lornoxicam by oral gavage at 0, 0.06, 0.16 or 0.40 mg/kg/day for 12 months or at 0, 0.01 or 0.06 mg/kg/day in a supplementary low-dose study of the same duration (main group: 20/sex/group; 4-wk recovery: five/sex/group; satellites for electrocardiography and toxicokinetics: five/sex/group). Drug-related toxicity mainly comprised mortality, reduced body weight gain, clinico-pathological changes indicative of anaemia resulting from blood loss, and renal damage, renal papillary necrosis and gastrointestinal mucosal lesions. The kidney-associated changes were not completely reversible during the recovery period. Toxicokinetic investigations demonstrated a dose-linear absorption of the drug. In female rats the terminal half-life was about twice that in males which led to a higher exposure of this gender to lornoxicam. A dose of 0.01 mg/kg/day was established as no-observed-effect level. In a 104-wk carcinogenicity study, lornoxicam was administered by oral gavage to male and female rats (50/sex/group) at 0 (control 1), 0 (control 2), 0.0625, 0.125 or 0.250 mg/ kg/day. In females only, the high dose was reduced twice during the study due to toxicity observed (0.250 to 0.200 to 0.160 mg/kg/day). Drug-related changes were similar to those in the chronic studies and consistent with the anticipated side-effects of NSAIDs. No carcinogenic potential was revealed.

Hydroxyl Radical Scavenging Activity of Nonsteroidal Anti-Inflammatory Drugs

The hydroxyl radical (.OH) -scavenging activity of d-2–[4–(3-methyl-2-thienyl)phenyl]propionic acid (M-5011), a novel nonsteroidal anti-inflammatory drug (NSAID), and that of several other NSAIDs were investigated by the hyaluronic acid (HA) degradation method and the electron spin resonance (ESR) spin-trapping technique. The superoxide anion (O2) -scavenging activity of M-5011 was also measured by the ESR technique. (1) M-5011 and the other NSAIDs examined inhibited the degradation of HA induced by the Fenton reaction system in a dose-dependent manner.(2) M-5011 and the other NSAIDs scavenged OH directly in a dose-dependent manner.(3) M-5011 was the most potent drug among the NSAIDs tested regarding the scavenging activity of OH as follows; M-5011 > indomethacin > ketoprofen = suprofen > aspirin. The OH-scavenging activity of M-5011 was potent in comparison with that of oxidized glutathione (GSSG), an endogenous OH scavenger.(4) M-5011 did not scavenge O2; nor did GSSG. These results suggest that M-5011 acts as a scavenger of OH at sites with inflammatory lesions.

Antinociceptive Activity of a Novel Non-Steroidal Anti-Inflammatory Drug (M-5011) with Low Ulcerogenic Effects in Mice

Both analgesic and ulcerogenic activities of d-2-[4-(3-methyl-2-thienyl)phenyl] propionic acid (M-5011), a novel non-steroidal anti-inflammatory drug (NSAID), were compared with those of indomethacin (IND), ketoprofen (KP), diclofenac sodium (DIF), zaltoprofen (ZLT) and tiaprofenic acid (TIA) in mice. All orally administered NSAIDs including M-5011 inhibited kaolin-induced writhing in a dose-dependent manner. M-5011 had an effective antinociceptive activity (ED50 value) of 0.63 mg/kg, being more potent than ZLT (16.80 mg/kg) and TIA (4.78 mg/kg), equipotent to DIF (0.68 mg/kg), and less potent than IND (0.21 mg/kg) and KP (0.28 mg/kg). All drugs tested significantly reduced peritoneal 6-keto-prostaglandin F1α (6-keto-PGF1α) levels at the peak kaolin-induced writhing time (7.5 min post-kaolin injection) without affecting peritoneal bradykinin (BK) levels. Antinociceptive effects of all drugs were closely correlated with inhibition of peritoneal 6-keto-PGF1α levels. Ulcerogenic activities (UD50 value) of M-5011 in the stomach and small intestines were 88.23 and 46.09 mg/kg, respectively. UD50 values of other drugs in the stomach and small intestines were as follows: 8.96 and 4.78 mg/kg, 20.04 and 10.75 mg/kg, 4.19 and 2.24 mg/kg, 62.86 and 46.55 mg/kg, and 110.92 and 54.78 mg/kg for IND, KP, DIF, TIA, and ZLT, respectively. Thus, the safety indexes (UD50/ED50) of the stomach (or small intestine) for M-5011, IND, KP, DIF, TIA and ZLT were 140.05 (73.16), 42.67 (22.76), 71.57 (38.39), 6.16 (3.29), 13.15 (9.74) and 6.60 (3.26), respectively. These findings suggest that M-5011 is a useful NSAID that shows potent antinociceptive effects with low ulcerogenic activities.

新規抗炎症薬ｚａｌｔｏｐｒｏｆｅｎのラット胃血流量に対する影響

Zaltoprofen, a novel nonsteroidal anti-inflammatory drug (NSAID), shows potent anti-inflammatory, analgesic and anti-pyretic effects. Although gastrointestinal dysfunction is a common side effect of NSAIDs, effects of zaltoprofen on the gastric functions have not yet fully clarified. In the present study, we report the effect of zaltoprofen on gastric blood flow (GBF) and on capacity to generate prostaglandin E2 (PGE2) in gastric mucosa of the rat. zaltoprofen (1 and 10 mg/kg, i.v.) showed no effect on the GBF, which was measured by the laser Doppler method. On the other hand, loxoprofen Na (1 mg/kg, i.v.) and diclofenac Na (10 mg/kg, i.v.) significantly decreased the GBF. Moreover loxoprofen Na (1 mg/ kg, p.o.), diclofenac Na (1 mg/kg, p.o.) and indomethacin (1 mg/kg, p.o.) significantly inhibited the gastric mucosal generation of PGE2, which was measured by the radioimmunoassay method. On the contrary, zaltoprofen (1 mg/kg, p.o.) did not inhibit the PGE2generation.These results suggest that zaltoprofen may not cause marked gastric dysfunction comparing with loxoprofen Na, diclofenac Na and indomethacin. This characteristic of zaltoprofen may be beneficial for long-term use for therapy of chronic inflammatory diseases such as rheumatoid arthritis.

Pharmacodynamics and pharmacokinetics of miloxicam in the horse

The novel non-steroidal anti-inflammatory drug (NSAID) miloxicam was administered intravenously to six New Forest ponies at a dosage rate of 0.6 mg/ kg in a two-part cross-over study. In each part, three horses received miloxicam and three were given a placebo preparation. The actions of miloxicam, compared to placebo, were assessed in a carrageenan-sponge model of acute inflammation. The rise in skin temperature over the site of the acute inflammatory reaction was less in treated ponies, but differences were not statistically significant. Concentrations of the enzymes acid phosphatase (AP) and lysozyme in inflammatory exudates harvested at 4, 8, 12 and 24 h were not significantly different in drug-treated animals compared with those receiving placebo. Concentrations of protein and lactate dehydrogenase (LDH) in exudate and exudate leucocyte numbers were significantly reduced in drug-treated horses when data for all sampling times were pooled. The differences were not significant, however, at each sampling time. Exudate concentrations of the eicosanoids, bicyclic-PGE 2, 6-keto-PGF 1α and TXB 2, were reduced significantly by miloxicam at most sampling times, and serum TXB 2 was also significantly reduced at 4 and 8 h but not at 12 and 24 h after drug administration. These pharmacodynamic findings correlated with the pharmacokinetic properties of miloxicam. The plasma concentration-time curve was defined by a three-compartment open model in one pony and by a two-compartment model in five ponies. Mean values for pharmacokinetic parameters for the five ponies were: t 1 2 α 0.40 h; t 1 2 β 2.70 h; Vdarea 0.158 l/kg; Cl B 41.87 ml/kg/h. Exudate concentrations of miloxicam were initially similar to and eventually greater than concentrations in plasma, and this may explain the more prolonged inhibition of eicosanoid synthesis in exudate than in serum. These findings demonstrate the value of relating, in a single experimental study, drug action on a range of variables to drug fate in the body.

THE EFECT OF NABUMETONE AND ITS PRINCIPAL ACTIVE METABOLITE ON IN VITRO HUMAN GASTRIC MUCOSAL PROSTANOID SYNTHESIS AND PLATELET FUNCTION

Nabumetone is a novel non-steroidal anti-inflammatory drug (NSAID) which although a weak cyclooxygenase inhibitor is converted by the liver to metabolites which are more potent inhibitors of cyclooxygenase. Nabumetone may thus avoid the occurrence of gastric erosion while maintaining its efficacy as an anti-inflammatory drug. We compared the effects of nabumetone and 6-methoxy-2-naphthylacetic acid (6MNA; the principal metabolite of nabumetone) with naproxen and indomethacin on in vitro synthesis of the gastroprotective prostaglandins I2 and E2 by human gastric mucosa. To study the effects of 6MNA on peripheral target tissues the effects of the above NSAIDs on human platelet aggregation and thromboxane A2 synthesis were also studied. Prostanoid synthesis by the human gastric mucosa was inhibited by indomethacin, naproxen and 6MNA (in this order of potency) whereas nabumetone was completely without effect. Platelet aggregation and thromboxane A2 synthesis were similarly inhibited by the NSAIDS (viz. indomethacin greater than naproxen greater than 6MNA greater than nabumetone). These results support the view that nabumetone does not inhibit gastroprotective prostanoid synthesis, whereas its active metabolite 6MNA is an effective inhibitor of prostanoid synthesis in target tissues.

Nonsteroidal Anti-Inflammatory Drug Therapy and Gastric Side Effects

Nabumetone is a novel nonsteroidal anti-inflammatory drug (NSAID) which, although a weak cyclo-oxygenase inhibitor (COI), is converted in the liver to the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), which is a more potent COI. Thus nabumetone may reduce gastric erosion while maintaining its efficacy as an anti-inflammatory drug peripherally. To investigate this novel 'prodrug' further we compared the effects of nabumetone and 6-MNA with those of naproxen and indomethacin on the synthesis of the gastroprotective prostaglandins (PG) epoprostenol (I2) and dinoprostone (E2) by rat and human gastric mucosa in vitro, and ex vivo in the rat. The effect of these NSAIDs on platelet aggregation and thromboxane A2 (TXA2) synthesis was also studied. In human and rat gastric mucosa the synthesis of epoprostenol and dinoprostone was inhibited by indomethacin, naproxen and 6-MNA (indomethacin greater than naproxen greater than 6-MNA) whereas nabumetone had no effect whatsoever. Platelet aggregation and TXA2 synthesis were inhibited in a similar manner. These results indicate that nabumetone does not inhibit gastroprotective prostaglandins, whereas its active metabolite, 6-MNA, is an effective inhibitor of prostanoid synthesis in target tissues.