Guenter Trummlitz

Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4′-isomer

Abstract.Objective and Design: Two structurally related compounds, meloxicam (Mel) and its structural 4′-isomer (4′-Mel), were compared to examine the role of a slightly different chemical structure on cyclooxygenase (COX) selectivity in in vitro and in vivo experimental models.¶Material or Subjects: In vitro studies were performed using human whole blood obtained from healthy volunteers, in vivo studies were performed in rats.¶Treatment: A concentration-response curve was obtained in the whole blood assay for Mel, 4′-Mel, indomethacin, piroxicam and diclofenac. These were used to calculate the respective IC50 values of either prostaglandin E2 (PGE2) or thromboxane B2 (TxB2). Similarly, a dose-response curve was obtained for Mel, 4′-Mel and piroxicam when measuring in vivo prostaglandin production, anti-inflammatory activity and gastric tolerance to determine the dose resulting in a 50% reduction of the each parameter.¶Methods: COX selectivity was investigated in vitro using a human whole blood assay. PGE2 synthesis in vivo was measured in inflammatory exudate, in the stomach and kidneys of rats. Anti-inflammatory effects were measured in an adjuvant arthritis model and gastric tolerance was tested in an ulcerogenicity model in vivo in rats.¶Results: In the human whole blood assay, the ratio of IC50 values for COX-1 vs. COX-2 inhibition was 13 for Mel and 1.8 for 4′-Mel. In inflammatory exudate in rats, Mel and 4′-Mel inhibited PGE2 synthesis to a similar extent, ID50 values ∼ 0.3 mg/kg. In contrast, Mel was a weaker inhibitor of PG synthesis than 4′-Mel in the rat stomach and in the rat kidney. Paw swelling was reduced by 50% with 0.1 and 0.2 mg/kg for Mel and 4′-Mel, respectively, in the rat adjuvant arthritis model. Gastric tolerance (UD50) was 2.4 mg/kg for Mel and 0.4 mg/kg for 4′-Mel.¶Conclusions: These data demonstrate that the in vitro and in vivo pharmacological profile of meloxicam is structurally dependent and that minor structural changes can lead to significant differences in the selectivity for COX-1 and COX-2 in vitro and to different profiles in vivo suggesting different therapeutic potential.

Meloxicam does not affect the antiplatelet effect of aspirin in healthy male and female volunteers.

This study determined if meloxicam, a selective cyclooxygenase (COX)‐2 inhibitor, interferes with the antiplatelet effect of aspirin using platelet aggregation and thromboxane (Tx) B2 endpoints in healthy volunteers. Eight male and 8 female volunteers participated in this open‐label, randomized, two‐treatment, two‐way crossover trial. Treatment 1 was meloxicam (15 mg qd) over 4 days, and then aspirin (100 mg qd) was ingested 2 hours after meloxicam for an additional 7 days. Blood samples were taken 2, 6, and 24 hours after the last dose. Treatment 2 consisted of only aspirin (100 mg) over 2 days. Samples were taken at the same time points. Each subject received both treatments with a 2‐week washout between the treatment periods. Treatments were safe and well tolerated. The initial 4‐day treatment with meloxicam had no effect on platelet aggregation but reduced serum TxB2 by 64% ± 19%. Addition of aspirin (100 mg qd) for 7 days resulted in complete inhibition of aggregation and TxB2 for 24 hours. Two‐day treatment with only 100 mg aspirin also resulted in complete inhibition of platelet aggregation and TxB2. These results indicate that meloxicam does not affect the ability of aspirin to inhibit COX‐1 in platelets, thereby allowing aspirin to effectively prevent platelet aggregation and reduce TxB2 levels, and that meloxicam is selective for COX‐2

The molecular and biological basis for COX-2 selectivity

Before the development of the first three-dimensional structure of cyclooxy-genase (COX) [1], it was difficult to understand why very chemically diverse inhibitors acted via similar mechanisms at this same enzyme. The information from X-ray analyses and from mutagenesis experiments now allow us to use molecular modelling approaches to gain insight into the molecular mechanism of selective COX-2 inhibition by at least eight different structural classes of inhibitors. The particular advantage of molecular modelling approaches is that they allow us to visualize and rationalize the recognition process of substrates and inhibitors by COX isoenzymes [2].