Lúcio M, Ferreira H, Lima José L F C, Reis Salette
Departamento de química Física, Faculdade de Farmácia da Universidade do Porto. Rua Aníbal Cunha, 164, 4050-047 Porto, Portugal.
Med Chem. 2006 Sep;2(5):447-56. doi: 10.2174/157340606778250199.
Meloxicam was launched as a major new NSAID for the treatment of arthritis following extensive published research confirming its selectivity for COX-2. Several studies proposed possible explanations for its effectiveness and superior safety profile. The proposed theories included chemical structural relationships between meloxicam and other effective NSAIDs with low gastrointestinal toxic effects. However, other oxicams have similar chemical groups, but despite this, are not considered COX-2 selective drugs and exhibit less gastric tolerance. Hence, the aim of this work was to investigate the interactions between oxicams and biomembrane models as it could influence their resorption from the upper gastrointestinal tract and may affect their local gastromucosal tolerability. The partition of oxicams within membranes was determined by calculating their partition coefficients between liposomes and water. Moreover, their location within the bilayer was determined by fluorescence quenching. Finally, zeta-potential measurements were made to complete the information about the binding behaviour of the oxicams and steady-state anisotropy measurements were made to determine their induced perturbation in membrane structure. These studies proved that, in spite of structural similarities, oxicams present different interactions with membranes making possible a virtual division of the class in two groups. Tenoxicam and piroxicam known as COX-1 inhibitors demonstrated higher partition capacity in liposomes/water systems together with a smaller ability to change the membrane fluidity and surface potential. In contrast lornoxicam and meloxicam, which demonstrated activity against COX-2, have revealed smaller partition capacity in liposomes/water systems together with a higher ability to change the membrane fluidity and surface potential.
美洛昔康作为一种主要的新型非甾体抗炎药被推出，用于治疗关节炎，此前大量已发表的研究证实了其对COX - 2的选择性。多项研究对其有效性和卓越的安全性提出了可能的解释。提出的理论包括美洛昔康与其他胃肠道毒性低的有效非甾体抗炎药之间的化学结构关系。然而，其他昔康类药物具有相似的化学基团，但尽管如此，它们不被认为是COX - 2选择性药物，并且对胃的耐受性较低。因此，这项工作的目的是研究昔康类药物与生物膜模型之间的相互作用，因为这可能会影响它们从上消化道的吸收，并可能影响它们对局部胃黏膜的耐受性。通过计算昔康类药物在脂质体和水之间的分配系数来确定其在膜内的分配情况。此外，通过荧光猝灭确定它们在双分子层中的位置。最后，进行ζ电位测量以完善关于昔康类药物结合行为的信息，并进行稳态各向异性测量以确定它们对膜结构的诱导扰动。这些研究证明，尽管结构相似，但昔康类药物与膜的相互作用不同，使得该类药物实际上可分为两组。作为COX - 1抑制剂的替诺昔康和吡罗昔康在脂质体/水体系中表现出更高的分配能力，同时改变膜流动性和表面电位的能力较小。相比之下，对COX - 2有活性的氯诺昔康和美洛昔康在脂质体/水体系中的分配能力较小，同时改变膜流动性和表面电位的能力较高。
