Copper complexes of non-steroidal anti-inflammatory drugs: an opportunity yet to be realized

Abstract

The proposed curative properties of Cu-based non-steroidal anti-inflammatory drugs (NSAIDs) have led to the development of numerous Cu(II) complexes of NSAIDs with enhanced anti-inflammatory activity and reduced gastrointestinal (GI) toxicity compared with their uncomplexed parent drug. These low toxicity Cu drugs have yet to reach an extended human market, but are of enormous interest, because many of today's anti-inflammatory drug therapies, including those based on the NSAIDs, remain either largely inadequate and/or are associated with problematic renal, GI and cardiovascular side effects. The origins of the anti-inflammatory and gastric-sparing actions of Cu-NSAIDs, however, remain uncertain. Their ability to influence copper metabolism has been a matter of debate and, apart from their frequently reported superoxide dismutase (SOD)-like activity in vitro, relatively little is known about how they ultimately regulate the inflammatory process and/or immune system. Furthermore, little is known of their pharmacokinetic and biodistribution profile in both humans and animals, stability in biological media and pharmaceutical formulations, or the relative potency/efficacy of the Cu(II) monomeric versus Cu(II) dimeric complexes. The following review will not only discuss the etiology of inflammation, factors influencing the metabolism of copper and historical overview of the development of the Cu-NSAIDs, but also outline the structural characteristics, medicinal and veterinary properties, and proposed modes of action of the Cu-NSAIDs. It will also compare the SOD, anti-inflammatory and ulcerogenic effects of various Cu-NSAIDs. If the potential opportunities of the Cu-NSAIDs are to be completely realized, a mechanistic understanding and delineation of their in vivo and in vitro pharmacological activity is fundamental, along with further characterization of their pharmacokinetic/pharmacodynamic disposition.

Introduction

The medicinal properties of both Cu and the anti-inflammatory agent salicin, a glycoside of salicylic acid (and prototype of many of today's non-steroidal anti-inflammatory drugs (NSAIDs)) (Fig. 1) have been known for thousands of years [1], [2], [3], [4]. Extracts of willow, a source of salicin, were used for the relief of pain and fever by the physicians Hippocrates (∼460–377 BC) and Dioscorides (∼40–90 AD) [1], [3], [5], [6]. Chewing willow leaves was recommended for analgesia in childbirth and a decoction of myrtle or willow leaves was a therapeutic treatment for joint pain [5]. Salicylic acid was first purified from salicin in 1838 [7]. Aspirin (AspH=acetylsalicylic acid), the first commercially available NSAID, was introduced into medicine by Frederick Bayer & Company in 1889 [8], [9].

As early as 3000 BC, the Egyptians used Cu as an antiseptic to sterilize drinking water [10]. The Papyus Ebers (∼1550 BC) describes the medicinal use of Cu-containing ointments [11], [12] and the Cu bracelet has long been used as a folk remedy for the treatment of arthritis [13]. The curative properties of Cu-based NSAIDs is not, therefore, without historical reference and has led to the development of numerous Cu(II) complexes of NSAIDs [14], [15], [16], [17], [18]. These are reported to have enhanced anti-inflammatory activity and reduced gastrointestinal (GI) toxicity compared with the parent constituents [10], [19], [20].

Despite the long history of the Cu-NSAIDs, they are yet to make a significant impact on the human market. Notwithstanding such intense interest, little is known about their mechanism(s) of action, pharmacology and disposition in biological matrices. The following review will, therefore, not only give an overview of the development of the Cu-NSAIDs, including a brief description of the etiology of inflammation, major shortcomings with the clinical application of the traditional NSAIDs, e.g. GI and renal toxicity, mode of action of the traditional NSAIDs and the role of Cu in inflammation, but will also discuss the proposed pharmacology and medicinal and veterinary properties of the Cu-NSAIDs. A comparison of the superoxide dismutase (SOD) activity, and the anti-inflammatory and ulcerogenic effects of various Cu-NSAIDs will be described, along with an outline of the solid-state structural characteristics of the Cu-NSAIDs.