Piroxicam-β-Cyclodextrin: A GI Safer Piroxicam

Abstract

Although NSAIDs are very effective drugs, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin and gut. Gastrointestinal (GI) side effects are the most common and constitute a wide clinical spectrum ranging from dyspepsia, heartburn and abdominal discomfort to more serious events such as peptic ulcer with life-threatening complications of bleeding and perforation. The appreciation that CV risk is also increased further complicates the choices of physicians prescribing anti-inflammatory therapy. Despite prevention strategies should be implemented in patients at risk, gastroprotection is often underused and adherence to treatment is generally poor. A more appealing approach would be therefore to develop drugs that are devoid of or have reduced GI toxicity. Gastro-duodenal mucosa possesses many defensive mechanisms and NSAIDs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. NSAIDs cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and systemic inhibition of gastric mucosal protection, through inhibition of cyclooxygenase (COX, PG endoperoxide G/H synthase) activity of the GI mucosa. However, against a background of COX inhibition by anti-inflammatory doses of NSAIDs, their physicochemical properties, in particular their acidity, underlie the topical effect leading to short-term damage. It has been shown that esterification of acidic NSAIDs suppresses their gastrotoxicity without adversely affecting anti-inflammatory activity. Another way to develop NSAIDs with better GI tolerability is to complex these molecules with cyclodextrins (CDs), giving rise to so-called “inclusion complexes” that can have physical, chemical and biological properties very different from either those of the drug or the cyclodextrin. Complexation of NSAIDs with β-cyclodextrin potentially leads to a more rapid onset of action after oral administration and improved GI tolerability because of minimization of the drug gastric effects. One such drug, piroxicam-β-cyclodextrin (PBC), has been used in Europe for 25 years. Preclinical and clinical pharmacology of PBC do show that the β-cyclodextrin inclusion complex of piroxicam is better tolerated from the upper GI tract than free piroxicam, while retaining all the analgesic and anti-inflammatory properties of the parent compound. In addition, the drug is endowed with a quick absorption rate, which translates into a faster onset of analgesic activity, an effect confirmed in several clinical studies. An analysis of the available trials show that PBC has a GI safety profile, which is better than that displayed by uncomplexed piroxicam. Being an inclusion complex of piroxicam, whose CV safety has been pointed out by several observational studies, PBC should be viewed as a CV safe anti-inflmmatory compound and a GI safer alternative to piroxicam. As a consequence, it should be considered as a useful addition t...

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“…[10] Cyclodextrins (CDs) are cyclic oligosaccharides consisting of six (a CD), seven (b CD), eight (g CD), or more glucopyranose units linked by a-(1, 4) bonds. [11] CDs can interact with drug molecules to form inclusion complexes, major changes in drug properties such as enhanced solubility, chemical stability, physical profile, and pharmacological bioavailability have been reported. [12][13][14] Therefore, CDs are widely used in the preparation of various pharmaceutical products.…”

Enhanced analgesic activity by cyclodextrins – a systematic review and meta-analysis

“…In addition, the PX-bCD complexes considerably increase the water solubility as well as the rate of dissociation of poorly soluble PX, leading to a higher rate of gastrointestinal absorption than PX [46,47]. Thus, the rapid onset of action, the long duration of activity, the favorable risk-benefit ratio and less gastrointestinal injury are the major clinical advantages of PX-bCD [12,48,49].…”

“…The sugar units adapt to a 4 C 1 chain conformation and are orientated in such a way that the molecule forms a toroidal truncated cone structure [12,13]. CDs are pharmaceutically useful due to the fact that they can interact with drug molecules to form inclusion complexes.…”

Comparative Study on the Effect of Matricaria chamomile and Achillea millefolium Capsules on Primary Dysmenorrhea Intensity of Dormitory Students of Kurdistan University of Medical Sciences, 2018

“…According to the results of the study, painful menstruation has led to a loss of 140 million working hours in the United States [9] and they estimated that the economic loss from one day of absence in japan could be about $ 4.2 billion [10]. The most common treatments used in this area are non-steroidal anti-inflammatory chemicals and oral contraceptives [11]; but longterm use of steroidal drugs and birth control pills is associated with side effects such as damage to the liver, kidneys, skin, intestines, Gastrointestinal bleeding and myocardial infarction [12,13], depression, loss of libido, and discontinuation of menstrual bleeding [14]. Currently, due to the apparent effects of chemical drug abuse, the willingness of people to use herbs has increased dramatically [15].…”