Comparing turmeric, glucosamine & Ibuprofen

This report shall seek to explore the pharmacokinetics, pharmacodynamics, efficacy and side effects of the commonly prescribed drug Ibuprofen, the mode of action of turmeric and glucosamine and the potential interaction between the two nutrients and ibuprofen. The assignment shall include a section where the mode of action of the drug and nutrients will be compared and contrasted and any contaminants or contraindications will be identified and discussed.

Drug Pharmacokinetics

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) commonly prescribed and used for its anti-inflammatory, analgesic and antipyretic properties (Davies, 1998). The drug relieves pain and inflammation, muscle ache, fever, headache, dysmenorrhea and bone fractures at over-the-counter doses of 800-1200mg/day (Mazaleuskaya at al 2015) and is used for long-term treatment of other chronic inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, osteoarthritis at 8800-2400 mg/day (Rainsford 2009).

Absorption

Ibuprofen is very quickly absorbed following oral administration (Mazaleuskaya at al 2015). At therapeutic does, Ibuprofen is extensively bound to plasma proteins (Davies, 1998) and exhibits a low apparent volume of distribution that approximates plasma volume (~0.1–0.2 l/kg), but it is able to penetrate into the central nervous system and accumulate at peripheral sites where its analgesic and anti-inflammatory effects are required (Mazaleuskaya at al 2015). Both peak plasma concentrations and maximal analgesic onset are achieved within 1.5-2 hours of oral administration (Albert and Gernaat 1984) and can be reached in 45 minutes after ingestion if taken on an empty stomach (eMC 2015).

The half-life of Ibuprofen is reached in 2 hours (eMC 2015) therefore frequent administration is needed to maintain therapeutic plasma concentrations (Mazaleuskaya at al 2015). Some studies have indicated that the rates of clearance in children are higher (Rainsford 2009). However the half-life in premature neonates is around 30-45 hours following intravenous administration (Rainsford 2009).

A randomised, single-dose, 3-way crossover, open-label, single-centre, pharmacokinetic study by Dewland (2009) showed that the rate of absorption of sodium ibuprofen was twice as fast as that of the standard ibuprofen acid formulation, likely to be due to faster dissolution and more rapid availability of ibuprofen particles for absorption (Sorgel et al 2005).

Metabolism

Ibuprofen is administered as a racemic mixture (equal amounts of left- and right-handed enantiomers of a chiral molecule) of R and S enantiomers (mirror images chiral molecules), with S-ibuprofen mainly being responsible for its pharmacologic action (Davies 1998). Around 50–65% of R-ibuprofen goes through inversion to the S enantiomer through an acyl-CoA thioester by the enzyme α-methylacyl-coenzyme A racemase (encoded by gene AMACR) (Davies 1998; Lloyd et al 2013; Rudy et al 1991) systemically in the liver (Davies 1998; Hall et al 1993) and non-systemically in the intestines (Jamali et al 1992).

Iburpofen is almost fully metabolised with little or no unaffected drug in the urine (Davies 1998; Rudy et al 1991; Kepp 1997). The main CYP isoform responsible for ibuprofen clearance is CYP2C9, which catalyses the formation of 3-hydroxy-ibuprofen (most of which is converted to carboxy-ibuprofen by cytosolic dehydrogenases (Kepp1997; Hamman 1997) and 2-hydroxy-ibuprofen (Hamman 1997; Chang 2008).

Around 10-15% of a therapeutic ibuprofen dose is glucuronidated to ibuprofen-acyl glucuronide (Rudy 1991; Davies 1998) and although glucuronidation is generally considered a detoxification pathway, acyl glucuronides are possibly reactive metabolites that can be intramolecularly rearranged making them capable of binding covalently to macromolecules and contributing to toxicity (Sallustio 2000).

Distribution

Ibuprofen interacts with different classes of transporters however it is not clear which transporters aid the uptake or efflux of ibuprofen in vivo and if this influences the distribution or clearance of the drug from the body (Mazaleuskaya et al 2015). It is possible that ibuprofen may be able to cross cell membranes without transporters as it is lipid soluble as a weak acid (Davies 1998).

Excretion

Oxidative metabolism is the first route of elimination by CYP enzymes to inactive metabolites followed by urinary excretion of the two major metabolites, carboxy-ibuprofen and 2-hydroxy-ibuprofen (and their corresponding acyl glucuronides) accounting for 25% of  a dose and small amounts of other hydroxylated metabolites (3-hydroxy-ibuprofen and 1-hydroxy-ibuprofen)  (Mazaleuskaya at al 2015).

Drug Pharmacodynamics

Ibuprofen acts by inhibiting both COX-1 and COX-2 isoforms of cyclooxygenase (COX) (Rabbie et al 2014). COX-1 is involved in gastroprotection from stomach acid and in thromboxane formation by platelets, while COX-2 is influenced by inflammatory mediators in a wide range of tissues and has been associated with inflammation (Moore et al 2015).

Of the two enantiomers, S-ibuprofen is more effective at inhibiting COX enzymes than R-ibuprofen, with COX-1 having a stronger inhibitory action than COX-2 in vitro (Mazaleuskaya at al 2015).

Arachidonic acid is released from the phospholipid cell membrane by phospholipase A2, PLA2, encoded by PLA2G4A (which is cytosolic and calcium-dependent) and PLA2G2A found in platelets and synovial fluid (Mazaleuskaya at al 2015). Arachidonic acid is then converted to the unstable intermediate prostaglandin H2 by cytosolic prostaglandin G/H synthases, termed cyclooxygenases, COX, that has two types, COX-1, encoded by PTGS1 and COX-2, encoded by PTGS2 (Mazaleuskaya at al 2015). PGH2 is then converted through tissue-specific synthases to numerous prostanoids, namely PGE2, PGD2, PGF2alpha, PGI2, and TxA2 (Mazaleuskaya at al 2015).

COX-1 and COX-2 work by catalysing the production of arachidonic acid to prostanoids – prostaglandins (PG) E2, PGD2, PGF2αlpha, PGI2 – also known as prostacyclin, and thromboxane – Tx A2, which are responsible for pain and inflammation (Moore et al 2015; Mazaleuskaya at al 2015).It is believed that suppressing prostaglandin synthesis is what gives the analgesic effects of Ibuprofen (Mazaleuskaya at al 2015).

Ibuprofen’s anti-inflammatory, analgesic and antipyretic effects are achieved mainly through COX-2 inhibition (Neupert 1997) as COX-2 produces prostaglandins that act as mediators of fever, inflammation and promoters of carcinogenesis (Kawamori et al 2003; Smith 2007 et al).

Drug Efficacy

The efficacy of a substance can be seen as how well the substance does what it intends to do.

Ibuprofen is intended for rapid pain relief, so a rapid rate of absorption is needed for it to be effective. Indeed, there is a remarkable correlation between plasma ibuprofen levels and the resulting degree of analgesic effect, particularly 1 hour after administration (Laksa et al 1986) suggesting a fair general efficacy of the product.

A recent review (Conaghan 2011) of the last decade analysed the classification, recent epidemiology of use, and the comparative efficacy and toxicity of different NSAIDs, with a focus on the gastrointestinal and cardiovascular risks. It found that whilst ibuprofen faired well in terms of bioavailability – less than 80%, it had a clearance of 1.5 liters per kg and 45-79% renal elimination (Conaghan 2011). Ketoprofen however seemed to do better with 90% bioavailability, 6.9 liters per hour clearance and 80% renal elimination (Conaghan 2011). Naproxen had a higher bioavailability at 95%, 95% renal elimination, however has an enormous 12-17 hour half life allowing only 0.0078 liters per hour per kg clearance (Conaghan 2011). Other NSAIDs that did not fare as well as ibuprofen in terms of bioavailability and/or renal elimination and clearance were diclofenac, meloxicam, celecoxib and Etoricoxib (Conaghan 2011).

The majority of animal studies and the few human studies that exist suggest ibuprofen inhibits or delays fracture healing (Cottrell and O’Connor 2010) as PG2 is used to stimulate vascular changes, bone absorption, proliferation of ostergenitors, chondrogenesis, chondrolysis, bone formation and metabolism (Chang et al 2000). However, in a placebo-controlled study that compared ibuprofen to rofecoxib, a longer-term use therapeutic NSAID for rabbit fibula osteomy healing, ibuprofen treatment appeared to delay bone healing however rofecoxib treatment produced worse fracture healing likely due to continuous COX-2 inhibition rather than cyclical COX-2 inhibition with ibuprofen (O’Connor et al 2009). On the whole, these points count against the analgesic efficacy of ibuprofen in bone healing and alternatives should be considered.

Ibuprofen’s efficacy can also be determined by the bioavailability of the product. For example, whilst ibuprofen has proven efficacy in a variety of acute pain situations, Rabbie et al (2014) could find no comprehensive systematic review of the efficacy of Ibuprofen as an intervention for migraines in adults. In a review of nine randomised, double-blind, placebo or active-controlled studies they found that ‘Ibuprofen is an effective treatment for acute migraine headaches, providing pain relief in about half of sufferers, but complete relief from pain and associated symptoms for only a minority’ (Rabbie et al 2014). Numbers needed to treat (NNTs) for all efficacy outcomes were better with 400 mg than 200 mg in comparisons with placebo, and soluble formulations provided more rapid relief’ likely to do with gastrointestinal issues impairing bioavailability (Rabbie et al 2014). This demonstrates the point that ibuprofen’s efficacy is potentially to some extent reduced when the bioavailability of the product is lowered, which can be due to gut dysbiosis, motility issues, leaky gut, obstruction, lowered hydrochloric acid production and low digestive enzyme production, as well as the formulation or form (for example,.sublingual, dissolvable or capsule, tablet, liquid) of the product.

Drug Side Effects

NSAIDs in general can cause liver damage (Purcell et al 1991), renal failure (Fored et al 2001), aseptic meningitis (Nguyen & Juurlink 2004) and can interfere with bone fracture healing (Wheeler and Batt 2005).

Gastrointestinal toxicity is one of the most common side effects of Ibuprofen, most commonly from inhibition of COX-1 in the gastric mucosa (Bancos et al 2009). Furthermore therapeutic doses of ibuprofen are associated with an increased risk for gastrointestinal injury (Moore et al 2015; Conaghan 2011). Gastrointestinal injury can be worsened when combined with alcohol, selective serotonin reuptake inhibitor (SSRIs), corticosteroids and anticoagulants (Moore et al 2015).

Ibuprofen can possibly cause adverse effects on the cardiovascular system at high doses (Davies 1998) over a prolonged period of time (1 year) (García Rodríguez & González-Pérez (2005).

Furthermore, a recent meta-analysis of 280 randomised trials of NSAIDs versus placebo and 474 trials of one NSAID versus another NSAID showed that compared with placebo, high-dose ibuprofen significantly increased the risk for major coronary events (nonfatal myocardial infarction or coronary death), although the number of events was low and, similarly to other NSAIDs, was associated with increased upper gastrointestinal complications (Mazaleuskaya at al 2015). In these studies, all NSAIDs, including ibuprofen, increased the risk for heart failure twofold (Mazaleuskaya at al 2015).

Efficacy of Nutrients in Relation to Drug

Turmeric, or Curcuma longa, and glucosamine are intended for different purposes and in order for their efficacy to be analysed in relation to the drug Ibuprofen, one must consider the mode of action as discussed above, as well as understand the function of the substances which shall be discussed later in the section below.

Turmeric, a hydrophobic polyphenol, has shown a promising efficacy in patients with a number of pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, inflammatory bowel diseases, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, lupus nephritis, renal conditions many more(Gupta et al 2013).

Turmeric is safe and nontoxic at high doses having been very well established by human clinical trials (Vogel and Pelletier 1815; Gupta et al 2012) as well as highly tolerated, sometimes of up to 12g per day over 3 months, inexpensive and readily available (Gupta et al 2013). Only few studies involving small cohorts demonstrated ‘minimal toxicity’ with participants experiencing nausea, diarrhoea, headache, rash, intractable abdominal pain and yellow stool indicating ‘more studies are required to evaluate the long-term toxicity’ (Nickel and Xiang 2008; Sharma et al 2004; Epelbaum 2010: Gupta 2013).

Turmeric does, however, have poor bioavailability due to poor absorption, rapid metabolism, and rapid systemic elimination which has been shown to limit its therapeutic effectiveness (Anand et al 2007).

A study (Kuptniratsaikul et al 2014) on turmeric showed its extracts are as effective as ibuprofen for the treatment of knee osteoarthritis with turmeric showing fewer gastrointestinal adverse reactions. Also in support of this notion, another study noted ‘remarkable decreases in gastrointestinal complications, distal edema, and the use of NSAIDs/painkillers by the patients… after Meriva (turmeric)treatment… (As well as)… the need for hospital admissions, consultations, and tests’ (Gupta et al 2013; Belcaro et al 2010).

The assertions from the above two papers combined with the fact that turmeric has high antioxidant activity comparable to vitamin C of offsetting oxidative stress caused by inflammation (Motterlini et al 2000), as well as it’s added value of being potential preventative nutrient (Aggarwal and Harikumar 2009), elevates the nutrient again as an effective anti-inflammatory, especially in comparison to ibuprofen for anti-inflammatory actions related to chronic disease and injury. Fast acting analgesic effects have not been noted by the author in a wide analysis of papers although some papers have reported turmeric as an analgesic nutrient (Mahdizabeh et al 2015).

Numerous studies comparing glucosamine and NSAIDs exist, however randomised, double-blind, placebo controlled studies comparing the efficacy of the two are rare. One randomised trial involving 60 patients compared ibuprofen and glucosamine demonstrated that glucosamine sulfate is more effective and safer for treating of patients with temporomandibular joint disorders (Haghighat et al 2013). Another randomised, double-blind parallel trial of glucosamine 500 mg three times daily or a placebo for 2 months found that glucosamine was not better than the placebo in reducing osteoarthritis of the knee related pain from group of 114 patients (Rindone et al 2000).

Therefore more research is needed to be able to fully understand the efficacy of glucosamine in relation to ibuprofen and turmeric in order to make a stronger argument.

Compare and Contrast Mode of Action of Drug and Nutrient

Mode of Action of Turmeric

Turmeric, a widely studied nutraceutical (Gupta et al 2013) possess anti-inflammatory, hypoglycemic, antioxidant, wound-healing, and antimicrobial activities (Aggarwal and Sung 2009).

Turmeric is shown to be gene inlufluencing, specifically pleiotropic (influences two or more unrelated phenotypic traits ) which come from its ability to modulate many signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF–κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT (Gupta et al 2013). In particular it down regulates COX-2, lipoxygenase, and inducible nitric oxide synthase (iNOS) enzymes; Inhibition of the inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, -2, -6, -8, and -12, monocyte chemoattractant protein, and migration inhibitory protein; and down-regulates mitogen-activated and Janus kinases (Dulbecco and Savarino 2013).

COX-2 inhibition and iNOS inhibition are likely achieved via turmeric’s suppression of nuclear factor kappa B (NF-κB) activation (Dulbecco and Savarino 2013) which is a ubiquitous eukaryotic transcription factor involved in the regulation of inflammation, cellular proliferation, transformation (Satou et al 2010).

In vitro studies have found that turmeric can inhibit inflammatory cytokines by suppressing cytokine gene expression and down-regulating intercellular signaling proteins like protein kinase (Anand et al 2008).

Mode of Action of Glucosamine

Glucosamine occurs naturally in the body and has an important role in the building of cartilage (Selvan et al 2012). Glucosamine is the most essential building block for biosynthesis of the glycolipids, glycoproteins, hyaluronate, and proteoglycans compounds (Creamer and Hochberg 1997; Felson et al 1995 .) Glucosamine has a role in the synthesis of cell membrane, lining, collagen, osteoid, and bone matrix (Selvan et al 2012) and is needed to form lubricants and protective agents such as mucin and mucous secretion (Mainil-Varlet et al 2003)

Glocosamine’s mode of action in humans is relatively unknown however it has been thought for many years that its administration could give symptomatic relief for osteoarthritis sufferers by providing the mechanism for cartilage repair to improve pain and disability (Fox and Stephens 2007). Although, a few studies in humans has shown that glucosamine HCl reduces IL-1 stimulated production of catabolic enzymes and inflammatory markers like prostaglandin E2 (Nakamura et al 2004; Uitterlinden et al 2006). Animal models however have shown that glucosamine has an anti-inflammatory effect by reducing the nuclear factor kappa beta induced by interleukin-1 (IL-1) (Gouze et al 2002 & 2006).

Discussion

Studies are also now showing that daily doses of ibuprofen have a modest effect on B cell viability, proliferation and/or differentiation due to it being expressed in activated B lymphocytes (Bancos et al 2009). However, Ibuprofen has been shown to reduce IgM antibody production by up to 97% and IgG antibody production by up to 70% (with doses of 50 µM or 100 µM ) in a concentration and time-dependant manner in human peripheral blood mononuclear cells (PBMC) especially when administered in the first few days after activation (Bancos et al 2009). Furthermore ibuprofen inhibits PGE2 synthesis synthesis in a concentration-dependent manner; doses of 50 µM or 100 µM ibuprofen statistically diminished PGE2 production in human PBMC in vitro (Bancos et al 2009).

However inflammation, characterised by swelling, paid, redness and fever in response to infections, irritations or injuries, is in part mediated by PGE2 production (Davies et al 1984). Therefore ‘administration of ibuprofen during the first stages of inflammation can have repercussions on the immune system by interfering with optimal antibody production’ (Bancos et al 2014).

Furthermore, if ibuprofen inhibits COX activity and COX-2 is expressed in activated B lymphocytes and is required for optimal antibody production, it is fair to suggest that ibuprofen can have consequences on antibody synthesis (Bancos et al 2014). This has the ability to weaken the immune system which can have serious consequences for children, the elderly and immune-compromised patients (Bancos et al 2014).

With glucosamine’s mode of action being relatively unknown, an incorporation of this nutrient in a comparison with ibuprofen and turmeric’s mode of action is limited. However, with some studies demonstrating that it reduces prostaglandin E2 (Nakamura et al 2004; Uitterlinden et al 2006), the same assertion can be made regarding ibuprofen’s impact on antibody production and its indirect effects through T cells and its direct effects on B cells (X et al 2002).

It can therefore be argued that ibuprofen as well as to some extent, glucosamine, may be offsetting an inflammatory response to produce other inflammatory factors later on and somewhere else in the body. For example, if antibody IgM synthesis can be lowered due to ibuprofen use, and as this is one of the first antibodies to appear in response to exposure to an allergen, then an appropriate immunological function may not occur, thus putting the person at risk of infection. Although this has little obvious relevance on the efficacy of ibuprofen and to some extent ibuprofen in relation to its intended functions, the fact that it may have other wider reaching and systemic implications on the immunological functioning of the body promotes the choice of other more effective and less adverse effect noted drugs or nutrients over ibuprofen and possibly glucosamine.

As chronic diseases, underlined by chronic inflammation, are caused in part by the agitation of multiple signalling pathways, attacking only one pathways with a mono-targeted drug is not likely to be effective (Mencher and Wang 2005). With turmeric having the ability to modulate many signalling molecules rather than working on inhibiting one pathway, like ibuprofen does, it is fair to suggest that turmeric may be more effective at reducing inflammation than ibuprofen. This is because, when one combines this idea with the above sentiments regarding turmeric’s safety, cost and availability, turmeric seems to have the edge over ibuprofen. As Kuptniratsaikul et al 2014 demonstrates above, turmeric showed its extracts are as effective as ibuprofen with fewer gastrointestinal adverse reactions.

Contaminant Use and Contraindications of Drug with Nutrients

Gaby, 2006 in the key textbook A-Z Guide to Drug-Herb-Vitamin Interactions, asserts that turmeric has no interactions or contraindications and does not list any interactions or contraindications for glucosamine either. Ibuprofen, as listed on Health Notes on Nutri Advanced’s website does not have an interactions or contraindications with either turmeric or glucosamine.

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Pharmacology, Physiology and Pathology: Assessment I: Drug/Nutrient Interactions