Non-steroidal Anti-inflammatory Drug Molecules Research Articles

Engineering NSAIDs imprinted UiO-66s for markedly enhanced adsorption of coexisting diclofenac sodium and Cu(II) and their synergistic adsorption mechanism

Competitive adsorption of complex nonsteroidal anti-inflammatory drugs (NSAIDs) from wastewater often reduces the adsorption capacity of object pollutants on most porous materials. To addressthis issue, NSAIDs molecules were proposed for engineering imprinted pores in UiO-66s to boost their adsorption capacity towards diclofenac sodium (DCF)and Cu(II) in a complex solution. Naproxen (NAP) with proper chemical structure was proved to introduce more imprinted pores (at ~19 Å) with enhanced mesoporous volume, abundant unsaturated metal sites, and terminal hydroxyl groups in UiO-66@NAP. These new intriguing properties awarded high adsorption affinity to UiO-66@NAP for DCF and Cu(II), and their adsorption capacities reached up to 385 and 52 mg/g for single DCF and Cu(II) components, respectively. When DCF and Cu(II) simultaneously appeared in an aqueous solution, DCF was proved to preferentially occupy adsorption sites on UiO-66@NAP with higher adsorption kinetics compared to Cu(II). Afterwards, these pre-adsorbed DCF acted as new adsorption sites to bridge more Cu(II) in the solution. Similarly, the adsorbed Cu(II) on UiO-66@NAP had the same reciprocal bridging effect towards DCF, which realized the synergistic adsorption of DCF and Cu(II) over UiO-66@NAP. Notably, DCF was found to greatly boost the synergistic effect of the Cu(II) adsorption. As a result, UiO-66@NAP exhibited 1.5 and 2.6 times higher uptakes for DCF (573 mg/g) and Cu(II) (135 mg/g) in the binary system compared to their single pollutant system, and its equilibrium adsorption capacity was much higher compared to several state-of-the-art adsorbents. The current work set out a new strategy to modify MOFs for enhanced adsorption of complex NSAID contaminants and revealed a deep understanding of the interactions between NSAIDs and heavy metals ions.

Non-steroidal anti-inflammatory drugs at embryo transfer on pregnancy rates in cows: A meta-analysis

Non-steroidal anti-inflammatory drugs (NSAIDs) at the time of embryo transfer (ET) are commonly used to improve pregnancy rates in cows. A meta-analysis was conducted on 16 trials from 9 publications involving control (n = 2335) and NSAID-treated (n = 2849) cows. The meta-analysis explained the relative risk (RR) with its 95% confidence interval (CI) for pregnancy per embryo transfer (P/ET) after NSAID treatment under various circumstances. NSAID treatment with was associated on average with a 15% higher P/ET compared to no treatment (RR = 1.15, 95% CI = 1.07 to 1.2). The results also highlight that the use of NSAIDs at the time of ET was particularly effective in cows with difficulty in passing the catheter from the cervix during ET, with 71% more likely P/ET (RR = 1.71, 95% CI = 1.07 to 2.74) with the use of NSAIDs for these cows compared to other cows. The data were too limited to analyse the influence of NSAID molecules (flunixin meglumine [FM] and meloxicam), cyclooxygenase (COX) inhibitor type (non-selective COX inhibitor [both COX-1 and COX-2] and selective COX inhibitor [only COX-2]), embryo processing (embryo production, embryo conservation and embryo quality), stress, synchronization, breed and parity on the relationship between NSAIDs and P/ET.

The chemoreactomic analysis of the central mechanisms of action of non-steroidal anti-inflammatory drugs

To perform a chemoreactome modeling of the pharmacological central effects of 4 non-steroidal anti-inflammatory drugs (NSAIDs): dexketoprofen, ketoprofen, aceclofenac, lornoxicam. An analysis of the pharmacological spectrum of the central action of dexketoprofen, ketoprofen, aceclofenac and lornoxicam was based on the chemoinformatic approach, which compared drug-likeness properties with public and commercial software. The effectiveness of NSAIDs is related to the inhibition of cannabinoid receptors CB-1, the vanilloid receptor TRPV1, NMDA and AMPA receptors and of the GABA reuptake transporter, with dexketoprofen being the most effective inhibitor. The safety of the central effects of NSAID is due to weak interactions of the NSAIDs studied with opioid, adrenergic, serotonin and dopamine receptors. Chemoreactome modeling made it possible to compare the particulars of the effects of the studied NSAIDs on experimental pain and cramps. Inhibition of CB-1, TRPV1, NMDA, AMPA, GABA transporter by the NSAID molecules corresponds to a decrease in the intensity of nociceptive signals. A weak intervention of the studied NSAIDs in opioid, adrenergic, serotonin and dopaminergic neurotransmission corresponds to a decrease in the central side-effects of NSAIDs and to a lessened antagonism of these NSAIDs towards exogenous and endogenous opioids.

Effect of thermolysis condition on characteristics and nonsteroidal anti-inflammatory drugs (NSAIDs) absorbability of Fe-MIL-88B-derived mesoporous carbons

Discharge of nonsteroidal anti-inflammatory drugs (NSAIDs) from wastewater has been increasingly alarmed, led to the advent of the treatment techniques. Among these methods, adsorption is regarded as a tunable and green approach with the utilization of mesoporous carbon (MC) as an efficient and recyclable adsorbent. Herein, we described the strategy for the synthesis of novel MC from Fe-MIL-88B as a self-sacrificial template. Three thermolysis temperatures (550, 750, and 950 °C) were investigated to compare the structural characteristics and absorbability towards selected NSAIDs compounds including diclofenac sodium (DCF), aspirin (APR), and ibuprofen (IBU). Effect of contact time (0–480 min), concentration (10–40 mg/L), pH (2–10), and MC dosage (0.1–0.5 g/L) was systematically studied. Kinetic and isotherm models were also used to find out the adsorption mechanism and behavior of NSAIDs pharmaceutical over MC materials. Proposed mechanism and recyclability test were rigorously studied to gain more insight into how the NSAIDs molecules adsorb on the MC materials and their potential towards drug treatment.

Design of l-Lysine-Based Organogelators and Their Applications in Drug Release Processes.

This work reports on the synthesis of three new l-lysine-based organogelators bis(N2-alkanoyl-N6-l-lysyl ethylester)oxalylamides, where alkanoyls are lauroyl, myristoyl, and palmitoyl. The gels of these gelators were prepared with high yields in eco-friendly solvents commonly used in cosmetics such as ethyl and isopropyl esters of lauric and myristic acids, liquid paraffin, 1-decanol, and 1,2-propanediol. Fourier transform infrared measurements revealed the involvement of intermolecular hydrogen bonds in the gelation. Scanning electron microscopy images of xerogels indicated different morphologic patterns with regard to the alkanoyl chain length and the solvent employed in their preparation. The gel formation was supported by rheological measurements. Three gels prepared in liquid paraffin were loaded with naproxen (Npx) with a quite high loading capacity (up to 166.6% as percentage of gelator) without gel disruption. The release of Npx from the gel matrix into the buffered solution at physiologic pH was evaluated using UV–vis spectroscopy. The results revealed that the release rate of Npx from the organogels significantly retarded with increasing organogelator concentration, whereas it enhanced with increasing Npx concentration. The rate was also found to be pH-dependent; the lower the pH, the lower the rate. Furthermore, molecular dynamic calculations performed on the octamer of myristoyl-bearing gelator (N2M/N6Lys) in 1,2-propanediol provided useful information regarding the structural properties of the gels, which may be of interest to interpret the structure of the gel matrix. Altogether, this work provided valuable outcomes, which may be relevant to the pharmaceutical industry. It may be suggested that l-lysine-based gels have potentials in the delivery of nonsteroidal anti-inflammatory drug molecules. Besides, the release of the drug can be fine-tuned by the correct choice of gelator–solvent combination.

Molecular interaction between nonsteroidal anti-inflammatory drug molecules with cucurbit[7]uril estimated by spectroscopy and calorimetry

Abstract The supramolecular interaction of nonsteroidal anti-inflammatory drug molecules with macrocyclic hosts is one of the interesting areas of research. In this study the interaction of Indomethacin and Acemetacin with macrocyclic cucurbit[7]uril in aqueous medium is reported. The supramolecular interaction of the drug molecules with macrocyclic host have been studied by using the steady state absorption, fluorescence, time resolved fluorescence emission spectroscopy and isothermal titration calorimetry. The modulation of spectral features of the drug molecules on addition of cucurbit[7]uril indicates that the interaction takes place between the drug molecules with cucurbit[7]uril, respectively. Indomethacin and Acemetacin form 1:1 complex with cucurbit[7]uril. The binding strength and stoichiometry of the drug molecules with cucurbit[7]uril have been estimated by using fluorescence and isothermal titration calorimetry measurements, respectively. The driving forces involved for the complexation of both the drug molecules with cucurbit[7]uril have been obtained from isothermal titration calorimetry measurement. This study will be helpful to get the knowledge about the modulation of photophysical properties of the studied drugs on addition of macrocyclic host cucurbit[7]uril. The changes in thermodynamic properties due to the complexation of the drug molecules with cucurbit[7]uril help to understand about the governing parameters involved in this complexation. This study will be helpful for the use of cucurbit[7]uril as a potential drug delivery system.

THE EUROPEAN SOCIETY FOR CLINICAL AND ECONOMIC ASPECTS OF OSTEOPOROSIS AND OSTEOARTHRITIS (ESCEO) ALGORITHM FOR THE MANAGEMENT OF KNEE OSTEOARTHRITIS IS APPLICABLE TO RUSSIAN CLINICAL PRACTICE: A CONSENSUS STATEMENT OF LEADING RUSSIAN AND ESCEO OSTEOARTHRITIS EXPERTS

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for the management of knee osteoarthritis (OA), published in December 2014, provides practical guidance for the prioritization of interventions. This current paper represents an assessment and endorsement of the algorithm by Russian experts in OA for use in Russian clinical practice, with the aim of providing easy-to-follow advice on how to establish a treatment flow in patients with knee OA, in support of the clinicians’ individualized assessment of the patient. Medications recommended by the ESCEO algorithm are available in Russia. In step 1, background maintenance therapy with symptomatic slow-acting drugs for osteoarthritis (SYSADOA) is advised, for which high-quality evidence is provided only for the formulations of patented crystalline glucosamine sulphate (pCGS) (Rottapharm/Meda) and prescription chondroitin sulfate. Paracetamol may be added for rescue analgesia only, due to limited efficacy and increasing safety signals. Topical non-steroidal anti-inflammatory drugs (NSAIDs) may provide additional symptomatic treatment with the same degree of efficacy as oral NSAIDs but without the systemic safety concerns. To be effective, topical NSAIDs must have high bioavailability, and among NSAIDs molecules like etofenamate have high absorption and bioavailability alongside evidence for accumulation in synovial tissues. Oral NSAIDs maintain a central role in step 2 advanced management of persistent symptoms. However, oral NSAIDs are highly heterogeneous in terms of gastrointestinal and cardiovascular safety profile, and patient stratification with careful treatment selection is advocated to maximize the risk: benefit ratio. Intra-articular hyaluronic acid as a next step provides sustained clinical benefit with effects lasting up to 6 months after a short-course of weekly injections. As a last step before surgery, the slow titration of sustained-release tramadol, a weak opioid, affords sustained analgesia with improved tolerability.

Organogels as novel carriers for dermal and topical drug delivery vehicles

Aminoalcohol based bis-(aminoalcohol)oxalamides (BAOAs) (1,6-amino alcohol=leucinol, isoleucinol, valinol, phenylglycinol, phenylalaninol and 2-amino-1-butanol) have been explored to develop drug depot systems and illustrated as a novel dermal and topical drug delivery vehicle for non-steroidal anti-inflammatory drug molecules. FAE's (Fatty acid ethyl and isopropyl esters) with different chain lengths, ethyl laurate, ethyl myristate, ethyl palmitate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, have been chosen as they are biocompatible organic fluids used typically in cosmetic industry. Ibuprofen (Ib), acting as a model drug, was entrapped in the supramolecular organogels. The release behavior of Ib molecules in the supramolecular organogels was investigated by using UV–vis spectroscopy. The influence of the organogelator and drug concentration, pH values of the accepting media, and nature of solvent (different FAE's) on the release behavior of Ib was investigated under static conditions. The results indicated that the release rate of Ib from the supramolecular organogels was effectively retarded with an increase of the organogelator concentration. Also, the release rates of Ib increased on increasing the Ib content. Furthermore, the release behavior of Ib was found to be different at various pH values in buffers as accepting media. The study of the release kinetics indicated that the release behavior of Ib was in accord with the Higuchi equation and the diffusion-controlled mechanism involved in the Fickian model. These observations indicate that bis-(aminoalcohol)oxalamides gels may act as delivery vehicles for non-steroidal anti-inflammatory drug molecules and also show that the release profiles for such systems can be fine-tuned by the correct choice of gelator-FAE combination.

Development and therapeutic potential of NOSH‐NSAIDs: A new class of anti‐inflammatory pharmaceuticals

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are mainly used to treat pain, reduce fever and inflammation; some also have utility as anti‐platelet agents. There is also a large body of data supporting the notion that NSAIDs are important for cancer prevention. However, their long‐term use is problematic on two accounts: (1) suboptimal efficacy, which is less than 50% and (2) side effects including gastrointestinal, cardiovascular, and renal, which precludes their widespread use. In our search for a “better NSAID”, we developed NOSH‐NSAIDs. These are regular NSAIDs such as aspirin, naproxen, sulindac and others to which nitric oxide (NO) and hydrogen sulfide (H2S) releasing moieties have been covalently attached. Both NO and H2S are gaseous signaling molecules of biological importance. The rational for incorporating these gaseous mediators into NSAID molecules was based on the observations that NO and H2S have some of the same properties as prostaglandins within the gastric mucosa, thus modulating some components of the local mucosal defense systems which should lead to reduced gastrointestinal toxicity and also should embark enhanced cardiovascular and renal safety profiles because NO and H2S have protective roles in the cardiovascular and renal systems. To date we have reported on the synthesis and some general characterizations of three such compounds. NOSH‐aspirin (NBS‐1120), NOSH‐naproxen (AVT‐219), and NOSH‐sulindac (AVT‐18A) have enhanced GI profiles yet they retain all the basic pharmacological activities of their respective native NSAID. Furthermore, we have also reported that these compounds are orders of magnitude more potent than their corresponding NSAID in inhibiting the growth of adenomatous, epithelial, and lymphocytic cancer cell lines, thus demonstrating a generalized property that was tissue‐type independent. In vivo, NBS‐1120 was shown to have chemo‐preventive properties that were superior to aspirin and AVT‐219 was shown to have chemotherapeutic properties. Of interest is also the observation that NBS‐1120 showed synergistic activity with 5‐flurouracil, an established chemotherapeutic agent, in inhibiting colon cancer cell growth. Encouraged by our initial observations, we have formed a company, Avicenna Pharmaceuticals, Inc., around this technology and have forged a path towards an IND application and phase‐1 clinical trials, hopefully to bring these compounds into the clinic.

Coordination Polymers Derived from Non-Steroidal Anti-Inflammatory Drugs for Cell Imaging and Drug Delivery.

A new series of Mn(II) coordination polymers, namely, [{Mn(L)(H2 O)2 }⋅2 Nap]∞ (CP1), [{Mn(L)(Ibu)2 (H2 O)2 }]∞ (CP2), [{Mn(L)(Flr)2 (H2 O)2 }]∞ (CP3), [{Mn(L)(Ind)2 (H2 O)2 }⋅H2 O]∞ (CP4), [{Mn2 (L)2 (μ-Flu)4 (H2 O)}⋅L]∞ (CP5), [{Mn2 (L)2 (μ-Tol)4 (H2 O)2 }]∞ (CP6) and [{Mn2 (L)2 (μ-Mef)4 (H2 O)2 }]∞ (CP7) (Nap=naproxen, Ibu=ibuprofen, Flr=flurbiprofen, Ind=indometacin, Flu=flufenamic acid, Tol=tolfenamic acid and Mef=mefenamic acid) derived from various non-steroidal anti-inflammatory drugs (NSAIDs) and the organic linker 1,2-bis(4-pyridyl)ethylene (L) have been synthesized with the aim of being used for cell imaging and drug delivery. Single-crystal X-ray diffraction (SXRD) studies revealed that the NSAID molecules were part of the coordination polymeric network either through coordination to the metal center (in the majority of the cases) or through hydrogen bonding. Remarkably, all the Mn(II) coordination polymers were found to be soluble in DMSO, thereby making them particularly suitable for the desired biological applications. Two of the coordination polymers (namely, CP1 and CP3) reported herein, were found to be photoluminescent both in the solid as well as in the solution state. Subsequent experiments (namely, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and PGE2 (prostaglandin E2 ) assays) established their biocompatibility and anti-inflammatory response. In vitro studies by using a macrophage cell line (i.e., RAW 264.7) revealed that both CP1 and CP3 were excellent cell imaging agents. Finally, biodegradability studies under simulated physiological conditions in phosphate-buffered saline (PBS) at pH 7.6 showed that slow and sustained release of the corresponding NSAID was indeed possible from both CP1 and CP3.

Biological evaluation of bismuth non-steroidal anti-inflammatory drugs (BiNSAIDs): Stability, toxicity and uptake in HCT-8 colon cancer cells

Recent studies showed that the metal-coordinated non-steroidal anti-inflammatory drug (NSAID), copper indomethacin, reduced aberrant crypt formation in the rodent colon cancer model, while also exhibiting gastrointestinal sparing properties. In the present study, the stability and biological activity of three BiNSAIDs of the general formula [Bi(L)3]n, where L=diflunisal (difl), mefenamate (mef) or tolfenamate (tolf) were examined. NMR spectroscopy of high concentrations of BiNSAIDs (24h in cell medium, 37°C) indicated that their structural stability and interactions with cell medium components were NSAID specific. Assessment of cell viability using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium]bromide (MTT) assay showed that the toxicity ranking of the BiNSAIDs paralleled those of the respective free NSAIDs: diflH<mefH<tolfH. While the IC50 values of the BiNSAIDs (ranging between 16 and 81μM) were lower than the free NSAIDs, it was apparent that the toxicity of the BiNSAIDs was due to the molar ratio of the three NSAID molecules contained in the BiNSAIDs, with the exception of [Bi(difl)3]. The highest cellular bismuth content was observed following treatment with [Bi(tolf)3]. Since NMR studies indicated that [Bi(tolf)3] was the most stable BiNSAID and that cellular uptake of bismuth correlated with structural stability it appears that bismuth uptake is assisted by the NSAID. Microprobe SR-XRF imaging showed that the intracellular fate of bismuth was independent of the specific BiNSAID treatment whereby all BiNSAID-treated cells showed bismuth accumulation in the cytoplasm within 24-h exposure. The size and location of the hot spots (0.3–5.8μm2), were consistent with cellular organelles such as lysosomes.

2-Hydroxy Arachidonic Acid: A New Non-Steroidal Anti-Inflammatory Drug

BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) are a family of COX1 and COX2 inhibitors used to reduce the synthesis of pro-inflammatory mediators. In addition, inflammation often leads to a harmful generation of nitric oxide. Efforts are being done in discovering safer NSAIDs molecules capable of inhibiting the synthesis of pro-inflammatory lipid mediators and nitric oxide to reduce the side effects associated with long term therapies.Methodology/Principal FindingsThe analogue of arachidonic acid (AA), 2-hydroxy-arachidonic acid (2OAA), was designed to inhibit the activities of COX1 and COX2 and it was predicted to have similar binding energies as AA for the catalytic sites of COX1 and COX2. The interaction of AA and 2OAA with COX1 and COX2 was investigated calculating the free energy of binding and the Fukui function. Toxicity was determined in mouse microglial BV-2 cells. COX1 and COX2 (PGH2 production) activities were measured in vitro. COX1 and COX2 expression in human macrophage-like U937 cells were carried out by Western blot, immunocytochemistry and RT-PCR analysis. NO production (Griess method) and iNOS (Western blot) were determined in mouse microglial BV-2 cells. The comparative efficacy of 2OAA, ibuprofen and cortisone in lowering TNF-α serum levels was determined in C57BL6/J mice challenged with LPS. We show that the presence of the –OH group reduces the likelihood of 2OAA being subjected to H* abstraction in COX, without altering significantly the free energy of binding. The 2OAA inhibited COX1 and COX2 activities and the expression of COX2 in human U937 derived macrophages challenged with LPS. In addition, 2OAA inhibited iNOS expression and the production of NO in BV-2 microglial cells. Finally, oral administration of 2OAA decreased the plasma TNF-α levels in vivo.Conclusion/SignificanceThese findings demonstrate the potential of 2OAA as a NSAID.

Abstract 1941: Development of novel NSAID conjugated molecules for lung cancer therapy

Abstract Background: Many promising chemopreventive Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as Flurbiprofen have acquired anti-cyclooxygenase 2 (COX2) effects with anti-cancer activities. Recently several phosphorylated-NSAID compounds were shown to improve the therapeutic potency over the parental NSAID molecules (JPET 111.183533, 2011) by 10 to 30 folds. Previously, we also reported several novel and potent molecules by the incorporation of NSAIDs such as aspirin, indomethancin, ketorolac, ketoprofen, and sulindac into the aclyting N-terminal of our lead mimetic molecules B317 (F5C-OC2Y-Atmp) (AACR 45: 476, 2004). Here we report a new series of highly potent molecules by replacing the N-terminal F5C with a flurbiprofen (Fbp). The resultant molecules effectively inhibit many cancer cell lines in vitro and in vivo, with efficacy much better than the unmodified parental NSAID molecules or those phosphorylated NSAID analogs. Methods: Standard MTT assays were used to access growth inhibitory effects of the parental and NSAID conjugated molecules. Effects of drugs on cell cycle and apoptosis were analyzed by flow cytometry. In vivo efficacy was evaluated in subcutaneous lung xenografts in athymic nude mice. Results: 32 lung cancer cell lines including 24 NSCLC and 8 SCLC cell lines were treated with various concentrations of some selected conjugated drugs for 4 days. The best compound had an average IC 50 value of 0.5 uM, with a range of 0.1 to 2 uM, while parental Flurbiprofen had IC50 value of 500 uM, with a range of 200 uM to 800uM. Cell cycle analysis showed that exposure of lung cancer cells to these new conjugates resulted in a significant shift of cells from S and G2 phases into G1 arrest, resulting in high percentage of apoptotic cell deaths in a dose- and time-dependent manner. Finally, our in vivo efficacy studies demonstrated that new NSAID conjugates at 5 mg/kg by daily ip injections significantly suppressed growth of subcutaneous xenografts of human lung adenocarcinoma in athymic nude mice without causing weight loss. Conclusion: Our new NSAID conjugate is a novel class of therapeutic agent with anti-growth effects against lung cancer cells in vitro and in vivo, with a 1000 fold increase in potency than the parental Flurbiprofen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1941. doi:1538-7445.AM2012-1941

Comparative Model Studies of Gastric Toxicity of Nonsteroidal Anti-Inflammatory Drugs

A high percentage of people treated with a long-term nonsteroidal anti-inflammatory drug (NSAID) therapy suffer NSAID-induced gastrointestinal-tract-related side effects. A current hypothesis states that the side effects are related to the topical action of NSAID molecules on gastric mucus that lowers its resistance to luminal acid. The main lipids in human mucus are palmitoyloleoylphosphatidylcholine (POPC) and cholesterol (Chol). In this study, both X-ray diffraction and molecular dynamics (MD) simulation methods were employed to investigate the effects of selected NSAIDs in protonated and deprotonated states on the structural parameters of a POPC-Chol bilayer. The drugs were three commonly used NSAIDs with apparently different gastric toxicity: ketoprofen (KET), aspirin (ASP), and piroxicam (PXM). Both methods revealed that the effects of the NSAIDs on the POPC-Chol bilayer parameters were moderate and only slightly differentiated among the drugs. Much larger differences among the drugs were noticed in their interactions with interfacial water and Na(+) as well as with the polar groups of POPC and Chol, mainly via H-bonds. Of the three NSAIDs, KET interacted with POPC and water the most extensively, whereas ASP interacted with Chol and Na(+) more than did the other two. Interactions of PXM with POPC and Chol polar groups as well as with water and Na(+) were limited.

The Structural Basis for the Prevention of Nonsteroidal Antiinflammatory Drug-Induced Gastrointestinal Tract Damage by the C-Lobe of Bovine Colostrum Lactoferrin

Nonsteroidal antiinflammatory drugs (NSAIDs), due to their good efficacy in the treatment of pain, inflammation, and fever, are among the most prescribed class of medicines in the world. The main drawback of NSAIDs is that they induce gastric complications such as peptic ulceration and injury to the intestine. Four NSAIDs, indomethacin, diclofenac, aspirin, and ibuprofen were selected to induce gastropathy in mouse models. It was found that the addition of C-terminal half of bovine lactoferrin (C-lobe) reversed the NSAID-induced injuries to the extent of 47–70% whereas the coadministration of C-lobe prevented it significantly. The C-lobe was prepared proteolytically using serine proteases. The binding studies of C-lobe with NSAIDs showed that these compounds bind to C-lobe with affinities ranging from 2.6 to 4.8 × 10−4 M. The complexes of C-lobe were prepared with the above four NSAIDs. All four complexes were crystallized and their detailed three-dimensional structures were determined using x-ray crystallographic method. The structures showed that all the four NSAID molecules bound to C-lobe at the newly identified ligand binding site in C-lobe that is formed involving two α-helices, α10 and α11. The ligand binding site is separated from the well known iron binding site by the longest and the most stable β-strand, βj, in the structure. Similar results were also obtained with the full length lactoferrin molecule. This novel, to our knowledge, binding site in C-lobe of lactoferrin shows a good complementarity for the acidic and lipophilic compounds such as NSAIDs. We believe this indicates that C-lobe of lactoferrin can be exploited for the prevention of NSAID-induced gastropathy.

Structure and Energetics of Biocompatible Polymer Nanocomposite Systems: A Molecular Dynamics Study

Isothermal-isobaric (NPT) molecular dynamics simulations have been performed to investigate the structure, morphology, and energetics of polymer organoclay nanocomposites based on seven nonsteroidal antiinflammatory drugs (NSAIDs), two biocompatible polymers, and hydrotalcite as the clay mineral, both in an anhydrous and in a solvated environment. The results of our theoretical computations show that nanoconfined conformations of smaller NSAIDs are more affected by the presence of water molecules in the clay gallery with respect to their larger counterparts. Moreover, the presence of water in the mineral interlayer space decreases the interaction energy between the NSAID molecules and the clay, and this detrimental effect is further enhanced by the presence of polar moieties onto the NSAIDs. Finally, from the thermodynamics standpoint, the best intercalation results in a solvated environment could be obtained with PVA in the case of less polar drugs, while PHB could be the polymer of choice in the case of highly polar NSAIDs.

Anionic Clays Containing Anti-Inflammatory Drug Molecules: Comparison of Molecular Dynamics Simulation and Measurements

Three representative nonsteroidal anti-inflammatory drug molecules, Ibuprofen, Diclofenac, and Indomethacin, have been intercalated within the galleries of an anionic clay, Mg-Al layered double hydroxide (LDH). X-ray diffraction, IR and Raman vibrational spectroscopy and (13)C cross-polarization magic-angle spinning NMR have been used to characterize the confined drug molecules, while molecular dynamics (MD) simulations were used to probe the interlayer structure, arrangement, orientation, and geometry of the intercalated species. All three drug molecules are arranged as bilayers in the interlamellar space of the anionic clay. But while the structure of the intercalated Ibuprofen is identical to that of the molecule outside the layers, spectroscopy as well as MD simulation shows that there is a change in the geometry of Diclofenac and Indomethacin upon confinement within the galleries of the LDH. The change in geometry of Diclofenac and Indomethacin upon intercalation is shown to originate from the electrostatic interaction between the electronegative chlorine atoms on the drug molecule and the positively charged metal hydroxide sheets of the anionic clay. It is shown that these changes in the geometry of the intercalated drug molecules allow for the observed interlayer spacing to be realized without the bilayers having to interdigitate, which would otherwise have been necessary if the structure of the drug molecules had remained identical to that outside the layers. Comparisons of experimental measurements with simulation have provided a more detailed understanding of the geometry and organization of flexible drug molecules confined in the anionic clay.