Effects of non-steroid anti-inflammatory drugs in membrane bilayers

Kyrikou, Ioanna; Hadjikakou, Sotiris K.; Kovala‐Demertzi, Dimitra; Viras, Kyriakos; Mavromoustakos, Thomas

doi:10.1016/j.chemphyslip.2004.06.005

Cited by 76 publications

(81 citation statements)

References 22 publications

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“…Indeed, the existence of this methyl side chain in meloxicam has been considered as responsible for an increased membrane penetration and may justify the enhanced membrane perturbing effect observed for this drug. 33 It should be also noticed that the presented measurements for meloxicam are made with smaller molar fractions than for all the other NSAIDs; for higher molar fractions, the diffraction peaks almost disappear, meaning that this NSAID induces a high perturbation of the bilayer order. In addition, the drug/lipid molar fractions studied were intentionally high to mimic the actual concentrations resulting from drugÀlipid interactions that lead to drug accumulation and, therefore, to much higher concentrations of drugs in the lipid membranes than in the aqueous phase.…”

Section: 27mentioning

confidence: 91%

“…Nonetheless, meloxicam has a higher affinity for the hydrophobic environment of lipids than piroxicam. 33 This differential behavior may be attributed to the difference in their chemical structures, particularly to the existence of a side methyl substituted ring instead of a pyridine group in meloxicam (see Figure 1). Indeed, the existence of this methyl side chain in meloxicam has been considered as responsible for an increased membrane penetration and may justify the enhanced membrane perturbing effect observed for this drug.…”

Section: 27mentioning

confidence: 99%

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Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

et al. 2011

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Cell membranes often constitute the first biological structure encountered by drugs, and binding or interactions of drugs with lipid components of the membrane may explain part of their mechanism of activity or their side effects. The present study provides evidence of alterations in the structural properties of phospholipid bilayers at acidic conditions that can be correlated with the mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) and with their local action effect on the gastrointestinal tract lipids, aiming a molecular biophysical approach to the interaction of these drugs with lipid membranes. In this context, the structural modifications of the 1,2-dipalmitoyl-sn-glycero-3-phosphocholine bilayers at pH 5.0, induced by increasing concentrations of five NSAIDs (piroxicam, meloxicam, tolmetin, indomethacin, and nimesulide), were studied by small-angle and wide-angle X-ray scattering. Results obtained highlight the effect of each NSAID in modulating the membrane structure properties. All the NSAIDs promoted distinct biophysical effects by perturbing the membrane arrangement to different degrees that are intimately related to their different physicochemical properties as well as with the initial organization of the lipids, depending if they are in the gel (Lβˈ) or in the liquid-crystalline phase (Lα).

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Section: 27mentioning

confidence: 91%

Section: 27mentioning

confidence: 99%

Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

et al. 2011

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“…Several reports have been published on interactions between drug compounds and lipid membrane bilayers as revealed by DSC. NSAIDS, cytostatics and antimicotics for example have been reported to interfere with phase transitions (Ambrosini et al, 1998;Beni et al, 2006;Kyrikou et al, 2004).…”

Section: Influence Of Drug Substances On the Phospholipid Vesicle Basmentioning

confidence: 99%

Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug–membrane interactions and the effect of agitation on the barrier integrity and on the permeability

Flaten¹,

Skar²,

Luthman³

et al. 2007

European Journal of Pharmaceutical Sciences

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Recently we reported on the development and structural characterization of a phospholipid vesicle based barrier useful for medium throughput screening of passive drug permeability.Here, we investigate the physical and functional integrity of the phospholipid vesicle based barriers to agitation by stirring or shaking, and whether agitation affects drug permeability of sulpiride, metoprolol and testosterone. In addition, three drugs (caffeine, naproxen and sulphasalazine) which were shown in a previous study to affect the electrical resistance of the barriers, were investigated for their influence on the permeability of a simultaneously applied hydrophilic marker (calcein), and on the thermotropic phase transition of the phospholipid bilayers using differential scanning calorimetry (DSC).Electrical resistance measurements indicated that the barriers should withstand shaking speeds up to 150 rpm without losing their integrity, but significant release of phospholipids from the membrane barriers to the donor and acceptor chambers was observed under agitation ≥150 rpm. When using agitation up to 100 rpm no increase in permeability was observed for sulpiride, metoprolol and testosterone. The phospholipid vesicle-based barrier thus differ from other permeability models in that agitation does not lead to an increase in permeability, not even for highly lipophilic drugs such as testosterone. This is explained by the different morphology of the vesicle-based barrier which is containing a 100 µm thick layer of mostly aqueous compartments immobilised within a matrix of phospholipids vesicles.Sulphasalazine and naproxen were shown to decrease the electrical resistance and increase the permeability of the hydrophilic marker calcein. The DSC experiments showed that these two drugs probably interact with the head groups of the phospholipids. In contrast, caffeine gave an increase in electrical resistance and a decrease in permeability of calcein. From the DSC experiments no signs of interaction of caffeine with the phospholipid bilayer could be observed.3

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“…[16,17] With less sensitive methods such as DSC, NMR, XRD, or traditional infrared and Raman spectroscopies, high drug and lipid concentrations are required, typically in the range of 10-100 mM. [5,18,19] While Raman scattering is a weak effect, this technique is well suited to study phospholipid structure; the method requires no labeling and is compatible with aqueous buffers, requiring a minimum of sample preparation. When integrated with a confocal microscope, the efficiency of Raman spectroscopy can be greatly improved for investigating small colloidal structures [20 -22] including lipid vesicles or liposomes.…”

Section: Introductionmentioning

confidence: 99%

Confocal Raman microscopy for simultaneous monitoring of partitioning and disordering of tricyclic antidepressants in phospholipid vesicle membranes

Fox

Harris

2009

J Raman Spectroscopy

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Characterization of drug-membrane interactions is important in order to understand the mechanisms of action of drugs and to design more effective drugs and delivery vehicles. Raman spectra provide compositional and conformational information of drugs and lipid membranes, respectively, allowing membrane disordering effects and drug partitioning to be assessed. Traditional Raman spectroscopy and other widely used bioanalytical techniques such as differential scanning calorimetry (DSC) and nuclear magnetic resonance (NMR) typically require high sample concentrations. Here, we describe how temperature-controlled, optical-trapping confocal Raman microscopy facilitates the analysis of drug-membrane interactions using micromolar concentrations of drug, while avoiding drug depletion from solution by working at even lower lipid concentrations. The potential for confocal Raman microscopy as an effective bioanalytical tool is illustrated using tricyclic antidepressants (TCAs), which are cationic amphiphilic molecules that bind to phospholipid membranes and influence lipid phase transitions. The interaction of these drugs with vesicle membranes of differing head-group charge is investigated while varying the ring and side-chain structure of the drug. Changes in membrane structure are observed in Raman bands that report intra-and intermolecular order versus temperature. The partitioning of drugs into the membrane can also be determined from the Raman scattering intensities. These results demonstrate the usefulness of confocal Raman microscopy for the analysis of drug-membrane systems at biologically relevant drug concentrations. Effective tools for monitoring drug-membrane interactions are crucial for rational design of new drugs.

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Effects of non-steroid anti-inflammatory drugs in membrane bilayers

Cited by 76 publications

References 22 publications

Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

Synchrotron SAXS and WAXS Study of the Interactions of NSAIDs with Lipid Membranes

Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug–membrane interactions and the effect of agitation on the barrier integrity and on the permeability

Confocal Raman microscopy for simultaneous monitoring of partitioning and disordering of tricyclic antidepressants in phospholipid vesicle membranes

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