Oxicam

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Munna Sarkar - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Lipid Molecule Headgroup Mismatch on Non Steroidal Anti-Inflammatory Drugs Induced Membrane Fusion
    2016
    Co-Authors: Sutapa Mondal Roy, Munna Sarkar
    Abstract:

    Membrane fusion is an essential process guiding many important biological events, which most commonly requires the aid of proteins and peptides as fusogenic agents. Small drug induced fusion at low drug concentration is a rare event. Only three drugs, namely, melOxicam (Mx), pirOxicam (Px), and tenOxicam (Tx), belonging to the Oxicam group of non steroidal anti-inflammatory drugs (NSAIDs) have been shown by us to induce membrane fusion successfully at low drug concentration. A better elucidation of the mechanism and the effect of different parameters in modulating the fusion process will allow the use of these common drugs to induce and control membrane fusion in various biochemical processes. In this study, we monitor the effect of lipid headgroup size mismatch in the bilayer on Oxicam NSAIDs induced membrane fusion, by introducing dimyristoylphosphatidylethanolamine (DMPE) in dimyristoylphosphatidylcholine (DMPC) small unilamellar vesicles (SUVs). Such headgroup mismatch affects various lipid parameters which includes inhibition of trans-bilayer motion, domain formation, decrease in curvature, etc. Changes in various lipidic parameters introduce defects in the membrane bilayer and thereby modulate membrane fusion. SUVs formed by DMPC with increasing DMPE content (10, 20, and 30 mol %) were used as simple model membranes. Transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) were used to characterize the DMPC-DMPE mixed vesicles. Fluorescence assays were used to probe the time dependence of lipid mixing, content mixing, and leakage and also used to determine the partitioning of the drugs in the membrane bilayer. How the inhibition of trans-bilayer motion, heterogeneous distribution of lipids, decrease in vesicle curvature, etc., arising due to headgroup mismatch affect the fusion process has been isolated and identified here. Mx amplifies these effects maximally followed by Px and Tx. This has been correlated to the enhanced partitioning of the hydrophobic Mx compared to the more hydrophilic Px and Tx in the mixed bilayer

  • Differential Effect of Oxicam Non-Steroidal Anti-Inflammatory Drugs on Membranes and Their Consequence on Membrane Fusion.
    The journal of physical chemistry. B, 2015
    Co-Authors: Anupa Majumdar, Debjyoti Kundu, Munna Sarkar
    Abstract:

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used analgesics and antipyretics, which form an interesting drug group because of their new and alternate functions. The ability of the NSAIDs belonging to the Oxicam chemical group to induce membrane fusion at low physiologically relevant concentrations is a new function that has drawn considerable attention. Membrane fusion is dependent on the interplay of physicochemical properties of both drugs and membranes. Here, we have elucidated the effects of different Oxicam drugs, MelOxicam, PirOxicam, TenOxicam, LornOxicam, and IsOxicam, on an identical membrane-mimetic system. This highlights only the differential effects of the drugs on drug–membrane interactions, which in turn modulate their role as membrane fusogens. The partitioning behavior and the location of the drugs in dimyristoylphosphatidylcholine vesicles have been studied using second-derivative absorption spectroscopy, fluorescence quenching, steady-state fluorescence anisotro...

  • Differential Effect of Oxicam Non-Steroidal Anti-Inflammatory Drugs on Membranes and Their Consequence on Membrane Fusion
    2015
    Co-Authors: Anupa Majumdar, Debjyoti Kundu, Munna Sarkar
    Abstract:

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used analgesics and antipyretics, which form an interesting drug group because of their new and alternate functions. The ability of the NSAIDs belonging to the Oxicam chemical group to induce membrane fusion at low physiologically relevant concentrations is a new function that has drawn considerable attention. Membrane fusion is dependent on the interplay of physicochemical properties of both drugs and membranes. Here, we have elucidated the effects of different Oxicam drugs, MelOxicam, PirOxicam, TenOxicam, LornOxicam, and IsOxicam, on an identical membrane-mimetic system. This highlights only the differential effects of the drugs on drug–membrane interactions, which in turn modulate their role as membrane fusogens. The partitioning behavior and the location of the drugs in dimyristoyl­phosphatidylcholine vesicles have been studied using second-derivative absorption spectroscopy, fluorescence quenching, steady-state fluorescence anisotropy, and time-resolved fluorescence lifetime measurements. Fusion kinetics has been monitored by fluorescence assays and dynamic light scattering was used to provide a snapshot of the vesicle diameter distribution at different time points. The differential perturbing effect of the drugs on the membrane is dependent both on their partitioning and location. Although partitioning governs the extent of fusion, the location modulates the rates of each step

  • Modulation of non steroidal anti-inflammatory drug induced membrane fusion by copper coordination of these drugs: anchoring effect.
    The journal of physical chemistry. B, 2014
    Co-Authors: Anupa Majumdar, Sreeja Chakraborty, Munna Sarkar
    Abstract:

    Membrane fusion, an integral event in several biological processes, is characterized by several intermediate steps guided by specific energy barriers. Hence, it requires the aid of fusogens to complete the process. Common fusogens, such as proteins/peptides, have the ability to overcome theses barriers by their conformational reorganization, an advantage not shared by small drug molecules. Hence, drug induced fusion at physiologically relevant drug concentrations is rare and occurs only in the case of the Oxicam group of non steroidal anti-inflammatory drugs (NSAIDs). To use drugs to induce and control membrane fusion in various biochemical processes requires the understanding of how different parameters modulate fusion. Also, fusion efficacy needs to be enhanced. Here we have synthesized and used Cu(II) complexes of fusogenic Oxicam NSAIDs, MelOxicam and PirOxicam, to induce fusion in model membranes monitored by using DSC, TEM, steady-state, and time-resolved spectroscopy. The ability of the complexes t...

  • Modulation of Non Steroidal Anti-Inflammatory Drug Induced Membrane Fusion by Copper Coordination of These Drugs: Anchoring Effect
    2014
    Co-Authors: Anupa Majumdar, Sreeja Chakraborty, Munna Sarkar
    Abstract:

    Membrane fusion, an integral event in several biological processes, is characterized by several intermediate steps guided by specific energy barriers. Hence, it requires the aid of fusogens to complete the process. Common fusogens, such as proteins/peptides, have the ability to overcome theses barriers by their conformational reorganization, an advantage not shared by small drug molecules. Hence, drug induced fusion at physiologically relevant drug concentrations is rare and occurs only in the case of the Oxicam group of non steroidal anti-inflammatory drugs (NSAIDs). To use drugs to induce and control membrane fusion in various biochemical processes requires the understanding of how different parameters modulate fusion. Also, fusion efficacy needs to be enhanced. Here we have synthesized and used Cu­(II) complexes of fusogenic Oxicam NSAIDs, MelOxicam and PirOxicam, to induce fusion in model membranes monitored by using DSC, TEM, steady-state, and time-resolved spectroscopy. The ability of the complexes to anchor apposing model membranes to initiate/facilitate fusion has been demonstrated. This results in better fusion efficacy compared to the bare drugs. These complexes can take the fusion to its final step. Unlike other designed membrane anchors, the role of molecular recognition and strength of interaction between molecular partners is obliterated for these preformed Cu­(II)-NSAIDs

Hirak Chakraborty - One of the best experts on this subject based on the ideXlab platform.

  • Membrane fusion: a new function of non steroidal anti-inflammatory drugs.
    Biophysical chemistry, 2008
    Co-Authors: Hirak Chakraborty, Sutapa Mondal, Munna Sarkar
    Abstract:

    Membrane fusion is an important event in many biological processes and is characterized by several intermediate steps of which content mixing between the two fusing vesicles signals the completion of the process. Fusion induced solely by small drug molecules is not a common event. Non Steroidal Anti-Inflammatory Drugs (NSAIDs), that control pain and inflammation, are also capable of exhibiting diverse functions. In this study we present a new function of NSAIDs belonging to the Oxicam group, as membrane fusogenic agents. Small Unilamellar Vesicles (SUVs) formed by the phospholipid, dimyristoylphosphatidylcholine (DMPC), were used as model membranes. Fluorescence assays using terbium/dipicolinic acid (Tb/DPA) were used to monitor content mixing and corresponding leakage in presence of the drugs. Transmission Electron Microscope (TEM) was also used to image fusion bodies in drug treated vesicles as compared to the untreated ones. The results show that the three Oxicam NSAIDs viz. MelOxicam, PirOxicam and TenOxicam can induce fusion of DMPC vesicles and lead the fusion process to completion at a very low drug to lipid ratio (D/L) of 0.045. The Oxicam drugs exhibit differential fusogenic behavior as reflected in the kinetics of content mixing and leakage, both of which can be described by a single exponential rate equation. Moreover, not all NSAIDs can induce membrane fusion. Indomethacin, an acetic acid group NSAID and ibuprofen, a propionic acid group NSAID, did not induce fusion of vesicles. This new property of NSAIDs has important applications in biochemical processes.

  • Interaction of Oxicam NSAIDs with DMPC vesicles: differential partitioning of drugs.
    Chemistry and physics of lipids, 2005
    Co-Authors: Hirak Chakraborty, Sujata Roy, Munna Sarkar
    Abstract:

    Small unilamellar vesicles (SUVs) formed by the dimyristoylphosphatidylcholine (DMPC), a phospholipid; serve as a membrane mimetic system that can be used to study the effect of absence of net surface charges on drug-membrane interaction. The targets of non-steroidal anti-inflammatory drugs (NSAIDs) are cyclooxygenases, which are membrane active enzymes. Hence, to approach their targets NSAIDs have to pass different bio-membranes. Different membrane parameters are expected to guide the first level of interaction of these drugs before they are presented to their targets. Our earlier studies have demonstrated the crucial role of surface charges of membrane mimetic systems like micelles and mixed micelles on the interaction of Oxicam NSAIDs. In order to see whether net surface charges of membranes are essential for the interaction of Oxicam NSAIDs, we have studied the incorporation of two Oxicam NSAIDs, viz., pirOxicam and melOxicam in DMPC vesicles using the intrinsic fluorescence properties of the drugs. To see whether different prototropic forms of the drugs can interact with DMPC vesicles, studies were carried out under different pH conditions. Transmission electron microscopy (TEM) was used to characterize the SUVs those were formed at different pH values. Steady state fluorescence anisotropy measurements show that both forms of the two drugs, viz., global neutral and anion can be incorporated into the DMPC vesicles. Partition coefficient (KP) between DMPC and the aqueous buffer used has been calculated in all cases from fluorescent intensity measurements. The KP values for the neutral and anionic forms of pirOxicam are 219.0 and 25.8, respectively, and that for melOxicam are 896.7 and 110.2, respectively. From the KP values it is evident that irrespective of the nature of the prototropic forms, melOxicam has a higher KP value than pirOxicam. This correlates with the previously calculated log KP values between n-octanol and aqueous phase, which demonstrates that in absence of net surface charges of DMPC vesicles the hydrophobic interaction is the principal driving force for incorporation. Our results imply that for bio-membranes having no net surface charges hydrophobic effect plays a principal role to guide these NSAIDs to their targets.

  • Interaction of Oxicam NSAIDs with DMPC vesicles: differential partitioning of drugs.
    Chemistry and Physics of Lipids, 2005
    Co-Authors: Hirak Chakraborty, Sujata Roy, Munna Sarkar
    Abstract:

    Small unilamellar vesicles (SUVs) formed by the dimyristoylphosphatidylcholine (DMPC), a phospholipid; serve as a membrane mimetic system that can be used to study the effect of absence of net surface charges on drug–membrane interaction. The targets of non-steroidal anti-inflammatory drugs (NSAIDs) are cyclooxygenases, which are membrane active enzymes. Hence, to approach their targets NSAIDs have to pass different bio-membranes. Different membrane parameters are expected to guide the first level of interaction of these drugs before they are presented to their targets. Our earlier studies have demonstrated the crucial role of surface charges of membrane mimetic systems like micelles and mixed micelles on the interaction of Oxicam NSAIDs. In order to see whether net surface charges of membranes are essential for the interaction of Oxicam NSAIDs, we have studied the incorporation of two Oxicam NSAIDs, viz., pirOxicam and melOxicam in DMPC vesicles using the intrinsic fluorescence properties of the drugs. To see whether different prototropic forms of the drugs can interact with DMPC vesicles, studies were carried out under different pH conditions. Transmission electron microscopy (TEM) was used to characterize the SUVs those were formed at different pH values. Steady state fluorescence anisotropy measurements show that both forms of the two drugs, viz., global neutral and anion can be incorporated into the DMPC vesicles. Partition coefficient ( KP) between DMPC and the aqueous buffer used has been calculated in all cases from fluorescent intensity measurements. The KP values for the neutral and anionic forms of pirOxicam are 219.0 and 25.8, respectively, and that for melOxicam are 896.7 and 110.2, respectively. From the KP values it is evident that irrespective of the nature of the prototropic forms, melOxicam has a higher KP value than pirOxicam. This correlates with the previously calculated log KP values between n-octanol and aqueous phase, which demonstrates that in absence of net surface charges of DMPC vesicles the hydrophobic interaction is the principal driving force for incorporation. Our results imply that for bio-membranes having no net surface charges hydrophobic effect plays a principal role to guide these NSAIDs to their targets. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • Host-guest complexation of Oxicam NSAIDs with β-cyclodextrin
    Biopolymers, 2004
    Co-Authors: Rona Banerjee, Hirak Chakraborty, Munna Sarkar
    Abstract:

    Spectroscopic and molecular modeling techniques have been employed to study the interaction of the Oxicam group of nonsteroidal antiinflammatory drugs (NSAIDs) with a polysaccharide such as beta-cyclodextrin (beta-cd). beta-cd is a good drug delivery system and is known to reduce harmful side effects of these drugs in the gastrointestinal tract and to increase their clinical efficacy. A detailed understanding of such host-guest interaction helps in designing a better drug delivery system coupled with increased therapeutic potential. However, there exists a controversy as to which prototropic form of pirOxicam, a drug belonging to the Oxicam group, becomes encapsulated in the host and also the stoichiometry of binding. In this study, we have revisited that controversy using steady state fluorescence, absorption, fluorescence anisotropy measurements, and molecular modeling techniques. In addition, we have for the first time studied the interactions of two other Oxicam drugs, viz. tenOxicam and melOxicam, with beta-cd in aqueous solution. In all cases the neutral forms of these drugs were incorporated in the beta-cd cavity with a binding stoichiometry of 1:1 host : guest. The values of the binding constants for pirOxicam, melOxicam, and tenOxicam with beta-cyclodextrin are 134 +/- 21, 114 +/- 15, and 115 +/- 13 M(-1), respectively. Molecular modeling studies show that the minimum energy configuration gives favorable interaction energy between the host and the guest in the complex with 1:1 stoichiometry when the conjugated rings of the drugs are inside the hydrophobic bucket-like cavity of beta-cd and the third ring is exposed to the solvent.

  • Incorporation of NSAIDs in micelles: implication of structural switchover in drug-membrane interaction.
    Biophysical chemistry, 2003
    Co-Authors: Hirak Chakraborty, Rona Banerjee, Munna Sarkar
    Abstract:

    Non-steroidal anti-inflammatory drugs (NSAIDs) of Oxicam group are not only effective as anti-inflammatory agents but also show diverse functions. Their principal targets are cyclooxygenases, which are membrane-associated enzymes. To bind with the targets these drugs have to pass through the membrane and hence their interactions with biomembranes should play a major role in guiding their interactions with cyclooxygenases. Here we have studied the interactions of three NSAIDs of Oxicam group viz. pirOxicam, melOxicam and tenOxicam with micelles having different headgroup charges, as simple membrane mimetic systems. Spectroscopic methods have been used to understand the interaction of these drugs with Cetyl N,N,N-trimethyl ammonium bromide (cationic), Sodium dodecyl sulphonate (anionic) and Triton X-100 (neutral) micelles. Our results demonstrate that the environment of the drugs i.e. the nature of the micelles plays a decisive role in choosing a specific prototropic form of the drugs for incorporation. Additionally it induces a switch over or change between different prototropic forms of pirOxicam, which is correlated with the change in their reactivities in presence of different surface charges, given by the change in pK(a) values. These results together, indicate that in vivo, the diverse nature of biomembranes might play a significant role in choosing the particular form of Oxicam NSAIDs that would be presented to their targets.

Claudia De Toma - One of the best experts on this subject based on the ideXlab platform.

Muhammad Hanif - One of the best experts on this subject based on the ideXlab platform.

  • Structural Modifications of the Antiinflammatory Oxicam Scaffold and Preparation of Anticancer Organometallic Compounds
    Organometallics, 2019
    Co-Authors: Adnan Ashraf, Farhana Aman, Waseeq Ahmad Siddiqui, Jóhannes Reynisson, Stephen M. F. Jamieson, Sanam Movassaghi, Ayesha Zafar, Mario Kubanik, Tilo Söhnel, Muhammad Hanif
    Abstract:

    Nonsteroidal antiinflammatory drugs (NSAIDs) have chemopreventive effects in several cancer types, and the Oxicam-based NSAIDs melOxicam and pirOxicam exhibit potential to treat cancer. We prepared a series of novel Oxicams and coordinated them to RuII(cym)Cl and OsII(cym)Cl moieties (η6-p-cymene = cym). The Oxicam ligands acted either as monodentate N-donors or bidentate N,O-chelators, depending upon the ligand structure as well as reaction conditions such as the pH value and solvent used in the reaction. The cytotoxic activity of the complexes toward carcinoma cells was investigated. The isoxazolyl motif-containing ligand 1 and its complexes with RuII(cym)Cl 1a and the Os analogue 1b proved to have anticancer activity with IC50 values in a range similar to that observed for the RuIII investigational drug IT-139, and in general the Os compounds were equally or even slightly more potent than the Ru derivatives. Since melOxicam is known as a selective inhibitor of COX-2, molecular docking studies were carr...

  • Structural Modifications of the Antiinflammatory Oxicam Scaffold and Preparation of Anticancer Organometallic Compounds
    2019
    Co-Authors: Adnan Ashraf, Farhana Aman, Waseeq Ahmad Siddiqui, Stephen M. F. Jamieson, Sanam Movassaghi, Ayesha Zafar, Mario Kubanik, Jóhannes Reynisson, Tilo Söhnel, Muhammad Hanif
    Abstract:

    Nonsteroidal antiinflammatory drugs (NSAIDs) have chemopreventive effects in several cancer types, and the Oxicam-based NSAIDs melOxicam and pirOxicam exhibit potential to treat cancer. We prepared a series of novel Oxicams and coordinated them to RuII(cym)Cl and OsII(cym)Cl moieties (η6-p-cymene = cym). The Oxicam ligands acted either as monodentate N-donors or bidentate N,O-chelators, depending upon the ligand structure as well as reaction conditions such as the pH value and solvent used in the reaction. The cytotoxic activity of the complexes toward carcinoma cells was investigated. The isoxazolyl motif-containing ligand 1 and its complexes with RuII­(cym)Cl 1a and the Os analogue 1b proved to have anticancer activity with IC50 values in a range similar to that observed for the RuIII investigational drug IT-139, and in general the Os compounds were equally or even slightly more potent than the Ru derivatives. Since melOxicam is known as a selective inhibitor of COX-2, molecular docking studies were carried out to understand the possible interactions of the compounds with COX-2, where the organic ligands gave higher scores than their organometallic counterparts

  • Anticancer Ruthenium(η 6 - p -cymene) Complexes of Nonsteroidal Anti-inflammatory Drug Derivatives
    Organometallics, 2014
    Co-Authors: Farhana Aman, Muhammad Hanif, Waseeq Ahmad Siddiqui, Adnan Ashraf, Lk Filak, Jóhannes Reynisson, Tilo Soehnel, Stephen M. F. Jamieson, Christian G. Hartinger
    Abstract:

    Oxicams are a versatile family of heterocyclic compounds, and the two representatives melOxicam and pirOxicam are widely used drugs for the treatment of a variety of inflammatory and rheumatic diseases in humans. As cancer-associated inflammation is known to occur in carcinogenesis, we aimed to combine compounds carrying bioactive Oxicam moieties with ruthenium(arene) fragments, known for anticancer activity. RuII(arene) complexes with methyl ester derivatives of the Oxicam scaffold were prepared and characterized by standard methods and crystallographically. The organoruthenium compounds formed from RuII(η6-p-cymene) chlorido moieties and Oxicam-based ligands were subjected to bioanalytical investigations to establish their physicochemical properties with regard to stability in DMSO and water as well as reactivity toward the amino acids l-histidine (His), l-methionine (Met), and l-cysteine (Cys) and the DNA model compound guanosine 5′-monophosphate (5′-GMP). The compounds hydrolyzed rapidly in water to g...

  • Anticancer Ruthenium(η6‑p‑cymene) Complexes of Nonsteroidal Anti-inflammatory Drug Derivatives
    2014
    Co-Authors: Farhana Aman, Muhammad Hanif, Waseeq Ahmad Siddiqui, Adnan Ashraf, Lk Filak, Stephen M. F. Jamieson, Jóhannes Reynisson, Tilo Söhnel, Christian G. Hartinger
    Abstract:

    Oxicams are a versatile family of heterocyclic compounds, and the two representatives melOxicam and pirOxicam are widely used drugs for the treatment of a variety of inflammatory and rheumatic diseases in humans. As cancer-associated inflammation is known to occur in carcinogenesis, we aimed to combine compounds carrying bioactive Oxicam moieties with ruthenium­(arene) fragments, known for anticancer activity. RuII(arene) complexes with methyl ester derivatives of the Oxicam scaffold were prepared and characterized by standard methods and crystallographically. The organoruthenium compounds formed from RuII(η6-p-cymene) chlorido moieties and Oxicam-based ligands were subjected to bioanalytical investigations to establish their physicochemical properties with regard to stability in DMSO and water as well as reactivity toward the amino acids l-histidine (His), l-methionine (Met), and l-cysteine (Cys) and the DNA model compound guanosine 5′-monophosphate (5′-GMP). The compounds hydrolyzed rapidly in water to give the respective aqua complexes, formed amino acid complexes with Met and His, but decompose with Cys, while interaction with 5′-GMP was through its phosphate residue. The anticancer activity of the complexes against the colon carcinoma HCT116 and breast cancer MDA MB 231 cancer cell lines was established using an in vitro assay. The cytotoxicity was found strongly dependent on the lipophilicity of the compound, as was shown through correlation with log kw and clog P values of the ligands. The most lipophilic compound [chlorido­(methyl 4-oxido-2-benzyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide)­(η6-p-cymene)­ruthenium­(II)] was the most active in the cell assays, with an IC50 of 80 μM in HCT116 cells

J. P. Tillement - One of the best experts on this subject based on the ideXlab platform.

  • Blood-to-Brain Transfer of Various Oxicams: Effects of Plasma Binding on Their Brain Delivery
    Pharmaceutical Research, 1997
    Co-Authors: Philippe Jolliet, Pierre-alain Carrupt, Bernard Testa, Françoise Brée, Nicolas Simon, Saïk Urien, Alessandra Pagliara, J. P. Tillement
    Abstract:

    Purpose . The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory Oxicams. Methods . The brain extraction of isOxicam, tenOxicam, melOxicam and pirOxicam was investigated in rats using the carotid injection technique. Blood protein binding parameters were determined by equilibrium dialysis using human serum, human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG) solutions at various concentrations. Results . All Oxicams had low values of brain extraction, between 19% and 39% when dissolved in serum, i.e. under physiological conditions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was inversely related to the polarity of the Oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialyzable drug fraction was inversely related to protein concentration. However, rat brain extraction was always higher than expected from in vitro measurements of the dialyzable fraction. Conclusions . Except for pirOxicam whose brain extraction was partially decreased in the presence of proteins, the serum unbound and initially bound fractions of Oxicams both seem available for transfer into the brain. Modest affinities for AAG rule out any related effect. More surprising is the apparent lack of effect on brain transfer of the high-affinity binding to HSA and serum. The enhanced brain uptake of melOxicam in the presence of AAG could be a result of interactions between this globular protein and the endothelial wall.

  • Blood-to-brain transfer of various Oxicams: effects of plasma binding on their brain delivery.
    Pharmaceutical research, 1997
    Co-Authors: Philippe Jolliet, Pierre-alain Carrupt, Bernard Testa, Françoise Brée, Nicolas Simon, Saïk Urien, Alessandra Pagliara, J. P. Tillement
    Abstract:

    Purpose. The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory Oxicams.

  • Physicochemical and Structural Properties of Non-Steroidal Anti-inflammatory Oxicams
    Helvetica Chimica Acta, 1993
    Co-Authors: Ruey-shiuan Tsai, Pierre-alain Carrupt, Bernard Testa, Nabil El Tayar, Yvan Giroud, Pedro Andrade, Françoise Brée, J. P. Tillement
    Abstract:

    Using the five therapeutic Oxicams 1-5, we showed that isosteric replacements result in remarkable changes in the physicochemical and structural properties of congeners. Thus. the acidity of the phenolic OH group is relatively higher in the Oxicams containing a pyridinyl moiety, i.e. in pirOxicam (1), tenOxicam (2), and lornOxicam (3), due to their zwitterionic nature- This consequently influences their lipophilicity profile at different ionization states. Furthermore, partitioning behaviour in octan-1-ol/H2O and heptane/H2O systems suggests an internal H-bond between the enolic OH and the amide C=O group. The anionic Oxicams readily partition into the octanol phase at pH 7.4 and not at all into the heptane phase. Only the partition coefficients of Oxicams measured in the heptane/H2O system, but not in the octanol/H2O system, correlate with their transfer across the blood-brain barrier- This implies that only the neutral form of Oxicams crosses the blood-brain barrier

  • Clinical pharmacology of Oxicams: new insights into the mechanisms of their dose-dependent toxicity.
    International journal of tissue reactions, 1993
    Co-Authors: E. Albengres, F. Brée, S. Urien, P. Nguyen, J. P. Tillement, J. Barre, Philippe Jolliet, Ruey-shiuan Tsai, Pierre-alain Carrupt, Bernard Testa
    Abstract:

    Six Oxicams, sudOxicam, isOxicam, pirOxicam, tenOxicam, melOxicam and lornOxicam, were compared in an attempt to understand why, despite close chemical structures, two of them were associated with an increased risk of toxicity in patients. Different factors have been revealed which may explain these differences. A weak association constant to human serum albumin (HSA), together with a high plasma concentration, favours a rapid increase in unbound concentration (Cu) when total plasma concentration rises (peak of absorption). Pathological states may enhance this increase when both HSA plasma concentration is decreased and free fatty acid concentrations are increased. However, the main cause of toxicity may be the existence in some subjects of HSA natural mutants whose ability to bind Oxicams is markedly lower than normal.

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