ABSTRACT
The understanding of the interaction between non-steroidal anti-inflammatory drugs and human serum albumin plays a fundamental role in the development of new drugs and new therapeutic strategies. Several studies have been performed, nevertheless, the interaction phenomena are still not fully understood. In this work, high-field solution Nuclear Magnetic Resonance (NMR) spectroscopy was applied to compare the strength of the interaction of diclofenac sodium salt, ketorolac tris salt and flurbiprofen sodium salt toward albumin. To this aim, mono- and bi-selective relaxation rate measurements were performed by applying selective π-pulses at the selected frequencies and by following magnetization recovery. On the basis of the dependence of relaxation parameters on albumin concentration, normalized affinity indexes were calculated for several protons of the drugs. Affinity indexes for diclofenac were about five-fold higher in comparison with ketorolac and flurbiprofen. Aromatic moieties of the three drugs and methine protons at the chiral centers of ketorolac and flurbiprofen were more involved in the interaction with albumin. In conclusion, NMR spectroscopy allows not only for the comparison of drug-to-protein affinities but also points out the nature of the drug sites that are more extensively involved in the interaction.
Subject(s)
Diclofenac , Flurbiprofen , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Binding Sites , Diclofenac/chemistry , Diclofenac/pharmacology , Humans , Ketorolac , Magnetic Resonance Spectroscopy , Protons , Serum Albumin, HumanABSTRACT
Mucoadhesive properties of tamarind seed polysaccharide (TSP) and larch arabinogalactan (AG), which are developed for ophthalmic applications, were investigated by NMR spectroscopy. Polysaccharide to mucin affinities were compared by using ketotifen fumarate as low molecular weight interaction probe. Proton selective relaxation rate measurements revealed enhanced affinity of TSP to mucin with respect to AG.
Subject(s)
Magnetic Resonance Spectroscopy , Mucins/chemistry , Ophthalmic Solutions/chemistry , Polysaccharides/chemistry , Adhesiveness , Galactans/chemistry , Galactans/isolation & purification , Galactans/pharmacology , Ketotifen/administration & dosage , Ketotifen/chemistry , Larix/chemistry , Models, Chemical , Polysaccharides/isolation & purification , Seeds/chemistry , Tamarindus/chemistryABSTRACT
An interaction between tamarind seed polysaccharide (TSP) and hyaluronic acid (HA) in aqueous solution has been ascertained. Various TSP/HA mixtures have been studied as the basis for the development of a potential excipient for eye drops synergistically improved over those of the separate polymers. Information about the nature of interpolymer interactions, and their dependence on TSP/HA ratios were obtained by NMR spectroscopy in solution. Superior mucin affinity of TSP/HA mixtures with respect to the single polysaccharides was assessed by NMR proton selective relaxation rate measurements. The mucoadhesivity of the TSP/HA (3/2) mixture, evaluated in vitro by NMR or viscometry, and in vivo by its mean and maximum residence time in rabbit precorneal area, is stronger than that of the component polysaccharides or the TSP/HA mixtures of different composition. TSP/HA (3/2) is little viscous and well tolerated by rabbit eyes. It stabilizes the tear film, thereby prolonging the residence of ketotifen fumarate and diclofenac sodium in tear fluid, but is unable to permeabilize the cornea. In conclusion, mucoadhesivity is responsible for the TSP/HA (3/2) synergistic enhancement of either extra- or intra-ocular drug bioavailability.
Subject(s)
Anti-Allergic Agents/administration & dosage , Cyclooxygenase Inhibitors/administration & dosage , Diclofenac/administration & dosage , Excipients/chemistry , Hyaluronic Acid/chemistry , Ketotifen/administration & dosage , Polysaccharides/chemistry , Tamarindus , Adhesiveness , Administration, Topical , Animals , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacokinetics , Biological Availability , Blinking , Chemistry, Pharmaceutical , Cornea/metabolism , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacokinetics , Diclofenac/chemistry , Diclofenac/pharmacokinetics , Drug Compounding , Excipients/metabolism , Hyaluronic Acid/metabolism , Ketotifen/chemistry , Ketotifen/pharmacokinetics , Magnetic Resonance Spectroscopy , Male , Mucins/metabolism , Ophthalmic Solutions , Permeability , Polysaccharides/metabolism , Rabbits , Rheology , Seeds , ViscosityABSTRACT
Nuclear magnetic resonance (NMR) spectroscopy demonstrated that, in aqueous solution, ketotifen fumarate bound more strongly to tamarind seed polysaccharide (TSP) than to hydroxyethylcellulose or hyaluronic acid. Results were confirmed by dynamic dialysis technique.
Subject(s)
Cellulose/analogs & derivatives , Hyaluronic Acid/chemistry , Ketotifen/chemistry , Polysaccharides/chemistry , Seeds/chemistry , Tamarindus/chemistry , Cellulose/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Structure-Activity RelationshipABSTRACT
Four cone resorc[4]arene octamethyl ethers (10, 11, ent-10, and ent-11) tetrafunctionalized at the feet with valyl-leucine [LL- (6); DD- (ent-6)] and leucyl-valine [LL- (9); DD- (ent-9)] methyl esters have been synthesized. These compounds, obtained by conjugation of macrocycle tetracarboxylic acid chlorides with the appropriate terminal amino groups of the above dipeptides, are N-linked peptidoresorc[4]arenes. We found that these macrocycles (M) are capable of recognizing the homologue dipeptides as guests (G), both in solution and in the gas phase, by forming relatively stable host-guest complexes ([M.G]), resistant to chromatographic purification but not to heating. Complexation phenomena between M and G in solution were investigated by NMR methods, including NMR DOSY experiments, for the detection of translational diffusion. Heteroassociation constants of 2030 and 186 M(-1) were obtained by the Foster-Fyfe method for the complexes [10.6] and [10.ent-6], respectively, the latter being comparable to the self-association constant of dipeptide itself. Conversely, the structural features of the proton-bound complexes [M.H.Gn]+ (n = 1, 2), generated in the gas phase by electrospray ionization mass spectrometry (ESI-MS), were investigated by collision-induced dissociation (CID) experiments. In both cases, the four N-linked peptidoresorc[4]arenes were shown to act as synthetic receptors and to recognize the homologue dipeptide by means of hydrogen bonds.
Subject(s)
Calixarenes/chemical synthesis , Peptides/chemistry , Resorcinols/chemistry , Carboxylic Acids/chemistry , Chlorides/chemistry , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Chemical , Spectrometry, Mass, Electrospray IonizationABSTRACT
Combination of the enantioselective properties of the two versatile gas-chromatographic chiral stationary phases (CSPs) octakis(3-O-butanoyl-2,6-di-O-n-pentyl)-gamma-CD (Lipodex E) 1 and L-valine-diamide-based CSP Chirasil-Val-C11 2 has been realized by doping the chiral polymer 2 with the nonpolymeric selector 1. The resulting mixed-mode CSP Chirasil-Val(gamma-Dex) 3 was found to have a greatly improved enantioselectivity toward proline and aspartic acid (as N-trifluoroacetyl ethyl or methyl esters) in comparison to the single-mode CSP 2. The presence of the CD selector in 3 extended the scope of gas-chromatographic enantioseparations achievable on 2 to underivatized alcohols, terpenes, and other chiral compounds that are exclusively enantioseparated on 1.
