Stereodifferentiation in the intramolecular singlet excited state quenching of hydroxybiphenyl-tryptophan dyads

The photochemical processes occurring in diastereomeric dyads (S, S)-1 and (S, R)-1, prepared by conjugation of (S)-2-(2-hydroxy-1,1'-biphenyl-4-yl) propanoic acid ((S)-BPOH) with (S)- and (R)-Trp, have been investigated. In acetonitrile, the fluorescence spectra of (S, S)-1 and (S, R)-1 were coincident in shape and position with that of (S)-BPOH, although they revealed a markedly stereoselective quenching. Since singlet energy transfer from BPOH to Trp is forbidden (5 kcal mol(-1) uphill), the quenching was attributed to thermodynamically favoured (according to Rehm-Weller) electron transfer or exciplex formation. Upon addition of 20% water, the fluorescence quantum yield of (S)-BPOH decreased, while only minor changes were observed for the dyads. This can be explained by an enhancement of the excited state acidity of (S)-BPOH, associated with bridging of the carboxy and hydroxy groups by water, in agreement with the presence of water molecules in the X-ray structure of (S)-BPOH. When the carboxy group was not available for coordination with water, as in the methyl ester (S)-BPOHMe or in the dyads, this effect was prevented; accordingly, the fluorescence quantum yields did not depend on the presence or absence of water. The fluorescence lifetimes in dry acetonitrile were 1.67, 0.95 and 0.46 ns for (S)-BPOH, (S, S)-1 and (S, R)-1, respectively, indicating that the observed quenching is indeed dynamic. In line with the steady-state and time-resolved observations, molecular modelling pointed to a more favourable geometric arrangement of the two interacting chromophores in (S, R)-1. Interestingly, this dyad exhibited a folded conformation in the solid state.Financial support from the Spanish Government (CTQ2010-14882, BES-2008-003314, JCI-2011-09926, PR2011-0581), from the Generalitat Valenciana (Prometeo 2008/090) and from the Universitat Politecnica de Valencia (PAID 05-11, 2766) is gratefully acknowledged.Bonancía Roca, P.; Vayá Pérez, I.; Markovitsi, D.; Gustavsson, T.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2013). Stereodifferentiation in the intramolecular singlet excited state quenching of hydroxybiphenyl-tryptophan dyads. Organic and Biomolecular Chemistry. 11(12):1958-1963. https://doi.org/10.1039/c3ob27278hS195819631112Jiménez, M. C., Pischel, U., & Miranda, M. A. (2007). Photoinduced processes in naproxen-based chiral dyads. Journal of Photochemistry and Photobiology C: Photochemistry Reviews, 8(3), 128-142. doi:10.1016/j.jphotochemrev.2007.10.001Abad, S., Pischel, U., & Miranda, M. A. (2005). Wavelength-Dependent Stereodifferentiation in the Fluorescence Quenching of Asymmetric Naphthalene-Based Dyads by Amines. The Journal of Physical Chemistry A, 109(12), 2711-2717. doi:10.1021/jp047996aAbad, S., Vayá, I., Jiménez, M. C., Pischel, U., & Miranda, M. A. (2006). Diastereodifferentiation of Novel Naphthalene Dyads by Fluorescence Quenching and Excimer Formation. ChemPhysChem, 7(10), 2175-2183. doi:10.1002/cphc.200600337Bonancía, P., Vayá, I., Climent, M. J., Gustavsson, T., Markovitsi, D., Jiménez, M. C., & Miranda, M. A. (2012). Excited-State Interactions in Diastereomeric Flurbiprofen–Thymine Dyads. The Journal of Physical Chemistry A, 116(35), 8807-8814. doi:10.1021/jp3063838Paris, C., Encinas, S., Belmadoui, N., Climent, M. J., & Miranda, M. A. (2008). Photogeneration of 2-Deoxyribonolactone in Benzophenone−Purine Dyads. Formation of Ketyl−C1′ Biradicals. Organic Letters, 10(20), 4409-4412. doi:10.1021/ol801514vBelmadoui, N., Encinas, S., Climent, M. J., Gil, S., & Miranda, M. A. (2006). Intramolecular Interactions in the Triplet Excited States of Benzophenone–Thymine Dyads. Chemistry - A European Journal, 12(2), 553-561. doi:10.1002/chem.200500345Lhiaubet-Vallet, V., Boscá, F., & Miranda, M. A. (2007). Stereodifferentiating Drug−Biomolecule Interactions in the Triplet Excited State:  Studies on Supramolecular Carprofen/Protein Systems and on Carprofen−Tryptophan Model Dyads. The Journal of Physical Chemistry B, 111(2), 423-431. doi:10.1021/jp066968kVayá, I., Pérez-Ruiz, R., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2010). Drug–protein interactions assessed by fluorescence measurements in the real complexes and in model dyads. Chemical Physics Letters, 486(4-6), 147-153. doi:10.1016/j.cplett.2009.12.091Seedher, N., & Bhatia, S. (2005). Mechanism of interaction of the non-steroidal antiinflammatory drugs meloxicam and nimesulide with serum albumin. Journal of Pharmaceutical and Biomedical Analysis, 39(1-2), 257-262. doi:10.1016/j.jpba.2005.02.031SEEDHER, N., & BHATIA, S. (2006). Reversible binding of celecoxib and valdecoxib with human serum albumin using fluorescence spectroscopic technique. Pharmacological Research, 54(2), 77-84. doi:10.1016/j.phrs.2006.02.008Nanda, R. K., Sarkar, N., & Banerjee, R. (2007). Probing the interaction of ellagic acid with human serum albumin: A fluorescence spectroscopic study. Journal of Photochemistry and Photobiology A: Chemistry, 192(2-3), 152-158. doi:10.1016/j.jphotochem.2007.05.018Zhou, B., Li, R., Zhang, Y., & Liu, Y. (2008). Kinetic analysis of the interaction between amphotericin B and human serum albumin using surface plasmon resonance and fluorescence spectroscopy. Photochemical & Photobiological Sciences, 7(4), 453. doi:10.1039/b717897bVahedian-Movahed, H., Saberi, M. R., & Chamani, J. (2011). Comparison of Binding Interactions of Lomefloxacin to Serum Albumin and Serum Transferrin by Resonance Light Scattering and Fluorescence Quenching Methods. Journal of Biomolecular Structure and Dynamics, 28(4), 483-502. doi:10.1080/07391102.2011.10508590Katrahalli, U., Kalalbandi, V. K. A., & Jaldappagari, S. (2012). The effect of anti-tubercular drug, ethionamide on the secondary structure of serum albumins: A biophysical study. Journal of Pharmaceutical and Biomedical Analysis, 59, 102-108. doi:10.1016/j.jpba.2011.09.013El-Kemary, M., Gil, M., & Douhal, A. (2007). Relaxation Dynamics of Piroxicam Structures within Human Serum Albumin Protein. Journal of Medicinal Chemistry, 50(12), 2896-2902. doi:10.1021/jm061421fTormo, L., Organero, J. A., Cohen, B., Martin, C., Santos, L., & Douhal, A. (2008). Dynamical and Structural Changes of an Anesthetic Analogue in Chemical and Biological Nanocavities. The Journal of Physical Chemistry B, 112(43), 13641-13647. doi:10.1021/jp803083yTardioli, S., Lammers, I., Hooijschuur, J.-H., Ariese, F., van der Zwan, G., & Gooijer, C. (2012). Complementary Fluorescence and Phosphorescence Study of the Interaction of Brompheniramine with Human Serum Albumin. The Journal of Physical Chemistry B, 116(24), 7033-7039. doi:10.1021/jp300055cVayá, I., Jiménez, M. C., & Miranda, M. A. (2007). Excited-State Interactions in Flurbiprofen−Tryptophan Dyads. The Journal of Physical Chemistry B, 111(31), 9363-9371. doi:10.1021/jp071301zCallis, P. R., & Burgess, B. K. (1997). Tryptophan Fluorescence Shifts in Proteins from Hybrid Simulations:  An Electrostatic Approach. The Journal of Physical Chemistry B, 101(46), 9429-9432. doi:10.1021/jp972436fLakowicz, J. R. (2000). On Spectral Relaxation in Proteins†¶‖. Photochemistry and Photobiology, 72(4), 421. doi:10.1562/0031-8655(2000)0722.0.co;2Schuler, B., & Eaton, W. A. (2008). Protein folding studied by single-molecule FRET. Current Opinion in Structural Biology, 18(1), 16-26. doi:10.1016/j.sbi.2007.12.003Shen, X., & Knutson, J. R. (2001). Subpicosecond Fluorescence Spectra of Tryptophan in Water. The Journal of Physical Chemistry B, 105(26), 6260-6265. doi:10.1021/jp010384vBeechem, J. M., & Brand, L. (1985). Time-Resolved Fluorescence of Proteins. Annual Review of Biochemistry, 54(1), 43-71. doi:10.1146/annurev.bi.54.070185.000355Callis, P. R. (1997). [7] 1La and 1Lb transitions of tryptophan: Applications of theory and experimental observations to fluorescence of proteins. Flourescence Spectroscopy, 113-150. doi:10.1016/s0076-6879(97)78009-1Basarić, N., & Wan, P. (2006). Competing Excited State Intramolecular Proton Transfer Pathways from Phenol to Anthracene Moieties. The Journal of Organic Chemistry, 71(7), 2677-2686. doi:10.1021/jo0524728Lukeman, M., & Wan, P. (2003). Excited-State Intramolecular Proton Transfer ino-Hydroxybiaryls:  A New Route to Dihydroaromatic Compounds. Journal of the American Chemical Society, 125(5), 1164-1165. doi:10.1021/ja029376yKeck, J., Kramer, H. E. A., Port, H., Hirsch, T., Fischer, P., & Rytz, G. (1996). Investigations on Polymeric and Monomeric Intramolecularly Hydrogen-Bridged UV Absorbers of the Benzotriazole and Triazine Class. The Journal of Physical Chemistry, 100(34), 14468-14475. doi:10.1021/jp961081hVollmer, F., & Rettig, W. (1996). Fluorescence loss mechanism due to large-amplitude motions in derivatives of 2,2′-bipyridyl exhibiting excited-state intramolecular proton transfer and perspectives of luminescence solar concentrators. Journal of Photochemistry and Photobiology A: Chemistry, 95(2), 143-155. doi:10.1016/1010-6030(95)04252-0Lukeman, M., & Wan, P. (2002). A New Type of Excited-State Intramolecular Proton Transfer:  Proton Transfer from Phenol OH to a Carbon Atom of an Aromatic Ring Observed for 2-Phenylphenol1. Journal of the American Chemical Society, 124(32), 9458-9464. doi:10.1021/ja0267831Jiménez, M. C., Miranda, M. A., Tormos, R., & Vayá, I. (2004). Characterisation of the lowest singlet and triplet excited states of S-flurbiprofen. Photochem. Photobiol. Sci., 3(11-12), 1038-1041. doi:10.1039/b408530bWeller, A. (1982). Photoinduced Electron Transfer in Solution: Exciplex and Radical Ion Pair Formation Free Enthalpies and their Solvent Dependence. Zeitschrift für Physikalische Chemie, 133(1), 93-98. doi:10.1524/zpch.1982.133.1.093Winget, P., Cramer, C. J., & Truhlar, D. G. (2004). Computation of equilibrium oxidation and reduction potentials for reversible and dissociative electron-transfer reactions in solution. Theoretical Chemistry Accounts, 112(4). doi:10.1007/s00214-004-0577-0ÇAKIR, S., & BÇER, E. (2010). SYNTHESIS, SPECTRAL CHARACTERIZATION AND ELECTROCHEMISTRY OF VANADIUM(V) COMPLEX WITH TRYPTOPHAN. Journal of the Chilean Chemical Society, 55(2). doi:10.4067/s0717-9707201000020002

Čvrsta disperzija meloksikama: faktorijalno dizajnirani dozirani pripravak za gerijatrijsku populaciju

The objective of the present work was to improve the dissolution properties of the poorly water-soluble drug meloxicam by preparing solid dispersions with hydroxyethylcellulose (HEC), mannitol and polyethylene glycol (PEG) 4000 and to develop a dosage form for geriatric population. Differential scanning calorimetry, X–ray diffractometry, Fourier transform infrared spectroscopy and scanning electron microscopy were used to investigate the solid-state physical structure of the prepared solid dispersions. Higher in vitro dissolution of solid dispersions was recorded compared to their corresponding physical mixtures and the pure drug. PEG 4000 in 1:9 drug to carrier ratio exhibited the highest drug release (100.2%), followed by mannitol (98.2%) and HEC (89.5%) in the same ratio. Meloxicam-PEG 4000 solid dispersion was formulated into suspension and optimization was carried out by 23 factorial design. Formulations containing higher levels of methyl cellulose and higher levels of either sodium citrate or Tween 80 exhibited the highest drug release.Cilj rada bio je poboljšati topljivost meloksikama u vodi pripravom čvrstih disperzija s hidroksietilcelulozom (HEC), manitolom i polietilen glikolom 4000 (PEG 4000) te razviti dozirani pripravaka za gerijatrijsku populaciju. Za ispitivanje fizičke strukture pripravljenih čvrstih disperzija korištene su diferencijalna pretražna kalorimetrija, difraktometrija rentgentskim zrakama, FTIR i pretražna elektronska mikroskopija. Čvrste disperzije su u in vitro uvjetima pokazale bolju topljivost u odnosu na fizičku smjesu i čistu ljekovitu tvar. Najbolje oslobađanje lijeka (100,2%). postignuto je iz disperzija s PEG 4000 (omjer ljekovite tvari i nosača 1:9). Slijede manitol (98,2%) i HEC (89,5%) (isti omjer meloksikama i polimera). Čvrsta disperzija meloksikama s PEG 4000 prevedena je u suspenziju te optimirana 23 faktorijalnim dizajnom. Najbolje oslobađanje ljekovite tvari postignuto je iz pripravaka koji sadrže veći udio etilceluloze i natrijevog citrata, odnosno Tween 80

Impact of changes to the interscreening interval and faecal immunochemical test threshold in the national bowel cancer screening programme in England: results from the FIT pilot study.

INTRODUCTION: The NHS Bowel Cancer Screening Programme (BCSP) faces endoscopy capacity challenges from the COVID-19 pandemic and plans to lower the screening starting age. This may necessitate modifying the interscreening interval or threshold. METHODS: We analysed data from the English Faecal Immunochemical Testing (FIT) pilot, comprising 27,238 individuals aged 59-75, screened for colorectal cancer (CRC) using FIT. We estimated screening sensitivity to CRC, adenomas, advanced adenomas (AA) and mean sojourn time of each pathology by faecal haemoglobin (f-Hb) thresholds, then predicted the detection of these abnormalities by interscreening interval and f-Hb threshold. RESULTS: Current 2-yearly screening with a f-Hb threshold of 120 μg/g was estimated to generate 16,092 colonoscopies, prevent 186 CRCs, detect 1142 CRCs, 7086 adenomas and 4259 AAs per 100,000 screened over 15 years. A higher threshold at 180 μg/g would reduce required colonoscopies to 11,500, prevent 131 CRCs, detect 1077 CRCs, 4961 adenomas and 3184 AAs. A longer interscreening interval of 3 years would reduce required colonoscopies to 10,283, prevent 126 and detect 909 CRCs, 4796 adenomas and 2986 AAs. CONCLUSION: Increasing the f-Hb threshold was estimated to be more efficient than increasing the interscreening interval regarding overall colonoscopies per screen-benefited cancer. Increasing the interval was more efficient regarding colonoscopies per cancer prevented

A Stiff Injectable Biodegradable Elastomer

Injectable materials often have shortcomings in mechanical and drug-eluting properties that are attributable to their high water contents. A water-free, liquid four-armed PEG modified with dopamine end groups is described which changes from liquid to elastic solid by reaction with a small volume of Fe3+ solution. The elastic modulus and degradation times increase with increasing Fe3+ concentrations. Both the free base and the water-soluble form of lidocaine can be dissolved in the PEG4-dopamine and released in a sustained manner from the cross-linked matrix. PEG4-dopamine is retained in the subcutaneous space in vivo for up to 3 weeks with minimal inflammation. This material's tailorable mechanical properties, biocompatibility, ability to incorporate hydrophilic and hydrophobic drugs and release them slowly are desirable traits for drug delivery and other biomedical applications.National Institute on Deafness and Other Communication Disorders (U.S.) (NIDCD R21 DC 009986)National Institutes of Health (U.S.) (NIH Ruth L. Kirschstein National Research Service Award (no. F32GM096546))National Institutes of Health (U.S.) (NIH R01 EB00244

Dissolution Enhancement and Formulation of Rapid-Release Lornoxicam Mini-Tablets

The aim was to enhance the dissolution of lornoxicam (LOR) and to produce mini-tablets with an optimised system to provide a rapid-release multi-particulate formulation. LOR systems were prepared through co-evaporation with either polyethylene glycol 6000 or Pluronic® F-68 (PLU) and adsorption onto Neusilin® US2 alone or co-adsorption in the presence of different amounts of polysorbate 80. All systems were characterised by FT-IR, differential scanning calorimetry, X-ray diffraction, flowability and dissolution techniques. Mini-tablets were prepared using the system with the optimum dissolution profile and flowability. Tensile strengths, content uniformity and dissolution profiles of the mini-tablets were evaluated. The effects of different excipients and storage conditions on mini-tablet properties were also studied. The optimised rapid-release LOR mini-tablets were further evaluated for their in vivo pharmacokinetic profile. The co-evaporate of LOR with PLU showed significantly faster dissolution and superior flowability and was evaluated together with three directly compressible excipients (Cellactose® 80, StarLac® (STA) and Emcompress®) for mini-tablet formulation. The formulation with STA provided the optimum results in terms of tensile strength content uniformity and rapid drug release following a 3-month stability study and was selected for further in vivo evaluation. The pharmacokinetic profile indicated the potential of the mini-tablets achieving rapid release and increased absorption of LO