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At least 685 records · Page 38Linked to original sources
PubMed2004

Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B.

BACKGROUND & AIMS: Lamivudine resistance occurs in patients with chronic hepatitis B at rates of 16%-32% after 1 year and 49% after 3 years. Adefovir dipivoxil, a nucleotide analogue recently approved by the Food and Drug Administration for the treatment of chronic hepatitis B, is effective against hepatitis B virus (HBV) but has been associated with renal toxicity at high doses. Tenofovir disoproxil fumarate is another nucleotide analogue with demonstrated antiviral activity against both wild-type and lamivudine-resistant HBV. Tenofovir, at its licensed dose, has not been associated with renal dysfunction. METHODS: We describe a series of 9 patients with lamivudine-resistant hepatitis B treated with tenofovir, 300 mg, once daily before the availability of adefovir. Levels of HBV DNA, alanine aminotransferase (ALT), hepatitis B e antigen (HBeAg), and antibody to HBeAg (anti-HBe) were monitored. RESULTS: The addition of tenofovir to the existing regimen of lamivudine resulted in a median decline of 4.5 log(10) copies/mL in HBV DNA levels (range, 3.2-6.3 log(10) copies/mL) after a median treatment duration of 12 months (range, 6-16 mo). HBeAg seroconversion was observed in 2 patients, with a third patient undergoing HBeAg loss while remaining anti-HBe negative. In 4 of 7 patients with elevated ALT levels at baseline, ALT levels normalized. No significant adverse events were encountered during treatment. CONCLUSIONS: In patients with lamivudine-resistant hepatitis B, treatment with tenofovir is well tolerated and results in significant virological, serological, and biochemical improvements on par with those seen with high-dose adefovir (30 mg/day) therapy, without the complication of renal toxicity.

Adenine↗
PubMed1995

Oxygen equilibrium properties of nickel(II)-iron(II) hybrid hemoglobins cross-linked between 82 beta 1 and 82 beta 2 lysyl residues by bis(3,5-dibromosalicyl)fumarate: determination of the first two-step microscopic Adair constants for human hemoglobin.

We have previously reported that cross-linked asymmetric Ni(II)-Fe(II) hybrid hemoglobin, XL[alpha (Fe) beta (Fe)][alpha (Ni) beta (Ni)], in which the alpha 1 beta 1 dimer containing ferrous protoporphyrin IX and the adjacent alpha 2 beta 2 dimer containing nickel(II) protoporphyrin IX were cross-linked between Lys-82 beta 1 and Lys-82 beta 2 by reaction with bis(3,5-dibromosalicyl)fumarate, represents an adequate model for determination of the alpha 1 beta 1 oxygenation properties of native hemoglobin [Shibayama, N., Imai, K., Morimoto, H., & Saigo, S. (1993) Biochemistry 32, 8792-8798]. To extend the approach using cross-linked Ni(II)-Fe(II) hybrids to all possible pathways for initial-half oxygenation of hemoglobin, we have prepared three other types of cross-linked Ni(II)-Fe(II) hybrids, carrying nickel(II) protoporphyrin IX in two subunits and ferrous protoporphyrin IX in the other two subunits, and have determined the two-step oxygen equilibrium curves of the ferrous subunits within these cross-linked hybrids. For the first step of oxygenation, the alpha subunit shows about 3-fold higher affinity than the beta subunit at all pH values examined, indicative of a significant functional heterogeneity of the subunits in deoxyhemoglobin. For the second step of oxygenation, the cooperativity represented by the Hill coefficient (nmax) increases in the order of beta 1 beta 2 (nmax = 1.36), alpha 1 beta 1 (nmax = 1.41), alpha 1 beta 2 (nmax = 1.64), and alpha 1 alpha 2 (nmax = 1.72) at pH 7.4 in the presence of 0.1 M Cl- at 25 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗
PubMed1991

Oxygen equilibrium properties of highly purified human adult hemoglobin cross-linked between 82 beta 1 and 82 beta 2 lysyl residues by bis(3,5-dibromosalicyl) fumarate.

We investigated oxygen equilibrium properties of highly purified human adult hemoglobin cross-linked between lysine-82 beta 1 and lysine-82 beta 2 by a fumaryl group, which is prepared by reaction of the CO form with bis(3,5-dibromosalicyl) fumarate. The cross-linked hemoglobin preparation isolated by the previous purification method, namely, gel filtration in the presence of 1 M MgCl2 followed by ion-exchange chromatography, was found to be contaminated with about 20% of an electrophoretically silent impurity that shows remarkably high affinity for oxygen. This impurity was separated from the desired cross-linked hemoglobin by a newly developed purification method, which utilizes a difference between the authentic hemoglobin and the impurity in reactivity of the sulfhydryl groups of cysteine-93 beta toward N-ethylmaleimide under a deoxygenated condition. After this purification procedure, the oxygen equilibrium properties of purified cross-linked hemoglobin in the absence of organic phosphate became very similar to those of unmodified hemoglobin with respect to oxygen affinity, cooperativity, and the alkaline Bohr effect. The functional similarity between the cross-linked hemoglobin and unmodified hemoglobin allows us to utilize this cross-linking for preparing asymmetric hybrid hemoglobin tetramers, which are particularly useful as intermediately liganded models. Previous studies on this type of cross-linked hemoglobin should be subject to reexamination due to the considerable amount of the impurity.

Adult↗
PubMed2001

Enzyme electrokinetics: energetics of succinate oxidation by fumarate reductase and succinate dehydrogenase.

Protein film voltammetry is used to probe the energetics of electron transfer and substrate binding at the active site of a respiratory flavoenzyme--the membrane-extrinsic catalytic domain of Escherichia coli fumarate reductase (FrdAB). The activity as a function of the electrochemical driving force is revealed in catalytic voltammograms, the shapes of which are interpreted using a Michaelis-Menten model that incorporates the potential dimension. Voltammetric experiments carried out at room temperature under turnover conditions reveal the reduction potentials of the FAD, the stability of the semiquinone, relevant protonation states, and pH-dependent succinate--enzyme binding constants for all three redox states of the FAD. Fast-scan experiments in the presence of substrate confirm the value of the two-electron reduction potential of the FAD and show that product release is not rate limiting. The sequence of binding and protonation events over the whole catalytic cycle is deduced. Importantly, comparisons are made with the electrocatalytic properties of SDH, the membrane-extrinsic catalytic domain of mitochondrial complex II.

Flavin-Adenine Dinucleotide↗
PubMed2005

FTIR difference spectra of Wolinella succinogenes quinol:fumarate reductase support a key role of Glu C180 within the "E-pathway hypothesis" of coupled transmembrane electron and proton transfer.

Electrochemically induced static FTIR difference spectroscopy has been employed to investigate redox-driven protonation changes of individual amino acid residues in the quinol:fumarate reductase (QFR) from Wolinella succinogenes. The difference spectra presented were taken in the mid-infrared region from 1800 to 1000 cm(-1), and the signals obtained represent transitions between the reduced and oxidized states of the enzyme. Analysis of the difference spectra shows evidence for structural reorganizations of the polypeptide backbone upon the induced redox reaction. Furthermore, spectral contributions were found above 1710 cm(-1) where stretching vibrations of protonated carboxyl groups from aspartic or glutamic acid side chains absorb. With the help of site-directed mutagenesis and hydrogen/deuterium isotope exchange, it was possible to identify amino acid residue Glu C180, which is located in the membrane-spanning, diheme-containing subunit C of QFR, as being partially responsible for the derivative-shaped spectral feature with a peak/trough at 1741/1733 cm(-1) in the reduced-minus-oxidized difference spectrum. This signal pattern is interpreted as a superposition of a protonation/deprotonation and a change of the hydrogen-bonding environment of Glu C180. This residue is the principal constituent of the recently proposed "E-pathway hypothesis" of coupled transmembrane proton and electron transfer in QFR [Lancaster, C. R. D. (2002) Biochim. Biophys. Acta 1565, 215-231]. Thus, the study presented yields experimental evidence which supports a key role of Glu C180 within the framework of the E-pathway hypothesis.

Amino Acids↗
PubMedDate not supplied

Synthesis of in situ cross-linkable macroporous biodegradable poly(propylene fumarate-co-ethylene glycol) hydrogels.

This study describes a synthesis method of biodegradable macroporous hydrogels suitable as in situ cross-linkable biomaterials. Macroporous hydrogels were based on poly(propylene fumarate-co-ethylene glycol) and prepared via coupled free radical and pore formation reactions. Cross-linking was initiated by a pair of redox initiators, ammonium persulfate and L-ascorbic acid. Pores were formed by the reaction between L-ascorbic acid and sodium bicarbonate, a basic component, which evolved carbon dioxide. Sol fraction of the hydrogels was varied from 0.06 +/- 0.01 to 0.64 +/- 0.01. A stereological approach was used to analyze the morphological properties of the macroporous hydrogels by relating the morphological properties of thin sections to the original three-dimensional macroporous hydrogel. Prepared macroporous hydrogels had porosities between 0.43 +/- 0.08 and 0.84 +/- 0.02 and surface area densities between 55 +/- 3 and 108 +/- 7 cm(-1). Sodium bicarbonate concentration had the greatest effect on both the porosity and surface area density. The effect of copolymer formulation on the porosity and surface area density was insignificant. From thin sections of the macroporous hydrogels, the profile size distributions were determined as an estimate of the pore size distribution. Two formulations synthesized with varying L-ascorbic acid concentration of 0.05 and 0.1 M had median profile sizes of 50-100 and 150-200 microm, respectively. This novel synthesis method allows for the in situ cross-linking of biodegradable macroporous hydrogels with morpholological properties suitable for consideration as an injectable tissue engineering scaffold.

Biodegradation, Environmental↗
PubMedDate not supplied

In vitro cytotoxicity of unsaturated oligo[poly(ethylene glycol) fumarate] macromers and their cross-linked hydrogels.

Currently, oligo[poly(ethylene glycol) fumarate] (OPF) hydrogels are being investigated as an injectable and biodegradable system for tissue engineering applications. In this study, cytotoxicity of each component of the OPF hydrogel formulation and the resulting cross-linked network was examined. Specifically, OPF synthesized with poly(ethylene glycol) (PEG) of different molecular weights (MW), the cross-linking agent [PEG-diacrylate (PEG-DA)], and the redox initiator pair [ammonium persulfate (APS) and ascorbic acid (AA)] were evaluated for cytotoxicity at 2 and 24 h using marrow stromal cells (MSCs) as model cells. The effect of leachable byproducts of OPF hydrogels on cytotoxicity was also investigated. Upon exposure to various concentrations of OPF for 2 h, greater than 50% of the MSCs were viable, regardless of OPF molecular weight or concentration in the media. After 24 h, the MSCs maintained more than 75% viability except for OPF concentrations higher than 25% (w/v). When examining the cross-linking agent, PEG-DA of higher MW (3400) demonstrated significantly higher viability compared to PEG-DA with MW 575 at all concentrations tested. Considering initiators, when MSCs were exposed to AA and APS, as well as the combination of AA and APS, higher viability was observed at lower concentrations. Once cross-linked, the leachable products from the OPF hydrogels had minimal adverse effects on the viability of MSCs (percentage of live cells was higher than 90% regardless of hydrogel types). The results suggest that, after optimization of cross-linking parameters, OPF-based hydrogels hold promise as novel injectable scaffolds or cell carriers in tissue engineering.

Animals↗
PubMedDate not supplied

In vitro cytotoxicity of redox radical initiators for cross-linking of oligo(poly(ethylene glycol) fumarate) macromers.

A novel hydrogel system based on oligo(poly(ethylene glycol) fumarate) (OPF) is currently being investigated as an injectable carrier for marrow stromal cells (MSCs) for orthopedic tissue engineering applications. This hydrogel is cross-linked using the redox radical initiators ammonium persulfate (APS) and ascorbic acid (AA). In this study, two different persulfate oxidizing agents (APS and sodium persulfate (NaPS)) with three reducing agents derived from ascorbic acid (AA, sodium ascorbate (Asc), and magnesium ascorbate-2-phosphate (Asc-2)) and their combinations were examined to determine the relationship between pH, exposure time, and cytotoxicity for rat MSCs. In addition, gelation times for specific combinations were determined using rheometry. pH and cell viability data after 2 h for combinations ranging from 10 to 500 mM in each reagent showed that there was a smaller pH change and a corresponding higher viability at lower concentrations, regardless of the reagents used. At 10 mM, there was less than a 1.5 unit drop in pH and greater than 90% viability for all initiator combinations examined. However, MSC viability was significantly reduced with concentrations of 100 mM and higher of the initiator combinations. At 100 mM, exposure to NaPS/Asc-2 resulted in significantly more live cells than exposure to APS/AA or NaPS/Asc, but at this concentration, NaPS/Asc-2 exhibited significantly longer OPF gelation onset times than APS/AA. At all combination concentrations, exposure time (10 min vs 2 h) did not significantly affect MSC viability. These data indicate that final pH and/or radical formation have a large impact on MSC viability and that multiple, intertwined testing procedures are required for identification of appropriate initiators for cell encapsulation applications.

Animals↗
PubMedDate not supplied

Thermally cross-linked oligo(poly(ethylene glycol) fumarate) hydrogels support osteogenic differentiation of encapsulated marrow stromal cells in vitro.

A novel polymer, oligo(poly(ethylene glycol) fumarate) (OPF), cross-linked with a thermal radical initiation system has recently been developed in our laboratory as an injectable, biodegradable cell carrier for regeneration of orthopaedic tissues. The cross-linking, swelling, and degradative properties of hydrogels prepared from OPF with poly(ethylene glycol) of two different chain lengths were assessed. The two OPF types had similar gelation onset times ( approximately 3.6 min) but, when cross-linked for 8 min at 37 degrees C, exhibited significantly different swelling characteristics (fold swelling: 17.5 +/- 0.2 vs 13.4 +/- 0.4). Rat marrow stromal cells (MSCs) were then directly combined with the hydrogel precursors and encapsulated in a model OPF formulation at approximately 14 million cells/mL, cultured in vitro in the presence of osteogenic supplements (dexamethasone), and monitored over 28 days via histology. MSC differentiation in these samples (6 mm diameter x 0.5 mm thick before swelling), as determined by Von Kossa staining for calcified matrix, was apparent by day 21. At day 28, mineralized matrix could be seen throughout the samples, many microns away from the cells. These experiments strongly support the usefulness of thermally cross-linked OPF hydrogels as injectable cell carriers for bone regeneration.

Animals↗
PubMed2004

Diastereoselective [2 + 2] photocycloaddition of stilbene to chiral fumarate. Direct versus charge-transfer excitation.

The selective excitation of the charge-transfer (CT) complex and the direct excitation of the substrate gave distinctly different product ratios and diastereomeric excesses (de's), as well as their temperature dependencies, in [2 + 2] photocycloaddition of (E)-stilbene to bis((R)-1-methylpropyl) fumarate, clearly demonstrating that the excited CT complex and the conventional exciplex differ in structure and reactivity. This conclusion is supported by the contrasting fluorescence behavior exhibited by the relevant excited species, particularly at low temperatures.

Journal Article↗
PubMed2005

Electron transfer and catalytic control by the iron-sulfur clusters in a respiratory enzyme, E. coli fumarate reductase.

Factors governing the efficacy of long-range electron relays in enzymes have been examined using protein film voltammetry in conjunction with site-directed mutagenesis. Investigations of the fumarate reductase from Escherichia coli, in which three Fe-S clusters relay electrons over more than 30 A, lead to the conclusion that varying the medial [4Fe-4S] cluster potential over a 100 mV range does not have a significant effect on the inherent kinetics of electron transfer to and from the active-site flavin. The results support a proposal that the reduction potential of an individual electron relay site in a multicentered enzyme is not a strong determinant of activity; instead, as deduced from the potential dependence of catalytic electron transfer, electron flow through the intramolecular relay is rapid and reversible, and even uphill steps do not limit the catalytic rate.

Amino Acid Sequence↗
PubMed2006

Fumarate of (S,S)-alpha,alpha'-bis(trifluoromethyl)-1,8-anthracenedimethanol. A chiral macrocycle for the Diels-Alder reaction with cyclopentadiene.

The synthesis and structural study of the fumarate of (S,S)-alpha,alpha'-bis(trifluoromethyl)-1,8-anthracenedimethanol by NMR spectroscopy are reported. The conformational study of the 13-membered macrocycle is presented. The cited alcohol is assayed as a chiral auxiliary in a Diels-Alder reaction with cyclopentadiene, and after methanolysis, provides the norbornene derivative with high enantioselectivity.

Journal Article↗
PubMed1996

Addition of Azoles and Amines to Unsymmetrical Fumaric Esters.

The regioselectivity of nucleophilic addition of azoles to unsymmetrical fumarates yielding the corresponding (+/-)-2-azol-1-ylsuccinates has been studied. The major regioisomer has been identified as the one obtained from the attack of the azole to the more congestive side of the double bond. These results have been interpreted in terms of HOMO-LUMO interactions using semiempirical AM1 molecular orbital calculations. Addition of amines as alternative heteronucleophiles has been also explored to confirm the regioselectivity. Neutral hydrolysis of the two n-butyl ethyl (+/-)-2-imidazol-1-ylsuccinate regioisomers 8a and 8b has shown that this hydrolysis takes place faster than with the corresponding symmetrical di-n-butyl (+/-)-2-imidazol-1-ylsuccinate, and the apparent rate of hydrolysis is independent of the size of the alcohol moiety.

Journal Article↗
PubMed2001

Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor.

[structure: see text] Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor, has been accomplished by a convergent approach. The C1-C8 and C9-C18 segments were derived efficiently from D-glucose and (S)-(-)-2-methyl-1-butanol, respectively, coupled by stereoselective Julia olefination, and converted to nafuredin.

Anthelmintics↗
PubMed2006

Switching of product's chirality in diastereodifferentiating [2+2] photocycloaddition of (E)- versus (Z)-stilbene to chiral fumarate upon direct and charge-transfer-band excitation.

[reaction: see text] Diastereodifferentiating [2+2] photocycloadditions of (E)- and (Z)-stilbenes to bis((R)-1-methylpropyl) fumarate were performed through the direct excitation of stilbenes and the selective excitation of the charge-transfer (CT) complex at various temperatures. The geometrical isomers of stilbene afforded the opposite diastereomers of mu-truxinate in both excitation modes, with a dramatic decrease in the product's diastereoselectivity upon prolonged irradiations.

Journal Article↗
PubMed2000

Liarozole fumarate (R85246): a novel imidazole in the treatment of receptor positive postmenopausal metastatic breast cancer.

This phase II study of liarozole fumarate (R85246, liarozole), a novel imidazole with retinomimetic and aromatase inhibitory effects, was designed to determine the efficacy and tolerability in postmenopausal women with advanced breast cancer in progression, to correlate these effects with hormonal levels, and to evaluate quality of life. Twenty-nine women with ER-positive or unknown metastatic disease who received > or = 2 prior hormonal therapies were treated with 150-300 mg liarozole twice daily until disease progression. All patients were evaluable for toxicity and 25 for response. Four patients (16.0%, 95% CI 5.3-37.4%) had partial remission (PR) of their disease for a median of 7.4 months (range 1.2-12.9) and 7 (28%) had disease stabilization for a median of 4.8 months (1.6-16.0). Estradiol decreased from pre-treatment levels of 9.2-52 pM (mean 17.1) to below detection (9.2 pM, p = 0.0005) after 1 month. Similarly estrone levels fell from 14-307 pM (mean 92.7) to below detection (9.2 pM, p = 0.0001). The most common toxicity was dermatological (96.6%) with features compatible with hypervitaminosis A syndrome such as rash, pruritus, dry skin, and brittle nails. The majority of these were mild to moderate in severity. No significant improvement in quality of life scores (FLI-C) were noted. Liarozole is an active new treatment for breast cancer in patients heavily pre-treated with hormone therapies. Further studies are needed to confirm its relative efficacy in both receptor positive and negative postmenopausal breast cancer.

Aged↗
PubMed2000

Liarozole fumarate (R85246): in the treatment of ER negative, tamoxifen refractory or chemotherapy resistant postmenopausal metastatic breast cancer.

Three phase II studies were conducted to determine the efficacy and tolerability of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1: 1n = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n = 27). Treatment was liarozole (150-300mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0-52.3%: median duration (MD) 20 months; range 2-36.5); 25% in group 2 (95% CI 11.0-52.3%; MD 6.5 months: range 3.5-38): 11% in group 3 (95% CI 4.2-29.2%; MD 7 months; range 3-8.5). No significant improvement in quality of life scores (FLI-C) was noted. Toxicities observed were predominantly dermatological (skin disorders: 88%; dry mouth/eyes/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1-1,839 pM) to below detection (9.2 pM) after 1 month. Liarozole, but not vorozole, partially inhibited estradiol induced uterine hypertrophy and demonstrated dose-dependent anti-tumor effects in the rats, only partially overcome by coadministration of estradiol. The clinical responses observed, together with our preclinical results, confirm liarozole's dual mechanism of action and provide a rationale for further evaluation of RAMBAs in the treatment of breast cancer.

Administration, Oral↗