The development of Wy-41,195, an orally effective antiallergic drug in animal models.
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Administration, Oral↗
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A comparison of the structures of apo dogfish M4 lactate dehydrogenase and its ternary complexes.
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Amino Acid Sequence↗
L-threonine aldolase is not a genuine enzyme in rat liver.
Activity of L-threonine aldolase in rat liver cytosolic extract was not affected by the omission of alcohol dehydrogenase in a previously established NADPH-linked alcohol dehydrogenase-coupled assay. The liver extract was able to catalyse the dehydrogenation of NADPH with either acetaldehyde (a product of L-threonine aldolase action) or 2-oxobutyrate (a product of L-threonine dehydratase action). When the liver extract was chromatographed on a Sephacryl S-200 column, no threonine aldolase activity was detected in the eluate. However, activity of threonine aldolase re-appeared when the fractions with highest activity of lactate dehydrogenase and threonine dehydratase were mixed. Activity of threonine aldolase could also be abolished by removing threonine dehydratase from the liver extract with a specific antibody. Hence L-threonine aldolase should not be a genuine enzyme in the rat liver, and the apparent enzyme activity may result from a combined effect of threonine dehydratase and lactate dehydrogenase (or an oxo acid-linked NADPH dehydrogenase) in the liver cytosolic extract.
Alcohol Dehydrogenase↗
Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy.
Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.
Amino Acid Sequence↗
One-pot solid-phase glycoblotting and probing by transoximization for high-throughput glycomics and glycoproteomics.
The development of rapid and efficient methods for high-throughput protein glycomics is of growing importance because the glycoform-focused reverse proteomics/genomics strategy will greatly contribute to the discovery of novel biomarkers closely related to cellular development, differentiation, growth, and aging as well as a variety of diseases such as cancers and viral infection. Recently, we communicated that rapid and efficient purification of carbohydrates can be achieved by employing sugar-specific chemical ligation with aminooxy-functionalized polymers, which we termed "glycoblotting" (see S.-I. Nishimura et al., Angew. Chem. 2005, 117, 93-98; Angew. Chem. Int. Ed. 2005, 44, 91-96). The chemoselective blotting of oligosaccharides present in crude biological materials onto synthetic polymers relies on the unique oxime-bond formation between aminooxy group displayed on the supporting materials and aldehyde/ketone group at the reducing terminal of all oligosaccharides, thus enabling highly selective and rapid oligosaccharide purification. Aiming to improve the detection sensitivity of the released oligosaccharides, we introduce here a novel strategy for one-pot solid-phase glycoblotting and probing by transoximization. We found that oligosaccharides captured by the polymer supports via the oxime bond can be released in the presence of excess O-substituted aminooxy derivatives in a weakly acidic condition. The released oligosaccharides could be recovered as newly formed oxime derivatives of the O-substituted aminooxy compound added, thus demonstrating the simultaneous releasing and probing. In addition, we synthesized a novel aminooxy-functionalized monomer, N-[2-[2-(2-tert-butoxycarbonylaminooxyacetylamino-ethoxy)ethoxy]ethyl]-2-methacrylamide, which allows for the large-scale preparation of a versatile polymer characterized by its high stability, high blotting capacity, and easy use. The one-pot protocol allowed to profile 23 kinds of N-glycan chains of human serum glycoproteins. This concept was further applied for the glycopeptides analysis in a crude mixture followed by galactose oxidase treatment to generate free aldehyde group at the non-reducing terminal of oligosaccharide moiety of glycopeptides. Our technique may be implemented in existing biochemistry and molecular diagnostics laboratories because enriched oligosaccharides and glycopeptides by solid-phase transoximization with high-sensitive labeling reagents are widely applicable in a variety of common analytical methods using two-dimensional HPLC, LC/MS, and capillary electrophoresis as well as modern mass spectrometry.
Acrylamides↗
Effect of inhaled iodoxamide tromethamine in prevention of antigen-induced bronchospasm.
Lodoxamide tromethamine, a new cromolyn-like drug, was studied to determine its effectiveness and duration of action in preventing antigen-induced bronchospasm in 15 subjects with clinically stable extrinsic asthma. All subjects underwent antigen inhalation challenge 15 min after inhalation of an aerosolized solution of 0.1 mg of lodoxamide in saline or of saline solution alone (placebo) administered on separate days according to a double-blind, random-allocation protocol. Those subjects demonstrating a protective effect of lodoxamide subsequently underwent antigen inhalation challenges at various time intervals (2 to 8 hr) after lodoxamide treatment. Thirteen of 15 subjects (87%) showed a protective effect of lodoxamide administered 15 min prior to antigen challenge. Six of the 13 subjects who were protected initially remained protected 4 hr after lodoxamide treatment and one of these six subjects was also protected at 6 to 8 hr. One additional subject not protected at 4 hr was protected at 3 hr. Lodoxamide exhibited no bronchodilator activity and was not associated with any significant side effects. Further studies are warranted to compare the effectiveness of lodoxamide with that of cromolyn sodium in protection against antigen-induced bronchospasm and to evaluate the relative efficacy and safety of lodoxamide in long-term clinical trials.
Adolescent↗
Prevention of antigen-induced bronchoconstriction by lodoxamide ethyl, a new orally active antiallergic drug.
Lodoxamide ethyl, an orally active drug with pharmacologic activity similar to that of cromolyn sodium, blocks passive cutaneous anaphylaxis (PCA) in rats and antigen-induced bronchoconstriction in guinea pigs and monkeys. Its effectiveness in preventing antigen-induced airway obstruction was studied in 12 asymptomatic asthmatic adults with immediate skin test sensitivity to ragweed, Alternaria, or animal dander. The dose required to reduce the forced expiratory volume in 1 sec (FEV1) by 20% (PD20) was determined by dosimeter bronchoprovocation challenge with the appropriate antigen. At 1-wk intervals each subject received either placebo of 1, 3, or 10 mg drug in a randomized, double-blind fashion 30 min prior to starting bronchoprovocation challenge. On average, 1 mg increased the PD20 fivefold, 3 mg about sixfold, and 10 mg about 27-fold. Dose-related side effects began 10 min after drug and lasted up to 40 min. Thus the oral administration of lodoxamide ethyl was effective in preventing antigen-induced bronchoconstriction, and both the beneficial effects and side effects are dose related.
Adult↗
Enhanced mucosal permeability and nitric oxide synthase activity in jejunum of mast cell deficient mice.
BACKGROUND: Recent reports have described a modulating influence of nitric oxide (NO) on intestinal mucosal permeability and have implicated a role for mast cells in this NO mediated process. AIMS: To assess further the contribution of mast cells to the mucosal permeability changes elicited by the NO synthase (NOS) inhibitor NG-nitro-L-arginine methylester (L-NAME), using mast cell deficient (W/Wv) and mast cell replete mice (+/+). METHODS: Chromium-51 EDTA clearance (from blood to jejunal lumen), jejunal NOS and myeloperoxidase (MPO) activities, and plasma nitrate/nitrite levels were monitored. RESULTS: The increased EDTA clearance elicited by intraluminal L-NAME in W/Wv mice (4.4-fold) was significantly greater than the response observed in control (+/+) mice (1.8-fold). The exacerbated response in W/Wv mice was greatly attenuated by pretreatment with either dexamethasone (1.3-fold) or the selective inducible NOS inhibitor, aminoguanidine (1.4-fold), and partially attenuated by the mast cell stabiliser, lodoxamide (2.9-fold). Jejunal inducible NOS activity was significantly higher in W/Wv than in +/+ mice, while jejunal MPO was lower in W/Wv mice than in +/+ mice, suggesting that the higher inducible NOS in W/Wv does not result from the recruitment of inflammatory cells into the gut. The higher inducible NOS activity in the jejunum of W/Wv was significantly reduced by dexamethasone treatment. CONCLUSIONS: Our results suggest that mast cells normally serve to inhibit inducible NOS activity tonically in the gut and that inhibitors of NOS elicit a larger permeability response when this tonic inhibitory influence is released by mast cell depletion.
Animals↗
The role of urinary physiological changes in the genesis of urothelial lesions in mice given 4-ethylsulfonylnaphthalene-1-sulfonamide, acetazolamide, and oxamide.
BALB/c female mice were administered several compounds, including 4-ethylsulfonylnaphthalene-1-sulfonamide, acetazolamide, and oxamide, in the diet for six weeks. Fresh urine samples were analyzed three times per week for pH, osmolality, micro-crystals, and protein; and a histopathological evaluation was made of the urothelium at the end of the six weeks test. Incidences of hyperplasia, nodular hyperplasia, vacuolization, ulceration and acute inflammation of the bladder urothelium appeared to be related to the osmolality of the urine and the micro-crystalluria experienced by the mice. Correlation coefficients between lesions and urinary osmolality or crystals were -0.69 (p less than 0.0001) and 0.31 (p less than 0.03), respectively, at the 5% significance level.
Acetazolamide↗
The development of cement and concrete additive: based on xylonic acid derived via bioconversion of xylose.
The present work attempted to utilize xylose by converting it to an aldonic acid. In the present study, xylose was converted to xylonic acid by using commercial glucose oxidase enzyme, palladium catalysis, and microbial bioconversion. The enzyme conversion was successfully done using a commercial glucose oxidase. The microbial conversion with Gluconobactor oxydans proceeded even with the presence of a large amount of lignosulfonate. Thus obtained xylonic acid products were evaluated as a cement dispersing agent in cement and concrete tests. It was found that xylonic acid is approximately twice as effective as lignosulfonate. Xylonic acid can be effectively utilized in concrete water reducer application.
Biotransformation↗
Peroxynitrite-induced reactions of synthetic oligonucleotides containing 8-oxoguanine.
8-Oxoguanine (8-oxo-G) is one of the most common DNA lesions present in normal tissues due to exposure to reactive oxygen species. Studies at this and other laboratories suggest that 8-oxo-G is highly susceptible to secondary oxidation, making it a likely target for endogenous oxidizing agents, such as peroxynitrite (ONOO-). Synthetic oligonucleotides containing 8-oxoguanine were treated with ONOO-, and the reaction products were analyzed by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI--MS). CCACAACXCAAA, CCAAAGGXAGCAG, CCAAAXGGAGCAG, and TCCCGAGCGGCCAAAGGXAGCAG (X is 8-oxo-G) were found to readily react with peroxynitrite via the same transformations as those observed for free 8-oxo-2'-deoxyguanosine. The composition of the reaction mixtures was a function of ONOO- concentration and of the storage time after exposure. The oligonucleotide products isolated at low [ONOO-]/[DNA] ratios (<5) were tentatively assigned as containing 3a-hydroxy-5-imino-3,3a,4,5-tetrahydro-1H-imidazo[4, 5d]imidazol-2-one, 5-iminoimidazolidine-2,4-dione, and its hydrolytic product, oxaluric acid. At a [ONOO-]/[DNA] ratio of >10, 2,4,6-trioxo[1,3,5]triazinane-1-carboxamidine- and cyanuric acid-containing oligomers were the major products. The exact location of a modified base within a DNA sequence was determined using exonuclease digestion of oligonucleotide products followed by LC/ESI--MS analysis of the fragments. For all 8-oxo-G-containing oligomers, independent of the sequence, the reactions with ONOO- took place at the 8-oxo-G residues. These results suggest that 8-oxo-G, if present in DNA, is rapidly oxidized by peroxynitrite and that oxaluric acid is a likely secondary oxidation product of 8-oxo-G under physiological conditions.
Chromatography, Liquid↗
Gentamicin accumulation by sensitive strains of Escherichia coli and Pseudomonas aeruginosa.
Gentamicin accumulation with time shows multiphasic kinetics in strains of Escherichia coli and Pseudomonas aeruginosa. All but first phase accumulation may be prevented or reduced by inhibitors of electron transport, by a sulfhydryl poison, by agents which uncouple electron transport and oxidative phosphorylation and by an inhibitor of protein synthesis. The phases of accumulation which are sensitive to these inhibitors are required for loss of cell viability. Gentamicin can be extracted from cells in an unchanged form as judged by paper chromatography and is concentrated 4 to 250 times over extracellular concentrations within the bacterial cell. Gentamicin accumulation has been shown to occur before there is any evidence or release of acid-soluble 3H-adenine from cells. These data demonstrate that productive gentamicin accumulation capable of causing cell death is by active transport.
Adenine↗
Inhibition studies on Vibrio cholerae neuraminidase.
A series of viral neuraminidase inhibitors showing no structural analogy to neuraminic acids have been tested to find whether they are effective inhibitors of V. cholerae neuraminidase, too. Here we report the results obtained with the N-phenyloxamic acid derivatives 2 to 6 (R-NH-CO-COOR'; R = -C6H5NO2, -C6H5OH, -C6H5NH2; R' = -H, -C2H5; see Table 1) and with simple aromatic compounds structurally related to R, i.e. 4-nitroaniline (7), N-acetyl-4-nitroaniline (8), 4-nitrophenol (9), 2,4-dinitrophenol (10), and 4-aminophenol (11) (see Table 2). The inhibitory effects of 2 to 11 were studied according to the method of Dixon[19] in 0.1m sodium acetate buffer, pH 5.5, 2mM CaCl2, at 37 degrees C using the benzyl-alpha-ketoside of N-acetyl-D-neuraminic acid (1) as a substrate. The compounds 2 to 11 are shown to be competitive inhibitors of the enzymatic hydrolysis of the alpha-ketoside 1. The competitive inhibition kinetics are supported by the method of Lineweaver and Burk[20]. The inhibition constants (Ki) are found to be in the range of 0.03 to 5.7 mM. The simple aromatic compounds 7 to 11 show higher inhibitory activities than the phenyloxamic acid derivatives 2 to 6. In addition, significant differences in the Ki values were observed within the two series of inhibitors, whereby those containing a nitro group were most effective.
Aniline Compounds↗
Arachidonic acid metabolites mediate early burn edema.
Standard burns were sequentially produced on the backs of Sprague-Dawley rats at 0, 1, 2, and 2 1/2 hr, followed by the IV injection of Evans blue dye. All animals were killed at 3 hr, and burns evaluated by wet/dry weight ratios, and Evans blue extravasation scored 1-4 by two observers. Five groups of rats were compared to controls. Rats made neutropenic by exposure to 137cesium showed no significant difference in wet/dry weight ratio or Evans blue extravasation compared to controls. At 1 1/2 hr four other groups were treated with various inhibitors of arachidonic acid metabolism including ibuprofen, a cyclo-oxygenase inhibitor; FPL 55712, a leukotriene (LT) receptor antagonist; ketoconazole, an inhibitor of thromboxane (Tx) synthetase; and lodoxamide, a calcium channel inhibitor. All treated groups showed significant reduction of Evans blue dye extravasation. Wet/dry weight ratios were significantly reduced in rats treated with FPL 55712 and ketoconazole before or after burning. These data support the postulate that oxygenation products of arachidonic acid, particularly Tx and LT, are important mediators in early burn edema.
Animals↗
Prevention of ischemia-reperfusion injury by the allergy drug lodoxamide tromethamine.
Lodoxamide tromethamine, an orphan antiallergy drug, inhibits degranulation of mast cells that reside in the myocardium and inhibits xanthine oxidase located in myocytes and predominantly in the vascular endothelium. The hypothesis evaluated was that lodoxamide tromethamine would attenuate oxygen free radical damage. Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing 0, 1, 10, 100, or 1,000 mumol/L lodoxamide tromethamine at 37 degrees and 24 degrees C with ischemic times of 22 and 93 minutes, respectively. These ischemic intervals yielded 50% survival and 50% return of function in untreated hearts. Lodoxamide treatment alone at the onset of reperfusion was also studied. Performance end points were aortic flow, pressure, and coronary flow. Biochemical analyses included serotonin collected from coronary effluent as a marker of mast cell degranulation, uric acid for xanthine oxidase inhibition, myocardial adenosine triphosphate, and carbonyl group concentrations. Performance data demonstrated that lodoxamide was beneficial in a log-linear dose response when given continuously at both temperatures. Percent of preischemic values for untreated and maximal responses at 1,000 mumol/L of lodoxamide were as follows: a mortality of 50% in nontreated hearts versus 0%; aortic flow, 47% to 94% (37 degrees C), 46% to 86% (24 degrees C); cardiac output, 60% to 98% (37 degrees C), 58% to 97% (24 degrees C); adenosine triphosphate, 59% to 90% (37 degrees C), 48% to 65% (24 degrees C). Serotonin was undetectable from any hearts. Uric acid concentrations and carbonyl group content did not change with increasing dose. Lodoxamide demonstrated no benefit when given only during reperfusion, suggesting injury occurred at times other than reperfusion.
Adenosine Triphosphate↗
Repair and mutagenic potential of oxaluric acid, a major product of singlet oxygen-mediated oxidation of 8-oxo-7,8-dihydroguanine.
Oxidative reactions within DNA commonly result in base modifications. Among the four DNA bases, guanine is the most susceptible to various oxidants, and its related oxidized form, 8-oxo-7,8-dihydroguanine, has been extensively studied in terms of repair and mutagenicity. However, 8-oxo-7,8-dihydroguanine is readily subjected to further oxidation, and this has become a point of interest. We recently found that singlet oxygen oxidation of 8-oxo-7,8-dihydroguanine led to the predominant formation of oxaluric acid as the final product. We report herein on the biological features of oxaluric acid dealing with in vitro DNA synthesis and its removal from DNA by repair enzymes. Nucleotide insertion opposite oxaluric acid, catalyzed by Kf exo(-) and Taq indicates, that oxaluric acid induces G to T and G to C transversions. On the other hand, oxaluric acid represents a block when synthesis is performed with pol beta. Interestingly, DNA repair experiments carried out with formamidopyrimidine DNA N-glycosylase (Fpg) and endonuclease III (endo III) show that oxaluric acid is a substrate for both enzymes. Values of k(cat)/K(m) for the Fpg-mediated removal of oxidative guanine lesions revealed that 8-oxoGua is only a slightly better substrate than oxaluric acid. Interestingly, the results obtained with endo III suggest that oxaluric acid is a much better substrate than is 5-hydroxycytosine (5-OHC), an oxidized pyrimidine base.
Animals↗
The pH-dependent role of superoxide in riboflavin-catalyzed photooxidation of 8-oxo-7,8-dihydroguanosine.
[reaction: see text]. The riboflavin-catalyzed photooxidation of 2',3',5'-tri-O-acetyl-8-oxo-7,8-dihydroguanosine generates a radical intermediate that is competitively trapped by H(2)O, O2(-)(*), or O(2). The products of H(2)O trapping have been previously described as the spiroiminodihydantoin (pH >or= 7) and iminoallantoin/guanidinohydantoin (pH < 7) nucleosides. Trapping by O2(-)(*) leads to the oxaluric acid (pH or= 8.6) pathways (R' ', R' ' = H or 2,3,5-tri-O-Ac-ribofuranosyl). The pH-dependent role of superoxide was probed using Mn-SOD and compared to guanosine and 8-methoxyguanosine photooxidation.
Catalysis↗
Xanthine oxidase inhibition attenuates ischemic-reperfusion lung injury.
Ischemic-reperfusion lung injury is a factor potentially limiting the usefulness of distant organ procurement for heart-lung transplantation. Toxic oxygen metabolites are considered a major etiologic factor in reperfusion injury. Although oxygen-free radicals may be generated by many mechanisms, we investigated the role of xanthine oxidase in this injury process by using lodoxamide, a xanthine oxidase inhibitor, to inhibit ischemic-reperfusion injury in an isolated rat lung model. Isolated rat lungs were perfused with physiologic salt solution (PSS) osmotically stabilized with Ficoll until circulating blood elements were nondetectable in the pulmonary venous effluent. Lungs were rendered ischemic by interrupting ventilation and perfusion for 2 hr at 37 degrees C. After the ischemic interval, the lungs were reperfused with whole blood and lung injury was determined by measuring the accumulation of 125I-bovine serum albumin in lung parenchyma and alveolar lavage fluid as well as by gravimetric measurements. Lung effluent was collected immediately pre- and postischemia for analysis of uric acid by high-pressure liquid chromatography. Lodoxamide (1 mM) caused significant attenuation of postischemic lung injury. Uric acid levels in the lung effluent confirmed inhibition of xanthine oxidase. Protection from injury was not complete, however, implying that additional mechanisms may contribute to ischemic-reperfusion injury in the lung.
Animals↗