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PubMed1990

Role of O2- in neutrophil recruitment into sites of dermal and pulmonary vasculitis.

Using analogous models of acute dermal vasculitis and alveolitis in rats, we have examined the role of oxygen-derived metabolities in the tissue damage associated with neutrophil influx into sites of immune complex deposition. In the lung, as previously reported, catalase and deferoxamine are highly protective, while superoxide dismutase (SOD) has a transient protective effect. The xanthine oxidase inhibitors, allopurinol, and lodoxamide, are also protective. In the skin, neither catalase (which has been covalently linked to the antibody) nor deferoxamine is protective, suggesting that H2O2 and iron are not absolutely required for the development of dermal vasculitis. In the skin, SOD, as well as the inhibitors of xanthine oxidase, have protective effects. These data suggest that the neutrophil-mediated pathways of immune complex injury in the dermal and pulmonary microvascular compartments are fundamentally different. As a measurement of neutrophil accumulation, measurements of myeloperoxidase in tissue extracts have been employed. In both the lung and skin, the protective effects of SOD and the xanthine oxidase inhibitors are paralleled by reductions in neutrophil influx into sites of injury. In contrast, catalase and deferoxamine have no effect on neutrophil accumulation. These data suggest that vascular beds in rat skin and lung are fundamentally different with respect to mechanisms of acute immune complex mediated injury. The data also provide evidence that O2- contributes significantly to the accumulation of neutrophils.

Allopurinol↗
PubMed2005

3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone.

Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a significant increase in binding potency compared to similar analogues that do not make this interaction.

Amides↗
PubMed2005

Identification of N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4.

We have identified two N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamide analogs as a novel class of human immunodeficiency virus type 1 (HIV-1) entry inhibitors that block the gp120-CD4 interaction, using database screening techniques. The lead compounds, NBD-556 and NBD-557, are small molecule organic compounds with drug-like properties. These compounds showed potent cell fusion and virus-cell fusion inhibitory activity at low micromolar levels. A systematic study showed that these compounds target viral entry by inhibiting the binding of HIV-1 envelope glycoprotein gp120 to the cellular receptor CD4 but did not inhibit reverse transcriptase, integrase, or protease, indicating that they do not target the later stages of the HIV-1 life cycle to inhibit HIV-1 infection. These compounds were equally potent inhibitors of both X4 and R5 viruses tested in CXCR4 and CCR5 expressing cell lines, respectively, indicating that their anti-HIV-1 activity is not dependent on the coreceptor tropism of the virus. A surface plasmon resonance study, which measures binding affinity, clearly demonstrated that these compounds bind to unliganded HIV-1 gp120 but not to the cellular receptor CD4. NBD-556 and NBD-557 were active against HIV-1 laboratory-adapted strains including an AZT-resistant strain and HIV-1 primary isolates, indicating that these compounds can potentially be further modified to become potent HIV-1 entry inhibitors.

Anti-HIV Agents↗
PubMed1994

Efficacy of lodoxamide 0.1% ophthalmic solution in resolving corneal epitheliopathy associated with vernal keratoconjunctivitis.

A multicenter, randomized, double-masked, parallel-group study compared the long-term efficacy and safety of lodoxamide 0.1% ophthalmic solution and placebo in 118 patients with vernal keratoconjunctivitis. The test drugs were instilled four times daily for 90 days. Lodoxamide 0.1% ophthalmic solution was significantly (P < .05) more effective than placebo in lowering severity scores for epithelial disease and corneal staining, evidence of the superior efficacy of lodoxamide 0.1% ophthalmic solution in reversing the corneal complications commonly associated with moderate to severe vernal keratoconjunctivitis. Additionally, lodoxamide 0.1% ophthalmic solution ameliorated the other key signs of vernal keratoconjunctivitis, including upper tarsal papillae, limbal signs (papillae, hyperemia, and Trantas' dots), and conjunctival discharge. The between-group differences in the relief of symptoms (itching, tearing, and photophobia) were clinically significant but not always statistically significant. Treatment-related adverse events were reported with similar frequency in both treatment groups, and none were serious.

Adolescent↗
PubMed1995

Lodoxamide tromethamine treatment for superior limbic keratoconjunctivitis.

PURPOSE: We studied the efficacy of topically applied lodoxamide tromethamine 0.1% in the treatment of superior limbic keratoconjunctivitis. METHODS: Three patients with clinical findings of bilateral superior limbic keratoconjunctivitis. were treated with topical lodoxamide tromethamine four times daily in both eyes. RESULTS: While the patients were taking lodoxamide tromethamine, symptoms and objective findings resolved. CONCLUSIONS: Topically applied lodoxamide tromethamine 0.1% is useful in the treatment of superior limbic keratoconjunctivitis. There may be a role for mast cell stabilizers in the treatment of this disorder.

Administration, Topical↗
PubMed1992

Efficacy and safety of lodoxamide 0.1% vs cromolyn sodium 4% in patients with vernal keratoconjunctivitis.

A multicenter, double-masked, parallel-group clinical study compared the efficacy and safety of lodoxamide 0.1% ophthalmic solution and cromolyn sodium 4% ophthalmic solution in 120 patients with vernal keratoconjunctivitis. On various follow-up visits, the clinical efficacy of lodoxamide 0.1% was statistically superior to cromolyn sodium 4% in alleviating four of the primary symptoms (itching, tearing, foreign-body sensation, and discomfort) and five of the primary signs (Trantas' dots, palpebral conjunctival changes, bulbar conjunctival hyperemia, erythema/swelling of the eyelids and periorbital tissues, and epithelial disease). At no time during the study was cromolyn sodium 4% statistically superior to lodoxamide 0.1% in demonstrating improvements in clinical signs and symptoms of vernal keratoconjunctivitis. The physician's clinical judgment of patients' response to treatment showed lodoxamide 0.1% effected a greater and earlier improvement than cromolyn sodium 4%. Both drugs were safe for topical ophthalmic use when used four times daily for up to 28 days.

Adolescent↗
PubMed2001

Crystal structure and solid state 13C NMR analysis of N-(methyl 3,4,6-tri-O-acetyl-alpha, and beta-D-glucopyranosid-2-yl)-oxamide derivative of p-chloroaniline, N,N-diethylamine, N-methylaniline and N-ethylaniline.

The X-ray diffraction analysis of N-(methyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranosid-2-yl)-N'-p-chlorophenyloxamide (1), N-(methyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranosid-2-yl)-N',N'-diethyloxamide (2), N-acetyl, N-(methyl 3,4,6-tri-O-acetyl-beta-D-glucopyranosid-2-yl), N'-methyl, N'-phenyloxamide (3), N-acetyl, N-(methyl 3,4,6-tri-O-acetyl-beta-D-glucopyranosid-2-yl), N'-ethyl, N'-phenyloxamide (4) was performed. It was found that the oxamide group in compounds 1-4 can be characterized as two structurally independent amides because there is no pi conjugation across the oxalyl OC-CO bond. Only the oxamide group of 1 is planar and adopts trans conformation stabilized as two intramolecular N-H...O hydrogen bonds.

Aniline Compounds↗
PubMed1998

Addition of a mast cell stabilizing compound to organ preservation solutions decreases lung reperfusion injury.

OBJECTIVE: Research in lung transplant preservation has generally focused on free radicals and enzyme release from neutrophils, parenchymal cells, macrophages, and endothelium. The lung has a large resident population of mast cells that, when activated, release potent inflammatory mediators. We hypothesized that adding an inhibitor of mast cell degranulation, lodoxamide tromethamine (10 micromol/L), to Euro-Collins and University of Wisconsin preservation solutions, would decrease lung preservation injury. METHODS: Rat lungs were isolated, flushed with the respective solution, and stored at 4 degrees C for 6 or 12 hours. The lungs were reperfused with fresh blood and ventilated with 100% oxygen. Alveolar-arterial oxygen difference, oxygen tension, capillary filtration coefficient, and compliance were determined. RESULTS: After 6 hours of ischemic storage: lodoxamide tromethamine-enhanced Euro-Collins solution decreased alveolar-arterial oxygen difference from 539 to 457 (p = 0.004), increased oxygen tension from 119 to 205 mm Hg (p = 0.006), and decreased capillary filtration coefficient from 3.9 to 2.0 (p < 0.001); lodoxamide tromethamine-enhanced University of Wisconsin solution decreased alveolar-arterial oxygen difference from 546 to 317 (p < 0.001), increased oxygen tension from 166 to 335 mm Hg (p < 0.001), and decreased capillary filtration coefficient from 3.0 to 1.7 (p < 0.001). After 12 hours of ischemic storage, lodoxamide tromethamine-enhanced Euro-Collins solution decreased alveolar-arterial oxygen difference from 588 to 485 (p < 0.001), increased oxygen tension from 100 to 161 mm Hg (p = 0.012), decreased capillary filtration coefficient from 6.2 to 2.6 (p < 0.001), and increased compliance from 0.12 to 0.21 (p < 0.001); lodoxamide tromethamine-enhanced University of Wisconsin solution decreased alveolar-arterial oxygen difference from 478 to 322 (p < 0.001), increased oxygen tension from 214 to 335 mm Hg (p < 0.001), decreased capillary filtration constant from 4.2 to 2.0 (p < 0.001), and increased compliance from 0.20 to 0.25 (p < 0.001). CONCLUSIONS: Addition of lodoxamide tromethamine to Euro-Collins or University of Wisconsin solution results in a marked decrease in lung reperfusion injury as demonstrated by increased oxygenation, decreased microvascular permeability, and increased compliance. These results are relevant as Euro-Collins and University of Wisconsin solutions are the most common clinically used lung preservation solutions. This study also highlights the deleterious role of resident mast cells in preservation injury.

Animals↗
PubMed2000

Finding minimal herbicide concentrations in ground water? Try looking for their degradates.

Extensive research has been conducted regarding the occurrence of herbicides in the hydrologic system, their fate, and their effects on human health and the environment. Few studies, however, have considered herbicide transformation products (degradates). In this study of Iowa ground water, herbicide degradates were frequently detected. In fact, herbicide degradates were eight of the 10 most frequently detected compounds. Furthermore, a majority of a herbicide's measured concentration was in the form of its degradates--ranging from 55 to over 99%. The herbicide detection frequencies and concentrations varied significantly among the major aquifer types sampled. These differences, however, were much more pronounced when herbicide degradates were included. Aquifer types presumed to have the most rapid recharge rates (alluvial and bedrock/karst region aquifers) were those most likely to contain detectable concentrations of herbicide compounds. Two indirect estimates of ground-water age (depth of well completion and dissolved-oxygen concentration) were used to separate the sampled wells into general vulnerability classes (low, intermediate, and high). The results show that the herbicide detection frequencies and concentrations varied significantly among the vulnerability classes regardless of whether or not herbicide degradates were considered. Nevertheless, when herbicide degradates were included, the frequency of herbicide compound detection within the highest vulnerability class approached 90%, and the median total herbicide residue concentration increased over an order of magnitude, relative to the parent compounds alone, to 2 microg/l. The results from this study demonstrate that obtaining data on herbicide degradates is critical for understanding the fate of herbicides in the hydrologic system. Furthermore, the prevalence of herbicide degradates documented in this study suggests that to accurately determine the overall effect on human health and the environment of a specific herbicide its degradates should also be considered.

Acetamides↗
PubMed2000

Mechanisms and comparison of anti-allergic efficacy of topical lodoxamide and cromolyn sodium treatment in vernal keratoconjunctivitis.

PURPOSE: To explore the mechanism of action of topical lodoxamide and cromolyn sodium treatment in vernal keratoconjunctivitis (VKC) and to compare the efficacy of these drugs to each other. DESIGN: Single-investigator, masked, randomized, clinical trial. PARTICIPANTS: Twenty male and 10 female patients between the ages of 6 and 19 years, who were diagnosed as having active VKC, were enrolled in this study. INTERVENTIONS: The patients were randomly divided into two equal groups (groups A and B). Group A patients received topical lodoxamide ophthalmic solution 0.1% (LOS); topical cromolyn sodium ophthalmic solution 4% (CSO) was prescribed to group B patients in a dose of two drops four times daily. MAIN OUTCOME MEASURES: The eye symptom severity scores and clinical signs of the patients were evaluated both in the pre- and post-treatment periods. In addition to the clinical data, conjunctival impression cytologic specimens were obtained from patients both before and after treatment. Impression cytologic specimens were stained using immunohistochemical methods to detect the percentages of CD4(+), CD8(+), CD45RA(+), and CD23(+) cells. Statistical analyses were performed within and between groups. RESULTS: The percentages of CD4(+) and CD23(+) cells in tear samples of patients in groups A and B were significantly higher in the pretreatment stage than post-treatment stage. In the post-treatment stage, group A patients had significantly lower CD4(+) and CD23(+) cell values compared with group B patients. Patient symptom scores and clinical signs were at a significantly lower level after treatment with either LOS or CSO in both groups A and B compared with their pretreatment values. Moreover, group A patients had significantly lower symptom scores and clinical signs than group B patients in the post-treatment stage. CONCLUSIONS: Clinical superiority of LOS over CSO may be linked to its greater effect on the CD4(+) cells, because CD4(+) cells plays a pivotal role in the pathogenesis of VKC.

Administration, Topical↗
PubMed1997

Efficacy of lodoxamide eye drops on mast cells and eosinophils after allergen challenge in allergic conjunctivitis.

PURPOSE: The purpose of the study is to evaluate in a double-blind, randomized study the efficacy of lodoxamide tromethamine 0.1% versus placebo. METHODS: Signs and symptoms, tear tryptase, and tear fluid cytology were evaluated in 20 asymptomatic subjects with allergic conjunctivitis. The study included three allergen challenges in skin test-positive patients. At the first visit, a threshold dose of allergen was established. At the second visit, a bilateral ocular challenge was performed without pretreatment. At the third visit, either lodoxamide or placebo eye drops were used for 1 week before ocular challenge. RESULTS: Lodoxamide significantly reduced tryptase levels (P < 0.01), neutrophils (P < 0.04), and eosinophils (P < 0.01) in the tear fluid and significantly inhibited ocular itching (P < 0.02) when compared with that of placebo. CONCLUSIONS: Lodoxamide is effective in reducing tryptase levels and the recruitment of inflammatory cells in the tear fluid after allergen challenge.

Administration, Topical↗
PubMed1997

Selective inhibition of the sperm-specific lactate dehydrogenase isozyme-C4 by N-isopropyl oxamate.

In the present study, we demonstrated that the attachment of the nonpolar isopropylic carbon chain in the nitrogen of oxamate, converted this competitive inhibitor of LDH isozymes into a powerful selective inhibitor of mouse LDH-C4. The comparative study of the inhibitory effect of oxamate and N-isopropyl oxamate on mouse LDH isozymes pointed out that the isopropylic carbon chain conferred upon N-isopropyl oxamate a high affinity for LDH-C4 and a marked decrease in the affinity for the other isozymes since oxamate showed more inhibitory effect on LDH-1 (Ki = 0.06 mM) and LDH-5 (Ki = 0.08 mM), and less inhibitory effect on LDH-C4 (Ki = 0.25 mM). On the other hand, N-isopropyl oxamate showed the highest inhibitory effect on LDH-C4 (Ki = 0.014 mM) and poor inhibitory effect on LDH-1 (Ki = 0.4 mM) and LDH-5 (Ki = 0.8 mM). Apparently, the enzymatic inactivation proceeded through a reversible binding of N-isopropyl oxamate, facilitated by nonpolar interactions with a hydrophobic region present only in the active site of mouse LDH-C4, resulting in a selective inhibition of this isozyme in comparison with the other LDH isozymes. N-isopropyl oxamate was also a powerful competitive inhibitor of LDH-C4 (Ki = 0.015 mM) compared with oxamate (Ki = 0.35 mM), using alpha-ketoisocaproate as a substrate.

Animals↗
PubMedDate not supplied

Methoxyoxalamido chemistry in the synthesis of novel amino linker and spacer phosphoramidites: a robust means for stability, structural versatility, and optimal tether length.

We have developed a general route to the synthesis of novel amino linker and spacer phosphoramidites utilizing methoxyoxalamido (MOX) chemistry. The synthesis makes use of readily available and inexpensive primary aliphatic amino alcohols and diamines to produce a rich and diverse variety of phosphoramidites. Among these are monomers with exceptionally long (up to 56 atoms in length) amphipathic tethering arms. The chemistry bestows exceptional control over the physical characteristics within the tethers through the selection of appropriate building blocks. Furthermore, MOX chemistry enables fairly rapid assembly of these discrete-length tethers in a modular fashion. All novel phosphoramidites were successfully used in automated syntheses of 5'-modified oligonucleotides.

Drug Stability↗
PubMed1995

Equilibrium isotope effect on ternary complex formation of [1-18O]oxamate with NADH and lactate dehydrogenase.

An equilibrium isotope effect on association of [1-18O]oxamate to form a ternary complex with lactate dehydrogenase and NADH of 0.9840 +/- 0.0027 has been measured by equilibrium dialysis and whole molecule isotope ratio mass spectrometry. Semiempirical calculations of vibrational frequencies using various models for solvent were shown to predict an inverse equilibrium isotope effect on association. However, the calculated effect cannot be directly attributed to one specific normal mode or vibrational force constant. Analysis of the carboxylate interaction with the guanidinium ion showed that the ionic interaction increased the torsional force constant for rotation about the carbon-carbon bond of oxamate. The minimum energy geometry for oxamate interacting with methyl guanidinium predicts that the plane of the oxamate carboxylate will be at an oblique angle to the plane defined by the guanidinium nitrogens. The combination of experimental and calculated equilibrium isotope effects on association holds the potential to improve the characterization of the interaction of ligands with protein active sites.

L-Lactate Dehydrogenase↗
PubMed1976

Thermodynamic studies of binary and ternary complexes of pig heart lactate dehydrogenase.

The thermodynamics of the reaction catalyzed by pig heart muscle lactate dehydrogenase (LDH; EC1.1.1,27) have been studied in 0,2 M potassium phosphate buffer, pH 7, over the temperature range of 10 to 35 degrees C by using oxamate and oxalate to simulate the corresponding reactions of the substrates pyruvate and lactate, respectively. The various complexes formed are characterized by Gibbs free energies, enthalpies, and entropies. The Gibbs free energies were determined by equilibrium dialysis investigations, fluorescence titrations, and ultraviolet difference spectroscopy, while the reaction enthalpies stem from direct calorimetric measurements, Formulas are given for both the temperature dependence of the equilibrium constants and the variation with temperature of the enthalpies involved in the four reactions between LDH and NADH or NAD, LDH-NADH and oxamate, and LDH-NAD and oxalate. All reactions show a marked negative temperature coefficient, deltacp, of the binding enthalpies indicating partial refolding to be associated with binary and ternary complex formation. This interpretation appears very probable in view of recent x-ray crystallographic studies on lactate dehydrogenase from dogfish, which demonstrate a volume decrease to occur on binding of oxamate to the LDH-NADH complex. The validity of the thermodynamic parameters, as derived with substrate analogues, for the actual catalytic reaction, gains strong support from the agreement between the sum of the heats involved in the four intermediary reactions reported in this study and direct determinations of the overall enthalpy associated with the catalytic process published in the literature.

Animals↗
PubMed1975

Cell contact-dependent ganglioside changes in mouse 3T3 gibroblasts and a suppressed sialidase activity on cell contact.

Certain enzyme activities for synthesis and degradation of gangliosides and the chemical quantity and incorporation of radioactivity from [14C] galactose into gangliosides have been studied in 3T3 cells and their transformed counterparts at various cell population densities. The chemical quantity of and the incorporation of radioactivity into GD1a ganglioside increased at the early stage of cell contact ("contact response" of ganglisoide), whereas response was not detectable in transformed 3T3 cells at any stage of cell contact. These phenomena were reproduced in five separate qualitative analyses and two quantitative determinations of gangliosides. As the basis of these phenomena, a membrane-bound sialidase activity which acted on gangliosides was suppressed in 3T3 cells at the "touching" stage of cell-to-cell contact. Transformed cells did not display the change of sialidase activity at any stage of cell contact.

Animals↗