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PubMed2001

Spectroscopic studies of interaction of chlorobenzylidine with DNA.

Electronic absorbance and fluorescence titrations are used to probe the interaction of chlorobenzylidine with DNA. The binding of chlorobenzylidine to DNA results in hypochromism, a small shift to a longer wavelength in the absorption spectra, and emission quenching in the fluorescence spectra. These spectral characteristics suggest that chlorobenzylidine binds to DNA by an intercalative mode. This conclusion is reinforced by fluorescence polarization measurements. Scatchard plots constructed from fluorescence titration data give a binding constant of 1.3 x 10(5) M(-1) and a binding site size of 10 base pairs. This indicates that chlorobenzylidine has a high affinity with DNA. The intercalative interaction is exothermic with a Van't Hoff enthalpy of -143 kJ/mol. This result is obtained from the temperature dependence of the binding constant. The interaction of chlorobenzylidine with DNA is affected by the pH value of the solution. The binding constant has its maximum at pH 3.0. Upon binding to DNA, the fluorescence from chlorobenzylidine is quenched efficiently by the DNA bases and the fluorescence intensity tends to be constant at high concentrations of DNA when the binding is saturated. The Stern-Volmer quenching constant obtained from the linear quenching plot is 1.6 x 10(4) M(-1) at 25 degrees C. The measurements of the fluorescence lifetime and the dependence of the quenching constant on the temperature indicate that the fluorescence quenching process is static. The fluorescence lifetime of chlorobenzylidine is 1.9 +/- 0.4 ns.

Animals↗
PubMed1976

Intestinal blood loss after a new anti-inflammatory drug, sulindac.

Sulindac was tested for fecal blood loss in 40 healthy male subjects whose red cells had been labeled with Na2 51 CrO4. Two daily dose levels of 240 mg and 400 mg were compared with 4.8 gm of aspirin and placebo for 2 wk. At day 15, aspirin-induced blood loss was greater than that of both dose levels of sulindac and of placebo (p less than 0.05). There were no significant differences between the two sulindac groups and the placebo group. Aspirin caused more adverse reactions than sulindac, 240 mg (p less than 0.05), 400 mg (p less than 0.05), and placebo (p less than 0.05).

Adult↗
PubMed1977

On the question of an interaction between sulindac and tolbutamide in the control of diabetes.

The effect of sulindac and tolbutamide on the control of diabetes was studied in 12 tolbutamide-treated maturity-onset diabetics with stable glycemic control. After one week of hospitalization on a metabolic ward for adjustment of diet and activity, the patients were treated with sulindac, 200 mg twice daily for one week. The time-to-peak plasma tolbutamide concentration was 3.1, 3.1, and 3.2 hr, respectively, after tolbutamide alone, after the first dose of sulindac, and after sulindac for a week. The areas under the plasma tolbutamide curve were 23.68, 22.10, and 22.78 for the same periods. The half-life for plasma tolbutamide was 7.46, 7.15, and 7.38 hr, respectively. None of the differences were statistically significant. The mean fasting plasma sugar was lower after the sulindac treatment (from 12.5 to 112.9 mg/100 ml, p less than 0.05), but the postprandial values increased slightly (from 137.7 to 142.6). It was concluded that there was no clinically significant interaction between sulindac and tolbutamide.

Adult↗
PubMed1977

The disposition of sulindac.

The disposition of sulindac, a new nonsteroid anti-inflammatory drug, has been studied in normal volunteers in five separate clinical studies. Based upon material balance considerations, a minimum of approximately 88% of an oral dose is absorbed. The major biotransformations involve irreversible oxidation of the sulfinyl group of sulindac to sulfone and reduction to the corresponding sulfide. The latter, which all available evidence indicates to be the pharmacologically active form of sulindac, is not excreted in urine, and has an apparent terminal half-life of 18.2 hr, well suited to twice daily dosage of its pro-drug. Following twice daily dosage of sulindac for 5 days, plasma levels of sulfide approach an apparent steady state with concentrations varying only within a twofold range over each dosage interval. The reversible biotransformation between sulindac and its active sulfide metabolite provides the basis for two therapeutic advantages relating to the gastrointestinal intolerance usually associated with anti-inflammatory drugs: (1) circumvention of initial exposure of gastric and small intestinal mucosa to the active form of the drug and (2) maintenance of systemic levels of active drug by means of enterohepatic recycling, principally of inactive pro-drug.

Adult↗
PubMed1977

A multicenter trial of sulindac in osteoarthritis of the hip.

Sulindac (cis-5-fluoro-2-methyl-l-[(p-methyl sulfinyl)-benzylidene]-indene-3-acetic acid) is a new nonsteroidal antirheumatic drug recently evaluated in a double-blind trial of 91 patients with hip osteoarthritis. Consecutive patients with documented flare following previous drug withdrawal were randomly assigned to one of 3 treatment groups: (1) sulindac given twice daily, (2) sulindac given 4 times daily, and (3) placebo. The dosage of sulindac, 100 to 300 mg daily, was adjusted according to patient global response and tolerance at 3- to 7-day intervals over 3 wk. Of 15 efficacy measurements evalulated, there was no difference between sulindac given 2 or 4 times daily, but differences were disclosed between one or both sulindac treatment groups and placebo in 11 of the 15 efficacy measurements (p less than 0.05, less than 0.01). The frequency of adverse reactions was of the same order for each treatment group. These included gastrointestinal upset, rash, and dizziness, usually transient and mild to moderate in severity. Serial laboratory studies revealed no evidence of renal, hepatic, or hematopoietic toxicity.

Adult↗
PubMed1992

Interleukin-1 induces protein tyrosine phosphorylation in T cells.

Interleukin (IL)-1 alpha activates multiple signal transmission pathways in the T helper type 2 cell line, D10A, and these pathways are linked to two separate IL-1 receptors (IL-1R). In the present report we show that IL-1 induces the activation of tyrosine kinase in these cells, leading to tyrosine phosphorylation of a subset of proteins of 38, 75, 97 and 115 kDa. This type of phosphorylation is prevented by a monoclonal antibody directed against the 80-kDa IL-1R and by tyrphostins which are specific inhibitors of tyrosine kinases. In addition, this inhibitor blocks IL-1-and IL-2-induced proliferation in D10A cells as well as the c-myc and c-myb proto-oncogene mRNA expression in response to IL-1. Interestingly, the inhibitor of cAMP-dependent kinase, H-8, only blocks IL-1-induced c-myb, but not c-myc mRNA expression. Altogether, our results demonstrate that the activation of a tyrosine kinase(s) is an early and major event that happens after IL-1/IL-1R interaction, leading to an increase in intracellular cAMP which results in c-myb and IL-5 mRNA expression. Independent of cAMP, by tyrosine phosphorylation of specific substrates IL-1 also induces c-myc and IL-6 mRNA expression and cellular proliferation.

Animals↗
PubMed1994

Dissection of T cell antigen receptor signaling using protein tyrosine kinase inhibitors.

T cell antigen receptor (TcR) recognition of appropriately presented antigen results in the rapid activation of protein tyrosine kinases. Subsequent events include activation of protein kinase C and increased intracellular free calcium which lead to the activation of transcription factors involved in regulating interleukin-2 gene expression. We have assayed the ability of a panel of protein tyrosine kinase (PTK) inhibitors to interfere with activation of the NF-AT transcription factor by TcR ligation or treatment with phorbol ester and calcium ionophore which bypass many of the early events of TcR signal transduction. The results indicate that PTK are involved in early and late stages of TcR signaling. Moreover, one inhibitor (genistein) revealed the existence of a PTK which down-regulates specifically calcium-mediated signaling at a point downstream of the PTK p56lck but upstream of calcium mobilization.

Benzylidene Compounds↗
PubMed1998

CD10 inhibitors increase f-Met-Leu-Phe-induced neutrophil transmigration.

A variety of bacterial enterocolitis in their active stages are characterized by the migration of polymorphonuclear leukocytes (PMNs) across epithelial surfaces. These mechanisms could explain some effects of enterotoxins observed in the intestinal mucosae. Here, using specific inhibitors, we investigated the potential role of CD10 (E.C. 3.4.24.11), present at the surface of human neutrophils, on formyl-Met-Leu-Phe (fMLP)-induced PMN migration across cultured monolayers of the human intestinal cell line T84. Transmigration of human neutrophils across T84 epithelial cells was observed for concentrations of fMLP as low as 10(-9) M, whereas maximal effect was achieved at 10(-7) M as determined by transepithelial resistances and PMN myeloperoxidase assays. RB25, a CD10 inhibitor, reduced by two orders of magnitude the concentration of fMLP required to obtain full neutrophil transmigration across T84 epithelial cell line. RB25 response was concentration dependent with half-maximal and maximal effect occurring at 10(-9) and 10(-7) M, respectively. These concentrations of RB25 corresponded exactly to the half-maximal and maximal inhibition of endopeptidase 24.11 at the neutrophil cell surface. However, the effect of CD10 inhibitors on PMN transmigration cannot be accounted for by a direct action on T84 epithelial cells, since these cells fail to express any detectable endopeptidase 24.11 activity. Moreover, blocking of CD10 enzymatic activity by various and selective inhibitors potentiated the effect of low concentrations of fMLP on PMN transmigration. Finally, RB25 failed to affect interleukin-8 (IL-8)-induced PMN transmigration across T84 epithelial cells, in agreement with the preference of CD10 for small peptidic substrates. Taken together, these results demonstrate that inhibition of CD10 significantly reduced the concentration of fMLP needed for eliciting transmigration of PMN across intestinal epithelia.

Benzylidene Compounds↗
PubMed1976

Synthesis of substituted anilino-3-methoxy-4-substituted acetoxy) benzylidenes and their monoamine oxidase inhibitory and anticonvulsant properties.

Several substituted anilino-(3-methoxy-4-substituted acetoxy) benzylidenes were synthesized and characterized by their sharp melting points and elemental analyses. All substituted benzylidenes competitively inhibited the in vitro monoamine oxidase activity of rat brain homogenates and possessed anticonvulsant activity against pentylenetetrazol-induced convulsions in mice.

Animals↗
PubMed1977

Analysis of sulindac and metabolites by combined isotope dilution-radioimmunoassay.

Sulindac, a new anti-inflammatory agent, and its sulfone and sulfide metabolites were conjugated to bovine serum albumin by the N-hydroxysuccinimide active ester procedure. Antiserum from rabbits immunized with each of these haptens exhibited extensive cross-reactivity, precluding differential analyses of the three species by displacement assay without prior separation. Therefore, an analytical method based on a combination of isotope dilution and radioimmunoassay was devised. A known mixture of the three chemical species, each labeled with tritium, was equilibrated with plasma or urine samples, reisolated chromatographically, and quantitated by binding to an appropriate immunoglobulin. The radiolabeled materials thus served as recovery standards as well as labeled antigens for each displacement assay. Sulindac and each of its metabolites in plasma or urine at concentrations as low as 500 ng/sample were differentially determined by this procedure. However, since an extraction is required, several milliliters of plasma can be used for each sample, thus increasing the actual sensitivity of the assay.

Animals↗
PubMed1978

Interaction of sulindac and metabolite with human serum albumin.

The binding of the newly developed nonsteroidal anti-inflammatory agent sulindac and its principal active metabolite, sunlindac sulfide, to human serum albumin was investigated. With the methods of dialysis, fluorescence quenching, and difference spectrophotometry, it was found that both agents were extensively bound to albumin. The binding affinity of the metabolite was considerably higher than that of sunlindac and this effect may be related to its prolonged plasma half-life versus the parent drug. Sulindac binding was albumin concentration dependent, which gave rise to an unfamilar Scatchard analysis of the dialysis data.

Anti-Inflammatory Agents↗
PubMed1996

Enzyme-linked immunosorbent assay for trkA tyrosine kinase activity.

A 96-well microtiter enzyme-linked immunosorbent assay was developed to assay the activity of the cytoplasmic domain of trkA tyrosine kinase. The assay involves immobilization of phospholipase C- gamma/glutathione S-transferase fusion protein on a microtiter plate, addition of the kinase reaction mixture, and detection by an antibody to phosphotyrosine followed by an alkaline phosphatase-conjugated second antibody. The substrate used in this system, phospholipase C-gamma, is one of several biologically important substrates for the phosphorylation reaction of receptor-linked tyrosine kinases. The assay was then used to characterize kinase inhibitory activities of various small molecules including analogs of K-252a.

Adenosine Triphosphate↗