Definitions

1. Sulindac is a pro drug, and is only active as a COX inhibitor when the methyl sulfoxide moiety on the molecule is reduced to the sulfide.
2. Sulindac is a pro-drug, containing a methyl sulfoxide group, that must be reduced to sulindac sulfide to be active as a COX inhibitor.
3. Sulindac is a prodrug that is metabolized to a Sulfide and Sulfone derivative in vivo.
4. Sulindac (Clinoril) is a nonsteroidal antiinflammatory medication (NSAID).
5. Sulindac is a sulfoxide compound that itself is believed to be inactive as an anti-arthritic agent.

Active Sulfide

1. MsrA and a membrane-associated Msr of bacteria were shown to be able to reduce sulindac to the active sulfide.

Acetyl Moiety

1. Compound 2a contains a methionine group linked through the amino group to the acetyl moiety of sulindac.

Compound 5A

1. In compound 5a, the sulindac structure and the N-acetyl methionine group are tethered by a diamine chain that can be of varying length.

Mixed

1. G93A mice were treated with sulindac at two different doses, i.e., 300 PPM and 450 PPM, which was mixed into their food beginning on postnatal day 30.

Studies

1. Studies with sulindac have indicated that it may also function as an anti-tumor agent by stimulating apoptosis.

Activation

1. Sulindac inhibits activation of the NF-kappaB pathway: Y. Yamamoto, et al.; J. Biol.

Metabolism

1. The most likely explanation for this finding is the metabolism of sulindac sulfide to inactive metabolites by the peroxidase activity of cyclooxygenase.

Commercially

1. In this particular synthetic method, the synthesis begins with commercially available sulindac (racemic form).

Warnings

1. Sulindac tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Substrate

1. This example provides evidence that sulindac, a known antioxidant containing a methyl sulfoxide moiety, can act as a substrate for MsrA.

Patients

1. Sulindac and its metabolites are not significantly removed from the blood in patients undergoing hemodialysis.

Human Milk

1. It is not known if sulindac is excreted in human milk.

Mixture

1. In these experiments either S, which is a mixture of the R and S epimers, or the R epimer of sulindac (see Methods) were used as substrates.

Urine

1. Less than 1% of the administered dose of sulindac appears in the urine as the sulfide metabolite.

Dca

1. The results clearly showed the presence of an enriched strong nucleosomal ladder only when both sulindac and DCA were used in combination.

Sulfone

1. Sulindac appears to be metabolized to sulindac sulfone by as yet unknown reactions.
2. Sulindac, and its sulfone and sulfide metabolites, are 93.1, 95.4, and 97.9% bound to plasma proteins, predominantly to albumin.
3. Sulindac sulfide and sulfone downregulated expression of both pEGFR and total EGFR in these cell lines as well (data not shown).

Absorbance

1. Because sulindac absorbs very strongly at this wavelength, the loss of absorbance at 340 nm could not be measured directly.

Fig

1. FIG. 5B illustrates yet another embodiment of an N-methionine derivative of sulindac indicated as compound 5a.

Cells

1. Once again a significant loss of mitochondrial membrane potential was only seen when the cells were exposed to both sulindac and DCA (FIG. 3B, panel 4).
2. After 24 h of treatment, Exisulind and Sulindac Sulfide treated cells showed only low levels of caspase-3 enzymatic activity, 0.7 and 3.5 Units respectively.
3. Sulindac sulfone is not an inhibitor of prostaglandin synthesis but has apoptotic activity against a wide array of cancer cells.

Derivatives

1. Thus, the Sulindac derivatives were shown to induce apoptosis in the presence of low caspase-3 activity.
2. Preferably, sulindac comprises the R-epimer of sulindac, derivatives, metabolites or variants thereof.

Effect

1. The effect of sulindac sulfide on this endocytic pathway was examined with an APP internalization assay described by Koo et al.
2. The effect of sulindac sulfone on basal EGFR activation and expression was also examined.

Drugs

1. Some studies have shown sulindac to be relatively less irritating to the stomach than other NSAID's except for drugs of the COX-2 inhibitor class.

Patient Labeling

1. Learn about the prescription medication Clinoril (Sulindac), drug uses, dosage, side effects, drug interactions, warnings, and patient labeling.

Sulfide

1. Either control or COX-2-expressing Caco-2 cells were treated with sulindac sulfide at the indicated concentrations for 24 hr prior to harvest.
2. Growth inhibition by sulindac sulfide was associated with a significant increase in percent G1 cells and activation of caspase-3.
3. Like sulindac sulfide, sulindac sulfone inhibits proliferation and induces apoptosis in human cancer cell lines in vitro (see Piazza et al.

Naproxen

1. The effects of naproxen and sulindac on renal function and their interaction with hydrochlorothiazide and piretanide in man.

Reduction

1. The loss of absorption at 340 nm, dependent on sulindac, is a measure of sulindac reduction.
2. Reduction of either epimer of sulindac, which is a prodrug, will yield sulindac sulfide, which is the active COX inhibitor.
3. The major biotransformations involve irreversible oxidation of the sulfinyl group of sulindac to sulfone and reduction to the corresponding sulfide.

Enzyme

1. Because free Met(O) Msr enzymes (i.e., FSMsr and FRMsr) cannot reduce sulindac (Table 2), MsrA is most likely the enzyme responsible for this activity.

Nsaid

1. Polyps virtually disappear when the NSAID that the patient takes is sulindac.

Nsaids

1. NSAIDs presently on the market that have been frequently associated with liver injury are aspirin (ASA), diclofenac (Voltaren), and sulindac (Clinoril).
2. Sulindac tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
3. This effect is specific to sulindac and is not seen with other NSAIDs.

Sulindac Sulfide

1. The two extractions essentially removed all of the sulindac and sulindac sulfide, leaving the NADPH in the aqueous phase, which was measured at 340 nm.
2. At micromolar concentrations, sulindac sulfide stimulated apoptosis and inhibited the growth of colorectal cancer cells on soft agar.
3. In separate experiments, COX-2-expressing Caco-2 cells were cultured in the presence of various concentrations of sulindac sulfide (indicated in Fig.

Normal Cells

1. In normal cells, but not cancer cells, the R-epimer of sulindac is not efficiently converted to the sulfide, the active COX inhibitor.
2. Either epimer of sulindac would be advantageous to other compounds if it would not be efficiently converted to a COX inhibitor in normal cells in vivo.
3. In addition, sulindac sulfide appeared to be more specific against CRC cells than normal cells.

Ibuprofen

1. Other NSAIDs, including piroxicam, ibuprofen, and sulindac had less of an effect.
2. Naproxen is a non-selective COX-inhibitor with an inhibition profile similar to sulindac and a structure similar to ibuprofen (see Cryer et al.

Indomethacin

1. No metabolism of sulindac or indomethacin was detected.

Sulindac Metabolites

1. Examples of sulindac metabolites include sulindac sulfide, sulindac sulfone.
2. No cleaved caspase-3 was detected by western blotting after 24 h and 48 h treatment with Sulindac metabolites or DHA (Fig.
3. In this study, we examined the effect of both Sulindac metabolites on two primary MPNST cell lines from NF1 patients in vitro.

Metabolites

1. Sulindac, sulindac metabolites, sulindac derivatives and an oxidating agent.
2. In addition, inhibition of apoptosis with the broad specificity caspase inhibitor ZVAD did not prevent EGFR downregulation by sulindac metabolites.
3. These results demonstrate that downregulation of EGFR by sulindac metabolites is not a consequence of the apoptotic effect of these drugs.

Plasma Levels

1. Neither propoxyphene hydrochloride nor acetaminophen had any effect on the plasma levels of sulindac or its sulfide metabolite.
2. The concomitant administration of aspirin with sulindac significantly depressed the plasma levels of the active sulfide metabolite.

Treatment

1. Nerve pathology in the type 1 diabetic dog: effects of treatment with sulindac.
2. We have been able to demonstrate that treatment with sulindac sulfide inhibits this activation (see Fig.
3. Increased invasiveness and prostaglandin production were reversed by treatment with sulindac sulfide, a known COX inhibitor.

Familial Adenomatous Polyposis

1. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.
2. Labayle D, Fischer D, Vielh P, et al.: Sulindac causes regression of rectal polyps in familial adenomatous polyposis.
3. The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis.

Sulindac

1. FIG. 2 shows the reduction of sulindac to sulindac sulfide, catalyzed by Msr.
2. Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased.
3. Upon completion, any further reduction seen upon addition of an enzyme fraction in a second incubation would be due to reduction of the R epimer of sulindac.

Categories

1. Familial Adenomatous Polyposis
2. Plasma Levels
3. Metabolites
4. Indomethacin
5. Normal Cells
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