Category: 59973-80-7

Ryan, Christopher W. published the artcileA phase I/II dose-escalation study of exisulind and docetaxel in patients with hormone-refractory prostate cancer, Application of Sulindac sulfone, the publication is BJU International (2005), 95(7), 963-968, database is CAplus and MEDLINE.

OBJECTIVE: To determine the safety and efficacy, in a dose-escalation study, of exisulind (an oral sulfone metabolite of sulindac thought to induce apoptosis in malignant cells by inhibiting cGMP-phosphodiesterase) combined with docetaxel in men with hormone-refractory prostate cancer (HRPC), as pre-clin. studies suggested activity against prostate cancer and synergy with cytotoxic agents. PATIENTS AND METHODS: Thirty-four patients with HRPC were treated with oral exisulind twice daily for 21-day cycles and i.v. docetaxel given for 1 h on the first day of each cycle. Three dose levels were assessed, combining exisulind 150 and 250 mg twice daily with docetaxel at 60 or 75 mg/m². Toxicity was then evaluated using standard criteria. RESULTS: The recommended phase II dose was determined to be exisulind 250 mg and docetaxel 60 mg/m², with escalation to 75 mg/m² after cycle 1, as tolerated. The most common grade 3-4 toxicities among all patients were neutropenia (56%), infection (24%) and hyperglycemia (18%). Twelve of 32 evaluable patients (38%, 95% confidence interval, CI, 23-55%) had a decline in PSA by at least half. Only four of 17 evaluable patients (95% CI, 1-47%) treated at the phase II dose level had such a decline in PSA. The median (95% CI) overall survival of all patients was 16 (12.9-19.7) months and median progression-free survival 4.7 (2.7-5.2) months. CONCLUSION: The combination of exisulind and docetaxel was tolerable in patients with HRPC. The PSA response rates do not suggest an improvement over historical data with single-agent docetaxel in this population.

BJU International published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Application of Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Agarwal, B. published the artcileCox-2 is needed but not sufficient for apoptosis induced by Cox-2 selective inhibitors in colon cancer cells, COA of Formula: C20H17FO4S, the publication is Apoptosis (2003), 8(6), 649-654, database is CAplus and MEDLINE.

The role of Cox-2 in NSAID-induced apoptosis is debated. We studied the role of Cox-2 inhibition in apoptosis induced by a selective Cox-2 inhibitor, SC 236 (a structural analog of celecoxib) in two colon cancer cell lines, HT29 (expressing Cox-2 protein) and HCT116 (not expressing Cox-2 protein). Apoptosis was quantified by flow cytometry. SC 236 0-75 μM decreased cell numbers and induced apoptosis to identical levels in HT29 and HCT116 cells. However, SC 236, concentrations >75 μM reduced Cox-2 protein expression in HT29 cells and induced greater levels of apoptosis in HT29 than in HCT116 cells. In contrast, sulindac sulfide (SSD) (which inhibits Cox-1 and Cox-2) 0-200 μM or sulindac sulfone (SSN) 0-500 μM (without significant activity against Cox-1 or Cox-2) caused identical decreases in cell number and increases in apoptosis in HT29 and HCT116 cells. Neither SSD nor SSN altered the expression of Cox-2 in HT29 cells. To determine that the higher levels of apoptosis in HT29 cells with SC 236 >75 μM were related to decreased Cox-2 protein levels, we decreased Cox-2 protein expression in HT29 cells with curcumin (diferuloylmethane) and studied its effect on SC 236-induced apoptosis. Curcumin augmented apoptosis induced by SC 236 in HT29 cells but not in Cox-2 lacking HCT116 cells. In conclusion, selective Cox-2 inhibitors can induce apoptosis independent of Cox-2 expression. However they may selectively target cells that express Cox-2 by decreasing their Cox-2 protein expression.

Apoptosis published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, COA of Formula: C20H17FO4S.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Tang, Weijuan published the artcileGas-phase ion-molecule reactions for the identification of the sulfone functionality in protonated analytes in a linear quadrupole ion trap mass spectrometer, Application In Synthesis of 59973-80-7, the publication is Rapid Communications in Mass Spectrometry (2016), 30(12), 1435-1441, database is CAplus and MEDLINE.

Rationale : The oxidation of sulfur atoms is an important biotransformation pathway for many sulfur-containing drugs. In order to rapidly identify the sulfone functionality in drug metabolites, a tandem mass spectrometric method based on ion-mol. reactions was developed. Methods : A phosphorus-containing reagent, tri-Me phosphite (TMP), was allowed to react with protonated analytes with various functionalities in a linear quadrupole ion trap mass spectrometer. The reaction products and reaction efficiencies were measured. Results : Only protonated sulfone model compounds were found to react with TMP to form a characteristic [TMP adduct-MeOH] product ion. All other protonated compounds investigated, with functionalities such as sulfoxide, N-oxide, hydroxylamino, keto, carboxylic acid, and aliphatic and aromatic amino, only react with TMP via proton transfer and/or addition The specificity of the reaction was further demonstrated by using a sulfoxide-containing anti-inflammatory drug, sulindac, as well as its metabolite sulindac sulfone. Conclusions : A method based on functional group-selective ion-mol. reactions in a linear quadrupole ion trap mass spectrometer has been demonstrated for the identification of the sulfone functionality in protonated analytes. A characteristic [TMP adduct-MeOH] product ion was only formed for the protonated sulfone analytes. The applicability of the TMP reagent in identifying sulfone functionalities in drug metabolites was also demonstrated. Copyright © 2016 John Wiley & Sons, Ltd.

Rapid Communications in Mass Spectrometry published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C26H45N5O7Si2, Application In Synthesis of 59973-80-7.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Huang, Wei-Hua published the artcileSimultaneous determination of sulindac and its metabolites sulindac sulfide and sulindac sulfone in human plasma by a sensitive UPLC-PDA method for a pharmacokinetic study, Synthetic Route of 59973-80-7, the publication is Analytical Methods (2014), 6(13), 4679-4685, database is CAplus.

A sensitive, rapid and reliable ultra-performance liquid chromatog. (UPLC) with Photo-Diode Array (PDA) detection method was developed for simultaneous determination of sulindac and its metabolites sulindac sulfide and sulindac sulfone in human plasma. The analytes were extracted by dichloromethane from human plasma using a liquid-liquid extraction method. The chromatog. separation was performed on a Waters Acquity UPLC with a Waters Acquity UPLC BEH C₁₈ column (2.1 × 50 mm i.d., 1.7 μm) within 5 min. The mobile phase used for gradient elution consisted of ammonium formate buffer (20 mM) containing 1% acetic acid and acetonitrile. The flow rate was maintained at 0.4 mL min^-1. The monitor wavelength was set at 328 nm for PDA detection. All calibration curves of the analytes showed good linearity within the test ranges. The validated method was successfully applied to a pharmacokinetic study of sulindac, sulindac sulfide and sulindac sulfone in 15 healthy Chinese male subjects with oral administration of sulindac tablets.

Analytical Methods published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Synthetic Route of 59973-80-7.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Quidville, Virginie published the artcile15-Hydroxyprostaglandin-dehydrogenase is involved in anti-proliferative effect of non-steroidal anti-inflammatory drugs COX-1 inhibitors on a human medullary thyroid carcinoma cell line, Recommanded Product: Sulindac sulfone, the publication is Prostaglandins & Other Lipid Mediators (2006), 81(1-2), 14-30, database is CAplus and MEDLINE.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin (PG) synthesis enzymes, the cyclooxygenases (COX-1 and 2). It is suggested that these enzymes are not their only targets. We reported that in tumoral TT cell, indomethacin, in vivo and in vitro, decreases proliferation and increases activity of 15-hydroxyprostaglandin-dehydrogenase (15-PGDH), the PG catabolism key enzyme. Here, we show that the COX-1 inhibitors, selective or not, and sulindac sulfone, a non-COX inhibitor, increased 15-PGDH activity and reduced PGE₂ levels. This increase was neg. correlated to the decrease in cell proliferation and suggested that 15-PGDH could be implicated in NSAIDs anti-proliferative effect. Indeed, the silencing of 15-PGDH expression by RNA interference using 15-PGDH specific siRNA enhanced TT cell proliferation and abolished the anti-proliferative effect of a representative non-selective inhibitor, ibuprofen. Moreover, a specific inhibitor of 15-PGDH activity, CAY 10397, completely reversed the effect of ibuprofen on proliferation. Consequently our results demonstrate that, at least in TT cells, 15-PGDH is implicated in proliferation and could be a target for COX-1 inhibitors specific or not. NSAIDs defined by their COX inhibition should also be defined by their effect on 15-PGDH.

Prostaglandins & Other Lipid Mediators published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Recommanded Product: Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Masuda, Yasusuke published the artcileIntrahepatic flow disturbance: possibility of a hidden cause of drug toxicity, Synthetic Route of 59973-80-7, the publication is Journal of Pharmacological Sciences (Tokyo, Japan) (2006), 100(3), 167-174, database is CAplus and MEDLINE.

The liver has an intricate microvascular system that allows homogenous perfusion throughout the organ. However, the regulatory mechanisms of intrahepatic circulation are still unclear, and the effects of drugs on this system have rarely been reported. Oxethazaine, a topical anesthetic, was incidentally found to induce a consistent increase in portal pressure in the isolated perfused rat liver, which led us to characterize this phenomenon. For this, a vital staining method was developed to detect microcirculatory alterations in the isolated liver. Using this method, not only vasoconstrictors like endothelin-1, but the drugs oxethazaine and clomipramine, a tricyclic antidepressant, were found to induce flow redistribution to the deeper and hilar portions of the liver with minimal perfusion at the periphery, which was due to a short-circuit flow at the center owing to the constriction of the intrahepatic portal vein branches. Hepatic nerve stimulation also produced a similar flow disturbance. Since the portal pressure increases by these compounds were inhibited by the Rho-kinase inhibitors Y27632 and HA1077, portal vein branches may employ a Rho-kinase-dependent pathway for sustained contraction. However, oxethazaine, clomipramine, and endothelin-1 may activate this pathway differently. The intrahepatic flow disturbance could play a hidden role in drug toxicity of certain drugs.

Journal of Pharmacological Sciences (Tokyo, Japan) published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Synthetic Route of 59973-80-7.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Malkinson, Alvin M. published the artcileRole of inflammation in mouse lung tumorigenesis: a review, Application of Sulindac sulfone, the publication is Experimental Lung Research (2005), 31(1), 57-82, database is CAplus and MEDLINE.

A review. Peritumoral and intratumoral macrophages are associated with human and mouse lung cancer. The mouse model allows manipulation of the macrophage population to exptl. evaluate its contribution to tumor growth. Genetic and pharmacol. strategies also permit testing the involvement of specific inflammatory mediators in tumor progression. Among those endogenous mediators thus identified are interleukin (IL)-10, glucocorticoids, prostacyclin, nitric oxide, and surfactant apoprotein D (SP-D); serum SP-D levels are a useful biomarker to monitor tumor growth rate. The importance of understanding the mutually antagonistic roles of individual prostaglandins downstream from cycloxygenase (COX) and how this affects the efficacy of COX-inhibitory drugs is discussed. Promising drug candidates include synthetic glucocorticoids such as budesonide and the sulfone derivative of sulindac, apotosyn.

Experimental Lung Research published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Application of Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Levine, Lawrence published the artcileDoes the release of arachidonic acid from cells play a role in cancer chemoprevention?, Recommanded Product: Sulindac sulfone, the publication is FASEB Journal (2003), 17(8), 800-802, database is CAplus and MEDLINE.

COX-2 is overexpressed in cancer cells and has become a major target for cancer preventive drugs. NSAIDs, retinoids, antioxidants, and PPAR agonists, reported to be chemopreventive, suppress COX-2 synthesis. NSAIDs also have been shown to be chemopreventive independent of COX-2 activity. Common to all of these compounds is their ability to release arachidonic acid (AA) from rat liver cells in culture. Most of these compounds inhibit induced PGI₂ production Vitamin D₃ and tamoxifen, however, not only stimulate the release of AA from cells: they amplify rather than inhibits induced COX activity. In view of the many activities attributable to AA, I propose that its release and accumulation could initiate mol. reactions that lead to apoptosis and eventually to suppression of cancer. Some drugs shown to release AA from cells and affect PGI₂ production-e.g., thiazolidinediones and statins are widely used for conditions unrelated to cancer. In vivo studies could reveal whether they can also function as cancer preventive agents.

FASEB Journal published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Recommanded Product: Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Galmarini, Carlos M. published the artcileOSI-461 (OSI), COA of Formula: C20H17FO4S, the publication is Current Opinion in Investigational Drugs (Thomson Scientific) (2004), 5(6), 648-656, database is CAplus and MEDLINE.

A review. OSI Pharmaceuticals is developing OSI-461, a potent analog of exisulind, for the potential treatment of cancer and inflammatory bowel disease. In August 2001, OSI-461 entered phase II trials involving patients with chronic lymphocytic leukemia. In July 2002, the company embarked on a pilot phase II study evaluating OSI-461 for the treatment of Crohn’s disease. By Oct. 2002, Cell Pathways had selected hormone-refractory prostate cancer as the lead cancer indication for clin. development of OSI-461.

Current Opinion in Investigational Drugs (Thomson Scientific) published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, COA of Formula: C20H17FO4S.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Anonymous published the artcileExisulind. aptosyn, FGN 1, prevatac, sulindac sulfone, Formula: C20H17FO4S, the publication is Drugs in R&D (2004), 5(4), 220-226, database is CAplus.

A review. Exisulind [Aptosyn, FGN 1, Prevatac, sulindac sulfone], the sulfone derivative of sulindac, is the lead compound in a series of selective apoptotic antineoplastic drugs (SAANDs) being developed by OSI Pharmaceuticals. The compounds were originally developed by Cell Pathways, which was acquired by, and integrated into, OSI Pharmaceuticals in June 2003. Exisulind inhibits the enzyme cGMP phosphodiesterase (GMP-PDE), overexpressed in precancerous and cancerous colorectal cells, and induces apoptosis in such cells with minimal effects on normal cells. This apoptotic effect is independent of COX I or COX II inhibition, p53, Bcl-2, or cell-cycle arrest. Preclin. evidence suggests that exisulind also inhibits angiogenesis. Cell Pathways has formed sales and distribution agreements with three healthcare-related companies in the US for its future marketing and support campaign for exisulind. Innovex will hire and train sales representatives for Cell Pathways to launch and promote exisulind, Livingston Healthcare Services will be responsible for customer service, order and distribution administration, and Lash Group will be responsible for the development and implementation of reimbursement support services for exisulind. Cell Pathways has issued an exclusive license for exisulind to Paladin Labs of Montreal, Canada. The agreement allows Paladin exclusive rights to commercialise the drug in Canada. In August 1999 Cell Pathways submitted an NDA application to the US FDA for exisulind (Aptosyn) for the treatment of familial adenomatous polyposis (FAP). However, in Sept. 2000, the FDA announced that it had found deficiencies in the safety and efficacy data of Cell Pathways’ NDA, and returned a non-approvable letter to the company. Cell Pathways then initiated another phase III study of the agent in combination with Aventis’ docetaxel and comparing combination therapy with docetaxel alone. Exisulind has fast-track designation for FAP in the US. Phase I and II pediatric trials are also underway in the US. Cell Pathways announced in Apr. 2000 that it had completed enrollment in an open-label phase II study in children with familial adenomatous polyposis (FAP). Patients will be evaluated to determine whether polyp numbers have been reduced after 1 yr relative to baseline. In June 2000, Cell Pathways announced the results of a 1-yr extension of a 1997-1999 phase III trial that showed that exisulind significantly reduced polyp formation in patients with FAP. Enrollment of 282 patients in a multicentre, placebo-controlled phase III trial for the treatment of sporadic colonic polyps was completed in the US in May 1999. In its 2003 Annual Report, Paladin Labs announced that it is conducting a phase III study of exisulind in patients with prostate cancer in Canada. Exisulind has completed a pivotal phase II/III trial for preventing the recurrence of prostate cancer in the US. Two phase II prostate cancer trials were initiated in June 1999. The first study assessed the efficacy of exisulind in 15 patients who had undergone prostatectomy, were receiving LHRH-agonist hormone therapy and had increasing PSA levels (study EX1001). The second trial was to enrol 20 hormone-refractory patients scheduled for radical prostatectomy within 2-8 wk of diagnosis (study EX1004). This study compared the effect of exisulind + docetaxel on the rate of apoptosis and GMP-PDE expression in premalignant or malignant and normal prostate tissue. Cell Pathways and Rhone-Poulenc Rorer (now Aventis) agreed to collaborate on clin. trials of.exisulind in combination with docetaxel in the treatment of various solid tumors. The first phase I/II trial (study 026) was to enrol previously untreated patients with non-small cell lung cancer (NSCLC). OSI Pharmaceuticals and Bristol-Myers Squibb are conducting a phase I/II trial (study EX 2002) of exisulind in combination with paclitaxel and carboplatin as first-line treatment for patients with NSCLC. Both companies will share costs and information gathered from the trial. A phase I/II trial (study EX 2006) of weekly paclitaxel and carboplatin combined with exisulind is also underway in patients with advanced NSCLC. Cell Pathways and Glaxo Wellcome are cooperating in supporting a clin. trial (study EX 2004) of exisulind in combination with vinorelbine as first-line treatment for elderly patients with advanced NSCLC. The study will be conducted at the University of Wisconsin, and the two companies will share the costs of the trial while maintaining the rights to their resp. compounds Cell Pathways and Eli Lilly have a phase I/II trial (study EX 2005) of exisulind in- combination with gemcitabine underway in patients with NSCLC. This study will investigate the efficacy and tolerability of escalating doses of exisulind in combination with a standard gemcitabine regimen. The Cancer and Leukemia Group B (CALGB) initiated a phase 11 study of exisulind in combination with etoposide and carboplatin in patients with small cell lung cancer in the US in Sept. 2002. The Eastern Cooperative Oncol. Group (ECOG) initiated a phase 11 study in NSCLC patients in Sept. 2002 that will investigate the effects of exisulind in combination with gemcitabine and carboplatin. The objectives of the two studies are to determine the 12-mo survival rate and response rates following treatment with the combination regimens. Patents covering the mechanism of action of exisulind have been allowed in Europe and Japan, and extend to the methods of identifying compounds that selectively stimulate apoptosis in precancerous and cancerous cell.

Drugs in R&D published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Formula: C20H17FO4S.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem