RESUMEN
The role of the Wnt/ß-catenin signaling pathway in epilepsy and the effects of its modulators as efficacious treatment options, though postulated, has not been sufficiently investigated. We evaluated the involvement of ß-catenin and GSK-3ß, the significant proteins in this pathway, in the lithium chloride-pilocarpine-induced status epilepticus model in rodents to study acute phase of temporal lobe epilepsy (TLE). The modulators studied were 6-BIO, a GSK-3ß inhibitor and Sulindac, a Dvl protein inhibitor. The disease group exhibited increased seizure score and seizure frequency, and the assessment of neurobehavioral parameters indicated notable alterations. Furthermore, histopathological examination of hippocampal brain tissues revealed significant neurodegeneration. Immunohistochemical study of hippocampus revealed neurogenesis in 6-BIO and sulindac groups. The gene and protein expression by RT-qPCR and western blotting studies indicated Wnt/ß-catenin pathway downregulation and increased apoptosis in the acute phase of TLE. 6-BIO was very efficient in upregulating the Wnt pathway, decreasing neuronal damage, increasing neurogenesis in hippocampus and decreasing seizure score and frequency in comparison to sulindac. This suggests that both GSK-3ß and ß-catenin are potential and novel drug targets for acute phase of TLE, and treatment options targeting these proteins could be beneficial in successfully managing acute epilepsy. Further evaluation of 6-BIO to explore its therapeutic potential in other models of epilepsy should be conducted.
Asunto(s)
Epilepsia del Lóbulo Temporal , Estado Epiléptico , Ratas , Animales , Pilocarpina , Vía de Señalización Wnt/fisiología , Litio/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , beta Catenina/metabolismo , Sulindac/efectos adversos , Sulindac/metabolismo , Hipocampo/metabolismo , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/tratamiento farmacológicoRESUMEN
Purpose: Dry eye disease (DED) is classified as aqueous deficient, evaporative, or mixed. We investigated the therapeutic effect of the novel anti-inflammatory drug phosphosulindac (PS) in rabbit models of DED encompassing its pathogenesis, and its transition to chronicity. Methods: We treated three rabbit models of DED with PS (hydrogel formulation) or vehicle topically applied 1 × /day. We induced aqueous-deficient DED (acute and chronic) by injecting Concanavalin A into lacrimal glands; evaporative DED by injecting into the upper eyelid inactivated Mycobacterium tuberculosis in complete Freund's adjuvant; and mixed DED through desiccative stress, induced by holding open the eye for 3 h. We determined corneal sensitivity, tear break-up time (TBUT), Schirmer's tear test (STT), tear osmolality, and fluorescein staining of the ocular surface. Results: PS reversed all abnormal DED parameters. In acute DED, PS dose dependently normalized corneal sensitivity and tear osmolality; and improved TBUT, STT, and fluorescein staining. PS normalized corneal sensitivity and improved all other parameters in chronic aqueous-deficient DED. In evaporative DED, PS normalized corneal sensitivity and improved TBUT and fluorescein staining (osmolality and STT were not significantly changed in this model). In the desiccative stress model, PS improved TBUT and fluorescein staining but had no effect on STT or tear osmolality. Conclusions: PS rapidly reversed almost all DED parameters in its three subtypes. The normalization of the suppressed corneal sensitivity suggests the possibility of marked symptomatic relief by PS. The hydrogel formulation allows once-daily dosing. PS merits further development as a potential treatment for DED.
Asunto(s)
Antiinflamatorios/farmacología , Síndromes de Ojo Seco/patología , Compuestos Organofosforados/farmacología , Sulindac/análogos & derivados , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Hidrogeles , Aparato Lagrimal/efectos de los fármacos , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/efectos adversos , Concentración Osmolar , Conejos , Sulindac/administración & dosificación , Sulindac/efectos adversos , Sulindac/farmacología , Lágrimas/efectos de los fármacosRESUMEN
BACKGROUND: Sulindac has been used for treating colorectal polyps widely. However, the efficacy and safety of sulindac for colorectal polyps are unclear. This study aims to evaluate the efficacy and safety of sulindac for colorectal polyps. METHODS: Randomized controlled trials of sulindac in the treatment of colorectal polyps will be searched in PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, the Chongqing VIP Chinese Science, and Technology Periodical Database, and China biomedical literature database (CBM) from inception to August, 2020. And Baidu Scholar, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry will be searched to obtain more relevant studies comprehensively. Two researchers will perform data extraction and risk of bias assessment independently. Statistical analysis will be conducted in RevMan 5.3. RESULTS: This study will summarize the present evidence by exploring the efficacy and safety of sulindac in the treatment of colorectal polyps. CONCLUSION: The findings of the study will provide helpful evidence for the efficacy and safety of sulindac in the treatment of colorectal polyps, facilitating clinical practice and further scientific studies. ETHICS AND DISSEMINATION: The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/N5GDH.
Asunto(s)
Antineoplásicos/uso terapéutico , Pólipos del Colon/tratamiento farmacológico , Sulindac/uso terapéutico , Antineoplásicos/efectos adversos , Humanos , Metaanálisis como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Recto , Proyectos de Investigación , Sulindac/efectos adversos , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUND: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).
Asunto(s)
Poliposis Adenomatosa del Colon/tratamiento farmacológico , Progresión de la Enfermedad , Eflornitina/uso terapéutico , Sulindac/uso terapéutico , Adulto , Quimioterapia Combinada , Eflornitina/efectos adversos , Femenino , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Sulindac/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Atherosclerosis is a chronic inflammatory disease, and retinoid X receptor-α (RXRα) is an intriguing anti-atherosclerosis target. This study investigated whether and how an RXRα modulator, K-80003, derived from a non-steroidal anti-inflammatory drug attenuates atherosclerotic plaque progression and destabilization. EXPERIMENTAL APPROACH: Our previously established ApoE-/- mouse model of carotid vulnerable plaque progression was treated with K-80003 or vehicle for 4 or 8 weeks. Samples of carotid arteries and serum were collected to determine atherosclerotic lesion size, histological features, expression of related proteins, and lipid profiles. In vitro studies were carried out in 7-ketocholesterol (7-KC)-stimulated macrophages treated with or without K-80003. KEY RESULTS: K-80003 significantly reduced lesion size, plaque rupture, macrophage infiltration, and inflammatory cytokine levels. Plaque macrophages positive for nuclear p65 (RelA) NF-κB subunit were markedly reduced after K-80003 treatment. Also, K-80003 treatment inhibited 7-KC-induced p65 nuclear translocation, IκBα degradation, and transcription of NF-κB target genes. In addition, K-80003 inhibited NF-κB pathway mainly through the reduction of p62/sequestosome 1 (SQSTM1), probably due to promotion of autophagic flux by K-80003. Mechanistically, cytoplasmic localization of RXRα was associated with decreased autophagic flux. Increasing cytoplasmic RXRα expression by overexpression of RXRα/385 mutant decreased autophagic flux in RAW264.7 cells. Finally, K-80003 strongly inhibited 7-KC-induced RXRα cytoplasmic translocation. CONCLUSIONS AND IMPLICATIONS: K-80003 suppressed atherosclerotic plaque progression and destabilization by promoting macrophage autophagic flux and consequently inhibited the p62/SQSTM1-mediated NF-κB proinflammatory pathway. Thus, targeting RXRα-mediated autophagy-inflammation axis by its noncanonical modulator may represent a promising strategy to treat atherosclerosis.
Asunto(s)
Apolipoproteínas E/metabolismo , Placa Aterosclerótica/tratamiento farmacológico , Sulindac/análogos & derivados , Animales , Apolipoproteínas E/deficiencia , Células Cultivadas , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Células RAW 264.7 , Sulindac/administración & dosificación , Sulindac/efectos adversos , Sulindac/farmacologíaRESUMEN
BACKGROUND: Molecular studies suggest inhibition of colorectal mucosal polyamines (PAs) may be a promising approach to prevent colorectal cancer (CRC). Inhibition of ornithine decarboxylase (ODC) using low-dose eflornithine (DFMO, CPP-1X), combined with maximal PA export using low-dose sulindac, results in greatly reduced levels of normal mucosal PAs. In a clinical trial, this combination (compared with placebo) reduced the 3-year incidence of subsequent high-risk adenomas by >90 %. Familial Adenomatous Polyposis (FAP) is characterized by marked up-regulation of ODC in normal intestinal epithelial and adenoma tissue, and therefore PA reduction might be a potential strategy to control progression of FAP-related intestinal polyposis. CPP FAP-310, a randomized, double-blind, Phase III trial was designed to examine the safety and efficacy of sulindac and DFMO (alone or in combination) for preventing a clinically relevant FAP-related progression event in individuals with FAP. METHODS: Eligible adults with FAP will be randomized to: CPP-1X 750 mg and sulindac 150 mg, CPP-1X placebo and sulindac 150 mg, or CPP-1X 750 mg and sulindac placebo once daily for 24 months. Patients will be stratified based on time-to-event prognosis into one of the three treatment arms: best (ie, longest time to first FAP-related event [rectal/pouch polyposis]), intermediate (duodenal polyposis) and worst (pre-colectomy). Stage-specific, "delayed time to" FAP-related events are the primary endpoints. Change in polyp burden (upper and/or lower intestine) is a key secondary endpoint. DISCUSSION: The trial is ongoing. As of February 1, 2016, 214 individuals have been screened; 138 eligible subjects have been randomized to three treatment groups at 15 North American sites and 6 European sites. By disease strata, 26, 80 and 32 patients are included for assessment of polyp burden in the rectum/pouch, duodenal polyposis and pre-colectomy groups, respectively. Median age is 40 years; 59 % are men. The most common reasons for screening failure include minimal polyp burden (n = 22), withdrawal of consent (n = 9) and extensive polyposis requiring immediate surgical intervention (n = 9). Enrollment is ongoing. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov ( NCT01483144 ; November 21, 2011) and the EU Clinical Trials Register( EudraCT 2012-000427-41 ; May 15, 2014).
Asunto(s)
Poliposis Adenomatosa del Colon/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Eflornitina/uso terapéutico , Sulindac/uso terapéutico , Poliposis Adenomatosa del Colon/metabolismo , Adulto , Antineoplásicos/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Progresión de la Enfermedad , Método Doble Ciego , Neoplasias Duodenales/tratamiento farmacológico , Neoplasias Duodenales/metabolismo , Eflornitina/efectos adversos , Femenino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Poliaminas/antagonistas & inhibidores , Poliaminas/metabolismo , Sulindac/efectos adversosRESUMEN
IMPORTANCE: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. OBJECTIVE: To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah. INTERVENTIONS: Participants with FAP were randomized to sulindac (150 mg) twice daily and erlotinib (75 mg) daily (n = 46) vs placebo (n = 46) for 6 months. MAIN OUTCOMES AND MEASURES: The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden. RESULTS: Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P < .001). Only 2 participants experienced grade 3 adverse events. [table: see text]. CONCLUSIONS AND RELEVANCE: Among participants with FAP, the use of sulindac and erlotinib compared with placebo resulted in a lower duodenal polyp burden after 6 months. Adverse events may limit the use of these medications at the doses used in this study. Further research is necessary to evaluate these preliminary findings in a larger study population with longer follow-up to determine whether the observed effects will result in improved clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 01187901.
Asunto(s)
Poliposis Adenomatosa del Colon/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Duodenales/tratamiento farmacológico , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/patología , Adulto , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Duodenales/genética , Neoplasias Duodenales/patología , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/efectos adversos , Femenino , Genes APC , Humanos , Masculino , Persona de Mediana Edad , Sulindac/administración & dosificación , Sulindac/efectos adversosRESUMEN
OBJECTIVE: Most studies of tocolytics are underpowered to assess drug effects on rare adverse neonatal outcomes. Our aim was to optimize statistical power to assess the influence of sulindac on the rare but severe outcome of necrotizing enterocolitis (NEC) by performing a case-control study. STUDY DESIGN: A priori sample size of 78 in each group was estimated to detect a 2.5-fold increase in nonsteroidal antiinflammatory drug exposure in NEC cases. Maternal-neonatal charts were reviewed from 2007 through 2012 to yield 110 NEC cases: 68 patients with confirmed NEC by Bell's stage II criteria, and 42 with suspected NEC. Cases and controls (N = 131, matched according to gestational age at delivery, plurality, and delivery date) were compared in rates of antenatal exposures to nonsteroidal antiinflammatory drugs, other tocolytics, and maternal-neonatal characteristics and complications. RESULTS: Cases and controls were delivered at a mean of 28 weeks. Approximately 52% of the total cohort received tocolytics (26% indomethacin, 15% sulindac, 32% calcium channel blockers, 32% beta-sympathomimetics), with no differences in frequency of use between cases and controls. While there was no difference in indomethacin exposure between cases and controls, antenatal exposure to sulindac was independently associated with increased risk of NEC (adjusted odds ratio, 5.33; 95% confidence interval, 1.38-20.57; P = .02), even after adjustment for other factors significantly associated with NEC. CONCLUSION: Our data demonstrate an adverse association of sulindac with NEC. These findings deserve further investigation and using sulindac as a tocolytic agent requires caution.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Enterocolitis Necrotizante/inducido químicamente , Enterocolitis Necrotizante/epidemiología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Sulindac/efectos adversos , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Recién Nacido , Embarazo , Estudios Retrospectivos , Medición de RiesgoAsunto(s)
Comparación Transcultural , Industria Farmacéutica/legislación & jurisprudencia , Etiquetado de Medicamentos/legislación & jurisprudencia , Medicamentos Genéricos/efectos adversos , Medicamentos Genéricos/normas , United States Food and Drug Administration/legislación & jurisprudencia , Humanos , Síndrome de Stevens-Johnson/inducido químicamente , Síndrome de Stevens-Johnson/etiología , Sulindac/efectos adversos , Sulindac/uso terapéutico , Equivalencia Terapéutica , Estados UnidosRESUMEN
BACKGROUND: Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group. PROCEDURES: Eligible patients were <19 years of age who had measurable DT that was recurrent or not amenable to surgery or radiation. The primary objective was to estimate progression-free survival (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging. RESULTS: Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT. CONCLUSIONS: Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Fibromatosis Agresiva/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Supervivencia sin Enfermedad , Femenino , Fibromatosis Agresiva/mortalidad , Humanos , Masculino , Sulindac/administración & dosificación , Sulindac/efectos adversos , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversosRESUMEN
INTRODUCTION: Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). METHODS: At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150mg bid or an identical placebo bid for 6 months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. RESULTS: Slower than anticipated recruitment led to trial closure after randomizing participants (n=31 and n=30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p=0.0005) and sulindac (30 versus 10; p=0.0003) arms, but the difference between arms was not statistically significant (p=0.92). CONCLUSIONS: Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.
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Antiinflamatorios no Esteroideos/administración & dosificación , Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/prevención & control , Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias Pulmonares/prevención & control , Sulindac/administración & dosificación , Adulto , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Quimioprevención/métodos , Femenino , Humanos , Estudios Interdisciplinarios , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Fumar , Sulindac/efectos adversos , Resultado del TratamientoAsunto(s)
Pancreatitis Crónica/inducido químicamente , Enfermedad Aguda , Anciano de 80 o más Años , Antihipertensivos/efectos adversos , Progresión de la Enfermedad , Femenino , Humanos , Hidroclorotiazida/efectos adversos , Lisinopril/efectos adversos , Imagen por Resonancia Magnética , Pancreatitis/inducido químicamente , Sulindac/efectos adversos , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors. METHODS: This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m(2) given on Day 1 of each 21-day cycle. RESULTS: OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response. CONCLUSION: The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mitoxantrona/administración & dosificación , Neoplasias/tratamiento farmacológico , Sulindac/análogos & derivados , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mitoxantrona/efectos adversos , Mitoxantrona/farmacocinética , Neoplasias de la Próstata/tratamiento farmacológico , Sulindac/administración & dosificación , Sulindac/efectos adversos , Sulindac/farmacocinética , Neoplasias Testiculares/tratamiento farmacológico , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
BACKGROUND AND AIMS: The non-steroidal anti-inflammatory drug sulindac is an effective chemopreventive agent in sporadic colorectal cancer but its potential benefit in mismatch repair deficient cancers remains to be defined. We wanted to determine whether genetic defects that are relevant for colorectal cancer, such as Msh2 or p53 deficiency, would influence the efficiency of sulindac chemoprevention or increase the side effects. METHODS: Msh2 or p53 deficient and wild-type mice received feed containing 160-320 ppm sulindac for up to 25 weeks with or without a concurrent treatment with the carcinogen azoxymethane. Colon tissue was analysed by histopathology and molecular biology methods. RESULTS: We show that sulindac prevented azoxymethane-induced distal colon tumours in all mice. In the proximal colon, however, sulindac induced new inflammatory lesions on the mucosal folds, which further developed into adenocarcinoma in up to 18-25% of the p53 or Msh2 deficient mice but rarely in wild-type mice. This region in the proximal colon was characterised by a distinct profile of pro- and anti-inflammatory factors, which were modulated by the sulindac diet, including upregulation of hypoxia inducible factor 1α and macrophage inflammatory protein 2. CONCLUSIONS: These data show that the sulindac diet promotes carcinogenesis in the mouse proximal colon possibly through chronic inflammation. Sulindac has both beneficial and harmful effects in vivo, which are associated with different microenvironments within the colon of experimental mice. Deficiency for the Msh2 or p53 tumour suppressor genes increases the harmful side effects of long-term sulindac treatment in the mouse colon.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Anticarcinógenos/uso terapéutico , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/prevención & control , Sulindac/uso terapéutico , Adenocarcinoma/inducido químicamente , Adenocarcinoma/metabolismo , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Anticarcinógenos/efectos adversos , Anticarcinógenos/farmacocinética , Apoptosis/efectos de los fármacos , Azoximetano , Carcinógenos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Colon/metabolismo , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 2 Homóloga a MutS/deficiencia , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/patología , Sulindac/efectos adversos , Sulindac/farmacocinética , Proteína p53 Supresora de Tumor/deficienciaRESUMEN
Sulindac is a commonly used nonsteroidal anti-inflammatory drug. This study tested the hypothesis that sulindac-mediated drug-drug interactions and/or hepatotoxicity may be caused, in part, by inhibition of proteins responsible for the hepatic transport of drugs and/or bile acids by sulindac and/or sulindac metabolites [sulindac sulfone (S-sulfone) and sulindac sulfide (S-sulfide)]. The uptake and excretion of model substrates, [(3)H]taurocholate (TC), [(3)H]estradiol 17-beta-glucuronide (E217G), and nitrofurantoin (NF), were investigated in rat and human suspended and sandwich-cultured hepatocytes (SCH). In suspended rat hepatocytes, S-sulfone and S-sulfide inhibited Na(+)-dependent TC initial uptake (IC(50) of 24.9 +/- 6.4 and 12.5 +/- 1.8 microM, respectively) and Na(+)-independent E217G initial uptake (IC(50) of 12.1 +/- 1.6 and 6.3 +/- 0.3 microM, respectively). In rat SCH, sulindac metabolites (100 microM) decreased the in vitro biliary clearance (Cl(biliary)) of TC, E217G, and NF by 38 to 83%, 81 to 97%, and 33 to 57%, respectively; S-sulfone and S-sulfide also decreased the TC and NF biliary excretion index by 39 to 55%. In suspended human hepatocytes, S-sulfone and S-sulfide inhibited Na(+)-dependent TC initial uptake (IC(50) of 42.2 and 3.1 microM, respectively); S-sulfide also inhibited the TC Cl(biliary) in human SCH. Sulindac/metabolites markedly inhibited hepatic uptake and biliary excretion of E217G by 51 to 100% in human SCH. In conclusion, sulindac and metabolites are potent inhibitors of the uptake and biliary clearance of bile acids in rat and human hepatocytes and also inhibit substrates of rat breast cancer resistance protein, rat and human organic anion-transporting polypeptides, and human multidrug resistance-associated protein 2. Inhibition of multiple hepatic transport proteins by sulindac/metabolites may play an important role in clinically significant sulindac-mediated drug-drug interactions and/or liver injury.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Proteínas Portadoras/antagonistas & inhibidores , Hepatocitos/efectos de los fármacos , Sulindac/análogos & derivados , Animales , Células Cultivadas , Estradiol/análogos & derivados , Estradiol/metabolismo , Hepatocitos/metabolismo , Humanos , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Nitrofurantoína/metabolismo , Transportadores de Anión Orgánico/antagonistas & inhibidores , Ratas , Sulindac/efectos adversos , Ácido Taurocólico/metabolismoAsunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Eosinofilia/inducido químicamente , Sulindac/efectos adversos , Adulto , Antiinflamatorios no Esteroideos/uso terapéutico , Asma/complicaciones , Diagnóstico Diferencial , Fatiga/inducido químicamente , Femenino , Fiebre/inducido químicamente , Cefalea/inducido químicamente , Hepatomegalia/inducido químicamente , Humanos , Náusea/inducido químicamente , Dolor/tratamiento farmacológico , Sulindac/uso terapéuticoRESUMEN
We have previously reported that sulindac, a non-steroidal anti-inflammatory drug, inhibited tumor formation in the small intestine but increased tumors in the colon of Apc(Min/+) mice, a model of human familial adenomatous polyposis. To further explore intestinal regional responses, we studied effects of sulindac on additional gene-targeted mouse models of human intestinal tumorigenesis; these were (i) Apc(1638N/+) mouse (chain termination mutation in exon 15 of the Apc gene); (ii) Mlh1(+/-) mouse (DNA mismatch repair deficiency, a mouse model of human hereditary non-polyposis colorectal cancer) and (iii) double-heterozygous Mlh1(+/-)Apc(1638N/+) mutant mouse. Mice were fed AIN-76A control diet with or without 0.02% sulindac for 6 months. Intestinal regional tumor incidence, multiplicity, volume and degree of inflammation were used as end points. The results showed the following: (i) sulindac inhibited tumor development in the small intestine of Apc(1638N/+) mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1(+/-)Apc(1638N/+) mutant mice; (iii) sulindac increased tumors in the cecum of all mice regardless of genetic background; (iv) sulindac decreased inflammation in the small intestine of Apc(1638N/+) mice, but it increased inflammation in the small intestine of Mlh1(+/-) mice and Mlh1(+/-)Apc(1638N/+) mice and (v) sulindac enhanced inflammation in the cecum of all mutant mice. Findings indicate that the effects of sulindac in the intestine of these mutant mouse models are probably related to genetic background and appear to be associated with its inflammatory-inducing response.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Neoplasias Colorrectales Hereditarias sin Poliposis , Mutación , Proteínas Nucleares/genética , Sulindac/efectos adversos , Sulindac/farmacología , Poliposis Adenomatosa del Colon/inducido químicamente , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/patología , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Antineoplásicos/uso terapéutico , Ciego/efectos de los fármacos , Ciego/patología , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/inducido químicamente , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Modelos Animales de Enfermedad , Humanos , Inflamación/inducido químicamente , Inflamación/genética , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Ratones , Homólogo 1 de la Proteína MutL , Sulindac/uso terapéuticoRESUMEN
BACKGROUND: When considering surgery for branch duct-intraductal papillary mucinous neoplasms (BD-IPMNs) with suspected malignancy, it should be recognized that these lesions are frequently multifocal and are usually found in elderly patients with potential comorbidities that could affect the outcome of surgery. Clinical trials of chemoprevention have been conducted for a wide variety of malignancies. METHODS: Twenty-two BD-IPMN patients participated in the trial at our institution from June 2004 to January 2007. Ten of the 22 patients who rejected surgical therapy although their lesions or clinical symptoms met the criteria for surgical resection of the International Association of Pancreatology guidelines were assigned to the treatment group. Sulindac (150 mg twice daily) and omeprazole (20 mg once daily) were administered to these patients for 18 months. The remaining 12 patients comprised the control group. Branch duct diameter and mural nodule heights were monitored by either magnetic resonance cholangiopancreatography (MRCP) or computed tomography (CT) and by endoscopic ultrasonography (EUS). RESULTS: Both branch duct diameter and mural nodule height of BD-IPMNs in the treatment group were significantly reduced, while those in the control group were unchanged. Immunohistochemical staining for cyclooxygenase-1 and -2 was negative in hyperplasia, adenoma and carcinoma portions of resected pancreatic specimens but was clearly positive for glutathione-S-transferase pi (GST-pi), suggesting that GST-pi is a putative target molecule for sulindac. CONCLUSIONS: Although a larger scale randomized controlled study is needed in future, the present results suggest the promise of chemoprevention of carcinoma derived from BD-IPMNs by sulindac.
Asunto(s)
Adenocarcinoma Mucinoso/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Sulindac/uso terapéutico , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Papilar/tratamiento farmacológico , Adenocarcinoma Papilar/patología , Anciano , Anciano de 80 o más Años , Antiulcerosos/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Pancreatocolangiografía por Resonancia Magnética/métodos , Sistemas de Liberación de Medicamentos , Endosonografía/métodos , Femenino , Gutatión-S-Transferasa pi/efectos de los fármacos , Gutatión-S-Transferasa pi/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Omeprazol/uso terapéutico , Neoplasias Pancreáticas/patología , Sulindac/efectos adversos , Sulindac/farmacología , Tomografía Computarizada por Rayos X/métodosRESUMEN
PURPOSE: To evaluate the safety, pharmacokinetics and determine the recommended dose of the selective apoptotic antineoplastic drug, OSI-461 administered on a twice-daily regimen to patients with advanced solid malignancies. METHODS: In this phase I trial, 33 patients were treated with OSI-461 doses ranging from 400 to 1,200 mg given twice daily in 4-week cycles. Pharmacokinetic studies were performed to characterize the plasma disposition of OSI-461 and the effect of food intake on OSI-461 absorption. Secondary biomarker studies were performed to assess the biologic activity of OSI-461 including the measurement of pGSK-3beta, a PKG substrate, and pharmacogenetic studies to identify polymorphisms of CYP3A that influence drug metabolism and of ABCG2, involved in drug resistance. RESULTS: Thirty-three patients were treated with 86 courses of OSI-461. The dose-limiting toxicities were grade 3 abdominal pain, found in one patient at the 1,000 mg BID fed dose level and all patients at the 1,200 mg BID fed dose level. There was also one episode each of grade 3 fatigue and grade 3 constipation at the 1,000 and 1,200 mg BID fed dose levels, respectively. Other common toxicities included mild to moderate fatigue, nausea, anorexia and mild elevation in bilirubin. Pharmacokinetic studies of OSI-461 revealed approximately a twofold increase in AUC(0-24) when OSI-461 was administered with food. An increase in pGSK-3beta post-dose was seen in the majority of patients and was greater at higher dose levels. No patients exhibited CYP3A4 polymorphisms, while 100% of patients were found to have the CYP3A5*3/CYP3A5*3 polymorphism. Two known polymorphisms of the ABCG2 gene, G34 --> A34 and C421 --> A421, occurred at frequencies of 11.76 and 29%, respectively. CONCLUSIONS: Toxicity and pharmacodynamic data show that the recommended oral dose of OSI-461 is 800 mg twice daily administered with food. The drug appears to be well-tolerated, and overall bioavailability appears to be markedly increased when the drug is administered with food. These results support further disease-directed evaluations of OSI-461 at a dose of 800 mg BID in combination with other chemotherapeutic agents.
Asunto(s)
Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Ayuno , Alimentos , Neoplasias/tratamiento farmacológico , Sulindac/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Área Bajo la Curva , Biomarcadores de Tumor/sangre , Cromatografía Líquida de Alta Presión , Estudios de Cohortes , Femenino , Glucógeno Sintasa Quinasa 3/sangre , Glucógeno Sintasa Quinasa 3 beta , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/fisiopatología , Farmacogenética , Estándares de Referencia , Sulindac/administración & dosificación , Sulindac/efectos adversos , Sulindac/farmacocinética , Sulindac/farmacología , Espectrometría de Masas en TándemRESUMEN
Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (> or =3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade > or =3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.