RESUMEN
Pancreatic ductal adenocarcinoma (PDAC) remains a highly malignant cancer with a grim prognosis due to its early metastasis and resistance to current chemotherapies, such as Gemcitabine (GEM). We have previously demonstrated that cAMP exclusion by MRP4 is critical for PDAC cell proliferation, establishing this transporter as a promising prognostic marker and therapeutic target. In search for novel therapeutic options to improve GEM efficacy, we conducted a drug repositioning screening to identify potential inhibitors of cAMP transport by MRP4. Several non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the transport of certain MRP4 substrates. In this study, we assessed the efficacy of sixteen NSAIDs in inhibiting cAMP transport mediated by MRP4, identifying seven potent inhibitors based on their IC50 values. The most potent inhibitors were further tested for their effect on cell proliferation and migration. Flurbiprofen emerged as the most potent inhibitor of both MRP4-mediated cAMP transport and cell proliferation. Overexpression of MRP4 in BxPC-3 cells significantly increased GEM resistance, and co-administration of flurbiprofen with GEM markedly enhanced the latter's potency inhibiting PDAC cells proliferation. These findings position flurbiprofen as a potent inhibitor of cAMP transport by MRP4 and a promising adjunctive therapy to enhance GEM effectiveness in PDAC treatment.
Asunto(s)
Carcinoma Ductal Pancreático , Movimiento Celular , Proliferación Celular , AMP Cíclico , Desoxicitidina , Flurbiprofeno , Gemcitabina , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , AMP Cíclico/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Flurbiprofeno/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Transporte Biológico/efectos de los fármacos , Sinergismo Farmacológico , Antiinflamatorios no Esteroideos/farmacologíaRESUMEN
We explored the effects of flurbiprofen axetil on interleukin (IL)-2 and IL-6 levels in postoperative patients with colorectal cancer. A total of 120 patients (American Society of Anesthesiologists I and II) scheduled to undergo colorectal cancer surgery were randomly divided into 3 groups (N = 40 in each group): flurbiprofen axetil group (group F), morphine group (group M), and tramadol group (group T). Group M received 0.1 mg/kg morphine, group T received 1.5 mg/kg tramadol, and group F received 1.5 mg/kg flurbiprofen axetil. Patients in the 3 groups were administered treatments through intravenous injection 10 min before surgery. Serum IL-2 and IL-6 levels were detected. Postoperative adverse reactions were recorded, such as nausea, vomiting, and pruritus. The serum IL-6 level of the 3 groups increased 3 h after surgery. Compared with group M, IL-6 level was higher in group T and group F at 1 day after the surgery, and the differences between group M and the other groups were significant (P < 0.05). Moreover, the incidence of adverse reactions was significantly different among 3 groups (P < 0.05). Flurbiprofen axetil promoted the secretion of IL-2 and inhibited IL-6; additionally, flurbiprofen axetil may have a lower incidence of adverse reactions compared to other treatments.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Neoplasias Colorrectales/sangre , Flurbiprofeno/análogos & derivados , Interleucina-2/sangre , Interleucina-6/sangre , Adulto , Anciano , Neoplasias Colorrectales/cirugía , Ensayo de Inmunoadsorción Enzimática , Femenino , Flurbiprofeno/farmacología , Humanos , Masculino , Persona de Mediana Edad , Periodo PosoperatorioRESUMEN
Chronic renal injury can be mediated by angiotensin II (ANG II) and prostanoids through hemodynamic and inflammatory mechanisms and attenuated by individual suppression of these mediators. In rats with (5/6) renal ablation (Nx), we investigated 1) the intrarenal distribution of COX-2, ANG II, and the AT(1) receptor (AT(1)R); 2) the renoprotective and antiinflammatory effects of an association between the AT(1)R blocker, losartan (Los), and the gastric sparing anti-inflammatory nitroflurbiprofen (NOF). Adult male Munich-Wistar rats underwent Nx or sham operation (S), remaining untreated for 30 days, after which renal structure was examined in 12 Nx rats (Nx(pre)). The remaining rats were followed during an additional 90 days, distributed among 4 treatment groups: Nx(V) (vehicle), Nx(Los) (Los), Nx(NOF) (NOF), and Nx(Los/NOF) (Los/NOF). Nx(pre) rats exhibited marked albuminuria, hypertension, glomerulosclerosis, interstitial expansion, and macrophage infiltration, accompanied by abnormal glomerular, vascular, and interstitial COX-2 expression. ANG II appeared in interstitial cells, in contrast to S, in which ANG II was virtually confined to afferent arterioles. Intrarenal AT(1)R distribution shifted from mostly tubular in S to predominantly interstitial in Nx(pre). All these changes were aggravated at 120 days and attenuated by Los and NOF monotherapies. Los/NOF treatment arrested renal structural injury and ANG II expression and reversed hypertension, albuminuria, and renal inflammation. In conclusion, abnormal expression of COX-2, ANG II, and AT(1)R may be key to development of renal injury in Nx. Concomitant COX-2 inhibition and AT(1)R blockade arrested renal injury and may represent a useful strategy in the treatment of chronic nephropathies.
Asunto(s)
Angiotensina II/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Antihipertensivos/farmacología , Flurbiprofeno/análogos & derivados , Flurbiprofeno/farmacología , Isoenzimas/metabolismo , Losartán/farmacología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Animales , Ciclooxigenasa 2 , Quimioterapia Combinada , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/metabolismo , Inmunohistoquímica , Riñón/efectos de los fármacos , Riñón/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Masculino , Nefrectomía , Ratas , Ratas WistarRESUMEN
Cyclooxygenase derivatives and nitric oxide (NO) may influence the pathogenesis of progressive nephropathies. We investigated the effect of nitroflurbiprofen (NOF), a NO-releasing nonsteroidal anti-inflammatory drug (NSAID) without gastrointestinal toxicity, in rats with 5/6 ablation (NX). The following four groups were studied: Sham, sham-operated rats; Sham + NOF, Sham receiving oral NOF two times daily; NX, rats subjected to NX; and NX + NOF, NX receiving NOF. NOF was barely detected in plasma but released the parent compound flurbiprofen. At 30 days, glomerular hydraulic pressure (PGC) was 76 +/- 3 mmHg in NX (52 +/- 1 in Sham, P < 0.05). NOF slightly reduced PGC to 69 +/- 2 mmHg in NX + NOF (P > 0.05 vs. NX). Glomerular volumes behaved similarly. At 60 days, tail cuff pressure was 152 +/- 6 mmHg, glomerulosclerosis index was 22.1 +/- 9.5, and interstitial fractional area was 9.9 +/- 1.2% in NX. NOF reduced these parameters to 137 +/- 4 mmHg, 3.5 +/- 0.7, and 6.4 +/- 0.8%, respectively (P < 0.05), without causing growth stunting or anemia. These beneficial effects could not be ascribed to NO donation and may reflect cyclooxygenase inhibition. This is the first evidence that chronic NSAID treatment may ameliorate progressive nephropathies.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Flurbiprofeno/análogos & derivados , Riñón/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacología , Flurbiprofeno/farmacocinética , Flurbiprofeno/farmacología , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Glomeruloesclerosis Focal y Segmentaria/prevención & control , Hemodinámica/efectos de los fármacos , Riñón/fisiología , Masculino , Nefrectomía , Óxido Nítrico/metabolismo , Ratas , Ratas WistarRESUMEN
We investigated the antinociceptive properties of dexketoprofen trometamol [S(+)-ketoprofen tromethamine salt; SKP], a new analgesic, antiinflammatory drug, using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. SKP was compared with racemic ketoprofen tromethamine salt (rac-KP), R(-)-ketoprofen tromethamine salt (RKP), ketorolac (KET), and morphine (MOR). We also assessed the effects of flurbiprofen (rac-FB) and its enantiomers (SFB and RFB) in the same model. Groups of six rats received either vehicle or analgesic drug and antinociception was evaluated by evaluating the dose-response curves over time. SKP was an effective antinociceptive drug in this model and was almost equally potent by either oral or intracerebroventricular administration. The oral potency of SKP was similar to that of oral KET and greater than that of oral MOR. No significant differences were observed between racemic ketoprofen and its enantiomers when administered orally. In the rat, significant bioinversion of RKP to SKP occurs when RKP is given orally. After oral administration of RKP, SKP was detectable in 30 min and surpassed the concentration of RKP after 3 h. Nevertheless, when the compounds were given intracerebroventricularly, some stereoselectivity in favor of SKP was observed. Stereoselectivity was observed with flurbiprofen, an analogue of ketoprofen that does not undergo significant metabolic inversion. Whereas SFB was an effective antinociceptive, RFB had no antinociceptive effect at the doses tested when given either orally or intracerebroventricularly.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Cetoprofeno/análogos & derivados , Dolor/tratamiento farmacológico , Trometamina/análogos & derivados , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/farmacocinética , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Biotransformación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Flurbiprofeno/administración & dosificación , Flurbiprofeno/farmacología , Inyecciones Intraventriculares , Cetoprofeno/farmacología , Cetoprofeno/toxicidad , Ketorolaco , Masculino , Morfina/administración & dosificación , Morfina/farmacología , Dolor/inducido químicamente , Dolor/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estereoisomerismo , Tolmetina/administración & dosificación , Tolmetina/análogos & derivados , Tolmetina/farmacología , Trometamina/farmacología , Trometamina/toxicidad , Ácido ÚricoRESUMEN
The flurbiprofen complex of copper(II) was prepared and characterized by IR, UV-VIS and EPR Spectroscopy, magnetic susceptibility, and thermogravimetric analysis. The compound was tested for in vivo anti-inflammatory and analgesic activities in rats. The inhibitory effect on carrageenin-induced paws inflammation and analgesic effect of copper flurbiprofen complex were similar to those of free flurbiprofen. However, the copper complex produced less gastric irritation than the parent drug.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Edema/tratamiento farmacológico , Flurbiprofeno/síntesis química , Flurbiprofeno/farmacología , Mucosa Gástrica/fisiología , Mucosa Intestinal/fisiología , Análisis de Varianza , Animales , Flurbiprofeno/química , Mucosa Gástrica/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Masculino , Estructura Molecular , Ratas , Ratas Endogámicas , Espectrofotometría InfrarrojaRESUMEN
Seventy-four patients were enrolled in this double-blind, randomized single-center study to evaluate the therapeutic effectiveness of 50 mg tid regimens of flurbiprofen or diclofenac sodium in patients with osteoarthritis of the knee. By chance, the flurbiprofen patients had a significantly more advanced disease status at baseline than their diclofenac-treated counterparts. However, at subsequent follow-up evaluations, both treatment groups experienced a significant reduction in disease severity regardless of the baseline differences. No serious safety problems were associated with either investigational therapy. The frequency of reported medical events were distributed equally between the flurbiprofen and diclofenac groups. Although the imbalance in disease severity between treatment groups made a rigorous statistical interpretation of the results very difficult, the data from this clinical trial tend to support the equiefficacy of 50 mg tid regimens of flurbiprofen versus diclofenac for treating osteoarthritis of the knee.