RESUMEN
BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.
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Ácidos Cafeicos , Cardiomiopatías , Sepsis , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Tubulina (Proteína)/metabolismo , Reprogramación Metabólica , Macrófagos/metabolismo , Succinatos/efectos adversos , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Ácido Succínico/efectos adversos , Lipopolisacáridos/efectos adversosRESUMEN
The objective of the present study was to evaluate the effects and safety of sarpogrelate hydrochloride (sarpogrelate) in patients with elevated blood viscosity (BV), after 12 and 24 weeks of twice (BID) or thrice (TID) daily administrations of sarpogrelate (100 mg). The participants received oral sarpogrelate administration for 24 weeks and visited the hospital every 12 ± 2 week for blood viscosity measurements at shear rates of 5 and 300 s-1. The BV measured at shear rate of 5 s-1 in male patients decreased significantly from 18.91 cP at the baseline to 16.3 cP after 24 weeks of sarpogrelate administration (13.6 % drop, p < 0.001). The BV measured at 5 s-1 in female decreased more significantly from 17.5 cP at the baseline to 13.4 cP after 24 weeks of sarpogrelate administration (23.0 % drop, p < 0.001). In summary, sarpogrelate may be considered as a possible therapeutic option for improving BV in patients with elevated blood viscosity. In particular, the reduction of the low-shear BV with the help of a viscosity-reducing drug such as sarpogrelate may be considered as a potentially new pharmacological tool for microvascular disease.
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Viscosidad Sanguínea , Succinatos , Humanos , Masculino , Femenino , Succinatos/efectos adversos , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/uso terapéutico , Inhibidores de Agregación Plaquetaria/farmacologíaRESUMEN
Both preclinical and established rheumatoid arthritis (RA) patients display alterations in the gut microbiome. Prevotella spp. are preferentially enriched in a subset of RA patients. Here, we isolated a Prevotella strain, P. copri RA, from the feces of RA patients and showed that colonization of P. copri RA exacerbated arthritis in a collagen-induced arthritis (CIA) model. With the presence of P. copri RA colonization, a high-fiber diet exacerbated arthritis via microbial alterations and intestinal inflammation. Colonization of P. copri together with a high-fiber diet enabled the digestion of complex fiber, which led to the overproduction of organic acids, including fumarate, succinate and short-chain fatty acids. Succinate promoted proinflammatory responses in macrophages, and supplementation with succinate exacerbated arthritis in the CIA model. Our findings highlight the importance of dysbiosis when evaluating the effects of dietary interventions on RA pathogenesis and provide new insight into dietary interventions or microbiome modifications to improve RA management.
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Artritis Experimental , Artritis Reumatoide , Animales , Humanos , Prevotella , Dieta , Succinatos/efectos adversosRESUMEN
Background: Perioperative hypersensitivity reaction (HR) is an IgE-FcϵRI-mediated hypersensitivity reaction with degranulation and activation of mast cells and basophils. Several studies have focused on assessing the degranulation and activation of mast cells and basophils to diagnose and predict the prognosis of drug induced HR. However, it is challenging to isolate sufficiently pure mast cells and basophils from human sources to investigate. Effective biomarkers to assess mast cells and basophils activation in vivo could potentially have high diagnostic and prognostic values. In the present study, we investigated EVs pelleted from serum in patients with succinylated gelatin induced HR. Methods: Extracellular vesicles (EVs) were isolated using a total exosome isolation kit and ultracentrifugation, characterized by Western blot, transmission electron microscopy, and nanoparticle tracking analysis. Basophils were isolated from fresh peripheral blood by negative selection using Basophil Isolation Kit II. Human mast cell line was stimulated with IL4. The expression levels of proteins related to the hypersensitive response were evaluated by Western blotting and flow Cytometer. Histamine and tryptase levels were tested using a commercial ELISA kit, and gene expression of inflammatory mediators was evaluated by qRT-PCR. The receiver operating characteristic (ROC) curve was used to evaluate the specificity and sensitivity of biomarker in predicting HR. Results: The concentration of EVs and protein expression level of CD63, FcϵRI, CD203c and tryptase were significantly (p< 0.05) increased in HR samples. The expression level of mast cell/basophil specific CD203c were significantly increased in EVs derived from serum and basophils of HR patients, and the CD203c+-EVs production in mast cells is dramatically increased in the presence of IL4, which positively correlated with histamine, tryptase and inflammatory mediators. Moreover, the ROC curve of EVs concentration and CD203c expression indicated that CD203c+-EVs had a strong diagnostic ability for HR. Conclusion: Serum CD203c+-EVs serves as a novel diagnostic and prognostic biomarker for HR.
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Hipersensibilidad a las Drogas/diagnóstico , Vesículas Extracelulares/metabolismo , Gelatina/efectos adversos , Hidrolasas Diéster Fosfóricas/sangre , Sustitutos del Plasma/efectos adversos , Pirofosfatasas/sangre , Succinatos/efectos adversos , Adulto , Anciano , Basófilos/efectos de los fármacos , Basófilos/inmunología , Basófilos/metabolismo , Biomarcadores/sangre , Estudios de Casos y Controles , Degranulación de la Célula/efectos de los fármacos , Línea Celular , Hipersensibilidad a las Drogas/sangre , Hipersensibilidad a las Drogas/inmunología , Femenino , Histamina/metabolismo , Liberación de Histamina/efectos de los fármacos , Humanos , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Mastocitos/metabolismo , Persona de Mediana Edad , Periodo Perioperatorio , Valor Predictivo de las Pruebas , Pronóstico , Triptasas/metabolismoRESUMEN
Objective: Oral supplementation with iron is a standard intervention for treating or preventing iron deficiency with or without anemia. Over the last few decades, various forms of oral iron have been developed to improve treatment tolerability and iron bioavailability. In this review, we gathered research data regarding the use of iron protein succinylate since it was first marketed in the 1980s.Methods: Electronic databases - PubMed and the Cochrane Library - were searched for studies published up to March 2019. Clinical or observational studies reporting data on the tolerability of oral iron protein succinylate were included. Results were statistically described to evaluate and compare the efficacy and safety of iron protein succinylate with the comparators under study.Results: Iron protein succinylate was investigated in 54 studies: 38 randomized clinical trials and 16 observational studies, with a total of 8454 subjects. Of them, 8142 were included in the efficacy analysis: patients were divided into three population subtypes: general (n = 1899), gynecological/obstetric (n = 5283), and pediatric (n = 960). In total, 6450 patients received iron protein succinylate, experiencing a significant change in hemoglobin and ferritin in all populations. The change in all parameters was similar or higher with iron protein succinylate compared to other iron treatments evaluated. Overall, study groups receiving iron protein succinylate reported the lowest rate of adverse events.Conclusions: Although all iron treatments analyzed are effective and safe, our results suggest that iron protein succinylate may be an excellent choice to treat iron deficiency and anemia due to its superior effectiveness and tolerability.
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Anemia Ferropénica/tratamiento farmacológico , Deficiencias de Hierro , Metaloproteínas/uso terapéutico , Succinatos/uso terapéutico , Administración Oral , Niño , Femenino , Humanos , Metaloproteínas/efectos adversos , Embarazo , Succinatos/efectos adversosRESUMEN
BACKGROUND & AIMS: Blood volume expanding properties of colloids are superior to crystalloids. In addition to oncotic/osmotic properties, the electrolyte composition of infusions may have important effects on visceral perfusion, with infusions containing supraphysiological chloride causing hyperchloremic acidosis and decreased renal blood flow. In this non-inferiority study, a validated healthy human subject model was used to compare effects of colloid (4% succinylated gelatin) and crystalloid fluid regimens on blood volume, renal function, and cardiac output. METHODS: Healthy male participants were given infusions over 60 min > 7 days apart in a randomized, crossover manner. Reference arm (A): 1.5 L of Sterofundin ISO, isoeffective arm (B): 0.5 L of 4% Gelaspan®, isovolumetric arm (C): 0.5 L of 4% Gelaspan® and 1 L of Sterofundin ISO (all B. Braun, Melsungen, Germany). Participants were studied over 240 min. Changes in blood volume were calculated from changes in weight and hematocrit. Renal volume, renal artery blood flow (RABF), renal cortex perfusion and diffusion, and cardiac index were measured with magnetic resonance imaging. RESULTS: Ten of 12 males [mean (SE) age 23.9 (0.8) years] recruited, completed the study. Increase in body weight and extracellular fluid volume were significantly less after infusion B than infusions A and C, but changes in blood volume did not significantly differ between infusions. All infusions increased renal volume, with no significant differences between infusions. There was no significant difference in RABF across the infusion time course or between infusion types. Renal cortex perfusion decreased during the infusion (mean 18% decrease from baseline), with no significant difference between infusions. There was a trend for increased renal cortex diffusion (4.2% increase from baseline) for the crystalloid infusion. All infusions led to significant increases in cardiac index. CONCLUSIONS: A smaller volume of colloid (4% succinylated gelatin) was as effective as a larger volume of crystalloid at expanding blood volume, increasing cardiac output and changing renal function. Significantly less interstitial space expansion occurred with the colloid. TRIAL REGISTRATION: The protocol was registered with the European Union Drug Regulating Authorities Clinical Trials Database (https://eudract.ema.europa.eu) (EudraCT No. 2013-003260-32).
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Volumen Sanguíneo/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Soluciones Cristaloides/administración & dosificación , Gelatina/administración & dosificación , Hemodinámica/efectos de los fármacos , Sustitutos del Plasma/administración & dosificación , Circulación Renal/efectos de los fármacos , Succinatos/administración & dosificación , Adulto , Gasto Cardíaco/efectos de los fármacos , Estudios Cruzados , Soluciones Cristaloides/efectos adversos , Método Doble Ciego , Inglaterra , Gelatina/efectos adversos , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Imagen por Resonancia Magnética , Masculino , Compuestos Orgánicos/administración & dosificación , Compuestos Orgánicos/efectos adversos , Sustitutos del Plasma/efectos adversos , Succinatos/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To investigate the association between synthetic colloids and biomarkers of acute kidney injury (AKI) in dogs with hemorrhagic shock. DESIGN: Experimental interventional study. SETTING: University. ANIMALS: Twenty-four healthy ex-racing Greyhounds. INTERVENTIONS: Anesthetized Greyhounds subjected to hemorrhage for 60 min were resuscitated with 20 mL/kg of fresh whole blood (FWB), 6% hydroxyethyl starch (HES) 130/0.4, 4% succinylated gelatin (GELO), or 80 mL/kg of isotonic crystalloid (CRYST) over 20 min (n = 6 per treatment). Concentrations of biomarkers of AKI were measured at baseline, end of hemorrhage, and at 40 (T60), 100 (T120), and 160 (T180) min after fluid bolus. Biomarkers included neutrophil gelatinase-associated lipocalin in urine and serum (uNGAL; sNGAL), and urine cystatin C (uCYSC), kidney injury molecule-1 (uKIM), clusterin (uCLUST), osteopontin, gamma-glutamyl transferase, monocyte chemoattractant protein-1 (uMCP), interleukin-6, interleukin-8, protein (uPROT), hyaluronan, and F2 -isoprostanes. Renal histology was scored for tubular injury and microvesiculation. Biomarker fold-change from baseline was compared between groups using mixed effects models (Bonferroni-Holm corrected P<0.05). Frequencies of histology scores were compared by Fisher's exact test. MEASUREMENTS AND MAIN RESULTS: In dogs treated with GELO, uNGAL fold-change was markedly greater compared with all other groups at T60, T120, and T180 (all P<0.001), and uCYSC was greater at T60 compared with CRYST (P<0.001), and at T120 and T180 compared with all other groups (all P<0.001). Smaller, albeit significant, between-group differences in uKIM, uCLUST, uMCP, and urine protein concentration were observed across the FWB, GELO, and HES groups, compared with CRYST. The GELO group more frequently had marked tubular microvesiculation than the other groups (P = 0.015) although tubular injury scores were comparable. CONCLUSION: In dogs with hemorrhagic shock, GELO was associated with greater magnitude increases in urine biomarkers of AKI and more frequent marked tubular microvesiculation, compared with FWB, CRYST, and HES.
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Lesión Renal Aguda/veterinaria , Biomarcadores/orina , Enfermedades de los Perros/tratamiento farmacológico , Lipocalina 2/orina , Choque Hemorrágico/veterinaria , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/orina , Animales , Cuidados Críticos , Modelos Animales de Enfermedad , Perros , Femenino , Gelatina/administración & dosificación , Gelatina/efectos adversos , Derivados de Hidroxietil Almidón/administración & dosificación , Derivados de Hidroxietil Almidón/efectos adversos , Masculino , Sustitutos del Plasma/administración & dosificación , Sustitutos del Plasma/efectos adversos , Choque Hemorrágico/tratamiento farmacológico , Succinatos/administración & dosificación , Succinatos/efectos adversosRESUMEN
BACKGROUND: The aim was to evaluate the significance of arteriosclerosis obliterans-related biomarkers in patients with type 2 diabetes mellitus (T2DM), and to compare the effects of sarpogrelate, eicosapentaenoic acid (EPA) and pitavastatin on these markers. PATIENTS AND METHODS: Seventy-two arteriosclerosis obliterans patients with T2DM were classified into two groups, pitavastatin with either sarpogrelate (PS) or EPA (PE). We observed no differences in all biomarkers between the PS and PE groups before treatments. RESULTS: The levels of body mass index, hemoglobin A1c, soluble E-selectin, soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1 and platelet-derived microparticle in the PE group decreased significantly after treatment. The ankle branchial pressure index and adiponectin levels significantly increased in the PE group after treatment compared with the PS group. CONCLUSION: These results suggest that combination therapy using pitavastatin and EPA possesses an antiatherosclerotic effect and may be beneficial for prevention of vascular complications in patients with T2DM.
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Arteriosclerosis Obliterante/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Ácido Eicosapentaenoico/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Quinolinas/uso terapéutico , Succinatos/uso terapéutico , Adiponectina/sangre , Anciano , Anciano de 80 o más Años , Índice Tobillo Braquial , Arteriosclerosis Obliterante/sangre , Arteriosclerosis Obliterante/diagnóstico , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Angiopatías Diabéticas/sangre , Angiopatías Diabéticas/diagnóstico , Quimioterapia Combinada , Ácido Eicosapentaenoico/efectos adversos , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Japón , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Inhibidores de Agregación Plaquetaria/efectos adversos , Quinolinas/efectos adversos , Factores de Riesgo , Succinatos/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Sarpogrelate is expected to reduce restenosis by protecting blood vessels from oxidative stress and vascular endothelial dysfunction as well as by acting as an antiplatelet agent after endovascular treatment (EVT). This trial was designed to compare aspirin plus sustained-release (SR) sarpogrelate with aspirin plus clopidogrel for the prevention of restenosis in patients with femoro-popliteal (FP) peripheral artery disease (PAD) who underwent EVT. METHODS/DESIGN: This is an open label, multicenter, prospective randomized controlled clinical trial. Patients will be eligible for inclusion in this study if they require EVT for stenosis or occlusion of a de novo FP lesion. Patients in each group will receive aspirin 100 mg with clopidogrel 75 mg or aspirin 100 mg with SR sarpogrelate 300 mg (Anplone®) orally once a day for six months. The primary outcome of the study is the restenosis rate, defined as > 50% luminal reduction by computed tomography angiography or catheter angiography in the six-month follow-up period. Secondary outcomes include target lesion revascularization, major bleeding, ipsilateral major amputation, all-cause mortality, and all adverse events that take place in those six months. DISCUSSION: This study is a multicenter randomized controlled trial designed to show non-inferiority in terms of the re-stenosis rate of SR sarpogrelate compared to clopidogrel for EVT for PAD in FP lesion patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02959606 . Registered on 9 November 2016.
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Procedimientos Endovasculares , Arteria Femoral/efectos de los fármacos , Enfermedad Arterial Periférica/terapia , Inhibidores de Agregación Plaquetaria/uso terapéutico , Arteria Poplítea/efectos de los fármacos , Succinatos/uso terapéutico , Amputación Quirúrgica , Aspirina/uso terapéutico , Protocolos Clínicos , Clopidogrel , Angiografía por Tomografía Computarizada , Constricción Patológica , Quimioterapia Combinada , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/fisiopatología , Hemorragia/inducido químicamente , Humanos , Recuperación del Miembro , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/mortalidad , Enfermedad Arterial Periférica/fisiopatología , Inhibidores de Agregación Plaquetaria/efectos adversos , Arteria Poplítea/diagnóstico por imagen , Arteria Poplítea/fisiopatología , Estudios Prospectivos , Recurrencia , República de Corea , Proyectos de Investigación , Factores de Riesgo , Succinatos/efectos adversos , Ticlopidina/análogos & derivados , Ticlopidina/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción Vascular/efectos de los fármacosRESUMEN
The aim of the study was to evaluate the effectiveness of cytoflavin in the complex treatment of patients with diabetic foot syndrome. MATERIAL AND METHODS: The research is based on the results of a comprehensive survey of 140 people with diabetic foot syndrome. Depending on the treatment, all patients were divided into 2 groups. The first group (n=35) received basic therapy. The second group (n=35) in addition to basic therapy received cytoflavin 10 ml (+200 ml 0.9% NaCl) for 10 days, followed by switching to the tablet form of the drug 2 tablets twice a day for 1 month. RESULTS: Analyzing the severity of polyneuropathy after treatment, we noted a more positive dynamic in patients who in addition to standard therapy received cytoflavin.
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Pie Diabético , Mononucleótido de Flavina , Inosina Difosfato , Niacinamida , Polineuropatías , Succinatos , Calcificación Vascular , Anciano , Arterias/diagnóstico por imagen , Arterias/patología , Pie Diabético/complicaciones , Pie Diabético/diagnóstico , Pie Diabético/terapia , Combinación de Medicamentos , Femenino , Mononucleótido de Flavina/administración & dosificación , Mononucleótido de Flavina/efectos adversos , Humanos , Inosina Difosfato/administración & dosificación , Inosina Difosfato/efectos adversos , Masculino , Persona de Mediana Edad , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Polineuropatías/complicaciones , Polineuropatías/diagnóstico , Índice de Severidad de la Enfermedad , Succinatos/administración & dosificación , Succinatos/efectos adversos , Resultado del Tratamiento , Ucrania , Calcificación Vascular/complicaciones , Calcificación Vascular/diagnósticoRESUMEN
AIM: To study the efficacy of cytoflavin in patients with somatoform disorders (SD). MATERIAL AND METHODS: The study included 60 patients with SD, aged from 27 to 43 years. The efficacy was assessed by the results of psychological and neurophysiological examinations. RESULTS AND CONCLUSION: The higher efficacy of cytoflavin (the improvement of patient's condition in 63,3% of cases) compared to that of ethylmethylhydroxypyridine succinate (56,7% of cases) was found. Patient's state was more stable after treatment with cytoflavin.
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Mononucleótido de Flavina/uso terapéutico , Inosina Difosfato/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Niacinamida/uso terapéutico , Trastornos Somatomorfos/tratamiento farmacológico , Succinatos/uso terapéutico , Adulto , Combinación de Medicamentos , Femenino , Mononucleótido de Flavina/efectos adversos , Humanos , Inosina Difosfato/efectos adversos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Niacinamida/efectos adversos , Trastornos Somatomorfos/fisiopatología , Trastornos Somatomorfos/psicología , Succinatos/efectos adversos , Resultado del TratamientoRESUMEN
Mastocytosis comprises a heterogeneous group of disorders characterized by mast cell accumulation and proliferation in distinct organs. Kounis syndrome is defined as the concurrence of acute coronary syndromes with mast cell activation in a setting of allergic or hypersensitivity reactions. This is the first reported case of an intraoperative Kounis syndrome as the onset of an indolent systemic mastocytosis probably triggered by succinylated gelatin infusion during general anesthesia. The presentation of this case is intended to contribute to the knowledge of mastocytosis and Kounis syndrome at the time of diagnostic workup during intraoperative anaphylaxis or myocardial ischemia.
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Anestesia General/efectos adversos , Gelatina/efectos adversos , Síndrome de Kounis/etiología , Mastocitosis Sistémica/inducido químicamente , Sustitutos del Plasma/efectos adversos , Succinatos/efectos adversos , Gelatina/administración & dosificación , Hemodinámica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Síndrome de Kounis/diagnóstico , Síndrome de Kounis/fisiopatología , Síndrome de Kounis/terapia , Masculino , Mastocitosis Sistémica/diagnóstico , Mastocitosis Sistémica/fisiopatología , Mastocitosis Sistémica/terapia , Persona de Mediana Edad , Procedimientos Ortopédicos , Sustitutos del Plasma/administración & dosificación , Factores de Riesgo , Succinatos/administración & dosificaciónRESUMEN
BACKGROUND AND AIMS: Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is a potential antiplatelet agent. We performed a randomized study to evaluate the effect of sarpogrelate on vascular health in Korean patients with diabetes. METHODS: Forty diabetic patients aged 58.6 ± 6.8 years with 10-75% coronary artery stenosis, as assessed by coronary computed tomography angiography, were randomly assigned to sarpogrelate 300 mg/day plus aspirin 100 mg/day (SPG + ASA group) or aspirin 100 mg/day alone (ASA group) for 6 months. The primary endpoint of this study was the change in coronary artery disease including the calcium score (CACS), maximal stenosis, and plaque volume (calcified vs. noncalcified). The secondary endpoints were changes in biochemical parameters related to glucose and lipid metabolism, and in subclinical atherosclerosis assessed by ankle-brachial index and pulse wave velocity. RESULTS: After 6-month treatment, there was no significant difference in the changes in CACS, coronary stenosis, ankle-brachial index, and pulse wave velocity, between groups. The total plaque volume decreased from 82.4 ± 14.5 mm3 to 74.6 ± 14.4 mm3 in the SPG + ASA group, but increased from 64.9 ± 16.0 mm3 to 68.6 ± 16.3 mm3 in the ASA group (p < 0.05), mainly driven by changes in the noncalcified component (SPG + ASA group 15.6 ± 4.6 mm3 to 11.2 ± 3.7 mm3vs. ASA group 21.2 ± 6.2 mm3 to 22.8 ± 6.6 mm3, p < 0.01). Serum C-reactive protein levels and homeostasis model assessment of insulin resistance tended to decrease in the SPG + ASA group, but they were not altered in the ASA group. CONCLUSIONS: The present study demonstrated that sarpogrelate treatment may decrease coronary artery plaque volume, particularly the noncalcified portion, in patients with diabetes.
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Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Estenosis Coronaria/tratamiento farmacológico , Vasos Coronarios/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Succinatos/uso terapéutico , Adulto , Anciano , Índice Tobillo Braquial , Antiinflamatorios/uso terapéutico , Aspirina/uso terapéutico , Biomarcadores/sangre , Angiografía por Tomografía Computarizada , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estenosis Coronaria/complicaciones , Estenosis Coronaria/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Quimioterapia Combinada , Femenino , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Tomografía Computarizada Multidetector , Placa Aterosclerótica , Inhibidores de Agregación Plaquetaria/efectos adversos , Análisis de la Onda del Pulso , República de Corea , Antagonistas del Receptor de Serotonina 5-HT2/efectos adversos , Índice de Severidad de la Enfermedad , Succinatos/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/tratamiento farmacológicoRESUMEN
BACKGROUND: Patients undergoing carotid artery stenosis who are prescribed aspirin, clopidogrel, or sarpogrelate as treatment options to inhibit platelet aggregation continues to increase. The purpose of this study was to compare the efficacy and safety of clopidogrel combined with aspirin (CA) versus sarpogrelate combined with aspirin (SA) treatment in carotid endarterectomy (CEA) patients. METHODS: This retrospective study included 197 CEA patients (mean age 61.4 years, mean follow-up time 42.5 months), who were divided into a CA group (Group A: 65 male and 44 female patients) and an SA group (Group B: 58 male and 30 female patients). Preoperative demographic and clinical characteristics and postoperative results were compared between the 2 groups and statistically analyzed. RESULTS: Preoperative demographic and clinical characteristics, transfusions, hospital stay, occurrence of transient ischemic attack, stroke, myocardial infarction, restenosis, general or life-threatening bleeding, and 30-day mortality showed no significant differences between the 2 CEA patient groups. However, the mean operative blood loss (P = 0.023) and the operative time (P = 0.040) were significantly higher in Group A compared with Group B. A highly significant incidence of neck hematoma (P = 0.024) was observed in patients of Group A. CONCLUSIONS: In this study on CEA patients, antiplatelet treatment with CA resulted in a significant risk of developing neck hematoma, increased operative blood loss, and operative time compared with SA treatment. Long-term prospective studies with larger study populations are needed to further confirm the utility of SA treatment for CEA patients.
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Aspirina/uso terapéutico , Estenosis Carotídea/cirugía , Endarterectomía Carotidea , Inhibidores de Agregación Plaquetaria/uso terapéutico , Succinatos/uso terapéutico , Ticlopidina/análogos & derivados , Anciano , Aspirina/efectos adversos , Pérdida de Sangre Quirúrgica , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/mortalidad , China , Clopidogrel , Quimioterapia Combinada , Endarterectomía Carotidea/efectos adversos , Endarterectomía Carotidea/mortalidad , Femenino , Hematoma/etiología , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Inhibidores de Agregación Plaquetaria/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Succinatos/efectos adversos , Ticlopidina/efectos adversos , Ticlopidina/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND/OBJECTIVES: Addition of cilostazol or sarpogrelate to the standard dual antiplatelet therapy of aspirin and clopidogrel has been implemented in patients that underwent percutaneous coronary intervention (PCI) with stents in Korea. This study aimed to evaluate the efficacy and safety of triple antiplatelet therapies. METHODS: This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service from January 1, 2009 to December 31, 2014. The study cohort population consisted of patients with ischemic heart diseases and a history of PCI. They were treated with antiplatelet therapy of aspirin, clopidogrel (AC); aspirin, clopidogrel, cilostazol (ACCi); or aspirin, clopidogrel, sarpogrelate (ACSa) during the index period from January 1, 2010 to December 31, 2011. During the follow-up period up to December 31, 2014, the major adverse cardiac or cerebral events (MACCE) including death, myocardial infarction, target lesion revascularization, and ischemic stroke were assessed. Bleeding complications were also evaluated as adverse drug events. RESULTS: Out of 93,876 patients with PCI during the index period, 69,491 patients started dual (AC) or triple therapy (ACSa or ACCi). The clinical outcomes of comparing ACSa and ACCi therapy showed beneficial effects in the ACSa group in the prevention of subsequent cardiac or cerebral events. After Propensity score-matching between ACSa and ACCi groups, there were significant differences in MI and revascularization, with corresponding HR of 0.38 (95% CI, 0.20-0.73) and 0.66 (95% CI, 0.53-0.82) in ACSa vs. ACCi at 12 months, respectively. At the 24-month follow-up, the triple therapy groups (ACS or ACC) had a higher incidence of MACCE compared to the dual therapy (AC) group; ACSa vs. AC HR of 1.69 (95% CI, 1.62-1.77); ACC vs. AC HR of 1.22 (95% CI, 1.06-1.41). There was no significant difference in severe or life-threatening bleeding risk among three groups; ACSa vs. AC, HR of 0.68 (95% CI, 0.37-1.24), ACCi vs. AC, HR of 0.91 (95% CI, 0.77-1.09). CONCLUSION: Sarpogrelate-containing triple antiplatelet therapy demonstrated comparable rates of MACCE prevention to the conventional dual antiplatelet therapy after PCI without significantly increasing bleeding risk during the two-year follow-up period.
Asunto(s)
Infarto del Miocardio/terapia , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/uso terapéutico , Succinatos/uso terapéutico , Tetrazoles/uso terapéutico , Aspirina/efectos adversos , Aspirina/uso terapéutico , Cilostazol , Clopidogrel , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Hemorragia/patología , Humanos , Seguro de Salud , Corea (Geográfico) , Infarto del Miocardio/epidemiología , Infarto del Miocardio/patología , Succinatos/efectos adversos , Tetrazoles/efectos adversos , Ticlopidina/efectos adversos , Ticlopidina/análogos & derivados , Ticlopidina/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: Sarpogrelate hydrochloride, a selective 5-hydroxytryptamine 2A antagonist, is a widely used antiplatelet agent for the treatment of peripheral arterial disease (PAD). DP-R202 is a new sarpogrelate hydrochloride product with an improved dosage regimen compared with the agent in current use. The aim of this study was to compare the efficacy and safety profile of DP-R202 and Anplag(â) Tab in patients with PAD. METHODS: This study was a 12-week, multicenter, randomized, double-blinded, active-controlled, parallel group comparative Phase III clinical trial. One hundred fifty-one volunteer patients with PAD were randomized to receive DP-R202 300 mg once daily or Anplag Table 100 mg TID for 12 weeks. The primary end point was a change in patient assessment of lower leg pain intensity with the use of a visual analog scale (VAS) after 12 weeks of treatment. Results after 4, 8, and 12 weeks of treatment were compared with baseline and between treatment groups, and all patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. FINDINGS: Two hundred thirty-one patients from 25 medical centers were assessed, and 151 were enrolled and randomly assigned to 1 of 2 treatment groups. Seventy-five patients received DP-R202 300 mg once daily and 76 patients received Anplag Table 100 mg TID for 12 weeks. Analysis of the change in lower leg pain intensity as determined by VAS score between baseline and week 12 (mean [SD], 20.72 [20.06] mm vs 15.55 [21.44] mm) suggested that DP-R202 was not inferior to Anplag Tab, and no significant differences were found in the secondary end points. No significant between-group differences were observed in the prevalence of drug-related clinical- or laboratory-determined AEs. For tolerability, no specific issue was found during the treatment period. IMPLICATION: The results of this study suggest that DP-R202 was not inferior to Anplag Tab for efficacy in patients with PAD and indicated a good safety profile.
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Enfermedad Arterial Periférica/tratamiento farmacológico , Succinatos/uso terapéutico , Anciano , Arterias , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/tratamiento farmacológico , Dimensión del Dolor , Succinatos/efectos adversosRESUMEN
BACKGROUND AND OBJECTIVES: Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin. METHODS: The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry. RESULTS: The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation. CONCLUSION: Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.
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Analgésicos no Narcóticos/farmacocinética , Curcumina/análogos & derivados , Profármacos/farmacocinética , Succinatos/farmacocinética , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/metabolismo , Animales , Disponibilidad Biológica , Biotransformación , Curcumina/administración & dosificación , Curcumina/efectos adversos , Curcumina/metabolismo , Curcumina/farmacocinética , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Heces/química , Glucurónidos/sangre , Glucurónidos/metabolismo , Glucurónidos/orina , Semivida , Eliminación Hepatobiliar , Hidrólisis , Inyecciones Intravenosas , Eliminación Intestinal , Masculino , Tasa de Depuración Metabólica , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/metabolismo , Ratas Wistar , Solubilidad , Succinatos/administración & dosificación , Succinatos/efectos adversos , Succinatos/metabolismo , Distribución Tisular , Orina/químicaRESUMEN
BACKGROUND: Hepatorenal syndrome (HRS) is a serious complication of advanced chronic liver disease. Abdominal compartment syndrome (ACS) occurs with dysfunction of multiple organs when abdominal pressure increases. Here, we report on a novel model of ACS with ascites and a model of HRS in rats to observe the urea transporter protein (UT) expression in the 2 models. MATERIAL AND METHODS: A liver cirrhosis model was induced by CCl4. After changes of liver histopathology were observed, rats were injected intraperitoneally with succinylated gelatin to establish a model of ACS and HRS. Then, changes in BUN, Cr, and renal histopathology were detected. Moreover, the UT in ACS and HRS were also quantified. RESULTS: The surfaces of liver in the cirrhotic group became coarse, with visible small nodules and became yellow and greasy. The normal structure of the hepatic lobules were destroyed, and hyperplasia of fibrotic tissue and pseudo-lobe was observed. The levels of BUN and Cr were significantly increased in rats suffering from ACS and HRS, respectively, compared to their control groups. In addition, the mRNA levels of UT-A2 and UT-A3 decreased in rats with HRS compared to cirrhotic rats. However, there was no significant difference between the mRNA levels of UT-A2, UT-A3, and UT-B in rats with ACS vs. normal rats. CONCLUSIONS: It is feasible to model ACS in rats by injecting succinylated gelatin into the abdominal cavity. Increasing the intra-abdominal pressure by succinylated gelatin is also a novel approach for modeling HRS in cirrhotic rats. Compared with control rats, there is an abnormal mRNA expression of UT in ACS rats and HRS rats.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Síndrome Hepatorrenal/metabolismo , Hipertensión Intraabdominal/patología , Cirrosis Hepática/fisiopatología , Proteínas de Transporte de Membrana/metabolismo , Animales , Nitrógeno de la Urea Sanguínea , Tetracloruro de Carbono , Modelos Animales de Enfermedad , Gelatina/efectos adversos , Síndrome Hepatorrenal/inducido químicamente , Hipertensión Intraabdominal/inducido químicamente , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Presión , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Succinatos/efectos adversos , Urea/química , Transportadores de UreaRESUMEN
The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of alkyl polyethylene glycol (PEG) sulfosuccinates, which function in cosmetics mostly as surfactants/cleansing agents. Although these ingredients may cause ocular and skin irritation, dermal penetration is unlikely because of the substantial polarity and molecular size of these ingredients. The Panel considered the negative oral carcinogenicity and reproductive and developmental toxicity data on chemically related laureths (PEG lauryl ethers) and negative repeated dose toxicity and skin sensitization data on disodium laureth sulfosuccinate supported the safety of these alkyl PEG sulfosuccinates in cosmetic products, but. The CIR Expert Panel concluded that the alkyl PEG sulfosuccinates are safe in the present practices of use and concentration when formulated to be nonirritating.
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Seguridad de Productos para el Consumidor , Cosméticos/efectos adversos , Cosméticos/química , Polietilenglicoles/efectos adversos , Succinatos/efectos adversos , Humanos , Medición de RiesgoRESUMEN
AIMS: To compare the pharmacokinetics, pharmacodynamics, and safety of sarpogrelate between controlled-release (CR) and immediate-release (IR) formulations after multiple-dose administration. METHODS: This study was a randomized, open-label, 2-period, 2-treatment, crossover study in healthy subjects. All subjects received CR sarpogrelate 300 mg once daily and IR sarpogrelate 100 mg three times daily by random order each for 3 days with a 7-day washout period. Serial blood sampling was performed over 24 h. Pharmacokinetic parameters were determined by noncompartmental methods. Platelet aggregation to collagen, measured by light transmission aggregometry, was reported as maximal platelet aggregation. RESULTS: Thirty-two subjects completed the study. CR sarpogrelate increased rapidly, reaching Cmax in 1.25 h (vs. 1.00 h in IR sarpogrelate) and declined with a t1/2 of 3.59 h (vs. 1.12 h in IR sarpogrelate). The 90% CIs for the geometric mean ratio of AUCτ and Cmax,ss between IR and CR formulations were 1.18 to 1.40 and 0.99 to 1.29, respectively. The degree of inhibition of platelet aggregation was similar between two formulations. CONCLUSIONS: CR sarpogrelate showed slightly higher systemic exposure and similar peak concentration compared with IR sarpogrelate. The profiles of pharmacodynamics and safety were comparable between two formulations.