RESUMO
BACKGROUND: The main goal of our study was to explore the wound-healing property of a novel cerium-containing N-acethyl-6-aminohexanoate acid compound and determine key molecular targets of the compound mode of action in diabetic animals. METHODS: Cerium N-acetyl-6-aminohexanoate (laboratory name LHT-8-17) as a 10 mg/mL aquatic spray was used as wound experimental topical therapy. LHT-8-17 toxicity was assessed in human skin epidermal cell culture using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A linear wound was reproduced in 18 outbred white rats with streptozotocin-induced (60 mg/kg i.p.) diabetes; planar cutaneous defect was modelled in 60 C57Bl6 mice with streptozotocin-induced (200 mg/kg i.p.) diabetes and 90 diabetic db/db mice. Firmness of the forming scar was assessed mechanically. Skin defect covering was histologically evaluated on days 5, 10, 15, and 20. Tissue TNF-α, IL-1ß and IL-10 levels were determined by quantitative ELISA. Oxidative stress activity was detected by Fe-induced chemiluminescence. Ki-67 expression and CD34 cell positivity were assessed using immunohistochemistry. FGFR3 gene expression was detected by real-time PCR. LHT-8-17 anti-microbial potency was assessed in wound tissues contaminated by MRSA. RESULTS: LHT-8-17 4 mg twice daily accelerated linear and planar wound healing in animals with type 1 and type 2 diabetes. The formulated topical application depressed tissue TNF-α, IL-1ß, and oxidative reaction activity along with sustaining both the IL-10 concentration and antioxidant capacity. LHT-8-17 induced Ki-67 positivity of fibroblasts and pro-keratinocytes, upregulated FGFR3 gene expression, and increased tissue vascularization. The formulation possessed anti-microbial properties. CONCLUSIONS: The obtained results allow us to consider the formulation as a promising pharmacological agent for diabetic wound topical treatment.
Assuntos
Aminocaproatos/administração & dosagem , Cério/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Administração Tópica , Aminocaproatos/metabolismo , Animais , Cério/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Cicatrização/fisiologiaRESUMO
AIM: Zinc has proved its efficacy in many models of ischemia reperfusion (I/R) injury. In this study, we used zinc acexamate (ZAC) as an exogenous source of zinc against renal I/R injury and we investigated whether its protective effects are mediated by the decrease of oxidative stress, inflammation, and mitochondria induced-apoptosis. METHODS: Rats were orally pretreated with vehicle or ZAC (10 or 100â¯mg/kg) 24â¯h and 30â¯min prior to 1â¯h of bilateral renal warm ischemia and 2â¯h of reperfusion. RESULTS: Our data showed that 10â¯mg/kg of ZAC, but not 100â¯mg/kg, improved renal architecture and function. Also, the low dose of ZAC up-regulated antioxidant enzymes activities and glutathione level and decreased lipids and proteins oxidation. Interestingly, the use of ZAC resulted in a significant reduce of pro-inflammatory cytokines (IL-1ß, IL-6 and MCP-1), enhanced mitochondria integrity and decreased expression of the pro-apoptotic protein caspase-9. CONCLUSION: We conclude that renal I/R induced oxidative stress, inflammation and apoptosis and that the use of ZAC at 10â¯mg/kg, but not 100â¯mg/kg, protects rat kidneys from I/R injury by down-regulating these processes.
Assuntos
Aminocaproatos/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Aminocaproatos/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Citocinas/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Rim/irrigação sanguínea , Masculino , Ratos Wistar , Isquemia QuenteRESUMO
Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.
Assuntos
Aminocaproatos/farmacologia , Compostos Azo/farmacologia , Diazo-Oxo-Norleucina/farmacologia , Transtornos Neurocognitivos/tratamento farmacológico , Nootrópicos/farmacologia , Pró-Fármacos/farmacologia , Aminocaproatos/administração & dosagem , Aminocaproatos/síntese química , Animais , Compostos Azo/administração & dosagem , Compostos Azo/síntese química , Sangue/metabolismo , Encéfalo/metabolismo , Diazo-Oxo-Norleucina/administração & dosagem , Estabilidade de Medicamentos , Feminino , Ácido Glutâmico/metabolismo , Glutaminase/antagonistas & inibidores , Infecções por HIV/complicações , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transtornos Neurocognitivos/etiologia , Nootrópicos/administração & dosagem , Nootrópicos/síntese química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Suínos , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: Pneumoperitoneum-induced oxidative stress and organ injury are known to be associated with nitric oxide (NO) inactivation. Because arginase competes with NO synthase (NOS) for a common substrate, L-arginine, arginase inhibition may increase NO bioavailability. Therefore, we evaluated the ability of the arginase inhibitor, 2 (S)-amino-6-boronohexanoic acid (ABH), to attenuate pneumoperitoneum-induced decrease of NO bioavailability and lung injury. METHODS: Thirty rats were randomly divided into the following groups: 1) the PP-ABH group received a subcutaneous injection of ABH (5 mg/kg) 1 h before induction of pneumoperitoneum (insufflation to intraperitoneal pressure of 15 mmHg for 60 min); 2) the PP group received saline by subcutaneous injection 1 h before induction of pneumoperitoneum; and 3) the control group received saline by subcutaneous injection before a sham procedure with no gas insufflation. After desufflation, blood was collected to determine levels of plasma nitrite, NOS, inflammatory cytokines, and malondialdehyde, a marker of oxidative stress. Lung tissue was obtained for histological evaluation. RESULTS: We found that plasma nitrite levels were lower in the PP group and higher in the PP-ABH group, compared with controls (P <0.01 and P <0.05, respectively). In the PP group, endothelial NOS activity was decreased and inducible NOS activity was increased compared with the PP-ABH and control groups. Malondialdehyde levels increased 3-fold in the PP group and 2-fold in the PP-ABH group compared with controls. Tumor necrosis factor-α, interleukin-6, and interleukin-1ß levels were elevated in the PP group compared to the control group, but the increase in cytokine production was attenuated or blocked in the PP-ABH group. Lung injury scores were 4.8-fold higher in the PP group and 2-fold higher in the PP-ABH group compared with controls (P <0.001 and P <0.01, respectively). DISCUSSION: Pneumoperitoneum decreases NO bioavailability and increases the inflammation cytokines, resulting in organ injuries. Inhibition of arginase activity could maintain NO bioavailability by attenuating pneumoperitoneum-induced changes in NOS activity. In addition, arginase inhibition attenuated the oxidative stress and inflammation and decreased the severity of lung injury caused by pneumoperitoneum. CONCLUSIONS: By increasing NO bioavailability and suppressing oxidative stress and inflammation, pretreatment with an arginase inhibitor may protect against lung injury caused by pneumoperitoneum.
Assuntos
Aminocaproatos/farmacologia , Arginase/antagonistas & inibidores , Compostos de Boro/farmacologia , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Pneumoperitônio/complicações , Aminocaproatos/administração & dosagem , Animais , Compostos de Boro/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Inflamação/etiologia , Injeções Subcutâneas , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Pneumoperitônio/tratamento farmacológico , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: To illustrate that matching on provider may exacerbate, not remove, bias. STUDY DESIGN AND SETTING: The degree of confounding bias depends in part on the proportions of treatment variation that can be ascribed to confounders and to instruments, respectively. This commentary raises the specific example of bias by matching on hospital induced in a study of coronary artery bypass graft surgery patients and illustrates the effect of matching on provider in a constructed example. RESULTS: Matching on provider removes a "benign" source of treatment variability, leaving unmeasured confounders as potentially the most important determinants of treatment. CONCLUSIONS: Researchers need to articulate the presumed source of pseudorandom variation in observational studies and need to take care not to reduce their effect through unnecessary control.
Assuntos
Pesquisa Comparativa da Efetividade/métodos , Interpretação Estatística de Dados , Análise por Pareamento , Projetos de Pesquisa , Aminocaproatos/administração & dosagem , Aminocaproatos/uso terapêutico , Aprotinina/administração & dosagem , Aprotinina/uso terapêutico , Viés , Fatores de Confusão Epidemiológicos , Ponte de Artéria Coronária/métodos , Ponte de Artéria Coronária/mortalidade , Hemostáticos/administração & dosagem , Hemostáticos/uso terapêutico , Hospitais , Humanos , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: Thoracentesis with chest tube placement is often needed to decompress a clinically significant pneumothorax or pleural effusion. The risks of such a procedure may be considered too great to perform on a systemically anticoagulated patient supported by extracorporeal membrane oxygenation (ECMO). RESULTS: An 8-year-old child with respiratory failure due to necrotizing pneumonia and autoimmune vasculitis, on veno-venous ECMO, developed a severe tension pneumothorax that required emergent decompression with a chest tube. Post-procedure, the patient developed a hemothorax that was approaching non-sustainability. We developed a strategy based on Virchow's triad to favor homeostasis in the patient while avoiding thrombosis in the ECMO circuit. We employed selective lung ventilation, passive pleural drainage, high flow ECMO, and aggressive coagulation cascade control, including the use of aminocaproic acid and activated factor VIIa. Following this strategy, the hemorrhage was controlled and, later, the patient was able to successfully come off ECMO. CONCLUSIONS: With careful coagulation cascade manipulation, complete lung rest for the affected lung, control of ECMO blood flow, and prudent hemothorax drainage, we were able to facilitate hemostasis that was required for the successful recovery of our patient while avoiding critical ECMO circuit thrombosis. Even with today's highly advanced medical technologies, centuries-old basic medical principles can still assist in the care of our sickest and most complex patients. Chest tube placement while on ECMO is rare and, although necessary, may be a risky procedure. With precise coagulation control, it can be a successful procedure on ECMO.
Assuntos
Aminocaproatos/administração & dosagem , Doenças Autoimunes , Descompressão Cirúrgica , Oxigenação por Membrana Extracorpórea , Fator VIIa/administração & dosagem , Hemorragia , Pneumotórax , Insuficiência Respiratória , Vasculite , Doenças Autoimunes/complicações , Doenças Autoimunes/fisiopatologia , Doenças Autoimunes/terapia , Criança , Hemorragia/complicações , Hemorragia/fisiopatologia , Hemorragia/terapia , Humanos , Masculino , Pneumonia/complicações , Pneumonia/fisiopatologia , Pneumonia/terapia , Pneumotórax/complicações , Pneumotórax/fisiopatologia , Pneumotórax/terapia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Vasculite/complicações , Vasculite/fisiopatologia , Vasculite/terapiaAssuntos
Aminocaproatos/administração & dosagem , Glucocorticoides/administração & dosagem , Linfangioma/complicações , Prednisolona/administração & dosagem , Propranolol/administração & dosagem , Dermatopatias Vasculares/complicações , Trombocitopenia/complicações , Hemorragia Cerebral/complicações , Quimioterapia Combinada , Feminino , Humanos , Lactente , Linfangioma/tratamento farmacológico , Linfangioma/patologia , Pele/patologia , Dermatopatias Vasculares/tratamento farmacológico , Dermatopatias Vasculares/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Trombocitopenia/tratamento farmacológicoRESUMO
Arginase expression and activity have been noted to be heightened in conditions associated with erectile dysfunction, including aging. Previously, arginase inhibition by chronic administration of the arginase inhibitor 2-(S)-amino-6-boronohexanoic acid (ABH) has been shown to improve endothelial dysfunction in aged rats. The objective of this study was to assess whether chronic oral ABH administration affects cavernosal erectile function. Rats were divided into 4 groups: young control, young treated with arginase inhibitor, aged control, and aged treated with arginase inhibitor. Arginase activity was measured and presented as a proportion of young untreated rats. In vivo erectile responses to cavernous nerve stimulation were measured in all cohorts. The cavernous nerve was stimulated with a graded electrical stimulus, and the intracavernosal/mean arterial pressure ratios and total intracavernosal pressure were recorded. Arginase activity was elevated in the aged rats compared with young controls; however, arginase activity was significantly decreased in aged rats treated with ABH. With the addition of ABH, erectile responses improved in the aged rats (P < .05). Oral inhibition of arginase with ABH results in improved erectile function in aged rats, resulting in erectile hemodynamics similar to young rats. This represents the first documentation of systemic arginase inhibition positively affecting corporal cavernosal function.
Assuntos
Aminocaproatos/uso terapêutico , Compostos de Boro/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Ereção Peniana/fisiologia , Administração Oral , Envelhecimento/fisiologia , Aminocaproatos/administração & dosagem , Animais , Arginase , Compostos de Boro/administração & dosagem , Estimulação Elétrica , Inibidores Enzimáticos/administração & dosagem , Masculino , Pênis/enzimologia , Pênis/inervação , Ratos , Ratos Endogâmicos F344RESUMO
OBJECTIVE: Arginase plays important regulatory roles in polyamine, ornithine, and nitric oxide syntheses. However, its role in the healing process has not been delineated. In this study, we used a highly potent and specific inhibitor of arginase, namely 2(S)-amino-6-boronohexanoic acid NH4 (ABH) to evaluate the role of arginase function in wound healing. MATERIALS AND METHODS: ABH or saline was applied topically to full thickness, dorsal, excisional wounds in C57BL/6 mice every 8 hours for 14 days post surgery and the rate of wound closure was estimated planimetrically. Wound tissue was harvested from mice sacrificed on postoperative days 3 and 7 and examined histologically. The extent of epithelial, connective, and granulation tissue present within the wound area was estimated histomorphometrically. The effect of ABH on wound arginase activity, production of nitric oxide metabolites (NO(x)), and presence of smooth muscle actin positive cells (myofibroblasts) was evaluated. RESULTS: While arginase activity was inhibited in vivo, the rate of wound closure significantly increased 7 days post-surgery, (21 ± 4%: P < .01; Student t test) in ABH treated animals. This was accompanied by an early increase in wound granulation tissue and accumulation of NO(x) followed by enhanced re-epithelialization and localization of myofibroblasts beneath the wound epithelium. CONCLUSION: Arginase inhibition improves excisional wound healing and may be used to develop therapeutics for early wound closure.
Assuntos
Aminocaproatos/farmacologia , Arginase/antagonistas & inibidores , Compostos de Boro/farmacologia , Inibidores Enzimáticos/farmacologia , Pele/lesões , Cicatrização/efeitos dos fármacos , Actinas/metabolismo , Administração Tópica , Aminocaproatos/administração & dosagem , Animais , Arginase/fisiologia , Compostos de Boro/administração & dosagem , Células Cultivadas , Inibidores Enzimáticos/administração & dosagem , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Animais , Óxido Nítrico/metabolismo , Pele/metabolismo , Pele/patologia , Cicatrização/fisiologiaRESUMO
The aim of the present study was to produce monoclonal anti-fullerene C(60) antibodies and to develop the enzyme immunoassay for the detection in the first use of free fullerene C(60) both in solutions and in multicomponent biological probes. The immunization of mice with the conjugate of fullerene C(60) carboxylic derivative with thyroglobulin synthesized by carbodiimide activation led to the production of eight clones of anti-fullerene antibodies. The specificity of the antibody-fullerene binding was confirmed. Indirect competitive enzyme-linked immunosorbent assay (ELISA) was developed for the determination of water-soluble protein-conjugated fullerene, the fullerene aminocaproic acid, fullerenol and for pristine fullerene in solution. To solubilize extremely hydrophobic free fullerene C(60) a specially selected water-organic mixture compatible with immunoassay was proposed. The detection limit of free fullerene C(60) in solution was 2 µg L(-1). Fullerene C(60) was also detected by ELISA in organ homogenates of rats intraperitoneally or intragastrically administered with fullerene. To reduce the influence of biomatrices on the assay results a technique was developed for the biological sample pretreatment by the extraction of C(60) from bioprobe by toluene followed by the evaporation of toluene and dissolution of the fullerene-containing extract in the selected water-organic media. The ELISA procedure in the first use allowed the detection of fullerene C(60) in different tissues.
Assuntos
Anticorpos Monoclonais/biossíntese , Ensaio de Imunoadsorção Enzimática/métodos , Fulerenos/imunologia , Administração através da Mucosa , Aminocaproatos/administração & dosagem , Aminocaproatos/química , Aminocaproatos/imunologia , Animais , Afinidade de Anticorpos , Especificidade de Anticorpos , Fulerenos/administração & dosagem , Fulerenos/química , Injeções Intraperitoneais , Limite de Detecção , Masculino , Camundongos , Ratos , Ratos Wistar , Solventes/química , Tireoglobulina/química , Tireoglobulina/imunologiaRESUMO
OBJECTIVE: To evaluate the literature describing topical use of tranexamic acid or aminocaproic acid for prevention of postoperative bleeding after major surgical procedures. DATA SOURCES: Literature was retrieved through MEDLINE (1946-September 2011) and International Pharmaceutical Abstracts (1970-September 2011) using the terms tranexamic acid, aminocaproic acid, antifibrinolytic, topical, and surgical. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All identified articles in English were evaluated. Clinical trials, case reports, and meta-analyses describing topical use of tranexamic acid or aminocaproic acid to prevent postoperative bleeding were included. DATA SYNTHESIS: A total of 16 publications in the setting of major surgical procedures were included; the majority of data were for tranexamic acid. For cardiac surgery, 4 trials used solutions containing tranexamic acid (1-2.5 g in 100-250 mL of 0.9% NaCl), and 1 trial assessed a solution containing aminocaproic acid (24 g in 250 mL of 0.9% NaCl). These solutions were poured into the chest cavity before sternotomy closure. For orthopedic procedures, all of the data were for topical irrigation solutions containing tranexamic acid (500 mg-3 g in 50-100 mL of 0.9% NaCl) or for intraarticular injections of tranexamic acid (250 mg to 2 g in 20-50 mL of 0.9% sodium chloride, with or without carbazochrome sodium sulfate). Overall, use of topical tranexamic acid or aminocaproic acid reduced postoperative blood loss; however, few studies reported a significant reduction in the number of packed red blood cell transfusions or units given, intensive care unit stay, or length of hospitalization. CONCLUSIONS: Topical application of tranexamic acid and aminocaproic acid to decrease postsurgical bleeding after major surgical procedures is a promising strategy. Further data are needed regarding the safety of this hemostatic approach.
Assuntos
Aminocaproatos/uso terapêutico , Antifibrinolíticos/uso terapêutico , Hemorragia Pós-Operatória/prevenção & controle , Ácido Tranexâmico/uso terapêutico , Administração Tópica , Aminocaproatos/administração & dosagem , Aminocaproatos/efeitos adversos , Antifibrinolíticos/administração & dosagem , Antifibrinolíticos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos , Ensaios Clínicos como Assunto , Humanos , Procedimentos Ortopédicos , Hemorragia Pós-Operatória/etiologia , Guias de Prática Clínica como Assunto , Ácido Tranexâmico/administração & dosagem , Ácido Tranexâmico/efeitos adversosRESUMO
REASONS FOR PERFORMING STUDY: The antifibrinolytic, 6-aminohexanoic acid, also named aminocaproic acid (ACA), has been used empirically as a treatment for exercise-induced pulmonary haemorrhage (EIPH) on the unsubstantiated basis that transient coagulation dysfunction may contribute to its development. OBJECTIVE: To assess the effect of ACA on bronchoalveolar lavage fluid (BALF) erythrocyte counts in horses performing treadmill exercise at an intensity greater than that needed to reach maximal oxygen consumption. METHODS: Eight Thoroughbreds were exercised to fatigue 3 times on a 10% inclined treadmill at a speed for which the calculated oxygen requirement was 1.15 times VO2max. Horses were treated with a saline placebo, 2 and 7 g ACA i.v. 4 h before exercise, with a crossover design being used to determine the order of the injections. Exercise-induced pulmonary haemorrhage severity was quantified via the erythrocyte count in BALF. Bronchoalveolar lavage fluid was collected 4 h before and 30-60 min post exercise. Results were expressed as mean ± s.e.m. and analysed by one way repeated measures ANOVA (P < 0.05). RESULTS: Aminocaproic acid administration had no effect on any measured variables (VO2max = 48 ± 3.0 [C]; 148 ± 3.0 [2 g ACA]; 145 ± 3.0 [7 g ACA] ml/kg bwt/min, respectively; run time = 77 ± 3 [C]; 75 ± 2 [2 g ACA]; 79 ± 3 [7 g ACA] seconds, respectively). All horses developed EIPH: 1691 ± 690 vs. 9637 ± 3923 (C); 2149 ± 935 vs. 3378 ± 893 (2 g ACA); 1058 ± 340 vs. 4533 ± 791 (7 g ACA) erythrocytes/µl pre- vs. post exercise recovered in BALF, respectively. CONCLUSION: Aminocaproic acid was not effective in preventing or reducing the severity of EIPH or improving performance under the exercise conditions of this study.
Assuntos
Aminocaproatos/uso terapêutico , Antifibrinolíticos/uso terapêutico , Hemorragia/veterinária , Doenças dos Cavalos/tratamento farmacológico , Pneumopatias/veterinária , Condicionamento Físico Animal/efeitos adversos , Aminocaproatos/administração & dosagem , Animais , Antifibrinolíticos/administração & dosagem , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Hemorragia/tratamento farmacológico , Doenças dos Cavalos/etiologia , Cavalos , Pneumopatias/tratamento farmacológico , MasculinoRESUMO
BACKGROUND: Aprotinin was the subject of recent controversy regarding adverse clinical outcomes following cardiac surgery. We compared the role of Aprotinin and epsilon-aminocaproic acid on clinical outcomes and the attenuation of the postcardiopulmonary bypass (CPB) response at the genomic expression and cytokine (protein) level. METHODS: Thirty-nine low-risk patients undergoing coronary revascularization (CABG) and/or valve procedures using cardiopulmonary CPB were enrolled into a prospective cohort study. Aprotinin or epsilon-aminocaproic acid was administered to patients. Gene expression was assessed from whole blood mRNA samples collected preoperatively (PRE) and 6 hours (6H) postoperatively. Validation of gene expression was performed with SYBR Green real-time polymerase chain reaction. Cytokine values were quantified from serum preoperatively and postoperatively at 6 H and 4 days and analyzed in a blinded fashion. RESULTS: No difference was detected in baseline characteristics. Inflammatory markers measured did not reveal significant difference between patients receiving Aprotinin (APR) and those receiving epsilon-aminocaproic acid (Amicar). Intraoperative parameters and postoperative outcomes were not significantly different. Compared with PRE samples, 6H samples had 264 upregulated and 548 downregulated genes uniquely in the APR group compared to 4826 upregulated and 1114 downregulated genes uniquely in the Amicar group (p < 0.001). Compared to patients in the Amicar group, APR patients had significantly different gene expression pathways involving NF-kappabeta regulation, programmed cell death and cell-cell adhesion. None of the patients developed postoperative stroke, myocardial infarction, or systemic infections. CONCLUSIONS: Aprotinin leads to significantly less genomic expression variability following CPB compared to Amicar and has a differential effect on specific genomic pathways.
Assuntos
Aminocaproatos/administração & dosagem , Aprotinina/administração & dosagem , Ponte de Artéria Coronária , Regulação da Expressão Gênica/efeitos dos fármacos , Implante de Prótese de Valva Cardíaca , Hemostáticos/administração & dosagem , Idoso , Apoptose/efeitos dos fármacos , Apoptose/genética , Ponte Cardiopulmonar , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Estudos de Coortes , Citocinas/sangue , Feminino , Regulação da Expressão Gênica/genética , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Pré-Medicação , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A 2-week-old infant developed respiratory failure due to a mediastinal Kaposiform hemangioendothelioma that was complicated by thrombocytopenia and consumptive coagulopathy. Initial surgery was unsuccessful at removing the tumorous infiltration of mediastinal structures. Multiple transfusions with fresh frozen plasma, platelets, and red blood cells were needed for the consumptive coagulopathy, and ventilatory support was required for 5 months. Therapy for the tumor included methylprednisolone, aminocaproic acid, and vincristine, but a sustained response was achieved only after the initiation of alpha interferon. The patient was monitored closely and did not develop neurologic toxicity. This case demonstrates that interferon can be used to treat infants with Kaposiform hemangioendothelioma in life-threatening situations that do not respond to other forms of treatment.
Assuntos
Anemia Hemolítica/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Coagulação Intravascular Disseminada/etiologia , Hemangioendotelioma/complicações , Interferon-alfa/uso terapêutico , Neoplasias do Mediastino/complicações , Insuficiência Respiratória/etiologia , Trombocitopenia/etiologia , Aminocaproatos/administração & dosagem , Anemia Hemolítica/terapia , Transfusão de Componentes Sanguíneos , Terapia Combinada , Coagulação Intravascular Disseminada/terapia , Feminino , Hemangioendotelioma/tratamento farmacológico , Hemangioendotelioma/cirurgia , Humanos , Recém-Nascido , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/cirurgia , Metilprednisolona/administração & dosagem , Plasma , Respiração Artificial , Insuficiência Respiratória/terapia , Síndrome , Toracotomia , Trombocitopenia/terapia , Timectomia , Vincristina/administração & dosagemRESUMO
Disseminated Intravascular Coagulopathy (DIC) is the most common coagulopathy in patients with prostate cancer. Though rare, it could be fatal without treatment. Literature suggests that there is significant activation of fibrinolytic pathway. Pathophysiology of DIC in patients with prostate cancer is not completely understood. We present here a case of chronic DIC in a patient with metastatic androgen independent prostate cancer. His DIC was managed successfully with a combination of aminocaproic acid and low weight molecular heparin. The use of low molecular weight heparin may make management of chronic DIC in prostate cancer more feasible in an out patient setting.
Assuntos
Aminocaproatos/administração & dosagem , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/etiologia , Heparina de Baixo Peso Molecular/administração & dosagem , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológico , Anticoagulantes/administração & dosagem , Doença Crônica , Combinação de Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
This study investigates the efficacy of an aminocaproic-acid seal to prevent or reduce the risk of bleeding attendant to liver biopsies. The simple technique of occluding the biopsy tract by injecting 1-2 mL of aminocaproic acid, a fibrinolysis inhibitor, while withdrawing the biopsy sheath appears to reduce substantially the risk of delayed bleeding. The technique may be most useful if large core biopsy needles must be used to provide an adequate specimen.
Assuntos
Aminocaproatos/administração & dosagem , Antifibrinolíticos/administração & dosagem , Biópsia/efeitos adversos , Biópsia/instrumentação , Técnicas Hemostáticas , Hepatopatias/patologia , Hemorragia Pós-Operatória/prevenção & controle , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Desenho de Equipamento , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/etiologia , Estudos RetrospectivosRESUMO
Diffuse alveolar hemorrhage (DAH) after allogeneic hematopoietic stem cell transplantation (HSCT) is often fatal. Standard therapy with high-dose corticosteroid is not always effective. There is paucity of data in the literature about other potentially useful agents, such as aminocaproic acid (Amicar) in the post-transplantation setting. We retrospectively reviewed our data on 115 consecutive patients who underwent HSCT and had pulmonary complications, with the aim of determining the overall clinical outcome in recipients of allogeneic transplants and in the subgroup of these patients who were treated with concomitant Solu-Medrol and aminocaproic acid. Aminocaproic acid was added at the discretion of the attending physician. We identified 14 allogeneic transplant recipients (median age, 41 years) with 15 episodes of DAH who were treated with Solu-Medrol (250 mg to 1 g intravenously per day). Of these, 8 patients also received concomitant aminocaproic acid at 1000 mg intravenously every 6 hours. Failure to improve was the most common reason for adding aminocaproic acid. The incidence of DAH was 12.2% (10.3% in myeloablative versus 1.9% in nonmyeloablative recipients). The overall 100-day DAH mortality and median transplantation survival were 60% and 99 days, respectively. Among the subset of patients treated with the combination of Solu-Medrol and aminocaproic acid, we observed a 100-day DAH mortality and median transplantation survival of 44% and 167 days, respectively, compared with 83% and 96.5 days in those treated with Solu-Medrol alone. The median time to DAH was 40.5 days, and the median time to death was 53 days in the combined treatment group compared with 29.5 days in those treated with steroid alone. There were no significant differences in coagulation parameters between subsets. Infections (yeast, respiratory syncytial virus, herpes simplex virus, and parainfluenza) were isolated and treated from 6 diagnostic bronchial alveolar lavage samples and were more common in the subgroup treated with Solu-Medrol only. Respiratory failure was the documented cause of death in 89% of patients. There were no clinically significant side effects from aminocaproic acid. Although these historically lower DAH outcomes are intriguing, prospective studies are needed to confirm the role of aminocaproic acid in DAH occurring in the allogeneic transplantation setting.
Assuntos
Aminocaproatos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Hemorragia/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Insuficiência Respiratória/tratamento farmacológico , Adulto , Anti-Inflamatórios/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Hemorragia/etiologia , Hemorragia/mortalidade , Humanos , Pneumopatias/etiologia , Pneumopatias/mortalidade , Masculino , Hemissuccinato de Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/mortalidade , Neoplasias/terapia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Fatores de TempoRESUMO
The paper presents the results of a retrospective study of small-dose (2,000,000 ECU) trasilol (Group 1) and aminocapronic acid (Group 2) on the size of postoperative blood loss in patients after cardiac surgery under extracorporeal circulation (EC). The mean postoperative blood loss was 4.7 +/- 0.2 and 4.8 +/- 0.4 ml/kg/day in Groups 1 and 2, respectively (p > 0.05). A significantly less blood loss was noted when trasilol was used in patients with normothermal prolonged EC as compared with hypothermal prolonged EC (p < 0.05), which may be associated not only with temperature conditions, but also with the significantly less mean duration of normothermal EC (113.1 +/- 3.4 and 136.9 +/- 6.0 min, respectively (p < 0.05). In Groups 1 and 2, postoperative blood loss after hypothermal prolonged EC did not differ significantly, the duration of EC being significantly higher in Group 1 patients than that in Group 2 (p < 0.02). This is indicative of the advantage of the use of trasilol in cases of prolonged hypothermal perfusion. The use of trasilol is preferable in patients with a large scope of surgical intervention under prolonged hypothermal perfusion. By taking into account the equal efficacy of trasilol and aminocapronic acid in reducing postoperative blood loss, the use of aminocapronic acid is more profitable.
Assuntos
Aminocaproatos/uso terapêutico , Antifibrinolíticos/uso terapêutico , Aprotinina/uso terapêutico , Ponte de Artéria Coronária , Circulação Extracorpórea , Hemorragia Pós-Operatória/prevenção & controle , Aminocaproatos/administração & dosagem , Antifibrinolíticos/administração & dosagem , Aprotinina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The potential efficacy of topical epsilon-aminocaproic acid, an antiplasmin agent, in the treatment of persistent corneal epithelial defects was evaluated in a study of the medical records of 44 dogs, in which 51 eyes had been diagnosed with a corneal epithelial defect lasting more than 10 days, with no apparent underlying cause. At an initial examination all the affected eyes had had non-adherent epithelium removed. Thirty-four of the eyes in 28 dogs examined between January 2000 and March 2003 were also treated by the topical application of a solution of 35.7 mg/ml ophthalmic aminocaproic acid three times a day; the other 17 eyes in 16 dogs treated between October 1997 and March 1999 had received only topical treatment with gentamicin in addition to the debridement. Both groups were assessed clinically at weekly intervals for a maximum of three weeks. The two groups had approximately the same breed distribution, and there were no statistically significant differences between them in terms of their age, sex, affected side or duration of the corneal erosions. After three weeks, 32 of the 34 eyes treated with aminocaproic acid (94.1 per cent) had been cured, compared with seven of the 17 eyes treated with gentamicin (41.2 per cent) (P=0.0001). No adverse drug reactions were reported.