1,071 results on '"Aminocaproates"'
Search Results
2. EPSILON AMINO CAPROIC ACID THERAPY AS A CAUSE OF INTRARENAL OBSTRUCTION IN HAEMATURIA OF HAEMOPHILIACS.
- Author
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STARK SN, WHITE JG, LANGE RL Jr, and KRIVIT W
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- Child, Humans, Aminocaproates, Aminocaproic Acid, Caproates, Drug Therapy, Hematuria, Hemophilia A, Kidney Diseases, Medicine, Toxicology
- Published
- 1965
- Full Text
- View/download PDF
3. Cerium-Containing N-Acetyl-6-Aminohexanoic Acid Formulation Accelerates Wound Reparation in Diabetic Animals
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Bashar A Alkhatatneh, Elena G. Lobanova, D. S. Blinov, Andrey Sukhov, Aleksandra Butenko, Oxana Tumutolova, O.V. Vasilkina, Vladimir Drozdov, Alexey I. Sokolov, Ilya Sorokvasha, Daniil Shmatok, Marina Kilmyashkina, Sofia Skachilova, Olga Vavilova, Denis Shimanovsky, Elena Samishina, Ekaterina V. Blinova, Dmitry Pakhomov, Yan A. Mazov, Olga Deryabina, and Tatiana Demura
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Male ,Administration, Topical ,proliferation ,micro-vessels ,anti-microbial activity ,Human skin ,02 engineering and technology ,Pharmacology ,medicine.disease_cause ,Microbiology ,Biochemistry ,Article ,Diabetes Mellitus, Experimental ,Mice ,03 medical and health sciences ,Diabetes mellitus ,medicine ,Animals ,Humans ,Potency ,Mode of action ,topical application ,Molecular Biology ,030304 developmental biology ,Aminocaproates ,diabetic wound ,Wound Healing ,0303 health sciences ,integumentary system ,Chemistry ,toxicity ,Cerium ,021001 nanoscience & nanotechnology ,medicine.disease ,QR1-502 ,cerium-containing formulation ,cytokines ,Rats ,Mice, Inbred C57BL ,Diabetes Mellitus, Type 1 ,Diabetes Mellitus, Type 2 ,inflammation ,Toxicity ,Immunohistochemistry ,Female ,0210 nano-technology ,Wound healing ,Oxidative stress - Abstract
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-1β 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-1β, 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.
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- 2021
- Full Text
- View/download PDF
4. The effect of zinc acexamate on oxidative stress, inflammation and mitochondria induced apoptosis in rat model of renal warm ischemia
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Carmen García Ruiz, Imed Messaoudi, Anna Baulies, Mohamed Amine Zaouali, Safa Ben Mimouna, Hassen Ben Abdennebi, José C. Fernández-Checa, Mohamed Bejaoui, Najet Hadj Abdallah, Ahlem Bouhlel, Ministère de l’Enseignement Supérieur et de la Recherche Scientifique (Tunisie), Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), National Institute on Alcohol Abuse and Alcoholism (US), National Institutes of Health (US), and Generalitat de Catalunya
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Male ,0301 basic medicine ,medicine.medical_specialty ,Antioxidant ,medicine.medical_treatment ,Ischemia ,Apoptosis ,Inflammation ,Mitochondrion ,Kidney ,medicine.disease_cause ,Antioxidants ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Warm Ischemia ,Rats, Wistar ,Aminocaproates ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,General Medicine ,Glutathione ,medicine.disease ,Mitochondria ,Disease Models, Animal ,Zinc ,030104 developmental biology ,Enzyme ,Endocrinology ,chemistry ,Oxidative stress ,Reperfusion Injury ,030220 oncology & carcinogenesis ,Cytokines ,Zinc acexamate ,medicine.symptom ,Ischemia reperfusion injury - Abstract
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 inducedapoptosis. Methods: Rats were orally pretreated with vehicle or ZAC (10 or 100 mg/kg) 24 h and 30 min prior to 1 h of bilateral renal warm ischemia and 2 h of reperfusion. Results: Our data showed that 10 mg/kg of ZAC, but not 100 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 10 mg/kg, but not 100 mg/kg, protects rat kidneys from I/R injury by down-regulating these processes., This work was supported by grants from: The Tunisian Ministry of Higher Education and Scientific Research (UR12ES11); SAF-2014- 57674-R, SAF-2015-69944-R from Plan Nacional de I + D, Spain and CIBEREHD; the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH; and AGAUR of the Generalitat de Catalunya2014-SGR785.
- Published
- 2018
5. Nanoparticle-Facilitated Delivery of Antioxidant Therapy following Aneurysmal Subarachnoid Hemorrhage
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Andrew F. Ducruet and Jacob F Baranoski
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Aminocaproates ,Antioxidant ,Subarachnoid hemorrhage ,business.industry ,medicine.medical_treatment ,Nanoparticle ,Subarachnoid Hemorrhage ,Pharmacology ,medicine.disease ,Antioxidants ,Aminocaproic Acid ,Humans ,Nanoparticles ,Medicine ,Surgery ,Neurology (clinical) ,business - Published
- 2019
6. Formation of persisters in Streptococcus mutans biofilms induced by antibacterial dental monomer
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Lei Cheng, Hockin K. H. Xu, Xiaodong Li, Michael D. Weir, Thomas W. Oates, Suping Wang, Biao Ren, Radi Masri, and Chenchen Zhou
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0301 basic medicine ,030106 microbiology ,Population ,Biomedical Engineering ,Biophysics ,Bioengineering ,Microbial Sensitivity Tests ,Drug resistance ,Dental Caries ,Biology ,Microbiology ,Streptococcus mutans ,Biomaterials ,Dental Materials ,03 medical and health sciences ,Minimum inhibitory concentration ,0302 clinical medicine ,Drug Resistance, Bacterial ,medicine ,Humans ,Potency ,education ,Aminocaproates ,education.field_of_study ,Chlorhexidine ,Biofilm ,030206 dentistry ,biology.organism_classification ,Anti-Bacterial Agents ,Resin Cements ,Quaternary Ammonium Compounds ,Biofilms ,Methacrylates ,Bacteria ,medicine.drug - Abstract
Antibacterial monomers can combat oral biofilm acids and caries; however, little is known on whether quaternary ammonium monomers (QAMs) would induce drug persistence in oral bacteria. The objectives of this study were to investigate the interactions of Streptococcus mutans (S. mutans) with dimethylaminohexadecyl methacrylate (DMAHDM), and determine for the first time whether DMAHDM could induce persisters in S. mutans. DMAHDM was synthesized using a modified Menschutkin reaction. Dose-dependent killing curves and time-dependent killing curves of planktonic S. mutans and biofilms were determined to evaluate drug persistence, using chlorhexidine (CHX) as control. The inheritability assay, minimum inhibitory concentration (MIC) and live/dead biofilm assay were determined to investigate persister characteristics. DMAHDM matched the killing potency of the gold standard CHX against S. mutans biofilms. DMAHDM and CHX induced drug persistence in S. mutans biofilms but not in planktonic bacteria. S. mutans biofilm persistence was not inheritable in that the tolerance to DMAHDM or CHX of the surviving persisters in the initial population was not transferred to subsequent generations, as displayed by the inheritability assay. The MIC of S. mutans parental strain and induced persisters remained the same. The induced persisters in S. mutans biofilms could be eliminated via higher doses of 300 μg/mL of DMAHDM and CHX. In conclusion, this study showed for the first time that (1) DMAHDM induced persisters only in biofilms, but not in planktonic bacteria; and (2) both DMAHDM-induced and CHX-induced S. mutans persister biofilms could be completely eradicated by even higher concentrations of DMAHDM and CHX. More studies are needed on the induction of persisters in oral biofilms for the development and use of a new generation of antibacterial dental monomers and resins.
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- 2017
7. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs
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Hartmut Grasemann, Rupinder Dhaliwal, Robert P. Jankov, Jaques Belik, Patrick J. McNamara, Crystal Kantores, Jeremy A. Scott, and Julijana Ivanovska
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Boron Compounds ,Pulmonary and Respiratory Medicine ,Physiology ,Hypertension, Pulmonary ,Vascular Remodeling ,030204 cardiovascular system & hematology ,Pharmacology ,Arginine ,Nitric Oxide ,medicine.disease_cause ,Bleomycin ,Nitric oxide ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,medicine ,Animals ,Lung ,Bronchopulmonary Dysplasia ,030304 developmental biology ,Aminocaproates ,chemistry.chemical_classification ,0303 health sciences ,Antibiotics, Antineoplastic ,Arginase ,Substrate (chemistry) ,Lung Injury ,Cell Biology ,respiratory system ,medicine.disease ,Pulmonary hypertension ,Rats ,3. Good health ,Bioavailability ,Disease Models, Animal ,Enzyme ,chemistry ,Biochemistry ,Collagen ,Oxidative stress - Abstract
Arginase is an enzyme that limits substrate l-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces l-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased l-arginine and l-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension.
- Published
- 2015
8. N-(Pivaloyloxy)alkoxy-carbonyl Prodrugs of the Glutamine Antagonist 6-Diazo-5-oxo-L-norleucine (DON) as a Potential Treatment for HIV Associated Neurocognitive Disorders
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Andrej Jančařík, Rana Rais, Caroline Garrett, Michael T. Nedelcovych, Ranjeet Prasad Dash, Alexandra J. Gadiano, Gerald Brandacher, Boe-Hyun Kim, Jennifer Kelschenbach, Georg J. Furtmüller, Eran Hadas, Eva Prchalova, Lukáš Tenora, Pavel Majer, Byoung Chol Oh, David J. Volsky, Wei Chao, Barbara S. Slusher, Jesse Alt, and Sarah C. Zimmermann
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0301 basic medicine ,Male ,Swine ,Diazooxonorleucine ,Neurocognitive Disorders ,Glutamic Acid ,HIV Infections ,Pharmacology ,Neurotransmission ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Stability ,Glutaminase ,Drug Discovery ,medicine ,Animals ,Humans ,Prodrugs ,Nootropic Agents ,Aminocaproates ,Microglia ,Glutamate receptor ,Antagonist ,Brain ,Prodrug ,Viral Load ,6-Diazo-5-oxo-L-norleucine ,Glutamine ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Blood ,chemistry ,Molecular Medicine ,Female ,Azo Compounds ,030217 neurology & neurosurgery ,Isopropyl - Abstract
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.
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- 2017
9. Matching on provider is risky
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Alexander M. Walker
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Comparative Effectiveness Research ,medicine.medical_specialty ,Matching (statistics) ,Epidemiology ,Matched-Pair Analysis ,Z-bias ,Comparative effectiveness research ,Amplification bias ,Instrumental variables ,Hemostatics ,Aprotinin ,Bias ,Econometrics ,medicine ,Matching ,Humans ,Coronary Artery Bypass ,Unmeasured confounding ,Intensive care medicine ,Unmeasured confounders ,Randomized Controlled Trials as Topic ,Aminocaproates ,business.industry ,Patient Selection ,Confounding ,Instrumental variable ,Reproducibility of Results ,Confounding Factors, Epidemiologic ,Hospitals ,Pseudorandomization ,Research Design ,Data Interpretation, Statistical ,Observational study ,business - Abstract
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.
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- 2013
10. Studies toward the Synthesis of Potent Anti-inflammatory Peptides Solomonamides A and B: Synthesis of a Macrocyclic Skeleton and Key Fragment 4-Amino-6-(2′-amino-4′-hydroxyphenyl)-3-hydroxy-2-methyl-6-oxohexanoic Acid (AHMOA)
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D. Srinivasa Reddy, N. Vasudevan, and K. Kashinath
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Aminocaproates ,Molecular Structure ,Chemistry ,Stereochemistry ,medicine.drug_class ,Fragment (computer graphics) ,Anti-Inflammatory Agents, Non-Steroidal ,Organic Chemistry ,Total synthesis ,Stereoisomerism ,Peptides, Cyclic ,Biochemistry ,Combinatorial chemistry ,Anti-inflammatory ,medicine ,Molecule ,Physical and Theoretical Chemistry - Abstract
A first synthetic effort toward total synthesis of highly potent solomonamides is disclosed. An efficient strategy to synthesize this class of compounds, along with the synthesis of a core macrocycle (shown in red) and the key fragment AHMOA, is described.
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- 2012
11. Controlling intrathoracic hemorrhage on ECMO: help from Factor VIIa and Virchow
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M R Rigby, A Vats, P Kamat, and M Heard
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Male ,Vasculitis ,medicine.medical_specialty ,Pleural effusion ,Decompression ,medicine.medical_treatment ,Hemorrhage ,Thoracentesis ,Factor VIIa ,Autoimmune Diseases ,Extracorporeal Membrane Oxygenation ,Extracorporeal membrane oxygenation ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Child ,Aminocaproates ,Advanced and Specialized Nursing ,business.industry ,Pneumothorax ,Pneumonia ,General Medicine ,Decompression, Surgical ,medicine.disease ,Hemothorax ,Surgery ,Chest tube ,surgical procedures, operative ,Anesthesia ,Aminocaproic acid ,Respiratory Insufficiency ,Cardiology and Cardiovascular Medicine ,business ,Safety Research ,medicine.drug - Abstract
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.
- Published
- 2012
12. Chronic Oral Administration of the Arginase Inhibitor 2(S)-amino-6-boronohexanoic Acid (ABH) Improves Erectile Function in Aged Rats
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Omer Kutlu, Arthur L. Burnett, Robert L. Segal, Jae Hyung Kim, Xiaopu Liu, Johanna L. Hannan, Trinity J. Bivalacqua, Dan E. Berkowitz, Jochen Steppan, and Hunter C. Champion
- Subjects
Boron Compounds ,Male ,Aging ,Mean arterial pressure ,medicine.medical_specialty ,Urology ,Endocrinology, Diabetes and Metabolism ,Administration, Oral ,Hemodynamics ,Article ,Nitric oxide ,chemistry.chemical_compound ,Endocrinology ,Erectile Dysfunction ,In vivo ,Oral administration ,Internal medicine ,medicine ,Animals ,Enzyme Inhibitors ,Endothelial dysfunction ,Aminocaproates ,Arginase ,business.industry ,Penile Erection ,medicine.disease ,Electric Stimulation ,Rats, Inbred F344 ,Rats ,Erectile dysfunction ,Reproductive Medicine ,chemistry ,business ,Penis - Abstract
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.
- Published
- 2012
13. Arginase inhibition promotes wound healing in mice
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Trinity J. Bivalacqua, Aarti R. Uzgare, Adrian Barbul, and Sandra L. Kavalukas
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Boron Compounds ,Male ,Administration, Topical ,Pharmacology ,Nitric Oxide ,Nitric oxide ,Mice ,chemistry.chemical_compound ,medicine ,Animals ,Enzyme Inhibitors ,Cells, Cultured ,Skin ,Aminocaproates ,Mice, Inbred BALB C ,Wound Healing ,Arginase ,integumentary system ,business.industry ,Granulation tissue ,Fibroblasts ,Ornithine ,Actins ,Epithelium ,Mice, Inbred C57BL ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Models, Animal ,Female ,Surgery ,business ,Polyamine ,Wound healing ,Myofibroblast - Abstract
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 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.
- Published
- 2012
14. Enhanced brain penetration of hexamethonium in complexes with derivatives of fullerene C60
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A. Yu. Bespalov, D. N. Nikolaev, E. E. Yakovleva, L. B. Piotrovskiy, E. V. Litasova, Olga A. Dravolina, and M. A. Dumpis
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Male ,Nicotine ,Fullerene ,Biophysics ,02 engineering and technology ,Hexamethonium Compounds ,Nicotinic Antagonists ,Pharmacology ,digestive system ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Seizures ,High doses ,medicine ,Animals ,Rats, Wistar ,Receptor ,Aminocaproates ,Dose-Response Relationship, Drug ,musculoskeletal, neural, and ocular physiology ,Brain ,General Chemistry ,General Medicine ,Penetration (firestop) ,021001 nanoscience & nanotechnology ,Locomotor stimulation ,chemistry ,Drug delivery ,Hexamethonium ,Anticonvulsants ,Fullerenes ,0210 nano-technology ,030217 neurology & neurosurgery ,Locomotion ,medicine.drug - Abstract
The present report describes development of hexamethonium complexes based on fullerene C60. Hexamethonium has a limited penetration into CNS and therefore can antagonize central effects of nicotine only when given at high doses. In the present studies conducted in laboratory rodents, intraperitoneal administration of hexamethonium-fullerene complexes blocked effects of nicotine (convulsions and locomotor stimulation). When compared to equimolar doses of hexamethonium, complexes of hexamethonium with derivatives of fullerene C60 were 40 times more potent indicating an enhanced ability to interact with central nicotine receptors. Thus, fullerene C60 derivatives should be explored further as potential carrier systems for polar drug delivery into CNS.
- Published
- 2015
15. Increased arginase activity contributes to airway remodelling in chronic allergic asthma
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Herman Meurs, Bart G. J. Dekkers, Anetta Zuidhof, Gunnar Flik, Johan Zaagsma, Theo Klein, Isabella Bos, Mark H. Menzen, Harm Maarsingh, Molecular Pharmacology, and Groningen Research Institute for Asthma and COPD (GRIAC)
- Subjects
Male ,Ornithine ,NITRIC-OXIDE INHIBITION ,Pulmonary Fibrosis ,SMOOTH-MUSCLE-CELLS ,Muscle hypertrophy ,Fibrosis ,Medicine ,GUINEA-PIG MODEL ,Anti-Asthmatic Agents ,Aminocaproates ,Interleukin-13 ,respiratory system ,Trachea ,Arginase ,medicine.anatomical_structure ,Airway Remodeling ,eosinophils ,Bronchial Hyperreactivity ,medicine.symptom ,Muscle Contraction ,Boron Compounds ,Pulmonary and Respiratory Medicine ,goblet cells ,Ovalbumin ,polyamines ,Guinea Pigs ,Inflammation ,S-NITROSYLATION ,airway remodelling ,Exocrine Glands ,Airway hyperresponsiveness ,INFLAMMATION ,HYPERRESPONSIVENESS ,Eosinophilia ,Animals ,MUCUS SECRETION ,Goblet cell ,Lung ,business.industry ,fibrosis ,Muscle, Smooth ,IN-VITRO ,Allergens ,Eosinophil ,medicine.disease ,Mucus ,Asthma ,respiratory tract diseases ,INDUCED UP-REGULATION ,Chronic Disease ,Immunology ,Citrulline ,business ,LUNG - Abstract
Airway remodelling, characterised by increased airway smooth muscle (ASM) mass, subepithelial fibrosis, goblet cell hyperplasia and mucus gland hypertrophy, is a feature of chronic asthma. Increased arginase activity could contribute to these features via increased formation of polyamines and L-proline downstream of the arginase product L-ornithine, and via reduced nitric oxide synthesis.Using the specific arginase inhitibor 2(S)-amino-6-boronohexanoic acid (ABH), we studied the role of arginase in airway remodelling using a guinea pig model of chronic asthma. Ovalbumin-sensitised guinea pigs were treated with ABH or PBS via inhalation before each of 12 weekly allergen or saline challenges, and indices of arginase activity, and airway remodelling, inflammation and responsiveness were studied 24 h after the final challenge.Pulmonary arginase activity of repeatedly allergen-challenged guinea pigs was increased. Allergen challenge also increased ASM mass and maximal contraction of denuded tracheal rings, which were prevented by ABH. ABH also attenuated allergen-induced pulmonary hydroxyproline (fibrosis) and putrescine, mucus gland hypertrophy, goblet cell hyperplasia, airway eosinophilia and interleukin-13, whereas an increased L-ornithine/L-citrulline ratio in the lung was normalised. Moreover, allergen-induced hyperresponsiveness of perfused tracheae was fully abrogated by ABH.These findings demonstrate that arginase is prominently involved in allergen-induced airway remodelling, inflammation and hyperresponsiveness in chronic asthma.
- Published
- 2011
16. Pharmacokinetic interaction between ϵ-acetamidocaproic acid (AACA) and cimetidine in indomethacin-induced acute gastric ulcer and control rats: inhibition of active renal secretion of AACA by cimetidine
- Author
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Euichaul Oh, Y. G. Kim, M. Lee, Unji Lee, Young-Hee Choi, Jung Hee Suh, and M. G. Lee
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Male ,medicine.medical_specialty ,Time Factors ,Health, Toxicology and Mutagenesis ,Indomethacin ,Administration, Oral ,Pharmacology ,Kidney ,Toxicology ,Biochemistry ,Rats, Sprague-Dawley ,Acute gastric ulcer ,Pharmacokinetics ,Oral administration ,Internal medicine ,medicine ,Animals ,Drug Interactions ,Stomach Ulcer ,Cimetidine ,Aminocaproates ,business.industry ,Blood Proteins ,General Medicine ,Drug interaction ,Anti-Ulcer Agents ,Rats ,Endocrinology ,Renal physiology ,Aminocaproic Acid ,Injections, Intravenous ,business ,Dialysis ,Pharmacokinetic interaction ,Protein Binding ,medicine.drug ,Clearance - Abstract
After both the intravenous and oral administration of zinc acexamate [ZAC; ion-pairing between zinc and ϵ-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CL(R)). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine. After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone.
- Published
- 2011
17. Synthesis and antibacterial activity of alaremycin derivatives for the porphobilinogen synthase
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Jumpei Oku, Kyosuke Nakayama, Tomoya Kitazume, and Noritaka Iwai
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Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,Chemical synthesis ,Inhibitory Concentration 50 ,Pseudomonas ,Drug Discovery ,medicine ,Molecular Biology ,IC50 ,Antibacterial agent ,Aminocaproates ,chemistry.chemical_classification ,Molecular Structure ,biology ,Chemistry ,Porphobilinogen synthase ,Organic Chemistry ,Porphobilinogen Synthase ,Anti-Bacterial Agents ,Enzyme ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Biological Assay ,Antibacterial activity ,Chlorofluorocarbons, Methane - Abstract
The preparation and the antibacterial activity of alaremycin derivatives such as their CF3-derivatives and (R)- and (S)-4-oxo-5-acetylaminohexanoic acid for the porphobilinogen synthase (PBGS), were described. The IC50 values of the antibacterial activity of the prepared materials for the inhibitor of PBGS, were determined using PBGS assay.
- Published
- 2011
18. Inhibition of Arginase Activity Ameliorates L-Arginine-Induced Acute Pancreatitis in Rats
- Author
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Péter Hegyi, Sándor Dósa, György Biczó, Viktória Venglovecz, Béla Iványi, Tamás Takács, Zsuzsanna Hracskó, Zoltán Rakonczay, Ilona Szőllősiné Varga, Sándor Berczi, and Tibor Wittmann
- Subjects
Male ,Ornithine ,medicine.medical_specialty ,Arginine ,Endocrinology, Diabetes and Metabolism ,Severity of Illness Index ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Internal Medicine ,medicine ,Citrulline ,Animals ,Rats, Wistar ,Pancreas ,Heat-Shock Proteins ,Peroxidase ,Aminocaproates ,chemistry.chemical_classification ,Glutathione Peroxidase ,Arginase ,Hepatology ,biology ,Glutathione peroxidase ,medicine.disease ,Rats ,Pancreatitis ,chemistry ,Myeloperoxidase ,Acute Disease ,Aminocaproic Acid ,biology.protein ,Acute pancreatitis ,Cattle - Abstract
Objectives Intraperitoneal (IP) injection of 3.5 g/kg L-arginine (known to induce acute pancreatitis) in rats will result in much greater increases in serum ornithine versus citrulline concentration (Crit Care Med. 2008;36:2117-2127). These data indicate a major role of arginase in the catabolism of L-arginine. Therefore, we tested the effects of the irreversible arginase inhibitor (+)-S-2-amino-6-iodoacetamidohexanoic acid (AIHA) on L-arginine-induced acute pancreatitis. Methods The inhibitory effect of AIHA on arginase activity was tested on rat liver homogenate and purified bovine arginase. Male Wistar rats were administered 15 mg/kg AIHA or its vehicle IP 1 hour before the injection of physiological saline or 3.5 g/kg L-arginine IP. Laboratory and histological parameters of pancreatitis were determined 24 hours after the last injection. Results Sixty micromolars of AIHA (equimolar to an in vivo dose of 15 mg/kg) significantly inhibited arginase activity by about 25%. Pretreatment with AIHA significantly ameliorated pancreatic damage caused by L-arginine administration. It decreased pancreatic weight/body weight ratio, pancreatic glutathione peroxidase and myeloperoxidase activities, and histological damage. Administration of AIHA in itself significantly increased levels of pancreatic heat shock proteins. Conclusions Pretreatment with AIHA reduces the severity of L-arginine-induced pancreatitis most likely by inhibiting arginase activity.
- Published
- 2010
19. Leptospiral Endostatin-Like Protein A Is a Bacterial Cell Surface Receptor for Human Plasminogen
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Amy Bowman, Samir T. Shah, Brian Stevenson, Ashutosh Verma, Catherine A. Brissette, and Peter F. Zipfel
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Plasmin ,medicine.medical_treatment ,Immunology ,Extracellular matrix component ,Plasma protein binding ,Microbiology ,Bacterial Proteins ,Laminin ,Protein Interaction Mapping ,medicine ,Humans ,Enzyme Inhibitors ,Aminocaproates ,Protease ,biology ,Plasminogen ,biology.organism_classification ,Molecular Pathogenesis ,Infectious Diseases ,Complement Factor H ,Factor H ,biology.protein ,Parasitology ,Leptospira interrogans ,Protein A ,Protein Binding ,medicine.drug - Abstract
The spirochete Leptospira interrogans is a highly invasive pathogen of worldwide public health importance. Studies from our laboratories and another have demonstrated that L. interrogans can acquire host plasminogen on its surface. Exogenous plasminogen activators can then convert bound plasminogen into the functionally active protease plasmin. In this study, we extend upon those observations and report that leptospiral endostatin-like protein A (LenA) binds human plasminogen in a dose-dependent manner. LenA-plasminogen interactions were significantly inhibited by the lysine analog ξ-aminocaproic acid, suggesting that the lysine-binding sites on the amino-terminal kringle portion of the plasminogen molecule play a role in the binding. Previous studies have shown that LenA also binds complement regulator factor H and the extracellular matrix component laminin. Plasminogen competed with both factor H and laminin for binding to LenA, which suggests overlapping ligand-binding sites on the bacterial receptor. Finally, LenA-bound plasminogen could be converted to plasmin, which in turn degraded fibrinogen, suggesting that acquisition of host-derived plasmin by LenA may aid bacterial dissemination throughout host tissues.
- Published
- 2010
20. Aprotinin in cardiac surgery patients: is the risk worth the benefit?
- Author
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Eric Skipper, Robert M. Stiegel, Marcy Nussbaum, Francis Robicsek, Sotiris C. Stamou, Mark K. Reames, Rachel Geller, and Kevin W. Lobdell
- Subjects
Adult ,Male ,Reoperation ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Antifibrinolytic ,Blood transfusion ,medicine.drug_class ,medicine.medical_treatment ,Blood Loss, Surgical ,Myocardial Infarction ,Postoperative Hemorrhage ,Preoperative care ,Hemostatics ,Young Adult ,Coronary artery bypass surgery ,Aprotinin ,Internal medicine ,medicine ,Humans ,Blood Transfusion ,Cardiac Surgical Procedures ,Coronary Artery Bypass ,Risk factor ,Aged ,Aged, 80 and over ,Aminocaproates ,business.industry ,Hazard ratio ,General Medicine ,Acute Kidney Injury ,Middle Aged ,Heart Valves ,Hemostasis, Surgical ,Cardiac surgery ,Anesthesia ,Cardiology ,Drug Evaluation ,Female ,Surgery ,Epidemiologic Methods ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Background: Aprotinin is the only Food and Drug Administration-approved agent to reduce haemorrhage related to cardiac surgery and its safety and efficacy has been extensively studied. Our study sought to compare the efficacy, early and late mortality and major morbidity associated with aprotinin compared with e-aminocaproic acid (EACA) in cardiac surgery operations. Methods: Between January 2002 and December 2006, 2101 patients underwent coronary artery bypass grafting (CABG), valve surgery or CABG and valve surgery in our institution with the use of aprotinin (1898 patients) or EACA (203 patients).Logistic regression and propensity score analysis were usedto adjust for imbalances in the patients’ preoperative characteristics. The propensity score-adjusted sample included 570 patients who received aprotinin and 114 who receivedEACA (1—5matching).Results:Operativemortalitywashigher in theaprotinin groupin univariate(aprotinin4.3% vs EACA1%,p = 0.023) butnotpropensityscore-adjustedmultivariateanalysis(4%vs0.9%,p = 0.16).Inpropensity score-adjustedanalysis,aprotininwasalso associated with a lower rate of blood transfusion (38.8% vs 50%, p = 0.04), a lower rate of haemorrhage-related re-exploration (3.7% vs 7.9%, p = 0.04) and a higher risk of in-hospital cardiac arrest (3.7% vs 0%, p = 0.03) and a marginally but not statistically significantly higher risk of acute renal failure (6.8% vs 2.6%,p = 0.09). In Cox proportional hazardsregression analysis, the riskof late death was higher in the aprotinin comparedto EACA group (hazard ratio = 4.33, 95% confidence interval (CI) = 1.60—11.67, p = 0.004). Conclusion: Aprotinin decreases the rate of postoperative blood transfusion and haemorrhage-related re-exploration, but increases the risk of in-hospital cardiac arrest and late mortality after cardiac surgery when compared to EACA. Cumulative evidence suggests that the risk associated with aprotinin may not be worth the haemostatic benefit. # 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.
- Published
- 2009
21. Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats
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Andre Camara, Hunter C. Champion, Gautam Sikka, Artin A. Shoukas, Monica Ilies, David W. Christianson, Sungwoo Ryoo, Kevin G. Soucy, Trinity J. Bivalacqua, Dan E. Berkowitz, Daniel Nyhan, Jae Hyung Kim, Young Jun Oh, Lakshmi Santhanam, Lukasz J. Bugaj, and Alanah Webb
- Subjects
Boron Compounds ,Male ,Senescence ,Aging ,medicine.medical_specialty ,Time Factors ,Nitric Oxide Synthase Type III ,Physiology ,Vasodilator Agents ,Nitric Oxide Synthase Type II ,Vasodilation ,Nitric Oxide ,Nitric oxide ,chemistry.chemical_compound ,Downregulation and upregulation ,Superoxides ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Enzyme Inhibitors ,Endothelial dysfunction ,Aorta ,Aminocaproates ,Arginase ,Dose-Response Relationship, Drug ,Chemistry ,Age Factors ,Articles ,S-Nitrosylation ,medicine.disease ,Acetylcholine ,Rats, Inbred F344 ,Rats ,Carotid Arteries ,NG-Nitroarginine Methyl Ester ,Endocrinology ,Endothelium, Vascular ,Protein Multimerization ,Oxidation-Reduction ,Compliance - Abstract
There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O2−) production than young. Acute inhibition of both NOS, with NG-nitro-l-arginine methyl ester, and arginase, with 2( S)-amino- 6-boronohexanoic acid (ABH), significantly reduced O2− production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692–702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O2− production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.
- Published
- 2009
22. RENAL MICROTHROMBOSIS
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Myhre-Jensen O, Butrago B, and Hansen Es
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Hemorrhagic Disorders ,Kidney ,Adrenocorticotropic Hormone ,Neoplasms ,Humans ,Medicine ,Child ,Aged ,Aminocaproates ,business.industry ,Microcirculation ,Incidence (epidemiology) ,Infant, Newborn ,Infant ,Thrombosis ,General Medicine ,Middle Aged ,Thrombophlebitis ,Child, Preschool ,Female ,Kidney Diseases ,Steroids ,Clinico pathological ,Autopsy ,business - Published
- 2009
23. DISAPPEARANCE OF CIRCULATING TUMOUR CELLS IN MICE TREATED WITH HEPARIN, COUMARIN AND EACA
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Bernt Boeryd and Björn Hagmar
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C57BL/6 ,Pathology ,medicine.medical_specialty ,Time Factors ,Antifibrinolytic ,medicine.drug_class ,medicine.medical_treatment ,Cell ,Pharmacology ,Mice ,Coumarins ,medicine ,Animals ,Neoplasm ,Thrombus ,Aminocaproates ,Chemotherapy ,biology ,Heparin ,business.industry ,Anticoagulant ,General Medicine ,Neoplastic Cells, Circulating ,medicine.disease ,biology.organism_classification ,medicine.anatomical_structure ,business ,medicine.drug - Abstract
In a syngeneic tumour-host system the disappearance of circulating tumour cells was studied in mice treated with heparin, a coumarin anticoagulant and an antifibrinolytic. The cells were injected intravenously in two doses and blood was drawn from the right heart at intervals after the cell transfusion and inoculated intraperitoneally into new recipients. Only minor changes in the disappearance rate of tumour cells from the blood were obtained by anticoagulant and antifibrinolytic treatment. Thus thrombus formation, if present, cannot play but a minor role for the retention of tumour cells in organs in this system. The coumarin anticoagulant delayed somewhat the removal from the blood of 2 × 106 injected tumour cells. This was in contrast to heparin which, if anything, seemed to hasten the removal of the cells from the blood.
- Published
- 2009
24. EXTRACTION OF CATARACT IN A PATIENT WITH SEVERE HAEMOPHILIA A
- Author
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Göte Österlind and Inga Marie Nilsson
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Aminocaproates ,Male ,medicine.medical_specialty ,Factor VIII ,business.industry ,Extraction (chemistry) ,Hemorrhage ,Cataract Extraction ,General Medicine ,Middle Aged ,Hemophilia A ,medicine.disease ,Ophthalmology ,Postoperative Complications ,Text mining ,medicine ,Humans ,Severe haemophilia A ,Blood Coagulation Tests ,Medical emergency ,Intensive care medicine ,business ,Vision, Ocular - Published
- 2009
25. Acute Right Heart Failure During Treatment with Epsilon Amino Caproic Acid (E-ACA)
- Author
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Stig-Arne Johansson
- Subjects
Aminocaproates ,Blood Platelets ,Heart Failure ,medicine.medical_specialty ,business.industry ,Fibrinogen ,Acute right heart failure ,Breast Neoplasms ,Middle Aged ,Caproic Acid ,Blood Cell Count ,Acute Disease ,Internal Medicine ,Humans ,Medicine ,Female ,Blood Coagulation Tests ,business ,Intensive care medicine - Published
- 2009
26. Clot Retention in the Kidneys as a Probable Cause of Anuria During Treatment of Haematuria with Epsilon-aminocaproic Acid
- Author
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Lennart Andersson and Gunnar Lingårdh
- Subjects
Aminocaproates ,medicine.medical_specialty ,business.industry ,Urology ,Middle Aged ,Anuria ,Hemorrhagic Disorders ,Surgery ,Celiac Disease ,Epsilon-Aminocaproic Acid ,Internal Medicine ,medicine ,Humans ,Female ,Kidney Diseases ,medicine.symptom ,business ,Hematuria - Published
- 2009
27. Long-term study of gamma-vinyl GABA in the treatment of epilepsy
- Author
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Søren A. Pedersen, Peder Klosterskov, Lennart Gram, and Mogens Dam
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Adult ,Male ,Adolescent ,Nausea ,medicine.medical_treatment ,Dizziness ,Vigabatrin ,Mice ,Epilepsy ,Dogs ,Animals ,Humans ,Medicine ,Child ,Fatigue ,Aged ,Aminocaproates ,Brain Diseases ,Chemotherapy ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Anticonvulsant ,Neurology ,Tolerability ,Child, Preschool ,Anesthesia ,Concomitant ,Vomiting ,Anticonvulsants ,Female ,Neurology (clinical) ,medicine.symptom ,Juvenile myoclonic epilepsy ,business - Abstract
– The purpose of this study was to investigate the long-term efficacy and tolerability of gamma-vinyl GABA (GVG) in the treatment of epilepsy. 36 patients with severe therapy resistant epilepsies participated, the majority exhibiting complex partial seizures. The mean follow-up period was 9.3 months. GVG was administered as add-on therapy, to keep serum levels of concomitant treatment constant. The mean dose of GVG was 2.6 g's per day. Fifty-six per cent of the patients, including three patients with juvenile myoclonic epilepsy, experienced more than a 50% reduction in seizure frequency. No signs of tolerance development to the antiepileptic effect of GVG was demonstrated. Two patients were withdrawn from GVG treatment due to increased seizure frequency, and two due to side effects in the form of vomiting and nausea. Incidentally, the side effects observed were harmless and transient. Fifty per cent of the patients experienced no side effects at all. GVG seems to be a valuable antiepileptic compound. The results of this long-term study confirm observations from several short controlled trials.
- Published
- 2009
28. Arginase inhibition protects against allergen-induced airway obstruction, hyperresponsiveness, and inflammation
- Author
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Annet B. Zuidhof, Johan Zaagsma, Herman Meurs, I. Sophie T. Bos, Harm Maarsingh, Marcel van Duin, Jean-Luc Boucher, Molecular Pharmacology, and Groningen Research Institute for Asthma and COPD (GRIAC)
- Subjects
Pulmonary and Respiratory Medicine ,Boron Compounds ,Allergy ,NF-KAPPA-B ,L-arginine ,Critical Care and Intensive Care Medicine ,UP-REGULATION ,Bronchoalveolar Lavage ,SMOOTH-MUSCLE RELAXATION ,Bronchial Provocation Tests ,Nitric oxide ,chemistry.chemical_compound ,2(S)-amino-6-boronohexanoic acid ,nitric oxide ,Intensive care ,medicine ,Animals ,NITRIC-OXIDE SYNTHASE ,Methacholine Chloride ,Aminocaproates ,CYSTIC-FIBROSIS ,biology ,Arginase ,EARLY ASTHMATIC REACTION ,business.industry ,L-ARGININE UTILIZATION ,HYPERREACTIVITY ,respiratory system ,Airway obstruction ,medicine.disease ,Asthma ,respiratory tract diseases ,Airway Obstruction ,Ovalbumin ,INHALED L-ARGININE ,chemistry ,Immunology ,Models, Animal ,biology.protein ,UNRESTRAINED GUINEA-PIGS ,Bronchial Hyperreactivity ,business ,allergic asthma ,guinea pigs ,Ex vivo ,Histamine - Abstract
Rationale: In a guinea pig model of allergic asthma, using perfused tracheal preparations ex vivo, we demonstrated that L-arginine limitation due to increased arginase activity underlies a deficiency of bronchodilating nitric oxide (NO) and airway hyperresponsiveness (AHR) after the allergen-induced early and late asthmatic reaction.Objectives: Using the same animal model, we investigated the acute effects of the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) and of L-arginine on AHR after the early and late reaction in vivo. In addition, we investigated the protection of allergen-induced asthmatic reactions, AHR, and airway inflammation by pretreatment with the drug.Methods: Airway responsiveness to inhaled histamine was measured in permanently instrumented, freely moving guinea pigs sensitized to ovalbumin at 24 hours before allergen challenge and after the allergen-induced early and late asthmatic reactions by assessing histamine PC(100) (provocative concentration causing a 100% increase of pleural pressure) values.Measurements and Main Results: Inhaled ABH acutely reversed AHR to histamine after the early reaction from 4.77 +/- 0.56-fold to 2.04 +/- 0.34 fold (P Conclusions: Inhalation of ABH or L-arginine acutely reverses allergen-induced AHR after the early and late asthmatic reaction, presumably by attenuating arginase-induced substrate deficiency to NO synthase in the airways. Moreover, ABH considerably reduces the airway sensitivity to inhaled allergen and protects against allergen-induced bronchial obstructive reactions, AHR, and airway inflammation. This is the first in vivo study indicating that arginase inhibitors may have therapeutic potential in allergic asthma.
- Published
- 2008
29. The Level of GAD67 Protein Is Highly Sensitive to Small Increases in Intraneuronal γ-Aminobutyric Acid Levels
- Author
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David L. Martin and Karin Rimvall
- Subjects
Male ,medicine.medical_specialty ,Carboxy-lyases ,Immunoblotting ,Central nervous system ,Glutamate decarboxylase ,Biology ,Biochemistry ,Aminobutyric acid ,Vigabatrin ,Cellular and Molecular Neuroscience ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,gamma-Aminobutyric Acid ,Aminocaproates ,Neurons ,Dose-Response Relationship, Drug ,Glutamate Decarboxylase ,Brain ,Rats ,Molecular Weight ,Dose–response relationship ,medicine.anatomical_structure ,Endocrinology ,Cerebral cortex ,GABAergic ,Synaptosomes ,medicine.drug - Abstract
Increases (> 2.5-fold) in GABA levels in rat brain lead to a large decrease in the level of the 67-kDa form of glutamate decarboxylase (GAD67) through a mechanism involving either a change in GAD67 protein stability or a change in GAD67 mRNA translation. In the present study, brain levels of GABA were manipulated by treating rats with various doses of gamma-vinyl-gamma-aminobutyric acid (GVG), and the dependence of total GAD activity and levels of GAD67 and GAD65 protein on the levels of GABA was analyzed. Initial studies showed that both GABA and GAD67 protein levels reached new steady-state levels after two to four daily injections; GABA increased 1.5- (30 mg of GVG/kg) and fourfold (150 mg of GVG/kg), and GAD67 protein content decreased by 30 and 70%. To assess the sensitivity of GAD67 to GABA, rats were injected with eight different doses of GVG (15-150 mg/kg) for 5 days. With increasing doses of GVG, we observed a gradual increase in both whole-tissue and synaptosomal GABA levels and a gradual decrease in GAD67 protein and GAD activity. The levels of GAD65 remained constant at all GVG doses. GAD67 was remarkably sensitive to GABA. The synaptosomal GAD67 level decreased approximately 12% and the whole-neuron GAD67 level decreased approximately 3% for each 1% increase in nerve terminal GABA content when it was close to its physiological level. Our results clearly demonstrate that GAD67 is tightly controlled by intraneuronal GABA, and we suggest that this regulatory mechanism has important implications for the physiological regulation of GABAergic function in the mammalian brain.
- Published
- 2008
30. A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery
- Author
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Dean A, Fergusson, Paul C, Hébert, C David, Mazer, Stephen, Fremes, Charles, MacAdams, John M, Murkin, Kevin, Teoh, Peter C, Duke, Ramiro, Arellano, Morris A, Blajchman, Jean S, Bussières, Dany, Côté, Jacek, Karski, Raymond, Martineau, James A, Robblee, Marc, Rodger, George, Wells, Jennifer, Clinch, Roanda, Pretorius, and C, Piché
- Subjects
Male ,medicine.medical_specialty ,Antifibrinolytic ,medicine.drug_class ,Kaplan-Meier Estimate ,Postoperative Hemorrhage ,law.invention ,Aprotinin ,Double-Blind Method ,Randomized controlled trial ,law ,Antifibrinolytic agent ,Humans ,Medicine ,Blood Transfusion ,Cardiac Surgical Procedures ,Aged ,Aged, 80 and over ,Aminocaproates ,business.industry ,Lysine ,General Medicine ,Length of Stay ,Middle Aged ,Antifibrinolytic Agents ,Cardiac surgery ,Surgery ,Treatment Outcome ,Tranexamic Acid ,Relative risk ,Anesthesia ,Female ,Aminocaproic acid ,business ,hormones, hormone substitutes, and hormone antagonists ,Tranexamic acid ,medicine.drug - Abstract
Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences.In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days.The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22).Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).
- Published
- 2008
31. Rendu-Osler-Weber Syndrome: case report and literature review
- Author
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Alfredo Rafael Dell'Aringa, Renato M. Perches Filho, José Carlos Nardi, Kazue Kobari, Vera Lúcia Muller Gradim Moron Rodrigues, and Antônio José Cortez Juares
- Subjects
Male ,medicine.medical_specialty ,Blood transfusion ,medicine.medical_treatment ,Disease ,rendu-osler-weber syndrome ,Gastrointestinal complications ,RENDU OSLER WEBER SYNDROME ,medicine ,hereditary hemorrhagic telangiectasia ,Humans ,Blood Transfusion ,Embolization ,Family history ,Telangiectasia ,Aminocaproates ,business.industry ,Hemostasis, Endoscopic ,Middle Aged ,medicine.disease ,Dermatology ,Embolization, Therapeutic ,Surgery ,Epistaxis ,Otorhinolaryngology ,Dysplasia ,Telangiectasia, Hereditary Hemorrhagic ,medicine.symptom ,business - Abstract
SummaryHereditary Hemorrhagic Telangiectasia or Rendu-Osler-Weber Disease is a rare fibrovascular dysplasia that makes vascular walls vulnerable to trauma and rupture, causing skin and mucosa bleeding. It is of dominant autosomal inheritance, characterized by recurrent epistaxis and telangiectasia on the face, hands and oral cavity; visceral arteriovenous malformations and positive family history. Epistaxis is often the first and foremost manifestation. It's associated to arteriovenous malformations in several organs. There are possible hematologic, neurologic, pulmonary, dermatologic and gastrointestinal complications. Treatment is supportive and helps prevent complications. This study is a case report of a patient with this syndrome who came to the ENT Outpatient Ward of the Faculdade de Medicina de Marília; and we have done a bibliographic review of the disease's etiopathogenesis, clinical manifestations and clinical-surgical treatment options.
- Published
- 2008
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32. Hemostatic Therapy for the Treatment of Intracranial Hemorrhage
- Author
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Xi Liu-DeRyke and Denise H. Rhoney
- Subjects
medicine.medical_specialty ,Subarachnoid hemorrhage ,Traumatic brain injury ,Factor VIIa ,Hemostatics ,Hematoma ,Antifibrinolytic agent ,medicine ,Humans ,Pharmacology (medical) ,Aminocaproates ,Intracerebral hemorrhage ,Clinical Trials as Topic ,business.industry ,medicine.disease ,Antifibrinolytic Agents ,Recombinant Proteins ,Surgery ,Tranexamic Acid ,Brain Injuries ,Hemostasis ,Anesthesia ,Aminocaproic acid ,business ,Intracranial Hemorrhages ,Tranexamic acid ,medicine.drug - Abstract
Intracranial hemorrhage results in poor neurologic outcomes and high mortality. Current management is limited to supportive care. In addition to the initial bleeding event, rebleeding and hematoma expansion have been identified as major risk factors for poor outcomes in these patients. The antifibrinolytic agents tranexamic acid, aminocaproic acid, and recombinant activated factor VII (rFVIIa) have been studied with the hopes of achieving early hemostasis and improving outcomes. Available data suggest that tranexamic acid and aminocaproic acid are more harmful than beneficial for this indication; therefore, they have no role in the treatment of intracranial bleeding. Alternatively, rFVIIa, has shown promising results in the management of spontaneous intracerebral hemorrhage. Clinicians should be aware of the available evidence regarding the use of these hemostatic agents in the management of intracranial hemorrhage, including traumatic brain injury, intracerebral hemorrhage, and subarachnoid hemorrhage.
- Published
- 2008
33. Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death
- Author
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Joan Landon, Alexander M. Walker, John D. Seeger, and Sebastian Schneeweiss
- Subjects
Adult ,Male ,Risk ,medicine.medical_specialty ,Antifibrinolytic ,medicine.drug_class ,medicine.medical_treatment ,Blood Loss, Surgical ,Coronary Disease ,Aprotinin ,Postoperative Complications ,medicine ,Humans ,Hospital Mortality ,Coronary Artery Bypass ,Risk factor ,Dialysis ,Aged ,Retrospective Studies ,Aminocaproates ,business.industry ,Absolute risk reduction ,Retrospective cohort study ,General Medicine ,Middle Aged ,Antifibrinolytic Agents ,Surgery ,Logistic Models ,Treatment Outcome ,Relative risk ,Multivariate Analysis ,Female ,Aminocaproic acid ,business ,medicine.drug - Abstract
BACKGROUND Aprotinin (Trasylol) is used to mitigate bleeding during coronary-artery bypass grafting (CABG). Accumulating evidence suggests that this practice increases mortality. METHODS Using electronic administrative records of the Premier Perspective Comparative Database, we studied hospitalized patients with operating-room charges for the use of aprotinin (33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. We tabulated the numbers of patients with a hospital-discharge status of death and performed three types of analyses: a multivariable logistic-regression analysis (primary analysis); propensity-score matching in the highly selected subcohort of patients who received full amounts of the study drug, who underwent CABG by surgeons who performed 50 or more CABG surgeries during the study period, and for whom information on 10 additional covariates was available because the surgery occurred on hospital day 3 or later; and an instrumental-variable analysis of data from patients whose surgeons showed a strong preference for one of the two study drugs. RESULTS In all, 1512 of the 33,517 aprotinin recipients (4.5%) and 1101 of the 44,682 aminocaproic acid recipients (2.5%) died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95% confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score-matched analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid. CONCLUSIONS Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference, which persisted through several approaches to control confounding.
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- 2008
34. The split abdominal wall muscle flap repair for large congenital diaphragmatic hernias on extracorporeal membrane oxygenation
- Author
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Peter F. Nichol, Peter B. Brant-Zawadzki, Stephen J. Fenton, Michael E. Matlak, and Eric R. Scaife
- Subjects
Male ,Reoperation ,medicine.medical_specialty ,medicine.medical_treatment ,Diaphragmatic breathing ,Platelet Transfusion ,Postoperative Hemorrhage ,Surgical Flaps ,Abdominal wall ,Plasma ,Extracorporeal Membrane Oxygenation ,Postoperative Complications ,Recurrence ,Extracorporeal membrane oxygenation ,medicine ,Humans ,Diaphragmatic hernia ,Hernia ,Retrospective Studies ,Aminocaproates ,Hernia, Diaphragmatic ,Surgical repair ,Factor VIII ,business.industry ,Abdominal Wall ,Infant, Newborn ,Anticoagulants ,Fibrinogen ,Congenital diaphragmatic hernia ,General Medicine ,Surgical Mesh ,medicine.disease ,Surgery ,surgical procedures, operative ,medicine.anatomical_structure ,Surgical mesh ,Hematocrit ,Pediatrics, Perinatology and Child Health ,Female ,Erythrocyte Transfusion ,Hernias, Diaphragmatic, Congenital ,business - Abstract
Background: Numerous techniques exist for repairing large congenital diaphragmatic hernias (CDHs) including prosthetic patches, tissue-engineered grafts, and various muscle flaps. A split abdominal wall muscle flap is a simple, durable way to repair a large diaphragmatic hernia. This technique has not gained widespread use, and some have suggested that it would be inappropriate in the setting of extracorporeal membrane oxygenation (ECMO) because of bleeding risk. We present our series of diaphragmatic hernias with a focus on those repaired with the split abdominal wall technique while on ECMO. Methods: A retrospective, single-institution chart review was performed on all patients who underwent surgical repair for CDH over 6 years beginning in August 2000. Results: Seventy-five patients underwent repair. Sixteen were performed with patients on ECMO. Of these, 4 were closed primarily, 7 used a prosthetic patch, and 5 used a split abdominal wall muscle flap. Two patients in the prosthetic group developed a recurrent hernia, and 2 required reoperation for bleeding while on ECMO. No reoperations for bleeding were required in the abdominal muscle flap group. Conclusions: The split abdominal wall muscle flap can be safely performed on anticoagulated patients. We believe it is a practical option for repairing large CDHs.
- Published
- 2007
35. Perioperative management of a patient with Bernard-Soulier syndrome for third molar surgery
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Michael J. Hartman, John F. Caccamese, and Stewart A. Bergman
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Male ,medicine.medical_specialty ,Adolescent ,Platelet disorder ,Blood Loss, Surgical ,Platelet Transfusion ,Hemostatics ,Bernard–Soulier syndrome ,Prolonged bleeding time ,medicine ,Humans ,General Dentistry ,Aminocaproates ,business.industry ,Bernard-Soulier Syndrome ,Perioperative ,medicine.disease ,Oral Hemorrhage ,Surgery ,Platelet transfusion ,Otorhinolaryngology ,Coagulation ,Dental Care for Chronically Ill ,Hemostasis ,Anesthesia ,Tooth Extraction ,Molar, Third ,Oral Surgery ,Aminocaproic acid ,business ,medicine.drug - Abstract
Bernard-Soulier Syndrome (BSS) is a disease characterized by prolonged bleeding time, thrombocytopenia, and extremely large platelets and has a prevalence of less than 1 in 1,000,000. Patients with disorders of coagulation and bleeding can be among the most difficult surgical patients to manage. Perioperative hemorrhage can contribute to life-threatening complications in even the most routine surgical procedures. Because of the rarity of BSS, there are no well-defined protocols for the management of perioperative bleeding associated with this condition. Treatment with preoperative and intraoperative systemic aminocaproic acid, HLA-matched platelets, and topical gelfoam and thrombin resulted in sustained hemostasis and a durable healing response. For those rare few afflicted with this disease, we present a combined systemic and topical approach that may be helpful in the control and prevention of perioperative hemorrhage in this and other similar platelet disorders.
- Published
- 2007
36. The effects of arginase inhibitor on lung oxidative stress and inflammation caused by pneumoperitoneum in rats
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Sungwon Na, Jin Sun Cho, Young Jun Oh, and Ok Soo Kim
- Subjects
Boron Compounds ,Male ,medicine.medical_specialty ,Injections, Subcutaneous ,030204 cardiovascular system & hematology ,Lung injury ,medicine.disease_cause ,Endothelial NOS ,Nitric oxide ,Rats, Sprague-Dawley ,03 medical and health sciences ,Subcutaneous injection ,chemistry.chemical_compound ,0302 clinical medicine ,Pneumoperitoneum ,Malondialdehyde ,Internal medicine ,medicine ,Animals ,Enzyme Inhibitors ,Aminocaproates ,Inflammation ,Arginase ,business.industry ,Lung Injury ,medicine.disease ,Rats ,Disease Models, Animal ,Anesthesiology and Pain Medicine ,Endocrinology ,chemistry ,Oxidative stress ,030220 oncology & carcinogenesis ,Anesthesia ,Cytokines ,Erratum ,business ,Research Article - Abstract
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
- Published
- 2015
37. Matrix metalloproteinases modulate ameboid-like migration of neutrophils through inflamed interstitial tissue
- Author
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Fritz Krombach, Bernd Uhl, Markus Rehberg, Annekathrin Eckart, Marc Praetner, Steffen Massberg, Christoph A. Reichel, Alexander G. Khandoga, Konstantin Stark, Daniel Puhr-Westerheide, Meike Miller, Kirsten Lauber, Gabriele Zuchtriegel, and Max Lerchenberger
- Subjects
Male ,Leukocyte migration ,Proteases ,Immunology ,Motility ,Mice, Transgenic ,Matrix metalloproteinase ,Peritonitis ,Biochemistry ,Phagocytes, Granulocytes, and Myelopoiesis ,Mice ,Aprotinin ,Transcellular Cell Migration ,In vivo ,Animals ,Actin ,Aminocaproates ,Inflammation ,Neutrophil extravasation ,Chemistry ,Cell Biology ,Hematology ,610 Medical sciences ,Medicine ,Matrix Metalloproteinases ,Cell biology ,Mice, Inbred C57BL ,Chemotaxis, Leukocyte ,Immune System Diseases ,Neutrophil Infiltration ,Tranexamic Acid ,ddc: 610 ,Leukocyte Disorders ,Chemotaxis assay - Abstract
Introduction: Recruitment of leukocytes to the site of inflammation is a crucial step in the development of inflammatory processes. The single steps of the leukocyte recruitment process, described as rolling, firm adherence and transendothelial migration have been studied in detail in the past decades,[for full text, please go to the a.m. URL], 132. Kongress der Deutschen Gesellschaft für Chirurgie
- Published
- 2015
38. DISC ELECTROPHORESIS OF I131-LABELED PROTEIN HORMONE PREPARATIONS AND THEIR REACTION PRODUCTS WITH ANTIBODIES*
- Author
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M. Lawrence Heideman
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Electrophoresis ,Chemical Phenomena ,Insulin Antibodies ,medicine.medical_treatment ,Thyrotropin ,Insulin Antibody ,Antibodies ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,History and Philosophy of Science ,Disc electrophoresis ,Iodine Isotopes ,medicine ,Insulin ,Urea ,Aminocaproates ,Pharmacology ,biology ,Chemistry, Physical ,Immune Sera ,Research ,General Neuroscience ,Electrophoresis, Disc ,chemistry ,Biochemistry ,Aminocaproic Acid ,biology.protein ,Antibody ,Aminocaproic acid ,medicine.drug ,Hormone - Published
- 2006
39. FIBRINOLYTIC BLEEDING AND ITS MANAGEMENT*
- Author
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Anthony P. Fletcher, Sol Sherry, and Norma Alkjaersig
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Liver Cirrhosis ,medicine.medical_specialty ,medicine.medical_treatment ,Hemorrhagic Disorders ,Fibrinogen ,Niacin ,Gastroenterology ,General Biochemistry, Genetics and Molecular Biology ,History and Philosophy of Science ,Internal medicine ,Fibrinolysis ,medicine ,Humans ,Blood coagulation test ,Aminocaproates ,business.industry ,Hemorrhagic diathesis ,General Neuroscience ,Nicotinic Acids ,Aminocaproic Acid ,Blood Coagulation Tests ,Aminocaproic acid ,business ,medicine.drug - Published
- 2006
40. Diffuse Alveolar Hemorrhage: Retrospective Review of Clinical Outcome in Allogeneic Transplant Recipients Treated With Aminocaproic Acid
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Rodney J. Folz, Nelson J. Chao, Gloria Broadwater, and Sam O. Wanko
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Adult ,Lung Diseases ,Male ,medicine.medical_specialty ,Time Factors ,Allogeneic transplantation ,medicine.medical_treatment ,Anti-Inflammatory Agents ,Hemorrhage ,Hematopoietic stem cell transplantation ,Neoplasms ,medicine ,Corticosteroids ,Humans ,Methylprednisolone Hemisuccinate ,Retrospective Studies ,Cause of death ,Aminocaproates ,Transplantation ,Aminocaproic acid ,Diffuse alveolar hemorrhage ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Surgery ,Respiratory failure ,Concomitant ,Allogeneic hematopoietic stem cell transplantation ,Female ,Respiratory Insufficiency ,business ,medicine.drug - Abstract
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.
- Published
- 2006
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41. The Kaolin-Activated Thrombelastograph® Predicts Bleeding After Cardiac Surgery
- Author
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Anthony M. Roche, Thomas L. Ortel, Kuiran Jiao, Tong J. Gan, Charles S. Brudney, Ian J. Welsby, and Elliott Bennett-Guerrero
- Subjects
Male ,medicine.medical_specialty ,Point-of-Care Systems ,Postoperative Hemorrhage ,law.invention ,law ,medicine ,Coagulopathy ,Coagulation testing ,Humans ,Cardiac Surgical Procedures ,Kaolin ,Aged ,Aminocaproates ,Prothrombin time ,Cardiopulmonary Bypass ,medicine.diagnostic_test ,Platelet Count ,business.industry ,Fibrinogen ,medicine.disease ,Intensive care unit ,Thoracostomy ,Antifibrinolytic Agents ,Thromboelastography ,Thrombelastography ,Surgery ,Cardiac surgery ,Anesthesiology and Pain Medicine ,Heparin Lyase ,Anesthesia ,Prothrombin Time ,Female ,Partial Thromboplastin Time ,Cardiology and Cardiovascular Medicine ,business ,Partial thromboplastin time - Abstract
Objective: The objective of this study was to determine the relationship of the kaolin-activated Thrombelastograph® (TEG) with postoperative bleeding and laboratory tests of coagulation in the setting of cardiac surgery with the routine use of ϵ-aminocaproic acid. Design: Prospective observational study. Setting: An adult heart center at a tertiary referral, university hospital. Participants: Thirty adult cardiac surgical patients. Interventions: The kaolin-activated TEG, platelet counts, prothrombin times, activated partial thromboplastin times, and fibrinogen levels were measured before induction of anesthesia, during cardiopulmonary bypass, and on arrival in the intensive care unit. Mediastinal and thoracostomy drainage were measured every hour for 4 hours after arrival in the intensive care unit. Measurements and Main Results: Correlation and multivariate linear regression modeling were used to describe relationships among coagulation tests, TEG parameters, and early postoperative bleeding. The TEG maximum amplitude (MA) parameter correlated well with postoperative bleeding (r = −0.6, p = 0.0018), more so than platelet count (r = −0.45, p = 0.02), fibrinogen level (r = −0.40, p = 0.06), or prothrombin time (r = 0.43, p = 0.02). The receiver operating characteristic curve c-index describing MA as a predictor for postoperative bleeding is 0.78. Abnormalities in all the laboratory test results were associated with an abnormal MA. Conclusions: In conclusion, the kaolin-activated TEG is associated with early coagulopathic bleeding. It may reflect the severity of a global coagulopathy affecting both platelets and coagulation factors and be a guide to incremental prohemostatic therapy in this setting.
- Published
- 2006
42. The Potential of P1 Site Alterations in Peptidomimetic Protease Inhibitors as Suggested by Virtual Screening and Explored by the Use of CC-Coupling Reagents
- Author
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Jark Böttcher, Hans-Gerhard Löffler, Andrej Hasilik, Gerhard Klebe, Torsten Luksch, Christoph A. Sotriffer, Jörg Rademann, Steffen Weik, and Andreas Evers
- Subjects
Models, Molecular ,Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,Isostere ,Peptidomimetic ,Stereochemistry ,medicine.medical_treatment ,Protozoan Proteins ,Cathepsin D ,Biochemistry ,Solid-phase synthesis ,Plasmepsin II ,HIV Protease ,Drug Discovery ,medicine ,Aspartic Acid Endopeptidases ,Humans ,Protease Inhibitors ,General Pharmacology, Toxicology and Pharmaceutics ,Racemization ,Aminocaproates ,Pharmacology ,Protease ,Chemistry ,Molecular Mimicry ,Organic Chemistry ,Stereoisomerism ,Combinatorial chemistry ,Molecular Medicine ,Indicators and Reagents ,Linker - Abstract
A synthetic concept is presented that allows the construction of peptide isostere libraries through polymer-supported C-acylation reactions. A phosphorane linker reagent is used as a carbanion equivalent; by employing MSNT as a coupling reagent, the C-acylation can be conducted without racemization. Diastereoselective reduction was effected with L-selectride. The reagent linker allows the preparation of a norstatine library with full variation of the isosteric positions including the P1 side chain that addresses the protease S1 pocket. Therefore, the concept was employed to investigate the P1 site specificity of peptide isostere inhibitors systematically. The S1 pocket of several aspartic proteases including plasmepsin II and cathepsin D was modeled and docked with approximately 500 amino acid side chains. Inspired by this virtual screen, a P1 site mutation library was designed, synthesized, and screened against three aspartic proteases (plasmepsin II, HIV protease, and cathepsin D). The potency of norstatine inhibitors was found to depend strongly on the P1 substituent. Large, hydrophobic residues such as biphenyl, 4-bromophenyl, and 4-nitrophenyl enhanced the inhibitory activity (IC50) by up to 70-fold against plasmepsin II. In addition, P1 variation introduced significant selectivity, as up to 9-fold greater activity was found against plasmepsin II relative to human cathepsin D. The active P1 site residues did not fit into the crystal structure; however, molecular dynamics simulation suggested a possible alternative binding mode.
- Published
- 2006
43. Heparin-Bonded Cardiopulmonary Bypass Circuits Reduce the Rate of Red Blood Cell Transfusion During Elective Coronary Artery Bypass Surgery
- Author
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Jose L. Cruzzavala, Jonathan D. Mahnken, Robert A. Vance, and Kenneth R. Kreisler
- Subjects
Male ,medicine.medical_specialty ,Red Blood Cell Transfusion ,Coronary Disease ,Hematocrit ,Placebo ,law.invention ,Coronary artery bypass surgery ,Double-Blind Method ,law ,Cardiopulmonary bypass ,Humans ,Medicine ,Prospective Studies ,Coronary Artery Bypass ,Aged ,Aminocaproates ,Cardiopulmonary Bypass ,medicine.diagnostic_test ,Heparin ,business.industry ,Anticoagulants ,Middle Aged ,Combined Modality Therapy ,Surgery ,Treatment Outcome ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Anesthesia ,Female ,Open label ,Erythrocyte Transfusion ,Cardiology and Cardiovascular Medicine ,business ,Artery ,medicine.drug - Abstract
This study compared the transfusion rates of patients treated with heparin-bonded circuits with the transfusion rates of patients treated with standard bypass circuits with and without -aminocaproic acid (EACA).Prospective double-blind (drugs), open trial (cardiopulmonary bypass circuits).University medical center.Seventy-one patients undergoing elective am admission coronary artery bypass graft surgery.Patients were randomized to receive either heparin-coated cardiopulmonary bypass circuits (HBCPB), nonheparin-coated cardiopulmonary bypass circuits and EACA (EACPB), or nonheparin-coated bypass circuits and placebo (control). Patients were transfused if their hematocrit was18% while on cardiopulmonary bypass or25% at any time after the cardiopulmonary bypass period. The rate and number of transfused packed red blood cells (pRBCs), platelets, fresh frozen plasma, and cryoprecipitate were measured. A Fisher exact test showed that the transfusion rate was as follows: the HBCPB group (5.0%), the EACPB group (18.2%), and the control group (36%), (p = 0.034).The heparin-bonded cardiopulmonary bypass-treated patients in this study received fewer pRBCs than did the control group. A nonsignificant reduction in the pRBC transfusion rate was found between those with heparin-bonded bypass circuits and those with standard circuits who received epsilon-aminocaproic acid.
- Published
- 2005
44. Isolation of a New Antibiotic, Alaremycin, Structurally Related to 5-Aminolevulinic Acid fromStreptomycessp. A012304
- Author
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Yuuki Awa, Kazuo Nagai, Masaaki Wachi, Junichi Yamagishi, Noritaka Iwai, Tomohiko Ueda, Shoji Asano, and Kenji Suzuki
- Subjects
Chemical structure ,Microbial Sensitivity Tests ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Biochemistry ,Streptomyces ,Analytical Chemistry ,chemistry.chemical_compound ,Biosynthesis ,medicine ,Molecular Biology ,Escherichia coli ,Aminocaproates ,biology ,Streptomycetaceae ,Organic Chemistry ,Aminolevulinic Acid ,General Medicine ,biology.organism_classification ,Anti-Bacterial Agents ,chemistry ,Actinomycetales ,Antibacterial activity ,Bacteria ,Biotechnology - Abstract
A new antibiotic, which is structurally related to 5-aminolevulinic acid, a precursor of heme biosynthesis, and named alaremycin, was isolated from the culture broth of an actinomycete strain through a random screening with the blue assay to detect the formation of anucleate cells in Escherichia coli. The producing strain was identified as Streptomyces sp. by morphological, physiological, chemical and genetic criteria. Alaremycin was purified from the culture supernatant by HP-20 hydrophobic-interaction chromatography, sequential solvent/water extraction in the acidic or alkaline pH range, and QMA cation-exchange chromatography. The chemical structure of alaremycin was determined as 5-acetamido-4-oxo-5-hexenoic acid by analyses of mass and NMR spectra. The antibacterial activity of alaremycin was enhanced in the presence of 5-aminolevulinic acid.
- Published
- 2005
45. Chylothorax after heart/lung transplantation
- Author
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Daniel Y. Sze, John L. Faul, Tomasz M. Ziedalski, Robert C. Robbins, John D. Mitchell, James Theodore, and Thomas A. Raffin
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Heart-Lung Transplantation ,medicine.medical_treatment ,Octreotide ,Chylothorax ,Postoperative Complications ,medicine ,Humans ,Aminocaproates ,Transplantation ,Lung ,business.industry ,Decision Trees ,Middle Aged ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Aminocaproic acid ,Cardiology and Cardiovascular Medicine ,Complication ,business ,Pleurodesis ,medicine.drug - Abstract
Chylothorax is a potentially serious complication of lung and heart–lung transplantation. This article describes the clinical course of chylothorax in 3 heart–lung allograft recipients. We discuss management options, including dietary modifications, octreotide infusion, thoracic duct ligation and emobolization, and surgical pleurodesis. In addition, we describe the novel use of aminocaproic acid to reduce lymph flow. We propose a multidisciplinary approach for the management of chylothorax that includes both medical and surgical options.
- Published
- 2004
46. Arginase and autoimmune inflammation in the central nervous system
- Author
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Brendan Hilliard, Youhai H. Chen, Hyunshun Shin, David W. Christianson, Ruaidhrí J. Carmody, Galit Tsabary, and Lingyun Xu
- Subjects
Boron Compounds ,Encephalomyelitis, Autoimmune, Experimental ,Necrosis ,Immunology ,Central nervous system ,Spleen ,Biology ,Nitric Oxide ,Nitric oxide ,Mice ,chemistry.chemical_compound ,medicine ,Animals ,Immunology and Allergy ,RNA, Messenger ,Enzyme Inhibitors ,Cells, Cultured ,Aminocaproates ,Arginase ,Microglia ,Experimental autoimmune encephalomyelitis ,Original Articles ,Blotting, Northern ,medicine.disease ,Up-Regulation ,Mice, Inbred C57BL ,Nitric oxide synthase ,medicine.anatomical_structure ,Spinal Cord ,chemistry ,biology.protein ,Cytokines ,medicine.symptom - Abstract
Using a high throughput gene microarray technology that detects approximately 22 000 genes, we found that arginase I was the most significantly up-regulated gene in the murine spinal cord during experimental autoimmune encephalomyelitis (EAE). By Northern blot and arginase enzyme assay, we detected high levels of arginase I mRNA and protein, respectively, in the spinal cord of EAE mice, but not in the spinal cord of normal mice or mice that had recovered from EAE. In vitro, both microglia and astrocytes produced arginase and nitric oxide synthase, two enzymes that are involved in arginine metabolism. To explore the roles of arginase in EAE, we injected the arginase inhibitor amino-6-boronohexanoic acid (ABH) into mice during the inductive and effector phases of the disease. Compared with mice that received vehicle control, mice treated with ABH developed milder EAE with delayed onset, reduced disease score and expedited recovery. Spleen mononuclear cells from ABH-treated mice produced more nitric oxide and secreted less interferon-gamma and tumour necrosis factor-alpha as compared to control mice. These results indicate that arginase plays important roles in autoimmune inflammation in the central nervous system.
- Published
- 2003
47. Miniaturizable homogenous time-resolved fluorescence assay for carboxypeptidase B activity
- Author
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Berta Strulovici, Shi-Shan Mao, Marc Ferrer, Carolyn Bailey, Richard Peltier, Stephen J. Gardell, Paul Zuck, Garrett D. Kolodin, and James Inglese
- Subjects
Streptavidin ,Swine ,medicine.drug_class ,Biophysics ,Biotin ,Fluorescent Antibody Technique ,Monoclonal antibody ,Sensitivity and Specificity ,Biochemistry ,chemistry.chemical_compound ,Europium ,Fluorescence Resonance Energy Transfer ,medicine ,Animals ,Enzyme Inhibitors ,Molecular Biology ,Aminocaproates ,chemistry.chemical_classification ,Miniaturization ,Allophycocyanin ,Chemistry ,C-terminus ,Phycocyanin ,Antibodies, Monoclonal ,Substrate (chemistry) ,Cell Biology ,Molecular biology ,Fluorescence ,Carboxypeptidase B ,Enzyme ,Förster resonance energy transfer ,Oligopeptides - Abstract
An epitope-unmasking, homogeneous time-resolved fluorescence (HTRF) assay has been developed for measuring carboxypeptidase B (CPB) activity in a miniaturized high-throughput screening format. The enzyme substrate (biotin-RYRGLMVGGVVR- oh ) is cleaved by CPB at the C terminus, causing release of the C-terminal Arg residue. The product (biotin-RYRGLMVGGVV- oh ) is recognized specifically by a monoclonal antibody (G2-10) which is labeled with Eu3+-cryptate ([Eu3+]G2-10 mAb), and the complex is detected by fluorescence resonance energy transfer using streptavidin labeled with allophycocyanin ([XL665]SA). The CPB HTRF assay is readily adapted from 96- to 1536-well format as a robust (Z′>0.5) assay for high-throughput screening.
- Published
- 2003
48. Receptor-Independent 4D-QSAR Analysis of a Set of Norstatine Derived Inhibitors of HIV-1 Protease
- Author
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Craig L. Senese and Anton J. Hopfinger
- Subjects
Models, Molecular ,Quantitative structure–activity relationship ,Stereochemistry ,medicine.medical_treatment ,Molecular Conformation ,Quantitative Structure-Activity Relationship ,Sensitivity and Specificity ,Set (abstract data type) ,Inhibitory Concentration 50 ,HIV Protease ,HIV-1 protease ,medicine ,Humans ,Binding site ,Receptor ,IC50 ,Aminocaproates ,Binding Sites ,Protease ,biology ,Chemistry ,Hydrogen Bonding ,HIV Protease Inhibitors ,General Chemistry ,Phenylbutyrates ,Computer Science Applications ,Computational Theory and Mathematics ,Test set ,biology.protein ,Hydrophobic and Hydrophilic Interactions ,Information Systems - Abstract
A training set of 27 norstatine derived inhibitors of HIV-1 protease, based on the 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acid core (AHPBA), for which the -log IC(50) values were measured, was used to construct 4D-QSAR models. Five unique RI-4D-QSAR models, from two different alignments, were identified (q(2) = 0.86-0.95). These five models were used to map the atom type morphology of the lining of the inhibitor binding site at the HIV protease receptor site as well as predict the inhibition potencies of seven test set compounds for model validation. The five models, overall, predict the -log IC(50) activity values for the test set compounds in a manner consistent with their q(2) values. The models also correctly identify the hydrophobic nature of the HIV protease receptor site, and inferences are made as to further structural modifications to improve the potency of the AHPBA inhibitors of HIV protease. The finding of five unique, and nearly statistically equivalent, RI-4D-QSAR models for the training set demonstrates that there can be more than one way to fit structure-activity data even within a given QSAR methodology. This set of unique, equally good individual models is referred to as the manifold model.
- Published
- 2003
49. Arginase expression and modulation of IL-1β-induced nitric oxide generation in rat and human islets of Langerhans
- Author
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James M Cunningham, J.-L. Boucher, S.K. Mistry, P. Stickings, and S.M. Morris
- Subjects
Boron Compounds ,endocrine system ,Cancer Research ,medicine.medical_specialty ,Arginine ,Physiology ,Blotting, Western ,Clinical Biochemistry ,Down-Regulation ,Nitric Oxide Synthase Type II ,Nitric Oxide ,Biochemistry ,Nitric oxide ,Islets of Langerhans ,chemistry.chemical_compound ,Downregulation and upregulation ,Internal medicine ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Aminocaproates ,Arginase ,biology ,Ornithine ,Blotting, Northern ,medicine.disease ,Rats ,Isoenzymes ,Nitric oxide synthase ,Endocrinology ,chemistry ,biology.protein ,Insulinoma ,Nitric Oxide Synthase ,Beta cell ,Insulitis ,Interleukin-1 - Abstract
Proinflammatory cytokine induction of NO synthesis may contribute to the destruction of pancreatic beta cells leading to type 1 diabetes. The NO synthase substrate arginine can also be metabolized to ornithine and urea in a reaction catalyzed by cytosolic (AI) or mitochondrial (AII) isoforms of arginase. Recent evidence suggests that the rate of NO generation is dependent on the relative activities of NO synthase and arginase. The objectives of this study were (i). to identify the arginase isoforms expressed in rat and human islets of Langerhans and a rat beta cell line, RINm5F and (ii). to investigate the competition for arginine between NO synthase and arginase in IL-1beta-treated rat islets. Arginase activity was detected in rat islets (fresh tissue, 346 mU/mg protein; cultured, 587 mU/mg), cultured human islets (56 mU/mg), RINm5F cells (376 mU/mg), rat kidney (238 mU/mg), and rat liver (6119 mU/mg). Using Western blots, AI was shown to be the predominant isoform expressed in rat islets and in RINm5F cells while human islets expressed far more AII than AI. Rat islets were cultured in medium containing 1.14, 0.1, and 0.01 mM arginine and treated with IL-1beta and the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH). IL-1beta-induced NO generation was unaffected by ABH at 1.14 mM arginine, but significantly increased at 0.1 and 0.01 mM arginine. These findings suggest that the level of islet arginase activity can regulate the rate of induced NO generation and this may be relevant to the insulitis process leading to beta cell destruction in type 1 diabetes.
- Published
- 2002
50. Predictors of pericardial effusion after orthotopic heart transplantation
- Author
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Michael E. Jessen, Donald D. McIntire, Patricia A. Kaiser, Jacquelyn A. Quin, W. Steves Ring, M.Peter Tauriainen, and Lynne M. Huber
- Subjects
Graft Rejection ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Heart disease ,medicine.medical_treatment ,Population ,Pericardial effusion ,Pericardial Effusion ,Postoperative Complications ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,medicine ,Humans ,Pericardium ,education ,Retrospective Studies ,Aminocaproates ,Heart transplantation ,education.field_of_study ,business.industry ,Incidence ,Length of Stay ,Middle Aged ,medicine.disease ,Survival Analysis ,Texas ,Antifibrinolytic Agents ,Surgery ,Cardiac surgery ,Transplantation ,Treatment Outcome ,medicine.anatomical_structure ,Effusion ,Multivariate Analysis ,Cardiology ,Heart Transplantation ,Female ,business ,Cardiology and Cardiovascular Medicine - Abstract
Objectives: Pericardial effusion occurs frequently after orthotopic heart transplantation, but the causes of this complication have not been well described. This study was designed to identify factors predisposing toward the development of significant postoperative pericardial effusions in a large, single-institution population of orthotopic heart transplant recipients. Methods: A retrospective review of more than 90 preoperative, intraoperative, and postoperative variables was conducted for 241 patients undergoing orthotopic heart transplantation from September 1988 to December 1999. Patients who had significant postoperative pericardial effusions develop were identified from postoperative echocardiograms by standard criteria. Factors associated with the development of significant pericardial effusions were determined by multivariate logistic regression analysis. Results: Echocardiographic data were available for 203 of 241 transplant recipients. Forty-two patients (21%) had significant effusions develop. According to multivariate analysis, pericardial effusions were less likely to occur in recipients with a history of previous cardiac surgery (odds ratio 0.13, 95% confidence interval 0.05-0.36, P
- Published
- 2002
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