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At least 937 records · Page 52Linked to original sources
PubMed1993

CGS-19755 is neuroprotective during repetitive ischemia: this effect is significantly enhanced when combined with hypothermia.

In small animals the damaging effects of repetitive ischemia are more severe than a single insult of similar duration. Prolonged release of glutamate may correlate with the degree of damage. We report the protective effects of CGS-19755 (an N-methyl-D-aspartate receptor blocker), hypothermia or CGS-19755 in combination with mild hypothermia, in a gerbil model of repetitive ischemia. We used 3 min of forebrain ischemia and repeated it for a total of three times as 1-h intervals. Damage was assessed seven days after the insult. In the group where only CGS-19755 was used, significant neuronal protection was evident in the hippocampus (CA1 and CA3), striatum, and medial geniculate nucleus. With hypothermia significantly less damage was seen in the cerebral cortex, hippocampus (CA1 and CA4), and substantia nigra reticulata. When CGS-19755 was combined with mild hypothermia the effects of repetitive ischemia were completely abolished in all but one gerbil. Compared to hypothermia alone, significant protection was seen in the cerebral cortex, hippocampus (sibiculum, CA1 and CA4), striatum, medial geniculate nucleus, thalamus, and substantia nigra reticulata. The use of N-methyl-D-aspartate receptor blockers may protect the brain in repetitive ischemia. Combination with hypothermia may further enhance this protection.

Animals↗
PubMed1993

Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris.

OBJECTIVES: In a Phase I clinical trial, we studied the antithrombotic and clinical effects of the synthetic competitive thrombin inhibitor, argatroban, in 43 patients with unstable angina pectoris. BACKGROUND: Thrombin has a pivotal role in platelet-mediated thrombosis associated with atheromatous plaque rupture in patients with an acute ischemic coronary syndrome. However, the efficacy of conventional heparin therapy to prevent ischemic events is limited and has been surpassed by that of specific thrombin inhibitors in experimental models of arterial thrombosis. METHODS: Intravenous infusion of the drug (0.5 to 5.0 micrograms/kg per min) for 4 h was monitored by sequential measurements of coagulation times and of indexes of thrombin activity in vivo followed by a 24-h clinical observation period. RESULTS: Significant dose-related increases in plasma drug concentrations and activated partial thromboplastin times (aPTT), but no bleeding time prolongation or spontaneous bleeding, was observed. Myocardial ischemia did not occur during therapy but, surprisingly, 9 of the 43 patients experienced an episode of unstable angina 5.8 +/- 2.6 h (mean +/- SD) after infusion. This early recurrent angina was correlated significantly with a higher argatroban dose and with greater prolongation of aPTT but not with other demographic, clinical, laboratory and angiographic characteristics. Pretreatment plasma concentrations of thrombin-antithrombin III complex and fibrinopeptide A were elevated two to three times above normal values. During infusion, thrombin-antithrombin III complex levels remained unchanged, whereas a significant 2.3-fold decrease in fibrinopeptide A concentrations was observed. By contrast, 2 h after infusion, thrombin-antithrombin III complex concentrations increased 3.9-fold over baseline measurements together with return of fibrinopeptide A levels to values before treatment with argatroban. CONCLUSIONS: In patients with unstable angina, argatroban inhibits clotting (aPTT prolongation) and thrombin activity toward fibrinogen (fibrinopeptide A decrease), but in vivo thrombin (thrombin-antithrombin III complex) formation is not suppressed. However, cessation of infusion is associated with rebound thrombin (thrombin-antithrombin III complex) generation and with an early dose-related recurrence of unstable angina. Although the mechanism of this clinical and biochemical rebound phenomenon remains to be determined, its implication for the clinical use of specific thrombin inhibitors in the management of ischemic coronary syndromes may be significant.

Aged↗
PubMed1991

Phenotypic heterogeneity in cultured skin fibroblasts from patients with disorders of peroxisome biogenesis belonging to the same complementation group.

We have studied fibroblast cell lines derived from a control subject (cell line 85AD5035F) and three patients clinically described as having the Zellweger syndrome (cell line W78/515), the infantile form of Refsum disease (cell line BOV84AD) and hyperpipecolic acidaemia (cell line GM3605), respectively. The mutant cell lines belonged to the same complementation group. The fibroblasts were cultured under identical conditions and were harvested at different time intervals after reaching confluence. Several peroxisomal parameters were determined. In agreement with previous reports, a lowered enzymic activity of acyl-CoA: dihydroxyacetonephosphate acyltransferase and a decrease in latent catalase clearly distinguished the patient cell lines from the control cell line. However, the cell lines exhibited a phenotypic heterogeneity. This was most strikingly encountered when cells were processed for indirect immunofluorescence microscopy and stained with anti-(catalase). The control cells exhibited a punctate fluorescence, which is indicative of the presence of catalase in peroxisomes. In the mutant cell line W78/515 a diffuse fluorescence was observed, indicative of the presence of catalase in the cytosol. In the other two mutant cell lines a punctate fluorescence was observed in some of the cells. Moreover, clear differences in the extent of proteolytic processing of acyl-CoA oxidase were detected. The mutant cell line BOV84AD displayed a control-like pattern with all molecular forms of acyl-CoA oxidase (72, 52 and 20 kDa) present, whereas in the W78/515 cell line only the 72 kDa component could be visualised. The GM3605 cell line was intermediate in this respect.

Acetyl-CoA C-Acetyltransferase↗
PubMed2003

Direct thrombin inhibitors for non-ST-segment elevation acute coronary syndromes: what, when, and where?

BACKGROUND: Unfractionated heparin has been the cornerstone of antithrombin therapy in the treatment of non-ST-segment elevation acute coronary syndromes for more than a decade. Several new anticoagulants have emerged in recent years and have been studied extensively in patients with unstable coronary syndromes and in the percutaneous coronary intervention setting. METHODS: Direct thrombin inhibitors comprise a family of agents with promising properties that offer several potential advantages over unfractionated heparin. Hirudin has been studied in patients with ST-elevation myocardial infarction, non-ST-elevation coronary syndromes, and coronary angioplasty. Bivalirudin has been studied in patients undergoing percutaneous coronary revascularization, with very promising efficacy and safety profile compared with unfractionated heparin. RESULTS: The clinical trials of direct thrombin inhibitors in non-ST-elevation acute coronary syndromes and coronary angioplasty are reviewed.

Angioplasty, Balloon, Coronary↗
PubMed2006

Argatroban: update.

Unfractionated heparin has historically been used as the anticoagulant of choice in the management of a number of thrombotic diseases. Recognition of the limitations of heparin has led to the development of a newer class of anticoagulants, the direct thrombin inhibitors. Argatroban is a synthetic small molecule that selectively inhibits thrombin at its active site. In preclinical studies, argatroban has been shown to be more effective than heparin in preventing arterial thrombosis and in promoting vessel patency in conjunction with thrombolysis in a number of animal models. In clinical trials, argatroban has been shown to be as effective as heparin in the management of ST-segment elevation myocardial infarction in conjunction with thrombolysis. It has been shown to be an effective anticoagulant in patients undergoing percutaneous coronary interventions. In patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia complicated by thrombosis, argatroban significantly decreases the risk of thrombotic events. Small studies have demonstrated a potential role for its use in ischemic stroke and hemodialysis. Additional studies are warranted to confirm argatroban's efficacy in a wide variety of clinical settings.

Animals↗
PubMed2004

Influence of conduction disturbances on clinical outcome in patients with acute myocardial infarction receiving thrombolysis (results from the ARGAMI-2 study).

Right bundle branch block and complete atrioventricular (AV) block are conduction disorders (CDs) that have been observed in 14% of patients admitted with ST-elevation acute myocardial infarction. CDs carry a poor prognosis, with a threefold increase in the mortality rate, mainly due to cardiogenic shock and recurrent fatal myocardial infarction at 1-year follow-up. According to multivariable analysis, CD was the second strongest predictor of death, after high Killip class. Compared with patients without CD, the 1-year outcome of patients with CD was identically worse, irrespective of whether CD appeared during admission, disappeared, or remained constant. Similar adverse outcomes were seen in patients with complete AV block and right bundle branch block.

Arginine↗
PubMed2004

Failure of argatroban anticoagulation during off-pump coronary artery bypass surgery.

Heparin-induced antibodies create vexing problems during cardiac surgery. Although alternative medications have been used for intraoperative anticoagulation, the results have been sufficiently variable that no one medication is recommended. In our case, due to the poor reversibility of the antithrombin agents, argatroban was chosen as a heparin substitute due to its short half-life and its anticoagulation assessment using the activated clotting time (ACT). Unfortunately, our experience was that argatroban does not provide adequate anticoagulation during off-pump coronary bypass surgery, even when the ACT is maintained at more than 380 sec.

Aged↗
PubMed2005

Spontaneous atrioventricular groove disruption during off-pump coronary artery bypass grafting.

Atrioventricular groove tear or disruption is a disastrous and technically challenging complication after mitral valve replacement surgery. This report details the untimely spontaneous occurrence of an atrioventricular tear during manipulation of the heart for off-pump coronary artery bypass grafting and its successful repair. Significant distortion of the mitral annulus and elevation of pulmonary artery pressures in the beating heart likely contributed to the spontaneous tear.

Aged↗
PubMed2004

Severe argatroban-induced coagulopathy in a patient with a history of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia is a serious complication of heparin therapy, and it remains a therapeutic challenge in the subset of patients requiring cardiopulmonary bypass. Alternative anticoagulation strategies include lepirudin, danaparoid, bivalirudin, and argatroban, or a combination of unfractionated heparin with a platelet antagonist. Argatroban is eliminated by a hepatic route, making it a practical option for patients with renal insufficiency. However, the lack of an effective antidote poses a significant problem. We present a patient with a history of heparin-induced thrombocytopenia with thrombosis who underwent a redo aortic valve replacement. Although the level of anticoagulation achieved with argatroban was initially adequate, its persistence after the completion of cardiopulmonary bypass proved to be life threatening.

Aged↗
PubMed2006

Recognition and management of heparin-induced thrombocytopenia in pediatric cardiopulmonary bypass patients.

Repeated exposure to unfractionated heparin is the rule in many congenital heart disease patients. Heparin-induced thrombocytopenia occurs in 1% to 3% of adult cardiac surgeries, and carries high thrombotic morbidity (38% to 81%) and mortality (approximately 28%). Although heparin-induced thrombocytopenia appears to be infrequent in pediatric patients, particularly neonates, our evolving experience suggests postcardiopulmonary bypass congenital heart disease patients may be at increased risk. Diagnostic and therapeutic challenges include frequency of thrombocytopenia after cardiopulmonary bypass, imperfect laboratory testing, lack of established dosing of alternative anticoagulants (such as argatroban and lepirudin), and increased anticoagulant-related bleeding in young children.

Adolescent↗
PubMed2004

Small-molecule direct antithrombins: argatroban.

Argatroban represents the first antithrombin agent that was approved for clinical use. It belongs to the peptidomimetic (arginomimetic) group of drugs with multiple pharmacological properties. Unlike the other antithrombin drugs, such as hirudins and hirulogs, argatroban is a reversible antithrombin agent and therefore exhibits a considerably different pharmacological profile. Although argatroban is considered to be a member of the antithrombin family, its mechanisms of action include several other processes that have not been explored fully to date. These include the inhibition of non-thrombin serine proteases, a direct effect on endothelial cells and the vasculature (generation of nitric oxide), and downregulation of various inflammatory and thrombotic cytokines. Due to its lower molecular weight, argatroban is capable of passing through endovascular and cellular barriers and may, therefore, be more effective than heparins and hirudins in the antithrombotic management of microvascular disorders. Argatroban is an effective anticoagulant agent that produces a stronger anticoagulant effect than heparins and hirudins at equivalent anticoagulant levels, as measured by the activated clotting time (ACT) and activated partial thromboplastin time (APTT). At comparable ACT (300 seconds) and APTT (75-90 seconds), argatroban produces stronger inhibition of thrombin generation, as measured by in-vitro assays. Argatroban does not generate any neutralizing or non-neutralizing antibodies, and has predictable antithrombotic effects in different patients. In addition to the inhibition of thrombogenesis, argatroban also facilitates blood flow, inhibition of platelet activation and endothelial cell stimulation, mechanisms that are not necessarily related to thrombin inhibition. Despite these pharmacological advantages, additional clinical investigations are needed to validate the use of argatroban in clinical indications other than those for which it is currently approved, namely, heparin-induced thrombocytopenia and support of percutaneous coronary angioplasty.

Animals↗
PubMed2006

Flavonoids inhibit the amidolytic activity of human thrombin.

The effect of a group of natural flavonoids on human thrombin amidolytic activity was investigated using a spectrophotometric inhibition assay while information on the kinetics and thermodynamics was obtained using optical biosensor techniques. All the flavonoids tested acted as reversible inhibitors, and the quercetin-thrombin complex was found to be most stable at pH=7.5. Docking analysis indicated that quercetin's inhibitory behavior could be related to its planar structure and low steric hindrance, and to its ability to form a critical H-bond with thrombin His57.

Amidohydrolases↗