[Elimination of labor pains and extension of active medical assistance during delivery by parametric conduction anesthesia].
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Anesthesia, Conduction↗
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Competitive as well as uncompetitive N-methyl-D-aspartate receptor antagonists affect cortical neuronal morphology and cerebral glucose metabolism.
The studies examined the effects of three antagonists (CPP, CGS 19755, and CGP 37849) that act competitively at the glutamate recognition site of the NMDA receptor complex on cortical neuronal morphology and cerebral limbic glucose metabolism. Responses were compared to the effects of dizocilpine, an uncompetitive NMDA receptor ion channel antagonist as a positive control. CGS 19755 and CGP 37849 (100 mg kg-1 i.p.) caused vacuolation in cortical pyramidal neurons in the posterior cingulate cortex four hours after dosing and this dose of CGP 37849 caused a pattern of limbic glucose metabolism activation similar to that seen after dizocilpine. CPP was without effect at 100 mg/kg i.p. probably due to poor brain penetration. The data indicates that the functional consequences (structural and metabolic) of NMDA receptor blockade with NMDA antagonists acting competitively at the glutamate recognition site and uncompetitively in the receptor ion channel are ultimately the same. Comparisons of the potential therapeutic window for CGS 19755 and CGP 37849 with dizocilpine (neuroprotection versus vacuolation) suggests that the window for the competitive antagonists is greater. This indicates that the potential therapeutic window for the different classes of NMDA antagonists may vary with the site in the receptor complex at which they interact.
2-Amino-5-phosphonovalerate↗
Induction of thrombolysis and prevention of thrombus formation by local drug delivery with a double-occlusion balloon catheter.
The efficacy of the local delivery of an antithrombotic drug in preventing thrombosis and enabling thrombolysis was investigated in 29 dogs. An antithrombotic drug (heparin, 25 U/kg), or an antithrombin (argatroban, 0.05 mg/kg) was infused into injured canine iliac arteries, using a double-occlusion balloon catheter, and the preventive effect of the drug was evaluated. Local delivery of low-dose tissue-type plasminogen activator (t-PA; Tisokinase, 50,000 U; Kowa, Nagoya and Asahi Chemical Industries, Fuji, Japan) into thrombosed canine iliac arteries, using the same catheter, or intravenous infusion of low-dose or high-dose t-PA (30,000 U/kg) was also performed. Angiographically, stenotic thrombosis was 2% by local delivery of argatroban and 7% by local delivery of heparin (P < 0.01 vs each control; 47% and 51% respectively). Thrombotic stenosis, as observed by angiography, decreased from 91% to 9% after local delivery of t-PA, and from 94% to 52% in controls. Local delivery of t-PA effectively reduced the thrombus size (P < 0.01 vs control). After systemic intravenous delivery of low-dose t-PA, no reduction of residual thrombotic stenosis, was observed. Reduction of residual thrombotic stenosis after intravenous delivery of high-dose t-PA, was similar to that achieved by local delivery of the drug. Angioscopy demonstrated a similar trend. High-dose drug delivery reduced systemic coagulability. Local delivery of an antithrombotic drug, using a double-occlusion balloon catheter, effectively prevented thrombus formation, and local delivery of t-PA induced thrombolysis without exerting a significant influence on coagulability.
Angioscopy↗
Local treatment with an antithrombotic drug reduces thrombus size in coronary and peripheral thrombosed arteries.
Since the treatment of thrombotic disease by antithrombotic drugs may be associated with bleeding complications, a local delivery technique for administration of the drug may be useful. The efficacy of low-dose local delivery of an antithrombotic drug on thrombosis was investigated in 73 dogs. The antithrombotic drug (heparin, 25 U/kg, antithrombin: argatroban, 0.05 mg/kg, or defibrinogenating agent: batroxobin, 0.05 U/kg) was infused locally to a 1-h-old thrombus, and no drug was given in controls. The effect of the local delivery on the thrombus was evaluated. Low- and high-dose systemic drug delivery was also evaluated. The mean reduction in thrombotic coronary stenosis observed by angiography was 30.3% with argatroban, 22% with heparin, and 20.8% with batroxobin (P < 0.005 vs controls). Systemic delivery of low-dose heparin or argatroban did not induce any change in thrombus size. With high-dose systemic drug delivery (heparin 250 U/kg, argatroban 0.5 mg/kg), the mean reduction of thrombotic stenosis was 15.2% with heparin and 32.8% with argatroban (P < 0.005 vs controls). In the iliac arterial thrombosis, after local delivery of the drugs, the mean reduction of thrombotic stenosis observed by angiography was 24.4% in the argatroban group, and 19.2% in the heparin group (P < 0.05 vs controls, respectively). With high-dose systemic heparin delivery, the mean reduction of the thrombotic stenosis was 13.2% (P < 0.01 vs control). Angioscopy also demonstrated a similar trend. The high-dose drug delivery reduced systemic coagulability. Thus, local delivery of an antithrombotic agent can reduce the thrombus size in the coronary and iliac arteries without having any significant influence on coagulability.
Angioscopy↗
Peroxisomal disorders: clinical characterization.
The peroxisomal disorders can be divided into three classes: firstly, those in which the activity of only one single enzyme is reduced; secondly, those in which the activities of multiple peroxisomal enzymes are deficient and also the number of peroxisomes is reduced; and thirdly, those in which the activities of multiple peroxisomal enzymes are lacking and at the same time the number of peroxisomes is normal at least in liver tissue. The cerebro-hepato-renal syndrome of Zellweger is the prototype of peroxisomal disorders of the second group. Clinical distinction between Zellweger syndrome and neonatal adrenoleukodystrophy or infantile Refsum disease can be impossible. The clinical abnormalities that should give rise to suspicion for the presence of a peroxisomal disorder and urge the necessity of further biochemical studies are proposed.
Adrenoleukodystrophy↗
Pyroglutamic aciduria (5-oxoprolinuria) without glutathione synthetase deficiency and with decreased pyroglutamate hydrolase activity.
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Adult↗
Off-pump coronary artery bypass for a heparin-allergic patient.
A 46-year-old man with no history of drug allergy developed acute myocardial infarction. Coronary angiographic findings revealed triple vessel disease. Serum hepatic enzymes were elevated due to heparin administered to control infarction, and an allergic reaction developed exclusively due to heparin. To avoid heparin use, we adopted heparin-free off-pump coronary artery bypass grafting through median sternotomy. The systemic anticoagulant agent argatroban was administered to maintain active clotting time over 200 seconds. The left internal thoracic artery was anastomosed to the left anterior descending artery, the radial artery to the diagonal branch, and the right gastroepiploic artery to the right coronary artery. Patency was confirmed by postoperative coronary angiography. No complications were noted. For patients with heparin allergy, off-pump coronary artery bypass grafting is a useful maneuver, because it can be conducted using anticoagulant agents other than heparin.
Anticoagulants↗
Gertel M: An evaluation of two new local anaesthetics for major conduction blockade.
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Anesthesia, Spinal↗
An evaluation of two new local anesthetics for major conductive blockade.
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Anesthesia, Conduction↗
Argatroban, an attractive anticoagulant, for left heart bypass with centrifugal pump for repair of traumatic aortic rupture.
Systemic heparinization often increases the risk of fatal bleeding from other injured organs in surgical repair of the aorta using extracorporeal circulation in patients with traumatic aortic rupture associated with multisystem injuries. We used an antithrombin agent, argatroban, as an alternative anticoagulant in left heart bypass with the Bio-Medicus centrifugal pump in 7 of 9 recent patients who underwent aortic repair using left heart bypass. All these patients survived without obvious evidence of systemic thromboembolization. Surgical treatments for other organ injuries were carried out in 3 patients concomitantly or immediately after aortic repairs without undue blood loss. Argatroban may have a complementary effect for preventing thrombus formation without aggravating bleeding tendency because of its monotarget specificity to thrombin. We believe intravenous administration (0.5 to 2 micrograms/kg/min) of argatroban is a safe anticoagulant for left heart bypass in repairs of traumatic aortic rupture associated with multiple organ injuries.
Adolescent↗
Clinical experience of Argatroban for anticoagulation in cardiovascular surgery.
PURPOSE: We have reviewed our experience with Argatroban-a direct thrombin inhibitor for anticoagulation--in a variety of cardiovascular operations, and in extracorporeal circulation, as a substitute for heparin. SUBJECTS AND METHODS: 60 patients receiving anticoagulation with Argatroban were classified into the following four groups. Group 1; 20 patients with anticoagulation therapy after cardiac surgery. Group 2; 8 patients with extracorporeal circulation for continuous hemofiltration for either pre- or post-operative control of acute renal failure. Argatroban was used alone or in combination with nafamostat mesilate. Group 3, one patient with replacement of the descending aorta with left heart assist and 15 patients with percutaneous cardiopulmonary support. And Group 4, 16 patients undergoing vascular surgery including the abdominal aorta. The target activated clotting time was individually set for each group. In Group 1, the coagulofibrinolytic activity and platelet function were measured precisely. Bleeding and complications were examined in all groups. RESULTS: Group 1; the targeted activated clotting time of 150-180 seconds was achieved by a dosage of 0.4-0.8 microgram/kg/min Argatroban. Group 2; the activated clotting time of 150-180 seconds was achieved by 0.05-1.6 micrograms/kg/min (concomitance), or by 0.02-2.5 micrograms/kg/min (alone). Group 3; the activated clotting time of 180-200 seconds by 0.05-3.86 micrograms/kg/min. And Group 4; the activated clotting time of around 150 seconds by 2.0 micrograms/kg/min with initial bolus infusion of 0.1 mg/kg. Argatroban did not promote post-surgery bleeding and had no unfavorable effect on coagulo-fibrinolysis or on platelet activity. CONCLUSION: Argatroban may be useful as an anticoagulant in the field of cardiovascular surgery as a substitute for heparin, without causing any post-surgery bleeding complication, or influencing the fibrinolytic activities or platelet functions.
Aged↗
[Direct thrombin antagonists].
BACKGROUND: Inhibiting thrombin as a key enzyme of the coagulation cascade is therapeutically useful in thromboembolic diseases. In coronary thrombosis, direct thrombin inhibitors promise to be useful for an efficacious therapy. Hirudin and recombinant or synthetic mimetics like hirulog, argatroban and melagatran have proven their efficacy in clinical studies. CONCLUSION: Therapy with direct thrombin inhibitors such as hirudin and analogous substances reduces coronary events. Moreover, the agents are useful for therapy of thromboembolic diseases, especially in the case of heparin induced thrombocytopenia type II.
Acute Disease↗
[Argatroban: pharmacological properties and anaesthesiological aspects].
Argatroban is a direct, selective and reversible active site thrombin inhibitor derived from L-arginine. It is a representative of a new class of antithrombotic drugs which offer inhibition of clot-bound as well as fluid-phase thrombin. Argatroban is characterised by favourable pharmacokinetics (beta-elimination half-time approximately 40-50 min) undergoing hepatic metabolism and mainly biliary excretion. Renal impairment will not result in altered or delayed elimination. For many years, argatroban has been used in Japan and in the United States and is approved by the FDA for anticoagulation in patients with heparin-induced thrombocytopenia (HIT type II). The ease of monitoring with the activated partial thromboplastin time, lack of induction of antibodies and adequate safety in renal failure patients, make this drug a favourable mode therapy in comparison with other anticoagulants such as lepirudin or heparinoids. Since June 2005 argatroban has been approved in Germany for the treatment of patients with HIT type II. The main characteristics of the drug with special considerations for anaesthesiologists and intensive care physicians are presented in this review.
Anesthesia↗
Argatroban as an alternative anticoagulant for patients with heparin allergy during coronary bypass surgery.
Although heparin allergy is a rare but well-documented entity, anticoagulation management for cardiac surgery in patients with the heparin allergy has not been established due to its rarity. Here we report a case that shows our anticoagulation strategy during a coronary bypass operation. A 67-year-old man with unstable angina pectoris developed an urticarial rash 10 h after the second exposure to heparin. Results of the drug lymphocyte stimulation test were positive for porcine heparin, coumadin, and nicorandil. Off-pump coronary bypass surgery was successfully performed with argatroban as an alternative anticoagulant to heparin, with activated clotting time kept over 200 s at the rate of 5 microg/kg per min of argatroban infusion.
Aged↗
Suppression of prostanoid formation and regulation of peripheral circulation after surgery using thrombin inhibitor (MD805).
We studied the effects of thrombin generation due to surgical stress on prostanoid formation and peripheral circulation in anesthetized dogs. Three experimental groups were used, consisting of a control group (group 1), a thoracotomized group (group 2), and a thoracotomized group treated with thrombin inhibitor (MD805: a synthetic arginine derivative) (group 3). The plasma concentrations of thrombin-antithrombin III complex (TAT) and prostanoids were measured along with the hemodynamic parameters. The plasma concentrations of TAT and thromboxane B2 significantly increased 1h after a thoracotomy in group 2. However, neither concentration increased after a thoracotomy in group 3. The flow ratio of the brachial and femoral arteries to cardiac output significantly decreased 1h after a thoracotomy in group 2. This study indicates that thromboxane A2 was thus synthesized by the stimulation of endogenous thrombin, while it also reduced the peripheral blood flow after surgery.
Animals↗
Isoenzyme profile of lactate dehydrogenase in the cranial cervical sympathetic ganglion under normal conditions and during synaptic blockade.
The isoenzyme profile of lactate dehydrogenase in the cranial cervical sympathetic ganglion of rabbits was studied under normal conditions and during blockade of nicotinic cholinergic synapses. Under normal conditions this profile was presented by 5 isoforms of the enzyme (lactate dehydrogenases 1, 2, 3, 4, and 5). Activity of H-isoforms prevailed. Blockade was accompanied by heterotropic allosteric inhibition of lactate dehydrogenase isoforms. H- and M-isoforms underwent simultaneous changes. Activity of H-isoforms sharply decreased. However, the ratio between lactate dehydrogenases 1 and 2 during complete or partial blockade did not differ from that observed in experiments with the intact ganglion. M-isoforms (lactate dehydrogenases 4 and 5) disappeared during partial blockade. Activity of hybrid lactate dehydrogenase 3 significantly decreased and was undetected during partial and complete blockade, respectively. Our results indicate that enzyme activity and isoenzyme profile of lactate dehydrogenase are determined by function of nicotinic synapses.
Animals↗
Assessing nonlinearity in compartment models via the relative curvature measure.
In pharmacokinetics, compartment models often play an important role in the description of the concentration of the drug in the blood over time after its administration to an individual. Statistical inference in these models can be conducted based on a linear approximation with respect to the parameter related to pharmacokinetic indices, in the same way that the usual nonlinear regression models are dealt with. Therefore, it is necessary to assess the degree of nonlinearity in a compartment model and to evaluate its effect on the linear approximation. The relative curvature measure that enables us to assess the intrinsic and parameter-effects (PE) nonlinearity can be used, but in practice it has not been applied to compartment models in pharmacokinetics. One reason may be that the relative curvature measure cannot be directly applied to blood drug concentration data that exhibit heteroscedasticity. Therefore, the relative curvature measure including the heteroscedastic variance function was utilized to assess the nonlinearity in the compartment models, and in particular, the influences of some of the reparameterizations that are empirically used in fitting the compartment models were examined. Several examples showed that the reparameterized compartment model had less PE nonlinearity than the original compartment model, but that several reparameterizations could increase the PE nonlinearity. In addition, by means of a simulation experiment with heteroscedastic blood drug concentration data, the accuracy, and precision of the relative curvature measure with the heteroscedastic variance function were evaluated and compared with those of the original relative curvature measure. The results showed that the relative curvature measure with the variance function was not affected by heteroscedastic blood drug concentration data and could be utilized for the assessment of the nonlinearity in compartment models.
Anti-Inflammatory Agents, Non-Steroidal↗
Argatroban anticoagulation in conjunction with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention: an open-label, nonrandomized pilot study.
BACKGROUND: Argatroban, a direct thrombin inhibitor, blocks clot-bound thrombin more effectively than does heparin. This multicenter, prospective pilot study evaluated the efficacy and safety of argatroban in combination with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention. METHODS: Patients (N = 152) received argatroban as a 250- or 300-mug/kg bolus, followed by a 15-mug/kg/min infusion during percutaneous coronary intervention. An additional 150-mug/kg bolus was administered if activated clotting times 5-15 min after initiating argatroban were <275 s. Abciximab (N = 150) or double-bolus eptifibatide (N = 2) was administered simultaneously. RESULTS: Median activated clotting times at the beginning and end of the procedure were approximately 300 s. The primary efficacy endpoint-a composite of death, myocardial infarction, or urgent revascularization at 30 days-occurred in 4 (2.6%) patients (no death, 4 myocardial infarctions, and 2 revascularizations). Two (1.3%) patients had major bleeding by the Thrombolysis in Myocardial Infarction criteria (1 retroperitoneal, 1 groin hematoma). CONCLUSIONS: Argatroban in combination with glycoprotein IIb/IIIa inhibition appears to provide adequate anticoagulation and be well tolerated with an acceptable bleeding risk for patients undergoing percutaneous coronary intervention. Additional studies are warranted.
Aged↗