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PubMed1993

Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-D-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats.

Behavioral activation following systemic administration of the N-methyl-D-aspartic acid receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d) cyclohepten-5,10-imine; dizocilpine] was examined in unlesioned control and in neonatal-6-hydroxydopamine (OHDA) lesioned rats. Neonatal-6-OHDA lesioned animals were found more sensitive than control rats and female rats more sensitive than males to this MK-801-induced behavioral activation. CGS-19755, a competitive NMDA antagonist, also increased activity in neonatally lesioned animals. The increased activity level following MK-801 administration to neonatally lesioned rats was reduced, but not eliminated, by pretreatment with alpha-methyltyrosine, indicating that endogenous catecholamines were partially responsible for this action of MK-801. Furthermore, neither a D1- nor a D2-dopamine antagonist was totally effective alone in reducing MK-801-induced behavioral activation in the neonatally lesioned rats, but MK-801-induced activity was reduced to the level observed after alpha-methyltyrosine when both dopamine antagonists were administered in combination. In contrast to these results, alpha-methyltyrosine virtually eliminated the MK-801-induced activity in adult-lesioned rats. When individual behaviors induced by MK-801 were examined in neonatal-6-OHDA lesioned rats, MK-801 did not produce the same behaviors as L-dihydroxyphenylalanine or a D1- or D2-dopamine agonist. Whereas MK-801 had no major effect on most behaviors induced by specific D1- or D2-dopamine agonists, it blocked some behaviors produced after L-dihydroxyphenylalanine administration, including the self-injurious behavior. Repeated MK-801 treatment resulted in increasingly greater motor activity, but this was not related to increased D1-dopamine receptor sensitization. In support of a regional action of MK-801, MK-801 induced c-fos-like immunoreactivity in the cerebral cortex, but not in the nucleus accumbens or striatum. The action of MK-801 to increase c-fos-like immunoreactivity in cerebral cortex was reduced, but not blocked, by SCH-23390. Additionally, MK-801 reduced, but did not eliminate, D1-dopamine agonist induced c-fos-like immunoreactivity in striatum. These data suggest that MK-801 not only can facilitate dopamine release within specific brain regions, but has behavioral and functional actions distinct from dopamine agonists.

Animals↗
PubMedDate not supplied

Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an intensely prothrombotic syndrome managed by discontinuation of heparin therapy and substitution of an alternative inhibitor of thrombin. We describe our experience with argatroban, a direct thrombin inhibitor, in patients with HIT or HIT with thrombosis (HITTS). METHODS: In this multicenter, nonrandomized prospective study, 418 patients with HIT were administered intravenous argatroban, 2 micro g/kg per minute, adjusted to maintain the activated partial thromboplastin time at 1.5 to 3 times the baseline value for a mean of 5 to 7 days. Comparisons were made with a historical control cohort (n = 185). The prospectively defined, primary efficacy end point was a composite of all-cause death, all-cause amputation, or new thrombosis in 37 days. Other end points included the components of the composite, death due to thrombosis, increased platelet count, and bleeding. RESULTS: In the HIT arm, the composite end point was significantly reduced in argatroban-treated patients vs controls (28.0% vs 38.8%; P =.04). In the HITTS arm, the composite end point occurred in 41.5% of argatroban-treated patients vs 56.5% of controls (P =.07). By time-to-event analysis of the composite end point, argatroban therapy was significantly better than historical control therapy in HIT (P =.02) and HITTS (P =.008). Argatroban therapy also significantly reduced new thrombosis in HIT and HITTS and death due to thrombosis in HITTS. There were no significant between-group differences in all-cause death or amputation. Platelet counts recovered more rapidly in argatroban-treated patients than in controls. Bleeding rates were similar between groups. CONCLUSION: Argatroban therapy, compared with historical control, improves outcomes, particularly new thrombosis and death due to thrombosis, in patients with heparin-induced thrombocytopenia.

Aged↗
PubMed2004

Treatment of heparin-induced thrombocytopenia: a critical review.

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy that has a high rate of morbidity (thrombosis and amputation) and mortality. In the past, a number of different anticoagulants have been used to treat HIT in an attempt to prevent these complications. More recently, direct thrombin inhibitors have become popular. This systematic review summarizes the risk for thrombosis in HIT patients when heparin therapy is stopped; evidence of the efficacy of thrombin inhibitors in patients with HIT with and without thrombosis; evidence supporting the use of thrombin inhibitors in patients with a history of HIT who require a coronary intervention procedure; and the risk for bleeding when antithrombotic agents are used.

Anticoagulants↗
PubMed2006

Argatroban tPA stroke study: study design and results in the first treated cohort.

BACKGROUND: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute stroke is linked to clot lysis and artery recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. There are no human data on this combination. DESIGN: We report the first phase of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose-escalation, safety and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 hours. After standard-dose intravenous rtPA administration, a 100-mug/kg bolus of argatroban followed by infusion of 1 mug/kg per minute for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times that of the control group. RESULTS: Fifteen patients (including 10 men) were enrolled, with a mean +/- SD age of 61 +/- 13 years. All patients had middle cerebral artery occlusions. Baseline median National Institute of Health Stroke Scale score was 14 (range, 4-25). The mean +/- SD time from symptom onset to argatroban bolus administration was 172 +/- 53 minutes. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 1 patient and there was 1 death. Recanalization was complete in 6 patients and partial in another 4, and reocclusion occurred in 3 within 2 hours of rtPA bolus administration. CONCLUSION: The safety of low-dose argatroban combined with intravenous rtPA may be within acceptable limits, and its efficacy for producing fast and complete recanalization is promising, but a larger cohort of patients is required to confirm these preliminary observations.

Adolescent↗
PubMed2000

Argatroban inhibits intraocular fibrin formation after vitrectomy in rabbits.

OBJECTIVES: To examine whether the specific thrombin inhibitor argatroban can prevent anterior chamber, pupillary area, and anterior vitreous fibrin formation after vitrectomy and lensectomy in rabbits. METHODS: Argatroban was infused into the vitreous cavities of Japanese albino rabbits for 5 minutes after pars plana vitrectomy and lensectomy. Slitlamp microscopy and indirect ophthalmoscopy were performed at postoperative hours 0.5, 1, 2, 3, and 6, and at postoperative days 1, 2, 3, and 7, and the amounts of fibrin formation in the anterior chamber, pupillary area, and anterior vitreous were scored from grade 0 to 4. RESULTS: Argatroban prevented fibrin formation from 0.5 hours postoperatively in a dose-dependent manner. In the eyes treated with 0.01% argatroban, the median score for postoperative fibrin formation was significantly less than that in control eyes between hours 1 and 3 (hour 1, P =.02; hour 2, P =.005; and hour 3, P =.003); the eyes treated with 0.003% argatroban also had significantly less fibrin than control eyes between 1 and 2 hours (hour 1, P =.005; hour 2, P =.03). CONCLUSION: These results indicate that argatroban inhibits intraocular fibrin formation in an experimental rabbit model. CLINICAL RELEVANCE: Argatroban may be useful clinically in cases that often produce fibrin postoperatively, such as proliferative vitreoretinopathy and proliferative diabetic retinopathy.

Animals↗
PubMed1996

Report of successful use of argatroban as an alternative anticoagulant during coronary stent implantation in a patient with heparin-induced thrombocytopenia and thrombosis syndrome.

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is a severe complication of heparin caused by an antibody response to the heparin-platelet factor 4 complex which results in severe thrombosis. Heparin rechallenge in HITTS patients carries a high risk of inducing thrombosis. Antithrombin agents represent treatment alternatives in HITTS patients who require anticoagulation. We report successful coronary stent implantation in a HITTS patient using the antithrombin agent argatroban.

Aged↗
PubMed1999

Experimental study of ectopic-free tissue transfer of rabbit epigastric flap using small-caliber vascular grafts.

Ectopic intraperitoneal free-tissue grafting using small-caliber artificial vascular grafts is reported. The vascular grafts were polyurethane tubes (inner diameter 1.4 mm; outer diameter 1.9 mm; length 15 mm) with a coating of the antithrombotic agents argatroban and 2-hydroxyethylmethacrylate-styrene block copolymer (HS)on the inner surface. The patency of the artificial vessels was investigated in an ectopic-free rabbit epigastric flap in which grafts were used for anastomosis between the femoral and renal vessels. The mean patent duration of uncoated controls (n = 10) was 128 +/- 37 min. Flap viability after one week (n = 17) and the patency of the coated grafts were investigated histologically. The flap take rate was 65%, the arterial graft patency rate 41%, and the venous graft patency rate 24%. The HS-treated surface combined with the argatroban slow-release system exhibited improvement of flap survival in an intraperitoneal ectopic -free grafting model.

Animals↗
PubMed1999

Local drug delivery of argatroban from a polymeric-metallic composite stent reduces platelet deposition in a swine coronary model.

Thrombus formation after intracoronary stent implantation provides a stimulus for neointimal hyperplasia and if excessive can result in stent thrombosis. We tested the hypothesis that local delivery of an antithrombin drug from a polymeric-metallic stent inhibits platelet thrombus formation. An uncoated metal slotted tube, a jellyroll slotted metal stent with an Argatroban-loaded polymeric sleeve, and a jellyroll slotted metal stent with a drug-leached polymeric sleeve were randomly deployed into the coronary arteries of eight juvenile farm swine. Platelet deposition in the stented segments was determined at 2 hr using autologous 111Indium oxime-labeled platelets. Platelet deposition was significantly less in the Argatroban-loaded stents compared to the Argatroban-leached stents (1.40 x 10(8) platelets/cm2 vs. 26.8 x 10(8) platelets/cm2; P=0.005). When corrected for differences in the metal surface area exposed to blood, platelet deposition was significantly lower in the Argatroban-loaded stent (1.74+/-1.95 x 10(8)/cm2) compared to the Argatroban-leached stent (33.5+/-39.1 x 10(8)/cm2; P=0.005) and the uncoated metal stent (36.2+/-73.3 x 10(8)/cm2; P=0.006). In this coronary stent thrombosis model Argatroban has local antithrombotic properties when delivered with a polymer-metallic stent. Improved polymeric designs may reduce risk of thrombus deposition at the site of stent implantation.

Animals↗
PubMed2002

Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparin-induced thrombocytopenia.

We report two patients with deep-vein thrombosis complicating immune heparin-induced thrombocytopenia who developed venous limb gangrene during overlapping therapy with a direct thrombin inhibitor (lepirudin or argatroban) and warfarin. In both patients, therapy with the direct thrombin inhibitor was interrupted during persisting severe athrombocytopenia while warfarin administration continued. Both patients exhibited the typical feature of a supratherapeutic international normalized ratio (INRs, 5.9 and 7.3) that has been linked previously with warfarin-associated venous limb gangrene. These data suggest that warfarin anticoagulation be postponed in patients with acute heparin-induced thrombocytopenia until substantial recovery of the platelet count has occurred.

Aged↗
PubMed1990

N-methyl-D-aspartate antagonist reduces stroke size and regional glucose metabolism.

Pharmacological inhibition of cell excitation during focal ischemia was studied in the rat middle cerebral artery occlusion model. The potent and selective N-methyl-D-aspartate antagonist CGS 19755, administered 5 minutes prior to or 5 minutes following permanent middle cerebral artery occlusion, caused a substantial decrease in infarct size, which was associated with reduction of postischemic cerebral glucose hypermetabolism. These data support a role for excitation-induced hypermetabolism in the pathogenesis of infarction following focal cerebrovascular occlusion.

Animals↗
PubMed2002

Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome associated with thrombosis. Alternative anticoagulation to heparin is needed for HIT patients during percutaneous coronary intervention (PCI). We evaluated argatroban, a direct thrombin inhibitor, for anticoagulation in this setting. Ninety-one HIT patients underwent 112 PCIs while on intravenous argatroban (25 microg/kg/min [350 microg/kg initial bolus], adjusted to achieve an activated clotting time of 300-450 sec). Primary efficacy endpoints were subjective assessments of the satisfactory outcome of the procedure and adequate anticoagulation during PCI. Among patients undergoing initial PCIs with argatroban (n = 91), 94.5% had a satisfactory outcome of the procedure and 97.8% achieved adequate anticoagulation. Death (zero patients), myocardial infarction (four patients), or revascularization (four patients) at 24 hr after PCI occurred in seven (7.7%) patients overall. One patient (1.1%) experienced periprocedural major bleeding. For patients who had subsequent hospitalizations (mean separation of 150 days) for repeat PCI using argatroban anticoagulation (n = 21), there were no unsatisfactory outcomes. Overall, outcomes were comparable with those historically reported for heparin. Argatroban therefore is a reasonable anticoagulant option in this setting, where current options are limited.

Adult↗
PubMed2003

Obstinate thrombosis during percutaneous coronary intervention in a case with heparin-induced thrombocytopenia with thrombosis syndrome successfully treated by argatroban anticoagulant therapy.

We describe a case of massive coronary thrombus after the coronary stenting due to heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Only argatroban was able to resolve the thrombus. This is the first case in which argatroban successfully treated massive thrombus during percutaneous coronary intervention in a patient with HITTS.

Angioplasty, Balloon, Coronary↗