Thrombin (Ki = 5-39 nM)

Because of its single target specificity for thrombin, argatroban (MD-805) may have a complementing effect in avoiding thrombosis without aggravating bleeding tendencies. In order to treat traumatic aortic rupture associated with multi-organ injury during left heart bypass surgery, a safe anticoagulant called argatroban (MD-805) is injected at a rate of 0.5 to 2 mcg/kg/minute [1]. Argatroban (MD-805) appears to improve TPA reperfusion in patients with AMI, especially those who present later than expected, as compared to heparin. Argatroban-treated patients experience fewer serious bleeding episodes and worse clinical outcomes [2].

Argatroban prevents the growth of microthrombi for three hours following middle cerebral artery (MCA) occlusion; after that, it has no further effect. Six hours following MCA occlusion, argatroban also significantly reduces the size of ischemic cerebral lesions. In [3] In the rat model of distal middle cerebral artery occlusion, Argatroban (0.3 mg/h/rat) significantly reduces the number of microthrombi 1 day after distal middle cerebral artery (dMCA) occlusion. One day after distal middle cerebral artery (dMCA) occlusion, a reduction in regional cerebral blood flow (rCBF) is significantly reversed by argatroban (0.1 and 0.3 mg/h/rat). Argatroban (0.3 mg/h/rat) also greatly diminishes the cerebral infarction's size.[4]

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1. The antithrombotic action of Argatroban, a synthetic thrombin inhibitor, was studied in three models of thrombosis in the rat, and in the tail transection bleeding time test. Heparin was studied as a reference anticoagulant. 2. In the model of venous thrombosis induced by thromboplastin followed by stasis of the abdominal vena cava, argatroban had an ED50 of 125 micrograms kg-1, when administered as an i.v. bolus 5 min prior to the thromboplastin injection: the ED50 of heparin was 42 micrograms kg-1, where ED50 is the dose which reduces the weight of the thrombus by 50% compared with that of the control animals. When the two compounds were administered by continuous i.v. infusion, argatroban (ED50 = 1.5 micrograms kg-1 min-1) had the same potency as heparin (ED50 = 1.2 micrograms kg-1 min-1). 3. Argatroban was active in the arterio-venous shunt model with an ED50 of 0.6 mg kg-1 when the compound was given as a bolus. The ED50 of heparin was 0.04 mg kg-1 under the same conditions. The two compounds had ED50 values of 6 micrograms kg-1 min-1 (argatroban) and 3 micrograms kg-1 min-1 (heparin), when administered by continuous i.v. infusion. 4. When tested against occlusive arterial thrombus formation by electrical stimulation of the left carotid artery, both compounds given as either an i.v. bolus or a continuous infusion led to dose-dependent increases in the duration of post-lesion vessel patency. [1]

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Ischemic cerebral infarcts induce hypercoagulation and microthrombosis in the surrounding region, thus leading to vascular occlusion. We determined whether microthrombi contribute to the spreading of ischemic lesions following thrombotic middle cerebral artery (MCA) occlusion and also determined whether Argatroban, a selective thrombin inhibitor, reduces the formation of the microthrombi and the area of the ischemic lesions. The rat left MCA was occluded by a platelet-rich thrombus formed following the photochemical reaction between rose bengal and green light. Microthrombi were histologically identified in the left hemisphere. The extent of ischemic lesions and microthrombi containing fibrin increased in a time-dependent manner after MCA occlusion. Argatroban inhibited the formation of microthrombi up to 3 hr after MCA occlusion; beyond 3 hr, it was ineffective. Argatroban also significantly (P < 0.01) reduced the size of ischemic cerebral lesions at 6 hr after MCA occlusion. It is concluded that the formation of microthrombi contributes to the progression of ischemic lesions in the early stage. It is likely that thrombin generated following thrombotic MCA occlusion contributes to the progression of ischemic lesions by promoting the formation of microthrombi. Argatroban can reduce the formation of microthrombi and ischemic lesions in the early stage. [3]

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To elucidate the role of thrombin in brain damage during focal cerebral ischemia, we investigated the effects of a selective thrombin inhibitor, Argatroban, on microthrombi formation, regional cerebral blood flow (rCBF), infarct areas and neurological deficits using a rat thrombotic distal middle cerebral artery (dMCA) occlusion model. The rat dMCA was occluded by a platelet-rich thrombus formed after photochemical reaction between rose bengal and green light. One day after dMCA occlusion, the number of microthrombi were counted. In the separate animals, rCBF was measured by using the iodoantipyrine method 1 day after dMCA occlusion. Three days after dMCA occlusion, behavioral tests were performed and the size of the cerebral infarction was determined. In the present study, argatroban was administered i.p. by continuous infusion after dMCA occlusion. Argatroban (0.3 mg/h/rat) significantly (P < .05) decreased the number of microthrombi 1 day after dMCA occlusion. Argatroban (0.1 and 0.3 mg/h/rat) significantly (P < .01) reversed a decrease in rCBF 1 day after dMCA occlusion. Argatroban (0.3 mg/h/rat) also significantly (P < .01) reduced the size of the cerebral infarction. Administration of argatroban (0.1 and 0.3 mg/h/rat) resulted in a significant improvement in neurological deficits 3 days after dMCA occlusion (P < .01 and P < .05, respectively). Argatroban decreased the size of the cerebral infarction and improved neurological deficits in the rat thrombotic dMCA occlusion model. These effects were thought to be due to the improvement of rCBF and to the reduction in secondary thrombus formation after dMCA occlusion[4].

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T2DM was associated with cardiac structural and functional disturbances as evidenced from impaired cardiac functional parameters and increased fibrosis. There was a significant increase in PAR expression after 20 weeks of diabetes induction. Four weeks argatroban treatment ameliorated metabolic alterations (reduced plasma glucose and cholesterol), ventricular dysfunctions (improved systolic and diastolic functions), cardiac fibrosis (reduced percentage area of collagen in picro-sirius red staining), and apoptosis (reduced TUNEL positive nuclei). Reduced expression of PAR1 and PAR4 in the argatroban-treated group indicates a response towards inhibition of thrombin. In addition, AKT (Ser-473), GSK-3β (Ser-9), p-65 NFĸB phosphorylation, TGF-β, COX-2, and caspase-3 expression were reduced significantly along with an increase in SERCA expression in argatroban-treated diabetic rats which indicated the anti-fibrotic, anti-inflammatory, and anti-apoptotic potential of argatroban in DCM. Conclusion: This study suggests the ameliorative effects of argatroban in diabetic cardiomyopathy by improving ventricular functions and reducing fibrosis, inflammation, apoptosis, and PAR expression [5].

Effect of argatroban on the expression of myosin heavy-chain isoform mRNA [2]
The effect of specific thrombin inhibitor, Argatroban, on phenotype conversion of cultured vascular smooth muscle cells was tested. The cultured vascular smooth muscle cells were detached by incubating with 0.01% trypsin–EDTA solution for 5 min and replated on 25-cm2 flask with 1.5×105 cells. After the cells were cultured in 10% fetal bovine serum–DMEM for 9 h, the medium was changed to serum-free DMEM containing PDGF-BB (10 and 50 ng/ml) or argatroban (10 and 50 μg/ml), and then incubated for 3 or 24 h. After incubation, total RNA was extracted to perform RT-PCR and the cells were fixed with 10% formalin–PBS for in situ hybridization to detect mRNA expressions of myosin heavy chain isoform.

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Effect of argatroban on the expression of SMemb protein [2]
To measure the protein level of SMemb after stimulation of the cultured vascular smooth muscle cells by Argatroban, the Western blots were performed according to the method by Towbin et al. (1979). Three and twenty-four hours after stimulations, crude myosin extracts were prepared according to the method by Rovner et al. (1986) with a minor modification. In brief, cultured vascular smooth muscle cells (1.5×105 cells) were removed from flasks by Rubber Policeman, rinsed with PBS, and were collected by centrifugation (1600 rpm, 4 °C) for 5 min. 50 μl of extraction buffer (50 mM NaH2PO4, 1 mM EGTA, 0.125 mM α-phenylmethanesulfonyl fluoride, pH 7.0) was added to cell pellet and homogenized by disposable pestles with Mini Cordless Grinder. After centrifugation (10,000 rpm, 4 °C) for 10 min, the pellets were dissolved in Gubba–Straub solution (150 mM NaH2PO4, 300 mM NaCl, 1 mM EGTA, 0.125 mM α-phenylmethanesulfonyl fluoride, 1 mM 2-mercaptoethanol, 10 mM ATP, pH 6.7), and then gently mixed at 4 °C for 1 h. After centrifugation (10,000 rpm, 4 °C) for 10 min, the supernatants were colleted as crude myosin extracts. To separate the proteins in the crude myosin extracts, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with 8–25% gradient gel was performed using a Phast System. The proteins in the gel were electrically blotted onto polyvinylidene difluoride (PVDF) membrane by PhastTransfer at 15 °C, 20 V, and 25 mA for 90 min. After blotting, the membrane was blocked with 3% non-fat milk in PBS for 2 h at room temperature, and then the membrane was incubated at 4 °C overnight with monoclonal anti-nonmuscle myosin heavy chain, which was diluted to 1:1000 by 3% non-fat milk in PBS. After washing five times with 0.1% Tween 20 in PBS (PBST) for 10 min each, the membrane was incubated with 1:3000 diluted sheep anti-mouse IgG2b in 1% non-fat milk in PBST at room temperature for 1 h. After washing four times by PBST and two times by PBS, substrate solution (0.1 mg/ml 3-amino-9-ethylcarbazole in 0.1 M sodium phosphate buffer) was added. The intensity of colored SMemb protein bands were analyzed by NIH image.

Experimental Design and Pharmacological Interventions [5]
Argatroban is a direct thrombin inhibitor that binds to the catalytic site of thrombin reversibly and thereby inhibits its action. Argatroban was used and the doses (0.3 and 1 mg/kg) were selected based on previous literature. Argatroban was dissolved in dimethyl sulfoxide (DMSO) and administered daily through i.p. route. Similarly, DMSO was administered through i.p. route in the HFD + STZ group and control group to negate the effect of the vehicle. After the 16th week of STZ injection, presence of diabetes was again reconfirmed and animals with plasma glucose ≥250 mg/dl were considered for further study. Argatroban and vehicle were administered at the dose of 1 ml/kg of body weight.

Animals were randomly assigned to the following groups.
1. Normal control group (Ctrl): Animals treated with vehicle dimethyl sulfoxide (DMSO) from the 16th to 20th week for 4 weeks to control animals on normal pellet diet (NPD).
2. High-fat diet + low-dose STZ 35 mg/kg group (T2DM): Vehicle (DMSO) was administered to T2DM animals for 4 weeks.
3.Low dose argatroban-treated diabetic animals group (T2DM + Arg 0.3 mg/kg): Argatroban was administered at the dose of 0.3 mg/kg, i.p. once daily for 4 weeks to T2DM animals.
4. High dose argatroban-treated diabetic animals group (T2DM + Arg 1 mg/kg): Argatroban was administered at the dose of 1 mg/kg, i.p. once daily for 4 weeks to T2DM animals.
5. Argatroban-treated per se group (Ctrl + Arg 1 mg/kg): Argatroban was administered at the dose of 1 mg/kg i.p., once daily for 4 weeks to control animals on NPD diet.

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Argatroban is suitable for constructing animal models to induce endogenous intestinal thrombosis. In hepatectomized rats, the pharmacokinetic parameters of Argatroban, such as area under the curve, volume of distribution, and elimination half-life, are significantly increased‌4. Argatroban is converted from the 21-(R) isomer to the 21-(S) diastereomer in the kidneys, with the latter exhibiting stronger antithrombotic activity and potentially higher hepatic clearance‌.

‌Thrombolysis Induction‌
‌Pathogenic Mechanism‌
Argatroban is a specific thrombin inhibitor that establishes thrombolysis models by inhibiting thrombin activity in animals.
‌Modeling Protocol‌
‌Animal‌: Wistar ST • Male • 8 weeks old
‌Administration‌: 2 mg/kg/h • IV • 1 h
‌Note‌: Allow free access to water and fast overnight before thrombolysis experiments.
‌Success Criteria‌
Relative rate of thrombus dissolution ↓

Absorption, Distribution and Excretion
Bioavailability is 100% (intravenous injection). Argatroban is primarily excreted in feces (65%), presumably through bile secretion; 22% is excreted in urine. 174 mL/kg 12.18 L [70 kg adult] 5.1 L/kg/hr [infusion dose up to 40 mcg/kg/min] Argatroban is primarily excreted in feces, presumably through bile secretion. In one study, (14)C-argatroban (5 μg/kg/min) was infused into healthy subjects for 4 hours, and approximately 65% of the radioactivity was recovered in feces within 6 days of the start of infusion, after which almost no radioactivity was detected. Within 12 hours of the start of infusion, approximately 22% of the radioactive material appeared in urine. After that, almost no additional urinary radioactivity was detected. The average recovery of the unchanged drug in urine was 16% relative to the total dose, and at least 14% in feces.
It is currently unclear whether argatroban can cross the human placenta. Its molecular weight (approximately 527 for hydrates), slow metabolism, and moderate serum protein binding suggest that embryo-fetal exposure to this drug should be expected, especially under continuous infusion.
Argatroban is primarily distributed in the extracellular fluid, with an apparent steady-state volume of distribution of 174 mL/kg (12.18 L for a 70 kg adult). Argatroban binds to 54% of human serum proteins, including 20% to albumin and 34% to α1-acid glycoprotein.
/Milk/ Argatroban has been detected in rat milk.
Metabolism/Metabolites

Primarily metabolized in the liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring. Age and sex have no significant effect on the pharmacodynamic or pharmacokinetic characteristics of argatroban.
The main metabolic pathway of argatroban is the hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of all four known metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450 enzyme CYP3A4/5. The major metabolite (M1) has an anticoagulant effect 3 to 5 times weaker than argatroban. The predominant component in plasma is unmetabolized argatroban. The plasma concentration of M1 is 0% to 20% of the parent drug. Other metabolites (M2 to M4) are present only in very low amounts in urine and are undetectable in plasma or feces. These data, along with the fact that erythromycin (a potent CYP3A4/5 inhibitor) has no effect on the pharmacokinetics of argatroban, suggest that CYP3A4/5-mediated metabolism is not an important clearance pathway in vivo. Argatroban is primarily metabolized in the liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring. Biological half-life: 39 and 51 minutes. The terminal elimination half-life is 39–51 minutes.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Argatroban is poorly absorbed orally and may not have adverse effects on breastfed infants. However, there is currently no information on the use of argatroban during lactation, so alternative medications are recommended.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Toxicity Overview Identification and Uses: Argatroban is an antithrombin and platelet aggregation inhibitor. Direct thrombin inhibitors, including argatroban, are commonly used anticoagulants in patients with known or suspected heparin-induced thrombocytopenia. Human Studies: Two case reports document the safe use of argatroban during human pregnancy. Argatroban did not show genotoxicity in the WI-38 human fetal lung cell unplanned DNA synthesis (UDS) assay. Animal studies: Single intravenous injections of argatroban at doses of 200, 124, 150, and 200 mg/kg were lethal in mice, rats, rabbits, and dogs, respectively. Acute toxicity symptoms included loss of righting reflex, tremor, clonic seizures, hind limb paralysis, and coma. No evidence of fetal harm was found in rats on days 7-17 of gestation with intravenous doses up to 27 mg/kg/day, or in rabbits on days 6-18 of gestation with intravenous doses up to 10.8 mg/kg/day. Argatroban did not show genotoxicity in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) positive mutation assay, the Chinese hamster lung fibroblast chromosomal aberration assay, the rat hepatocyte assay, or the mouse micronucleus assay.

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Use during pregnancy and lactation
◉ Overview of use during lactation
Due to poor oral absorption of argatroban, it may not have adverse effects on nursing infants. However, there is currently no information regarding the use of argatroban during lactation, therefore alternative medications are recommended.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding rate
54%

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Drug interactions
Concomitant use of argatroban with warfarin has a combined effect on the international normalized ratio (INR) and alters the relationship between INR and bleeding risk. Daily monitoring of INR is recommended during concomitant use of argatroban and warfarin. During conversion to warfarin therapy, the effects of argatroban should continue to be monitored using activated partial thromboplastin time (aPTT). Argatroban treatment can be discontinued when the INR exceeds 4 after concomitant use. INR values should be repeated 4–6 hours after discontinuation of argatroban infusion and should be within the ideal therapeutic range for warfarin monotherapy.
Potential drug interactions (increased risk of bleeding) may exist when used in combination with thrombolytics, antiplatelet drugs, or other anticoagulants. No pharmacokinetic or pharmacodynamic interactions have been observed with low-dose oral aspirin (162.5 mg, administered 26 hours and 2 hours before argatroban infusion) or oral acetaminophen (1 g every 6 hours for 5 doses, starting 12 hours before argatroban infusion). The manufacturer states that the safety and efficacy of argatroban in combination with platelet glycoprotein (GP) IIb/IIIa receptor antagonists have not been established.
Heparin is contraindicated in patients with heparin-induced thrombocytopenia (HIT). Sufficient time should be allowed before initiating argatroban treatment to allow for the reduction of heparin's effect on activated partial thromboplastin time (aPTT).
Pharmacodynamic interactions (increased prothrombin time (PT) and international normalized ratio (INR) compared to warfarin alone).

[1]. Br J Pharmacol. 1994 Dec;113(4):1209-14.

[2]. Eur J Pharmacol. 2003 Feb 7;461(1):9-17.

[3]. Jpn J Pharmacol. 1995 Oct;69(2):143-8.

[4]. J Pharmacol Exp Ther. 1996 Aug;278(2):780-5.

[5]. Cardiovasc Drugs Ther. 2017 Jun;31(3):255-267.

Argatroban is an anticoagulant and a direct thrombin inhibitor. Argatroban's mechanism of action is as a thrombin inhibitor. Argatroban is a synthetic derivative of L-arginine with antithrombotic activity. Argatroban is a monovalent direct inhibitor of fibrin-binding thrombin. This drug reversibly binds to the active site of thrombin, thereby preventing thrombin-dependent reactions, including the conversion of fibrinogen to fibrin; activation of factors V, VIII, and XI; activation of protein C; and platelet aggregation. Argatroban is highly selective for thrombin, inhibiting the activity of both free thrombin and thrombin-binding thrombin. Therefore, thrombus stability and the coagulation process are inhibited. (2R,4R)-1-[(2S)-5-(diaminomethyleneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinoline-8-yl)sulfonamide]-1-oxopentyl]-4-methyl-2-piperidinic acid is a peptide. Argatroban is a direct, selective thrombin inhibitor. The American College of Cardiology (ACC) recommends the use of bivalirudin or argatroban in patients with a history of heparin-induced thrombocytopenic purpura (HIT) who are undergoing percutaneous coronary intervention. Argatroban is a non-heparin anticoagulant that has been shown to both normalize platelet counts in HIT patients and prevent thrombosis. Parenteral anticoagulants must be discontinued and baseline activated partial thromboplastin time (APT) must be measured before administering argatroban. Anhydrous argatroban is both an anticoagulant and a direct thrombin inhibitor. The mechanism of action of anhydrous argatroban is as a thrombin inhibitor. Argatroban is a synthetic derivative of L-arginine with antithrombotic activity. Argatroban is a monovalent direct inhibitor of fibrin-binding thrombin. This drug reversibly binds to the active site of thrombin, thereby preventing thrombin-dependent reactions, including the conversion of fibrinogen to fibrin; activation of factors V, VIII, and XI; activation of protein C; and platelet aggregation. Argatroban is highly selective for thrombin, inhibiting the activity of both free thrombin and thromboconjugated thrombin. Therefore, thrombus stabilization and the coagulation process are inhibited. Anhydrous argatroban is the anhydrous form of argatroban, a synthetic derivative of L-arginine with antithrombotic activity. Argatroban is a monovalent direct inhibitor of fibrin-binding thrombin. This drug reversibly binds to the active site of thrombin, thereby preventing thrombin-dependent reactions, including the conversion of fibrinogen to fibrin; activation of factors V, VIII, and XI; activation of protein C; and platelet aggregation. Argatroban is highly selective for thrombin, inhibiting the activity of both free thrombin and thromboconjugated thrombin. Therefore, thrombus stabilization and the coagulation process are inhibited. Drug Indications Argatroban is indicated for the prevention and treatment of thrombosis caused by heparin-induced thrombocytopenic purpura (HIT). It is also indicated for patients with HIT undergoing percutaneous coronary intervention or at risk of HIT. FDA Label Mechanism of Action Argatroban exerts its anticoagulant effect by inhibiting thrombin-catalyzed or induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation. Therapeutic Uses Antithrombin; Platelet aggregation inhibitor. /Clinical Trials/ ClinicalTrials.gov is a registry and results database that catalogs human clinical studies funded by public and private institutions worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov contains summary information about the study protocol, including: disease or condition; intervention (e.g., the medical product, behavior, or procedure being studied); study title, description, and design; participation requirements (eligibility criteria); study location; contact information for the study location; and links to relevant information from other health websites, such as NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Argatroban is listed in the database. Argatroban injection is indicated for use as an anticoagulant in adult patients undergoing percutaneous coronary intervention (PCI) who have or are at risk of developing heparin-induced thrombocytopenia (HIT). /Listed on US Product Label/ Argatroban injection is indicated for the prevention or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT). /Included on US Product Label/ For more complete data on the therapeutic uses of argatroban (out of 10), please visit the HSDB record page.

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Drug Warnings
In patients undergoing percutaneous coronary intervention (PCI) for HIT/HITTS, at least 2% of patients experience other non-hemorrhagic adverse reactions, including chest pain, back pain, headache, bradycardia, and myocardial infarction.
In patients undergoing non-surgical HIT/HITSS treated with argatroban, 2% or more of patients report hemorrhagic adverse reactions including: major or minor bleeding, minor genitourinary bleeding or hematuria, minor decrease in hemoglobin/hematocrit, minor groin or brachial artery bleeding (e.g., catheter insertion site), and hemoptysis;
Non-hemorrhagic adverse reactions include dyspnea, hypotension, fever, diarrhea, sepsis, cardiac arrest, nausea, ventricular tachycardia, pain, urinary tract infection, vomiting, infection, pneumonia, atrial fibrillation, cough, renal dysfunction, abdominal pain, and cerebrovascular disease. The safety and efficacy of argatroban in pediatric patients have not been fully established; however, it has been evaluated in a small number of critically ill pediatric patients under 16 years of age with heparin-induced thrombocytopenic purpura (HIT) or heparin-induced thrombocytopenic purpura syndrome (HITTS). In a small, multicenter, open-label study, 18 critically ill pediatric patients requiring non-heparin anticoagulation therapy received argatroban at an initial dose of 1 μg/kg/min, titrated according to aPTT target values (1.5–3 times the baseline value). During the 30-day study period, thrombotic events occurred in 5 patients, and 2 patients reported major hemorrhage (intracranial hemorrhage). All patients had serious comorbidities and were taking multiple medications concurrently; most patients were diagnosed with or suspected of having heparin-induced thrombocytopenic purpura (HIT). Pharmacokinetic analysis showed that argatroban clearance was reduced by 50% in severely ill children compared to healthy adults; and by approximately 80% in children with elevated bilirubin levels compared to children with normal bilirubin levels. Based on these results, a reduction in the argatroban dose for these children is recommended. There are currently no data on the presence of argatroban in human milk or its effect on milk production. Argatroban is present in rat milk. The benefits of breastfeeding for infant development and health, the mother's clinical need for argatroban, and any adverse effects that argatroban or underlying maternal disease may have on breastfed infants should be considered. For more complete (16) drug warnings for argatroban, please visit the HSDB record page. Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine, indicated for the prevention or treatment of thrombosis in patients with heparin-induced thrombocytopenia. Argatroban is a direct thrombin inhibitor that reversibly binds to the active site of thrombin. Argatroban's antithrombotic activity does not require the cofactor antithrombin III. Argatroban exerts its anticoagulant effect by inhibiting thrombin-catalyzed or induced reactions (including fibrin formation); activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation. Argatroban is highly selective for thrombin, with an inhibition constant (K_i) of 0.04 μM. At therapeutic concentrations, argatroban has little effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein). Argatroban inhibits the activity of both free thrombin and thrombin-bound thrombin. Objective: Chronic diabetes is associated with cardiovascular dysfunction. Diabetic cardiomyopathy (DCM) is one of the serious cardiovascular complications associated with diabetes. Despite significant efforts to understand the pathophysiology of DCM, its treatment remains unsatisfactory due to its complex pathophysiological mechanisms. In recent years, it has been speculated that protease-activating receptors (PARs) may be involved in the development and progression of cardiovascular disease. These receptors can be activated by thrombin, trypsin, or other serine proteases. PAR expression is elevated in cardiac diseases such as myocardial infarction, viral myocarditis, and pulmonary hypertension. However, the role of PAR in dilated cardiomyopathy (DCM) remains unclear. Therefore, this study used pharmacological methods to investigate the role of PAR in DCM. We used the direct thrombin inhibitor argatroban to target PAR. Methods: Male Sprague-Dawley rats were induced to develop type 2 diabetes mellitus (T2DM) by a high-fat diet combined with a low-dose streptozotocin (STZ 35 mg/kg, single intraperitoneal injection). After 16 weeks of diabetes induction, rats were administered argatroban at doses of 0.3 mg/kg and 1 mg/kg, respectively, once daily for 4 weeks. After 20 weeks, ventricular function was measured using ventricular catheterization. Myocardial fibrosis, DNA fragmentation, and the expression levels of different proteins were assessed using cardiac histology, TUNEL staining, and Western blotting. Results: Type 2 diabetes mellitus is associated with cardiac structural and functional disorders, manifested as impaired cardiac function parameters and increased fibrosis. After 20 weeks of diabetes induction, PAR expression was significantly increased. After 4 weeks of argatroban treatment, metabolic disturbances (decreased plasma glucose and cholesterol), ventricular dysfunction (improved systolic and diastolic function), myocardial fibrosis (decreased percentage of collagen area in picric acid-Sirius red staining), and apoptosis (reduced TUNEL-positive cell nuclei) were all improved. The decreased expression of PAR1 and PAR4 in the argatroban treatment group indicated a response to thrombin inhibition. Furthermore, in argatroban-treated diabetic rats, the expression of AKT (Ser-473), GSK-3β (Ser-9), p-65 NFκB phosphorylation, TGF-β, COX-2, and caspase-3 was significantly decreased, while SERCA expression was significantly increased, suggesting that argatroban has anti-fibrotic, anti-inflammatory, and anti-apoptotic potential in diabetic cardiomyopathy. Conclusion: This study demonstrates that argatroban can improve diabetic cardiomyopathy by improving ventricular function and reducing fibrosis, inflammation, apoptosis, and PAR expression.

C23H38N6O6S

526.653

508.24679

C, 52.45; H, 7.27; N, 15.96; O, 18.23; S, 6.09

141396-28-3

Argatroban;74863-84-6

92721

White to off-white solid powder

1.5±0.1 g/cm3

801.3±75.0 °C at 760 mmHg

-41.5 °C

438.4±37.1 °C

0.0±3.0 mmHg at 25°C

1.674

2.56

6

9

9

36

887

3

S(C1=C([H])C([H])=C([H])C2=C1N([H])C([H])([H])C([H])(C([H])([H])[H])C2([H])[H])(N([H])[C@@]([H])(C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N([H])[H])C(N1C([H])([H])C([H])([H])[C@@]([H])(C([H])([H])[H])C([H])([H])[C@]1([H])C(=O)O[H])=O)(=O)=O.O([H])[H]

AIEZTKLTLCMZIA-CZSXTPSTSA-N

InChI=1S/C23H36N6O5S.H2O/c1-14-8-10-29(18(12-14)22(31)32)21(30)17(6-4-9-26-23(24)25)28-35(33,34)19-7-3-5-16-11-15(2)13-27-20(16)19;/h3,5,7,14-15,17-18,27-28H,4,6,8-13H2,1-2H3,(H,31,32)(H4,24,25,26);1H2/t14-,15?,17+,18-;/m1./s1

(2R,4R)-1-[(2S)-5-(diaminomethylideneamino)-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]pentanoyl]-4-methylpiperidine-2-carboxylic acid;hydrate

MCI-9038; MCI9038; MCI9038; MD-805; MD 805; MD805; DK-7419; DK7419; DK 7419; GN1600; GN-1600; GN 1600; MMTQAP; MPQA; Novastan; Argatroban; OM 805; Argipidine; Slonnon

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~189.88 mM)
H2O : ~1 mg/mL (~1.90 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.75 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)