Early high-dose intravenous immunoglobulin for refractory heparin-induced thrombocytopenia with stroke: Two case reports.

BACKGROUND: High-dose intravenous immunoglobulin (IVIg) can be effective for patients with refractory autoimmune heparin-induced thrombocytopenia (HIT). We report two patients with autoimmune HIT (aHIT) successfully treated with early high-dose IVIg. CASE DESCRIPTION: Case 1 was a 48-year-old male who had persisting HIT with recurrent ischemic stroke after mitral valve replacement. Case 2 was a 71-year-old male who had flush heparin HIT with cerebral venous thrombosis after total hip arthroplasty. High-dose IVIg was administered 6 and 4 days after starting argatroban due to non-improved thrombocytopenia and persistently high D-dimer values, respectively. Both patients achieved favorable functional recovery at discharge as well as improvements of thrombocytopenia and hypercoagulation. CONCLUSIONS: Early high-dose IVIg may be effective for patients with aHIT and hypercoagulability.

Dual Antiplatelet Therapy Plus Argatroban Prevents Early Neurological Deterioration in Branch Atherosclerosis Disease.

[Figure: see text].

Dabigatran Use after Argatroban for Heparin-induced Thrombocytopenia with Thrombosis: A Case Series and Literature Review.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is immune-mediated thrombotic thrombocytopenia following the use of heparin, which contributes to a high limb-amputation rate and mortality if not appropriately handled. There is growing evidence suggesting that novel oral anticoagulants (NOACs) may be effective for treating HIT. METHODS: We described five rare cases of patients with HIT associated with deep vein thrombosis treated with dabigatran, a member of NOACs. We also reviewed representative cases and literature investigating the use of NOACs to treat patients with HIT to further discuss the efficacy and safety. RESULTS AND CONCLUSIONS: Following the treatment of dabigatran after argatroban, the platelet count of patients with HIT gradually elevated and reached the normal range eventually. There was no incidence of new symptomatic, objectively-confirmed arteriovenous thromboembolism observed within the 90-day-period follow up. The patient in case 3 presented with gastric bleeding after dabigatran treatment and died in the end. The results suggested that dabigatran use after argatroban may be effective in the treatment of patients with HIT. However, safety should be reconsidered since severe complications were observed in case 3.

Rivaroxaban and apixaban for the treatment of suspected or confirmed heparin-induced thrombocytopenia.

WHAT IS KNOWN AND OBJECTIVE: Heparin-induced thrombocytopenia (HIT) is an adverse hematologic drug reaction that results in thrombocytopenia. This potentially life-threatening event is due to the administration of heparin products, such as unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH). The incidence of HIT occurs in <0.1%-7% of hospitalized patients treated with heparin products, with a risk of thrombosis as high as 50%. In 2018, the American Society of Hematology (ASH) recommended the utilization of direct oral anticoagulants (DOACs) in clinically stable patients at average bleeding risk with HIT. The objective of this study was to evaluate the prescribing patterns of rivaroxaban and apixaban for the treatment of suspected or confirmed HIT. METHODS: This was a retrospective chart review from January 2013 through October 2019 at the University of Chicago Medicine. Twelve patients were identified to have received a DOAC for suspected or confirmed HIT. RESULTS: Rivaroxaban was utilized in seven (58%) patients, six of whom received argatroban prior to starting rivaroxaban. Five (71%) of these patients were started on the recommended dose of rivaroxaban for VTE. Apixaban was utilized in five (42%) patients; four patients were started on argatroban and transitioned to apixaban. One patient was started on the suggested dose of apixaban for VTE. WHAT IS NEW AND CONCLUSION: After starting DOACs for suspected HIT, no patients had new thrombosis during hospitalization. Eight patients (67%) followed up at our institution within 6 months of their discharge date. No subsequent thrombi formation were identified for any of these patients. The results of this study add to the expanding literature regarding the safety and efficacy of DOAC use in HIT, and indicate DOACs are being increasingly utilized for the treatment of confirmed or suspected HIT.

Using Nonheparin Anticoagulant to Treat a Near-Fatal Case With Multiple Venous Thrombotic Lesions During ChAdOx1 nCoV-19 Vaccination-Related Vaccine-Induced Immune Thrombotic Thrombocytopenia.

OBJECTIVES: To describe the successful recovery from multiple and life-threatening venous thrombosis after ChAdOx1 nCoV-19 vaccination. DESIGN: Case report. SETTING: University Hospital. PATIENT: Few days after the first dose of the ChAdOx1 nCoV-19 vaccine, a 21-year-old woman experienced massive thrombosis in the deep and superficial cerebral veins together with seizures, neurologic focal deficit, and thrombocytopenia. In the neurointensive care unit, her condition worsened despite early decompressive craniectomy. She developed bilateral segmental pulmonary embolism, left hepatic, and left external iliac venous thrombosis. INTERVENTION: Argatroban (0.5-2.2 µg/kg/min) and high-dose IV immunoglobulin (1 g/kg/d for 2 consecutive days) were initiated on day 6 after admission. With these therapies, there was a gradual resolution of multiple sites of venous thrombosis, and platelet count returned to normal. The patient left the ICU with full consciousness, expressive aphasia, and right hemiparesis. CONCLUSIONS: This case of vaccine-induced immune thrombotic thrombocytopenia shows that a good outcome can be obtained even with multiple and life-threatening venous thrombotic lesions. Argatroban and high-dose IV immunoglobulin along with management of severe cerebral venous thrombosis played a major role in this epilogue.

Early argatroban and antiplatelet combination therapy in acute non-lacunar single subcortical infarct associated with mild intracranial atherosclerosis.

BACKGROUND: Patients with acute non-lacunar single subcortical infarct (SSI) associated with mild intracranial atherosclerosis (ICAS) have a relatively high incidence of early neurological deterioration (END), resulting in unfavorable functional outcomes. Whether the early administration of argatroban and aspirin or clopidogrel within 6-12 h after symptom onset is effective and safe in these patients is unknown. METHODS: A review of the stroke database of Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University and Qingdao Center Hospital, Qingdao University Medical College in China was undertaken from May 2017 to January 2020 to identify all patients with non-lacunar SSI caused by ICAS within 6-12 h of symptom onset based on MRI screening. Patients were divided into two groups, one comprising those who received argatroban and mono antiplatelet therapy with aspirin or clopidogrel on admission (argatroban group), and the other those who received dual antiplatelet therapy (DAPT) with aspirin and clopidogrel during hospitalization (DAPT group). The primary outcome was recovery by 90 days after stroke based on a modified Rankin scale (mRS) score (0 to 1). The secondary outcome was END incidence within 120 h of admission. Safety outcomes were intracranial hemorrhage (ICH) and major extracranial bleeding. The probability of clinical benefit (mRS score 0-1 at 90 days) was estimated using multivariable logistic regression analysis. RESULTS: A total of 304 acute non-lacunar SSI associated with mild ICAS patients were analyzed. At 90 days, 101 (74.2%) patients in the argatroban group and 80 (47.6%) in the DAPT group had an mRS score that improved from 0 to 1 (P < 0.001). The relative risk (95% credible interval) for an mRS score improving from 0 to 1 in the argatroban group was 1.50 (1.05-2.70). END occurred in 10 (7.3%) patients in the argatroban group compared with 37 (22.0%) in the DAPT group (P < 0.001). No patients experienced symptomatic hemorrhagic transformation. CONCLUSIONS: Early combined administration of argatroban and an antiplatelet agent (aspirin or clopidogrel) may be beneficial for patients with non-lacunar SSI associated with mild ICAS identified by MRI screening and may attenuate progressive neurological deficits. TRIAL REGISTRATION: Our study is a retrospectively registered trial.

Evaluation of direct thrombin inhibitors during a critical heparin shortage.

A recent heparin shortage related to an outbreak of African Swine Flu in China led to substantial increase in the use of direct thrombin inhibitors (DTI) as an alternative. We evaluated the safety and efficacy of DTIs by assessing the anticoagulation assays within the initial 48 h of therapy comparing before and during shortage. A retrospective evaluation of bivalirudin and argatroban was conducted at a single center before (May 24, 2018 through August 25, 2019) and during heparin shortage (August 26, 2019 through February 20, 2020). The primary outcome was time to first therapeutic activated partial thromboplastin time (aPTT). Secondary outcomes included the percentage of time in therapeutic aPTT range, in-hospital mortality, incidence of recurrent thrombosis, and hemorrhagic events. Of the 204 patients included in the study, 95 patients [bivalirudin (n = 35), argatroban (n = 60)] were included in the pre-shortage cohort and 109 patients [bivalirudin (n = 68), argatroban (n = 41)] were during shortage. No significant difference was observed in the time to first therapeutic aPTT pre- and during shortage (8.9 h ± 10.8 vs 8.8 h ± 10.2, P = 0.62). Compared to pre-shortage cohort, a greater percentage of time was spent in therapeutic aPTT range within the initial 48 h (32% (0-50) vs. 41.6% (0-63), P = 0.04) during shortage without statistically significant differences in the rates of in-hospital mortality, thrombosis, or bleeding. While the optimal DTI protocol is still be determined, the protocols presented in this study allowed for wide-spread utilization of DTIs during a critical heparin shortage without compromising patient safety and effectiveness, likely reflective of the enhancement of DTI protocols, clinician education, and multidisciplinary collaboration and guidance from pharmacy and hematology.

Effect of Argatroban Injection on Clinical Efficacy in Patients with Acute Cerebral Infarction: Preliminary Findings.

OBJECTIVE: The aim is to observe the effects of argatroban injection and butylphthalide injection on blood flow rheology, clinical efficacy, and safety in patients with acute cerebral infarction. METHODS: 344 patients with acute cerebral infarction within 48 h after admission were divided into treatment group and control group, with 172 cases in each group. The control group received routine treatment. The treatment group received argatroban injection 60 mg on the basis of the control group, intravenously guttae (ivgtt) was used for 2 days and then changed to argatroban injection 10 mg, ivgtt bid for 5 days, and the total course of treatment was 7 days. The neurological changes, activities of daily living, and the rheology indicators (fibrinogen [Fib], platelet aggregation rate [Pag], whole blood high shear viscosity [Whsv], hematocrit [Hct]) were compared between the 2 groups, clinical efficacy and adverse drug reactions. RESULTS: After treatment, the total effective rates of the treatment group and the control group were 90.70% (156 /172 cases) and 74.41% (128 and 172 cases), respectively, and the difference was statistically significant (p < 0.05). After treatment, the National Institutes of Health Stroke Scale scores of the treatment group and the control group were (7.05 ± 1.97) and (8.30 ± 1.79), respectively, and the Barthel index was (68.02 ± 11.07) and (62.32 ± 11.46), respectively. The difference was statistically significant (p < 0.05). After treatment, the treatment group and the control group were (2.66 ± 0.22) g/L and (3.50 ± 0.22) g/L, respectively, and Pag were (0.68 ± 0.06)% and (0.81 ± 0.09)%, respectively, and Whsv was (6.44 ± 0.76) mPs/s and (6.87 ± 0.91) mPs/s, Hct were (8.19 ± 1.21)% and (10.44 ± 1.04)%, respectively, and the differences were statistically significant (p < 0.05). The incidence of adverse reactions in the treatment group and the control group was 6.97 and 5.81%, respectively, and the difference was not statistically significant (p > 0.05). CONCLUSION: Argatroban injection is effective in the treatment of acute cerebral infarction, which can significantly improve the hemorheology of patients with good safety.

Aortic Arch Thrombus and Pulmonary Embolism in a COVID-19 Patient.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with endothelial inflammation and a hypercoagulable state resulting in both venous and arterial thromboembolic complications. We present a case of COVID-19-associated aortic thrombus in an otherwise healthy patient. CASE REPORT: A 53-year-old woman with no past medical history presented with a 10-day history of dyspnea, fever, and cough. Her pulse oximetry on room air was 84%. She tested positive for severe acute respiratory syndrome coronavirus 2 infection, and chest radiography revealed moderate patchy bilateral airspace opacities. Serology markers for cytokine storm were significantly elevated, with a serum D-dimer level of 8180 ng/mL (normal < 230 ng/mL). Computed tomography of the chest with i.v. contrast was positive for bilateral ground-glass opacities, scattered filling defects within the bilateral segmental and subsegmental pulmonary arteries, and a large thrombus was present at the aortic arch. The patient was admitted to the intensive care unit and successfully treated with unfractionated heparin, alteplase 50 mg, and argatroban 2 µg/kg/min. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Mural aortic thrombus is a rare but serious cause of distal embolism and is typically discovered during an evaluation of cryptogenic arterial embolization to the viscera or extremities. Patients with suspected hypercoagulable states, such as that encountered with COVID-19, should be screened for thromboembolism, and when identified, aggressively anticoagulated.

Randomized trial of argatroban plus recombinant tissue-type plasminogen activator for acute ischemic stroke (ARAIS): Rationale and design.

BACKGROUND: Previous studies have implied the efficacy and safety of argatroban plus recombinant tissue-type plasminogen activator (r-tPA) in patients with acute ischemic stroke. Further trials are needed to establish convincing conclusions in a large sample size. RESEARCH DESIGN AND METHODS: Argatroban plus r-tPA for Acute Ischemic Stroke (ARAIS) trial is a multicenter, prospective, randomized, open-label, and blind-end point trial. The trial proposes to randomize 808 patients with acute ischemic stroke National Institutes of Health Stroke Scale (NIHSS score≥ 6 at the time of randomization) within 4.5 hours of symptom onset to receive argatroban (100 µg/kg bolus followed by an infusion of 1.0 µg/kg per minute for 48 hours) plus r-tPA or r-tPA alone. The primary end point is the proportion of patients with an excellent outcome of no clinically significant residual stroke deficits (modified Rankin scale 0-1) at 90 days. Secondary end points include the proportion of patients with a good outcome (modified Rankin scale 0-2) at 90 days, early neurological improvement (NIHSS score ≥2-point decrease) at 48 hours, early neurological deterioration (NIHSS score ≥4-point increase) at 48 hours, decrease in the NIHSS score from baseline to 14 days, and stroke recurrence or other vascular events at 90 days. Safety end points include symptomatic intracerebral hemorrhage, parenchymal hematoma type 2, and major systemic bleeding. CONCLUSION: ARAIS trial will evaluate whether argatroban plus r-tPA is superior to r-tPA alone in improving functional outcomes in acute ischemic stroke patients in a large sample population.

Clinical study of argatroban for preventing vascular thrombosis in the early period after pediatric living-related donor liver transplantation.

OBJECTIVE: To evaluate the effect of heparin and argatroban on coagulation function and vascular thrombosis in the early period after pediatric LRDLT. METHOD: Eighty-four congenital biliary atresia pediatric patients who had undergone LRDLT were studied. Patients were divided into two groups according to the method of anticoagulation (heparin or argatroban). AT-Ⅲ activity, APTT, and INR of the two groups were measured in the first 5 days after LRDLT. Vascular thrombosis was investigated by Doppler ultrasound daily. RESULTS: There were no significant differences in gender, age, weight, graft-recipient weight ratio, and Kasai procedure between the two groups. The AT-Ⅲ activity of the two groups was low and increased gradually after surgery, with no significant difference between the two groups. There was no significant difference of APTT between the two groups immediately after and in the first day after surgery. After anticoagulation treatment, a significant difference in APTT between the two groups was observed. The incidences of vascular thrombosis were 4.76% (3/63) and 0% (0/21) in the heparin and argatroban groups, respectively, with no significant difference between the two groups. During the treatment, no serious complications such as active hemorrhage or drug allergy were observed in the two groups. CONCLUSION: Argatroban is a direct anticoagulant, which is independent of AT-Ⅲ activity. Argatroban might be an alternative to heparin in uncomplicated LRDLT with recovered hepatic and coagulation function.

Argatroban Increased the Basal Vein Drainage and Improved Outcomes in Acute Paraventricular Ischemic Stroke Patients.

BACKGROUND Since venous drainage in acute arterial ischemic stroke has not been thoroughly researched, we evaluate the effect of argatroban, a selective direct thrombin inhibitor, as a therapy to increase the rate of basal vein Rosenthal (BVR) drainage and improve patients' post-stroke outcomes. MATERIAL AND METHODS In this multicenter clinical trial, 60 eligible patients at 4.5 to 48 hours after the stroke onset were recruited. After being randomly allocated into 2 groups, they were treated with standard therapy either alone or with argatroban. RESULTS Compared to the contralateral brain hemisphere, the mean flow velocity (MFV) in BVR drainage was significantly reduced in the stroke-afflicted ipsilateral hemisphere. After treatment with argatroban for 7 days, the MFV from BVR of the ipsilateral hemisphere in the argatroban treated group was significantly increased when compared to the control group. At 90 days after the onset of stroke, the MFV of BVR in the ipsilateral hemisphere was similar in both groups. Compared with controls, the argatroban-treated patients had smaller lesions from baseline to 7 days. Argatroban also improved National Institutes of Health Stroke Scale (NIHSS) scores on day 7 after the onset of stroke. Furthermore, the argatroban group's neurological functions were superior to those of their untreated counterparts after 90 days. No difference was found in the incidence of adverse reactions between the 2 groups. CONCLUSIONS These observations indicate that vein drainage change may contribute to the acute phase of brain edema and the outcomes of ischemic stroke patients.

Prostate-Specific Membrane Antigen-Specific Antitumor Activity of a Self-Immolative Tubulysin Conjugate.

Prostate-specific membrane antigen (PSMA) is a biomarker that is overexpressed on prostate cancer, and it is also present on the neovasculature within many non-prostate solid tumors. Herein, we report on the construction and biological testing of novel tubulysin B-containing therapeutic agents for the treatment of PSMA-expressing cancer. One of these compounds, EC1169, emerged as a lead candidate for preclinical development and phase 1 clinical testing. This water-soluble conjugate was shown to have high affinity for PSMA-positive cells. When tested in vitro, EC1169 was found to inhibit the growth of PSMA-positive cells, but it displayed no activity against PSMA-negative cells. Brief treatment of nude mice bearing PSMA-positive LNCaP human xenografts with EC1169 led to complete remissions and cures. Furthermore, this activity occurred in the absence of weight loss. In contrast, the nontargeted tubulysin B drug proved to be inactive against the LNCaP tumor model when administered at doses near to or greater than the maximum tolerated level. PSMA-negative KB tumors did not appreciably respond to EC1169 therapy, thereby confirming this compound's targeted specificity for PSMA-positive cells. Finally, treatment of LNCaP-bearing mice with docetaxel (the most active chemotherapeutic agent approved for late stage prostate cancer therapy) was found to produce only modest anti-tumor activity, and this outcome was also associated with severe weight loss. Taken together, these results strongly indicate that PSMA-positive tumors may be effectively treated using highly potent, PSMA-targeted small-molecule drug conjugates using regimens that do not cause undesirable side effects.

Heparin-Induced Thrombocytopenia in Infants after Heart Surgery.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) in infants is a rare disorder, and the diagnosis and management of HIT still remains challenging. Argatroban is a synthetic direct thrombin inhibitor (DTI) that is widely used for treating HIT. However, little is known about the efficacy of the activated clotting time (ACT) test in monitoring DTI treatment as an alternative to the routinely used activated partial thromboplastin time (aPTT). METHODS: Between July 2013 and January 2015, four infants were diagnosed with HIT after surgical correction of congenital anomalies. In all cases, heparin was used during cardiopulmonary bypass (CPB). Diagnosis of HIT was based on the "4 Ts" pretest clinical scoring system, and platelet factor 4 (PF4) antibody was detected using enzyme-linked immunosorbent assay. Argatroban was used in treating HIT. When argatroban was infused, anticoagulation tests (aPTT, prothrombin time [PT], thrombin time [TT], and fibrinogen) were performed every 4 to 12 hours. ACT was used in addition to monitor the anticoagulation effect of argatroban. The target ACT was 1.5 to 3.0 times the baseline. ACT was measured every 2 to 4 hours and remeasured 1 hour after each dosage adjustment. RESULTS: Thrombocytopenia (defined as a 50% decrease in platelet count) occurred during the 3rd to 6th day postoperatively. After the diagnosis of HIT, argatroban was started immediately, and platelet counts stabilized and gradually increased. Anticoagulation effect of argatroban was successful monitored by ACT and aPTT. Poor correlation between the ACT test and aPTT test (R = 0.270, p = 0.092) was noted in one patient. ACT values increased rapidly after 3 to 7 days on argatroban treatment. In most cases, low dosage of argatroban was given ranging from 0.04 to 5.00 µg/kg/min. CONCLUSION: Argatroban may be an effective medicine in treating HIT in infants, in a reduced dosage. The great fluctuation in argatroban dosage during the course of HIT treatment necessitates close monitoring. ACT test may be reliable and convenient for monitoring HIT treatment and may contribute to positive clinical outcomes in infants. The efficacy of argatroban and the use of ACT monitoring in the management of HIT infants needs further study.

A 24-hour perioperative case study on argatroban use for left ventricle assist device insertion during cardiopulmonary bypass and veno-arterial extracorporeal membrane oxygenation.

A 44-year-old male with ongoing chest pain and left ventricular ejection fraction <20% was transferred from a peripheral hospital with intra-aortic balloon pump placement following a non-ST-elevation myocardial infarction (STEMI). The patient underwent emergent multi-vessel coronary artery bypass grafting requiring veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) on post-operative day (POD)#9 secondary to cardiogenic shock with biventricular failure. Due to clot formation, an oxygenator change-out was necessary shortly after initiation. Following a positive heparin-induced thrombocytopenia (HIT) assay, a total circuit exchange was required to eliminate all heparin coating and argatroban was deemed the anticoagulant of choice due to acute kidney injury. On POD#24, the decision was made to implant a left ventricle assist device (LVAD) as a bridge to heart transplantation. There was difficulty achieving an activated clotting time (ACT) >400 s: multiple argatroban bolus doses were required, along with accelerated up-titration of infusion dosing. Despite maintaining an ACT >484 s, clot formation was observed in the cardiotomy reservoir prior to separation. Subsequently, the patient developed severe disseminated intravascular coagulopathy, with both intra-cardiac and intravascular thrombi, requiring massive transfusion and continuous cell saving due to severe hemorrhage post cardiopulmonary bypass (CPB). The patient received a total of 105 units of plasma, 74 units of packed red cells, 19 units of platelets, 13 bottles of 5% albumin, 6 units of cryoprecipitate and 2 doses of factor VIIa intraoperatively over the course of 24 hours. A total of 19.7 L of washed red blood cells were returned to the patient from the cell saver. With the LVAD in place, the patient developed transfusion-related acute lung injury and acute respiratory distress syndrome with right ventricular dysfunction requiring VA ECMO once again. On POD#30, ECMO was discontinued and the patient was discharged from the intensive care unit (ICU) on POD 66. After a very complex post-operative stay with numerous surgeries and extensive rehabilitation, the patient was discharged home with the LVAD on POD#112.

Targeted Tubulysin B Hydrazide Conjugate for the Treatment of Luteinizing Hormone-Releasing Hormone Receptor-Positive Cancers.

The targeted delivery of chemotherapeutic agents to receptors that are overexpressed on cancer cells has become an attractive strategy to concentrate drugs in cancer cells while avoiding uptake by healthy cells. Luteinizing hormone-releasing hormone receptor (LHRH-R) has attracted considerable interest for this application, since LHRH-R is upregulated in ∼86% of prostate cancers, ∼80% of endometrial cancers, ∼80% of ovarian cancers, and ∼50% of breast cancers, but virtually absent from normal tissues. Although LHRH and related peptides have been used to deliver cytotoxic drugs to LHRH-R overexpressing cancer cells, they have suffered from off-target delivery of the therapeutic agents to the liver and kidneys. To reduce such unwanted uptake by peptide scavenger receptors in the liver and kidneys, we have explored the use of a nonpeptidic LHRH-R antagonist (NBI42902) to construct an LHRH-R targeted tubulysin conjugate (BOEPL-L3-TubBH). In vitro studies with BOEPL-L3-TubBH demonstrate that the conjugate can kill LHRH-R expressing triple-negative breast cancer cells (MDA-MB-231 cells) with low nanomolar IC50. Related studies on tumor-bearing mice further reveal that the same conjugate can eradicate MDA-MB-231 solid tumors without any measurable side-effects, yielding mice that gain weight during therapy and show no evidence of tumor recurrence for at least 5 weeks after termination of treatment. That these complete responses are LHRH-R targeted was then established by showing that identical treatment of receptor-negative (SKOV3) tumors yields no antitumor response. Overall, these data provide a proof-of-concept that LHRH-R specific targeting of an extremely toxic drug like tubulysin B can treat LHRH-R positive tumors without causing significant toxicity to healthy cells.

Development of a Small Molecule Tubulysin B Conjugate for Treatment of Carbonic Anhydrase IX Receptor Expressing Cancers.

Carbonic anhydrase IX (CAIX) is a membrane-spanning zinc metalloenzyme that catalyzes the reversible consumption of CO2 and water to form H+ + HCO3-. Many human cancers upregulate CAIX to help control the pH in their hypoxic microenvironments. The consequent overexpression of CAIX on malignant cells and low expression on normal tissues render CAIX a particularly attractive target for small molecule inhibitors, antibody-drug conjugates, and ligand-targeted drugs. In this study, CAIX-targeted fluorescent reporter molecules were initially exploited to investigate CAIX-specific binding to multiple cancer cell lines, where they were shown to display potent and selective binding to CAIX positive cells. A small molecule CAIX-targeted tubulysin B conjugate was then synthesized and examined for its ability to kill CAIX-expressing tumor cells in vitro. Potent therapeutic conjugates were subsequently tested in vivo and demonstrated to eliminate solid human tumor xenografts in murine tumor models without exhibiting overt signs of toxicity. Because most solid tumors contain hypoxic regions where CAIX is overexpressed, development of a method to selectively deliver drugs to these hypoxic regions could aid in the therapy of otherwise difficult to treat tumors.

Heparin-induced thrombocytopaenia.

Heparin-induced thrombocytopaenia (HIT) is a severe and potentially life-threatening adverse drug reaction. Patients become extremely hypercoagulable, and this can lead to life-threatening and limb-threatening thrombosis with a mortality of 5%-10%. HIT is an antibody-mediated process in which platelet activation occurs. Diagnosis requires a high index of suspicion along with a scoring system and laboratory testing. Patients suspected of having HIT must not receive any further heparin or low-molecular weight heparin and must be started on an alternative anticoagulant such as argatroban or danaparoid. Fondaparinux may also be considered but is not licenced for this indication.

Retrospective Analysis of Argatroban in 353 Patients with Acute Noncardioembolic Stroke.

BACKGROUND: Argatroban is a thrombin inhibitor agent for acute noncardioembolic ischemic stroke in Japan. We studied the prognosis in patients with acute stroke treated by argatroban in comparison with the control group with ozagrel in our hospital. SUBJECTS AND METHODS: A total of 513 patients with acute noncardioembolic ischemic stroke were enrolled retrospectively from our hospital database. Of all patients with stroke, 353 were administered with argatroban. The other 160 control patients were administered with ozagrel. The patients were examined as to their stroke types, the neurological severity according to the National Institutes of Health Stroke Scale (NIHSS), and clinical outcomes on discharge were determined according to the modified Rankin Scale (mRS). RESULTS: A total of 353 patients with acute noncardioembolic stroke, including 138 with lacunar infarction (LIs) and 215 with atherothrombotic infarction (ATI) showed functional recovery by argatroban, but the effectiveness of argatroban was not superior to ozagrel therapy defined by the control group. A total of 255 patients with ATI who were treated with both argatroban and ozagrel showed improvement by 1 point. We could not find any significant difference between argatroban and ozagrel in the 2 stroke subtypes, LI and ATI. We also found that combination therapy of argatroban and edaravone was not superior to argatroban monotherapy in clinical outcome. CONCLUSIONS: Argatroban therapy was not superior to control with ozagrel therapy in acute noncardioembolic ischemic stroke, including LI and ATI, regardless of the use of edaravone.