Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting

Abstract Managing patients in the perioperative setting receiving novel oral anticoagulation agents for thromboprophylaxis or stroke prevention with atrial fibrillation is an important consideration for clinicians. The novel oral anticoagulation agents include direct Factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran. In elective surgery, discontinuing their use is important, but renal function must also be considered because elimination is highly dependent on renal elimination. If bleeding occurs in patients who have received these agents, common principles of bleeding management as with any anticoagulant (including the known principles for warfarin) should be considered. This review summarizes the available data regarding the management of bleeding with novel oral anticoagulation agents. Hemodialysis is a therapeutic option for dabigatran-related bleeding, while in vitro studies showed that prothrombin complex concentrates are reported to be useful for rivaroxaban-related bleeding. Additional clinical studies are needed to determine the best method for reversal of the novel oral anticoagulation agents when bleeding occurs.

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Synthetic and semi-synthetic drugs as promising therapeutic option for the treatment of COVID-19

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666201204162103 ◽

2020 ◽

Vol 20 ◽

Author(s):

Ekta Shirbhate ◽

Preeti Patel ◽

Vijay K Patel ◽

Ravichandran Veerasamy ◽

Prabodh C Sharma ◽

...

Keyword(s):

Therapeutic Option ◽

Antiviral Treatment ◽

The Novel ◽

Clinical Experiences ◽

Synthetic Compounds ◽

Synthetic Drugs ◽

Global Pandemic ◽

The World ◽

Novel Coronavirus

: The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China has today travelled all around the world, so far 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 update dated August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine prevails. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID-19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in their clinical experiences or studies against COVID-19 and also focuses on mode of action of drugs being repositioned against COVID-19.

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Use of Oral Anticoagulation and Diabetes Do Not Inhibit the Angiogenic Potential of Hypoxia Preconditioned Blood-Derived Secretomes

Biomedicines ◽

10.3390/biomedicines8080283 ◽

2020 ◽

Vol 8 (8) ◽

pp. 283 ◽

Cited By ~ 1

Author(s):

Philipp Moog ◽

Maryna Jensch ◽

Jessica Hughes ◽

Burak Salgin ◽

Ulf Dornseifer ◽

...

Keyword(s):

Oral Anticoagulation ◽

Oral Anticoagulants ◽

Vascular Endothelial ◽

Platelet Factor ◽

Angiogenic Potential ◽

Tissue Ischemia ◽

The Past ◽

Endothelial Cell Cultures ◽

Endothelial Growth Factor

Patients suffering from tissue ischemia, who would greatly benefit from angiogenesis-promoting therapies such as hypoxia preconditioned blood-derived secretomes commonly receive oral anticoagulation (OA) and/or have diabetes mellitus (DM). In this study, we investigated the effect of OA administration on the in vitro angiogenic potential of hypoxia preconditioned plasma (HPP) and serum (HPS), prepared from nondiabetic/diabetic subjects who did not receive OA (n = 5) or were treated with acetylsalicylic acid (ASA, n = 8), ASA + clopidogrel (n = 10), or nonvitamin K antagonist oral anticoagulants (n = 7) for longer than six months. The effect of DM was differentially assessed by comparing HPP/HPS obtained from nondiabetic (n = 8) and diabetic (n = 16) subjects who had not received OA in the past six months. The concentration of key proangiogenic (vascular endothelial growth factor or VEGF) and antiangiogenic (thrombospondin-1 or TSP-1 and platelet factor-4 or PF-4) protein factors in HPP/HPS was analyzed via ELISA, while their ability to induce microvessel formations was examined in endothelial cell cultures. We found that OA use significantly reduced VEGF levels in HPP, but not HPS, compared to non-OA controls. While HPP and HPS TSP-1 levels remained largely unchanged as a result of OA usage, HPS PF-4 levels were significantly reduced in samples obtained from OA-treated subjects. Neither OA administration nor DM appeared to significantly reduce the ability of HPP or HPS to induce microvessel formations in vitro. These findings indicate that OA administration does not limit the angiogenic potential of hypoxia preconditioned blood-derived secretomes, and therefore, it does not prohibit the application of these therapies for supporting tissue vascularization and wound healing in healthy or diabetic subjects.

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Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma

Cells ◽

10.3390/cells10102503 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2503

Author(s):

Hitomi Sudo ◽

Atsushi B. Tsuji ◽

Aya Sugyo ◽

Mika K. Kaneko ◽

Yukinari Kato ◽

...

Keyword(s):

Malignant Mesothelioma ◽

Competitive Inhibition ◽

Therapeutic Option ◽

The Novel ◽

Absorbed Doses ◽

Biodistribution Studies ◽

Biodistribution Data ◽

Body Weights ◽

Necrotic Change

The prognosis of advanced mesothelioma is poor. Podoplanin (PDPN) is highly expressed in most malignant mesothelioma. This study aimed to evaluate the potential alpha-radioimmunotherapy (RIT) with a newly developed anti-PDPN antibody, NZ-16, compared with a previous antibody, NZ-12. Methods: The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing H226 mesothelioma cells. The biodistribution of 111In-labeled antibodies was studied in tumor-bearing mice. The absorbed doses were estimated based on biodistribution data. Tumor volumes and body weights of mice treated with 90Y- and 225Ac-labeled NZ-16 were measured for 56 days. Histologic analysis was conducted. Results: The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ-12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12, providing higher absorbed doses to tumors. RIT with 225Ac- and 90Y-labeled NZ-16 had a significantly higher antitumor effect than RIT with 90Y-labeled NZ-12. 225Ac-labeled NZ-16 induced a larger amount of necrotic change and showed a tendency to suppress tumor volumes and prolonged survival than 90Y-labeled NZ-16. There is no obvious adverse effect. Conclusions: Alpha-RIT with the newly developed NZ-16 is a promising therapeutic option for malignant mesothelioma.

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Abstract P233: Inhibition Of Aldosterone Synthesis In Non-human Primates By PB6440, The Novel Highly Selective And Potent CYP11B2 Inhibitor

Hypertension ◽

10.1161/hyp.76.suppl_1.p233 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Bertram Pitt ◽

Deepak L Bhatt ◽

Karen Morris ◽

J. David Becherer ◽

William Hoekstra ◽

...

Keyword(s):

Oral Bioavailability ◽

Multiple Dose ◽

Therapeutic Option ◽

Dependent Manner ◽

The Novel ◽

Aldosterone Synthase ◽

Acth Challenge ◽

High Doses ◽

Synthase Inhibitor

Aldosterone is an important mineralocorticoid responsible for fluid and electrolyte homeostasis produced by aldosterone synthase (CYP11B2). An aldosterone synthase inhibitor (ASI) may be a therapeutic option for primary aldosteronism-related conditions such as resistant hypertension. An ASI with sufficient selectivity for CYP11B2 versus the similar cortisol-producing enzyme CYP11B1 has remained elusive. PB6440 is a novel ASI that is potent and highly selective for CYP11B2. In vitro studies demonstrated 200-300-fold selectivity of PB6440 for human CYP11B2 compared to human CYP11B1. In single and multiple dose cynomolgus monkey studies of orally administered PB6440, dose-and concentration-dependent reduction of plasma aldosterone after ACTH challenge was observed with >90% reduction at higher doses. Consistent with its high selectivity, PB6440 had little effect on the CYP11B1 cortisol pathway. Plasma levels of cortisol, 11-deoxycortisol, and deoxycorticosterone, remained unchanged even at high doses of PB6440. Systolic and diastolic blood pressure was reduced in a dose-dependent manner. Circulating half-life of PB6440 was approximately 17 hours with high oral bioavailability. In summary, PB6440 is a highly selective ASI that demonstrated sustained aldosterone suppression for 14 days with no effect on the CYP11B1 pathway in non-human primates. In single and multiple dose studies, PB6440 appeared well tolerated, demonstrating good oral bioavailability, and a PK profile supportive of once daily dosing. These results suggest that PB6440 may be useful in humans as a novel therapeutic for treating hypertension or other conditions caused by excess aldosterone.

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Treatment of Darier’s disease with oral magnesium: a case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x18795071 ◽

2018 ◽

Vol 6 ◽

pp. 2050313X1879507

Author(s):

Heidi Oi-Yee Li ◽

Sophia Colantonio ◽

Nordau Kanigsberg

Keyword(s):

Endoplasmic Reticulum ◽

Magnesium Chloride ◽

Therapeutic Option ◽

The Novel ◽

Darier’S Disease ◽

Darier Disease ◽

Darier's Disease ◽

Effective Therapeutic Option ◽

Oral Magnesium

Darier’s disease, an autosomal dominant genodermatosis, arises from a mutation in the ATP2A2 gene that codes for sarco/endoplasmic reticulum Ca2+-ATPase in the endoplasmic reticulum and is characterized by greasy keratotic papules commonly found in seborrheic regions. Conventional treatments, including topical corticosteroids, antibiotics, antifungals and retinoids, often have limited efficacy. The present article reports the novel use of oral magnesium chloride supplementation (300 mg daily) in the treatment of Darier disease. After 5 years of limited improvement using conventional therapies, significant improvements in neck lesions were observed within 1 month of starting oral magnesium chloride. This suggests that oral magnesium chloride may be an effective therapeutic option for Darier disease, although further in vitro and clinical trials are necessary to evaluate its clinical efficacy.

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Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with The Novel Antibody NZ-16 for Malignant Mesothelioma

10.21203/rs.3.rs-691419/v1 ◽

2021 ◽

Author(s):

Hitomi Sudo ◽

Atsushi B Tsuji ◽

Aya Sugyo ◽

Mika K. Kaneko ◽

Yukinari Kato ◽

...

Keyword(s):

Malignant Mesothelioma ◽

Competitive Inhibition ◽

Therapeutic Option ◽

Body Weight Loss ◽

The Novel ◽

Ki 67 ◽

Absorbed Doses ◽

Biodistribution Studies ◽

Biodistribution Data

Abstract Purpose This study aimed to evaluate the potential of podoplanin (PDPN)-targeted alpharadiotherapy (RIT) for treating malignant mesothelioma.Methods A newly developed anti-PDPN antibody, NZ-16, and a previous anti-PDPN antibody, NZ-12, were assessed. The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing NCI-H226 (H226) mesothelioma cells. The biodistribution of 111 In-labeled antibodies was studied in tumorbearing mice. Tumor volumes and body weights of mice treated with 90 Y- and 225 Ac-labeled NZ-16 were measured for 56 days. The absorbed doses were estimated on the basis of the biodistribution data. Pathologic analysis of tumors and organs was conducted.Results The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12. RIT with 225 Ac-labeled NZ-16 (11.1 and 18.5 kBq) had a significantly higher antitumor effect than RIT with 90 Y-labeled NZ-16 (3.7 MBq; P < 0.01). 225 Ac-labeled NZ-16 induced more necrosis compared with 90 Y-labeled NZ-16, but the Ki-67 index and apoptosis rate were similar. The estimated absorbed doses were expected to be tolerable in mice. Temporary body weight loss occurred, but recovered within several days. No visible damage to major organs was detected.Conclusion The novel anti-PDPN antibody NZ-16 was a more effective RIT agent than NZ12. Radiolabeled NZ-16, especially 225 Ac-labeled NZ-16, markedly suppressed tumor growth and prolonged survival without inducing severe adverse effects. RIT with radiolabeled NZ-16 is a promising therapeutic option for malignant mesothelioma.

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New oral anticoagulant drugs in cardiovascular disease

Thrombosis and Haemostasis ◽

10.1160/th09-05-0327 ◽

2010 ◽

Vol 104 (07) ◽

pp. 49-60 ◽

Cited By ~ 151

Author(s):

Gregory Lip ◽

Karlheinz Peter ◽

Ingo Ahrens

Keyword(s):

Cardiovascular Disease ◽

Oral Anticoagulation ◽

Clinical Investigation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Novel Oral Anticoagulants ◽

Response To Treatment ◽

Coagulation System ◽

Thrombin Inhibitor

SummaryOral anticoagulation has been limited to vitamin K antagonists (VKAs) for over 60 years. VKAs are effective and recommended for the prevention of venous and arterial thromboembolism in cardiovascular disease, but their pharmacodynamics are difficult to predict and the highly variable interindividual and intraindividual response to treatment accounts for the need of continuous monitoring. This prompted the intensive exploration of numerous substances within the last decade in an attempt to meet the shortcomings of current oral anticoagulation with VKAs. The development and clinical investigation of two novel groups of oral anticoagulants targeting central factors of the coagulation system either factor Xa or thrombin (factor IIa) has now reached the daily clinical practice with the approval of the oral direct thrombin inhibitor dabigatran etexilate and the oral direct factor Xa inhibitor rivaroxaban. Ongoing clinical trials are investigating these substances and other novel oral anticoagulants with similar mechanisms of action in patients with atrial fibrillation and acute coronary syndromes. This review article discusses the clinical evaluation and pharmacological properties of novel oral anticoagulants in late and earlier stages of clinical development, thereby providing a critical analysis and an outlook on the future of oral anticoagulation in cardiovascular disease.

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Role of non-macrophage cell-derived HMGB1 in oxaliplatin-induced peripheral neuropathy and its prevention by the thrombin/thrombomodulin system in rodents: negative impact of anticoagulants

Journal of Neuroinflammation ◽

10.1186/s12974-019-1581-6 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 10

Author(s):

Maho Tsubota ◽

Ryotaro Fukuda ◽

Yusuke Hayashi ◽

Takaya Miyazaki ◽

Shin Ueda ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Negative Impact ◽

Oral Anticoagulants ◽

Intraperitoneal Administration ◽

Raw264.7 Cells ◽

Thrombin Inhibitor ◽

Enzyme Linked Immunosorbent Assay ◽

Causative Role

Abstract Background Macrophage-derived high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, plays a key role in the development of chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel in rodents. Endothelial thrombomodulin (TM) promotes thrombin-induced degradation of HMGB1, and TMα, a recombinant human soluble TM, abolishes peripheral HMGB1-induced allodynia in mice. We thus examined whether HMGB1, particularly derived from macrophages, contributes to oxaliplatin-induced neuropathy in mice and analyzed the anti-neuropathic activity of the TM/thrombin system. Methods CIPN models were created by the administration of oxaliplatin in mice and rats, and the nociceptive threshold was assessed by von Frey test or paw pressure test. Macrophage-like RAW264.7 cells were stimulated with oxaliplatin in vitro. Proteins were detected and/or quantified by Western blotting, immunostaining, or enzyme-linked immunosorbent assay. Results Intraperitoneal administration of an anti-HMGB1-neutralizing antibody (AB) at 1 mg/kg prevented the oxaliplatin-induced allodynia in mice and rats. Antagonists of Toll-like receptor (TLR) 4, receptor for advanced glycation end products (RAGE) and CXCR4 among the HMGB1-targeted pro-nociceptive receptors, also mimicked the anti-neuropathic activity of AB in mice. Macrophage accumulation in the sciatic nerve was observed in mice treated with paclitaxel, but not oxaliplatin, and neither macrophage depletion nor inhibitors of macrophage activation affected oxaliplatin-induced allodynia. Oxaliplatin was 10- to 100-fold less potent than paclitaxel in releasing HMGB1 from macrophage-like RAW264.7 cells. Like AB, TMα at 10 mg/kg prevented the oxaliplatin-induced allodynia in mice as well as rats, an effect abolished by argatroban at 10 mg/kg, a thrombin inhibitor. The anti-neuropathic activity of TMα in oxaliplatin-treated mice was suppressed by oral anticoagulants such as warfarin at 1 mg/kg, dabigatran at 75 mg/kg, and rivaroxaban at 10 mg/kg, but not antiplatelet agents such as aspirin at 50 mg/kg and clopidogrel at 10 mg/kg. Repeated administration of the anticoagulants gradually developed neuropathic allodynia and elevated plasma HMGB1 levels in mice treated with a subeffective dose of oxaliplatin. Conclusions Our data thus suggests a causative role of HMGB1 derived from non-macrophage cells in oxaliplatin-induced peripheral neuropathy and a thrombin-dependent anti-neuropathic activity of exogenous TMα and, most probably, endogenous TM.

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Spectrophotometric Assays of Prothrombin in Plasma of Patients Using Oral Anticoagulants

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657025 ◽

1979 ◽

Vol 42 (04) ◽

pp. 1296-1305 ◽

Cited By ~ 29

Author(s):

R M Bertina ◽

W van der Marel-van Nieuwkoop ◽

E A Loeliger

Keyword(s):

Prothrombin Time ◽

Vitamin K ◽

Oral Anticoagulation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Factor V ◽

Anticoagulant Treatment ◽

Factor Ii ◽

K Deficiency

SummaryTwo spectrophotometric assays for prothrombin have been developed and compared with a one stage coagulant and an immunological assay. One of these assays (called the XAPC assay) uses a combination of factor Xa, phospholipid, Ca2+ and factor V as activator of prothrombin, and measures only normal prothrombin. The second (the ECAR assay) uses Echis carinatus venom as activator. This assay measures both normal prothrombin and PIVKA II (protein induced by vitamin K antagonists/absence). Combination of the results obtained by the XAPC and ECAR assays provides rapid and reliable information on the degree of “subcarboxylation” of prothrombin (oral anticoagulation, vitamin K deficiency).For patients on long term anticoagulant treatment the prothrombin time (Thrombotest) shows better correlation with the ratio prothrombin/prothrombin plus PIVKA II (XAPC/ ECAR) than with the factor II concentration. For patients starting the anticoagulant treatment there is no correlation between the Thrombotest time and the XAPC/ECAR ratio.It seems doubtful that (a) spectrophotometric factor II assay(s) will be as useful as the prothrombin time in the control of oral anticoagulation.

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Combined Thrombin and Platelet Inhibition Treatment for HIT Patients

Hämostaseologie ◽

10.1055/s-0038-1660400 ◽

1999 ◽

Vol 19 (03) ◽

pp. 128-133 ◽

Cited By ~ 1

Author(s):

B.E. Lewis ◽

W. P. Jeske ◽

F. Leya ◽

Diane Wallis ◽

M. Bakhos ◽

...

Keyword(s):

Standard Dose ◽

Combined Therapy ◽

Platelet Inhibition ◽

Thrombin Inhibitors ◽

Thrombin Inhibitor ◽

Heparin Induced Thrombocytopenia ◽

Acute Thrombosis ◽

Anti Platelet Drug ◽

Receptor Inhibitor

SummaryDespite the use of potent anticoagulants such as r-hirudin and argatroban, the morbidity and mortality in heparin-induced thrombocytopenia (HIT) patients remains unacceptable. Data from our in vitro investigations show that thrombin inhibitors do not block platelet activation induced by heparin antibodies and heparin but that GPIIb/IIIa receptor inhibitors do block this process. We have treated four HIT positive patients with a combined therapy of thrombin inhibitor and GPIIb/IIIa receptor inhibitor when treatment with thrombin inhibitor alone failed to alleviate acute thrombosis. Combination therapies included r-hirudin (Refludan®) with tirofiban (Aggrastat®) and argatroban (Novastan®) with abciximab (ReoPro®). A reduced dose of the thrombin inhibitor was used with the standard dose of the anti-platelet drug. In all cases, there was no overt bleeding which required intervention, and all patients exhibited clinical improvement or full recovery. These case studies suggest that treatment of active thrombosis in HIT patients with adjunct GPIIb/IIIa receptor inhibitor therapy may be more effective than thrombin inhibitor treatment alone.

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