Pharmacological Activities and Mechanisms of Hirudin and Its Derivatives - A Review

Hirudin, an acidic polypeptide secreted by the salivary glands of Hirudo medicinalis (also known as “Shuizhi” in traditional Chinese medicine), is the strongest natural specific inhibitor of thrombin found so far. Hirudin has been demonstrated to possess potent anti-thrombotic effect in previous studies. Recently, increasing researches have focused on the anti-thrombotic activity of the derivatives of hirudin, mainly because these derivatives have stronger antithrombotic activity and lower bleeding risk. Additionally, various bioactivities of hirudin have been reported as well, including wound repair effect, anti-fibrosis effect, effect on diabetic complications, anti-tumor effect, anti-hyperuricemia effect, effect on cerebral hemorrhage, and others. Therefore, by collecting and summarizing publications from the recent two decades, the pharmacological activities, pharmacokinetics, novel preparations and derivatives, as well as toxicity of hirudin were systematically reviewed in this paper. In addition, the clinical application, the underlying mechanisms of pharmacological effects, the dose-effect relationship, and the development potential in new drug research of hirudin were discussed on the purpose of providing new ideas for application of hirudin in treating related diseases.

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The Venous Antithrombotic Profile of Naroparcil in the Rabbit

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648977 ◽

1994 ◽

Vol 72 (06) ◽

pp. 874-879 ◽

Cited By ~ 11

Author(s):

Jean Millet ◽

Jocelyne Theveniaux ◽

Neil L Brown

Keyword(s):

Oral Administration ◽

Bleeding Time ◽

Dermatan Sulfate ◽

Factor Xa ◽

Bleeding Risk ◽

Thrombin Time ◽

Heparin Cofactor Ii ◽

Antithrombotic Activity ◽

Thrombin Inhibition ◽

Maximal Reduction

SummaryThe venous antithrombotic profile of naroparcil or (4-[4-cyanoben-zoyl]-phenyl)-1.5-dithio-β-D-xylopyranoside was investigated in the rabbit following single i. v. and oral administration. Naroparcil attenuated thrombus development in a Wessler stasis model of venous thrombosis (jugular vein) employing bovine factor Xa as a thrombogenic stimulus giving ED50 values of 21.9 mg/kg and 36.0 mg/kg after respectively i. v. and oral administration. Venous antithrombotic activity was maximal 2-3 h after i. v. administration and 4-8 h after oral administration. Four hours after the oral administration of maximal antithrombotic (Wessler model, factor Xa) doses (100 and 400 mg/kg), naroparcil had no significant effect on bleeding time. In platelet poor plasma obtained from animals treated 4 h previously with various doses (25 to 400 mg/kg) of naroparcil, there was no detectable anti-factor Xa nor antithrombin activity. Similarly, naroparcil had no effect on APTT nor on thrombin time. A sensitized thrombin time (to about 35 s) was modestly but significantly increased following oral administration of the compound at 400 mg/kg. However, thrombin generation by the intrinsic pathway was reduced in a dose-related manner, maximal reduction being 65% at 400 mg/kg. The same doses of naroparcil enhanced the formation of thrombin/heparin cofactor II complexes at the expense of thrombin/antithrombin III complexes in plasma incubated with (125I)-human a-thrombin and induced the appearance of dermatan sulfate-like material in the plasma of treated rabbits, as measured by a heparin cofactor II-mediated thrombin inhibition assay. The results suggest that naroparcil could have a safe venous antithrombotic profile following oral administration (antithrombotic effect compared to bleeding risk). It is probable that part of the mechanism of action of the β-D-xyloside, naroparcil, is due to the induction of chondroitin sulfate-like glycosaminoglycan biosynthesis, this material being detectable in the plasma.

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A Comprehensive Review on the Therapeutic Versatility of Imidazo [2,1-b]thiazoles

Current Medicinal Chemistry ◽

10.2174/0929867326666190729152440 ◽

2020 ◽

Vol 27 (40) ◽

pp. 6864-6887 ◽

Cited By ~ 1

Author(s):

Mohd Adil Shareef ◽

Irfan Khan ◽

Bathini Nagendra Babu ◽

Ahmed Kamal

Keyword(s):

Literature Review ◽

Medicinal Chemistry ◽

Therapeutic Agents ◽

Present Review ◽

Thiazole Derivatives ◽

Pharmacological Activities ◽

Comprehensive Review ◽

Derivatives Of

Background:: Imidazo[2,1-b]thiazole, a well-known fused five-membered hetrocycle is one of the most promising and versatile moieties in the area of medicinal chemistry. Derivatives of imidazo[2,1-b]thiazole have been investigated for the development of new derivatives that exhibit diverse pharmacological activities. This fused heterocycle is also a part of a number of therapeutic agents. Objective:: To review the extensive pharmacological activities of imidazo[2,1-b]thiazole derivatives and the new molecules developed between 2000-2018 and their usefulness. Method:: Thorough literature review of all relevant papers and patents was conducted. Conclusion:: The present review, covering a number of aspects, is expected to provide useful insights in the design of imidazo[2,1-b]thiazole-based compounds and would inspire the medicinal chemists for a comprehensive and target-oriented information to achieve a major breakthrough in the development of clinically viable candidates.

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RPR120844, a Novel, Specific Inhibitor of Coagulation Factor Xa Inhibits Venous Thrombosis in the Rabbit

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614434 ◽

1999 ◽

Vol 81 (01) ◽

pp. 157-160 ◽

Cited By ~ 14

Author(s):

Ross Bentley ◽

Suzanne Morgan ◽

Karen Brown ◽

Valeria Chu ◽

Richard Ewing ◽

...

Keyword(s):

Jugular Vein ◽

Drug Effect ◽

Ex Vivo ◽

Thrombus Formation ◽

Specific Inhibitor ◽

Factor Xa ◽

Coagulation Factor ◽

Antithrombotic Activity ◽

Fxa Inhibitor

SummaryThe in vivo antithrombotic activity of RPR120844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TM, measured at the end of a 50 min infusion, was significantly reduced (p <0.05 vs saline-treated animals) by RPR120844 at 30 and 100 μg/kg/min. At doses of 10, 30 and 100 μg/kg/min, APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8 ± 0.3, 1.5 ± 0.9 and 2.4 ± 0.6 μM, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.

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The synthesis of the isomeric N-methyl derivatives of murexine

Australian Journal of Chemistry ◽

10.1071/ch9811739 ◽

1981 ◽

Vol 34 (8) ◽

pp. 1739 ◽

Cited By ~ 8

Author(s):

CC Duke ◽

JV Eichholzer ◽

JK Macleod

Keyword(s):

Imidazole Ring ◽

The Other ◽

Pharmacological Activities ◽

Tautomeric Forms ◽

Methyl Derivatives ◽

Paramagnetic Ions ◽

Nucella Emarginata ◽

Derivatives Of

The two isomeric N-methyl derivatives of murexine have been synthesised by independent routes and shown to be different from an 'N- methylmurexine' reportedly isolated from the mollusc Nucella emarginata. 1H n.m.r. studies have shown a marked difference in the extent of binding to paramagnetic ions of the two N-methyl derivatives of murexine in water while pharmacological results show substantially different pharmacological activities of the two isomers. Both results can be rationalized in terms of the observed activities being associated with the presence of one or the other of the tautomeric forms of the imidazole ring.

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Impact of Oxysterols on Cell Death, Proliferation, and Differentiation Induction: Current Status

Cells ◽

10.3390/cells10092301 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2301

Author(s):

Fábio Alessandro de Freitas ◽

Débora Levy ◽

Amira Zarrouk ◽

Gérard Lizard ◽

Sérgio Paulo Bydlowski

Keyword(s):

Cell Death ◽

Adipogenic Differentiation ◽

Current Status ◽

Pharmacological Activities ◽

Oxidation Processes ◽

Proliferation And Differentiation ◽

Induction Current ◽

Enzymatic Pathways ◽

Derivatives Of ◽

Oxidized Derivatives Of Cholesterol

Oxysterols are oxidized derivatives of cholesterol produced by enzymatic activity or non-enzymatic pathways (auto-oxidation). The oxidation processes lead to the synthesis of about 60 different oxysterols. Several oxysterols have physiological, pathophysiological, and pharmacological activities. The effects of oxysterols on cell death processes, especially apoptosis, autophagy, necrosis, and oxiapoptophagy, as well as their action on cell proliferation, are reviewed here. These effects, also observed in several cancer cell lines, could potentially be useful in cancer treatment. The effects of oxysterols on cell differentiation are also described. Among them, the properties of stimulating the osteogenic differentiation of mesenchymal stem cells while inhibiting adipogenic differentiation may be useful in regenerative medicine.

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Curcumin Enhanced Busulfan-Induced Apoptosis through Downregulating the Expression of Survivin in Leukemia Stem-Like KG1a Cells

BioMed Research International ◽

10.1155/2015/630397 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 11

Author(s):

Guangyang Weng ◽

Yingjian Zeng ◽

Jingya Huang ◽

Jiaxin Fan ◽

Kunyuan Guo

Keyword(s):

Specific Inhibitor ◽

Annexin V ◽

Chemotherapeutic Agents ◽

Combination Group ◽

Hematopoietic Stem ◽

Leukemia Relapse ◽

Conditioning Regimens ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Related Proteins

Leukemia relapse and nonrecurrence mortality (NRM) due to leukemia stem cells (LSCs) represent major problems following hematopoietic stem cell transplantation (HSCT). To eliminate LSCs, the sensitivity of LSCs to chemotherapeutic agents used in conditioning regimens should be enhanced. Curcumin (CUR) has received considerable attention as a result of its anticancer activity in leukemia and solid tumors. In this study, we investigated the cytotoxic effects and underlying mechanisms in leukemia stem-like KG1a cells exposed to busulfan (BUS) and CUR, either alone or in combination. KG1a cells exhibiting BUS-resistance demonstrated by MTT and annexin V/propidium iodide (PI) assays, compared with HL-60 cells. CUR induced cell growth inhibition and apoptosis in KG1a cells. Apoptosis of KG1a cells was significantly enhanced by treatment with CUR+BUS, compared with either agent alone. CUR synergistically enhanced the cytotoxic effect of BUS. Seven apoptosis-related proteins were modulated in CUR- and CUR+BUS-treated cells analyzed by proteins array analysis. Importantly, the antiapoptosis protein survivin was significantly downregulated, especially in combination group. Suppression of survivin with specific inhibitor YM155 significantly increased the susceptibility of KG1a cells to BUS. These results demonstrated that CUR could increase the sensitivity of leukemia stem-like KG1a cells to BUS by downregulating the expression of survivin.

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Breviscapine: A Review on its Phytochemistry, Pharmacokinetics and Therapeutic Effects

The American Journal of Chinese Medicine ◽

10.1142/s0192415x21500646 ◽

2021 ◽

pp. 1-29

Author(s):

Luan Wen ◽

Ting He ◽

AXiang Yu ◽

Siqi Sun ◽

Xiang Li ◽

...

Keyword(s):

Active Component ◽

Drug Research ◽

Preparation Method ◽

Pharmacological Action ◽

Structural Features ◽

Clinical Applications ◽

Pharmacokinetic Studies ◽

Therapeutic Effects ◽

Comprehensive Understanding ◽

Pharmacological Activities

Breviscapine is one of the extracts of several flavonoids of Erigeron breviscapus. Scutellarin is the main active component of breviscapine, and the qualitative or quantitative criteria as well. Scutellarin and its analogs share a similar skeleton of the flavonoids. Breviscapine has been widely used in the treatment of cerebral infarction and its sequelae, cerebral thrombus, coronary heart disease (CHD), and angina pectoris. Breviscapine has a broad spectrum of pharmacological activities, such as increasing blood flow, improving microcirculation, dilating blood vessels, decreasing blood viscosity, promoting fibrinolysis, inhibiting platelet aggregation, and thrombosis formation, etc. In addition, breviscapine and its analogs have significant value for drug research and development because of the superiority of those significant bioactivities. Furthermore, an increasing number of pharmacokinetic studies have explored the mechanism of scutellarin and its analogs. To provide a comprehensive understanding of the current research on breviscapine, scutellarin, and the analogs, the structural features, distribution situation, preparation method, content determination method, clinical applications, pharmacological action as well as pharmacokinetics are summarized in the present review.

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PYRIMIDINES AS POTENT CYTOTOXIC AND ANTI-INFLAMMATORY AGENTS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i6.17343 ◽

2017 ◽

Vol 10 (6) ◽

pp. 237 ◽

Cited By ~ 1

Author(s):

Ishwar Bhat K ◽

Abhishek Kumar

Keyword(s):

Acetic Acid ◽

Cytotoxic Activity ◽

Glacial Acetic Acid ◽

Antimalarial Activity ◽

Biological Activities ◽

Cytotoxic Agents ◽

Pyrimidine Derivatives ◽

Pharmacological Activities ◽

Anti Inflammatory ◽

Derivatives Of

Objective: Many derivatives of pyrimidine are known for the broad-spectrum biological activities such as antimicrobial, antitumor, antibacterial, antitubercular, anti-inflammatory, and cytotoxic activity. Chalcones with an enone group show potent pharmacological activities such as antiinflammatory, antibacterial, antifungal, and antimalarial activity. A series of pyrimidines from chalcones have been synthesized and screened for anti-inflammatory and cytotoxic activity studies.Methods: Chalcones [1-(4-nitrophenyl)-3-substituted-phenylprop-2-en-1-one] were synthesized from various substituted aldehydes with 4-nitroacetophenone and cyclized with urea and glacial acetic acid to give pyrimidine derivatives [4-(4-nitrophenyl)-6-substituted-phenylpyrimidin-2-ol].Results: Anti-inflammatory and cytotoxic activity studies revealed that some of the synthesized compounds have shown significant activity.Conclusion: The observed results proved that pyrimidines are found to be interesting lead molecules for the synthesis of anti-inflammatory and cytotoxic agents

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Advances in Studies on the Pharmacological Activities of Fucoxanthin

Marine Drugs ◽

10.3390/md18120634 ◽

2020 ◽

Vol 18 (12) ◽

pp. 634

Author(s):

Han Xiao ◽

Jiarui Zhao ◽

Chang Fang ◽

Qi Cao ◽

Maochen Xing ◽

...

Keyword(s):

Biological Activities ◽

Intestinal Flora ◽

Small Molecular Weight ◽

Pharmacological Activities ◽

Beneficial Effects ◽

Wide Range ◽

Cell Components ◽

Underlying Mechanisms ◽

Organ Fibrosis ◽

Active Can

Fucoxanthin is a natural carotenoid derived mostly from many species of marine brown algae. It is characterized by small molecular weight, is chemically active, can be easily oxidized, and has diverse biological activities, thus protecting cell components from ROS. Fucoxanthin inhibits the proliferation of a variety of cancer cells, promotes weight loss, acts as an antioxidant and anti-inflammatory agent, interacts with the intestinal flora to protect intestinal health, prevents organ fibrosis, and exerts a multitude of other beneficial effects. Thus, fucoxanthin has a wide range of applications and broad prospects. This review focuses primarily on the latest progress in research on its pharmacological activity and underlying mechanisms.

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The Emerging Role of GC-MSCs in the Gastric Cancer Microenvironment: From Tumor to Tumor Immunity

Stem Cells International ◽

10.1155/2019/8071842 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Zhaoji Pan ◽

Yiqing Tian ◽

Guoping Niu ◽

Chengsong Cao

Keyword(s):

Gastric Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Wound Repair ◽

Critical Role ◽

The Novel ◽

Potential Biomarker ◽

Underlying Mechanisms ◽

Gastric Cancer Progression

Mesenchymal stem cells (MSCs) have been declared to not only participate in wound repair but also affect tumor progression. Tumor-associated MSCs, directly existing in the tumor microenvironment, play a critical role in tumor initiation, progression, and development. And different tumor-derived MSCs have their own unique characteristics. In this review, we mainly describe and discuss recent advances in our understanding of the emerging role of gastric cancer-derived MSC-like cells (GC-MSCs) in regulating gastric cancer progression and development, as well as the bidirectional influence between GC-MSCs and immune cells of the tumor microenvironment. Moreover, we also discuss the potential biomarker and therapeutic role of GC-MSCs. It is anticipated that new and deep insights into the functionality of GC-MSCs and the underlying mechanisms will promote the novel and promising therapeutic strategies against gastric cancer.

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