Antithrombotic Effects of YS-49 and YS-51—1-Naphthylmethyl Analogs of Higenamine

doi:10.1016/S0049-3848(01)00372-3

Thrombosis Research

Volume 104, Issue 4, 15 November 2001, Pages 249-255

https://doi.org/10.1016/S0049-3848(01)00372-3 Get rights and content

Abstract

The antiplatelet and antithrombotic effects of YS-49 and YS-51—l-naphthylmethyl analogs of higenamine, which is a benzyl-tetrahydroisoquinoline alkaloid isolated from Aconitum japonicum (Ranunculaceae)—were investigated. YS-49 and YS-51 showed inhibitory activities to both human and rat platelet aggregation induced by ADP, collagen and epinephrine. They were more inhibitory to epinephrine-induced aggregation (IC₅₀; 3.4 and 1.7 μM of YS-49, and 6.0 and 6.3 μM of YS-51 to human and rat platelets, respectively) than ADP- or collagen-induced aggregation. The antithrombotic effects of YS-49 and YS-51 were also observed in both mouse acute thrombosis model and rat arterio-venous shunt (AV shunt) model. The oral administration of YS-49 and YS-51 (50 or 100 mg/kg) increased the recovery rates from the acute thrombotic challenge in mice and lowered the weight of thrombus formed inside the AV shunt tube in rats.

Section snippets

Materials and Animals

1-(α-Naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS-49) and 1-(β-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (YS-51) were synthesized as hydrobromide salts according to the previously described method [12], [13] (Fig. 1). Collagen and ADP (adenosine 5′-diphosphate dicyclohexylammonium salts) were purchased from Chrono-Log (Havertown, Pa, USA). Epinephrine for platelet aggregation was obtained from Sigma (St. Louis, Mo, USA) and epinephrine (1 mg/ml, injectable

Antiaggregating Activities of YS-49 and YS-51 on Human and Rat Platelets

The inhibitory effects of YS-49 and YS-51 on human and rat platelet aggregation were examined and compared with the effects of acetylsalicylic acid (ASA) in Table 1. All of the tested compounds showed dose-dependent inhibitory activities to either ADP-, collagen- or epinephrine-induced aggregation on both human and rat platelets. YS-49 and YS-51 were more inhibitory to epinephrine-induced aggregation than to ADP- or collagen-induced aggregation. The effects of YS-49 and YS-51 on ADP-induced

Discussion

Thrombosis may occur if the hemostatic stimulus is improperly regulated either due to impaired capacity of inhibitory pathway, or more commonly when the capacity of the natural anticoagulant mechanism is overwhelmed by the intensity of the stimulus. Platelets also play a key role in the pathogenesis of thrombosis. Platelets are activated by various endogenous factors and a platelet-rich thrombus is formed subsequently in the lumen of the injured vessel. Platelet deposition by aggregation at

Acknowledgements

This work was supported partially by the Ministry of Health and Welfare (HMP-96-D-1008 and HMP-98-D-4-0045) and partially by the Brain Korea 21 project of the Ministry of Education. The authors are grateful for the financial support.

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There are more references available in the full text version of this article.

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Mechanism of platelet activation and potential therapeutic effects of natural drugs
2023, Phytomedicine
Cardiovascular disease is one of the most concerning chronic diseases in the world. Many studies have shown that platelet overactivation is a very important factor in the occurrence and development of cardiovascular diseases. At present, the widely used antiplatelet drugs have some defects, such as drug resistance and adverse reactions.
The purpose of this article is to summarize the main mechanisms and pathways of platelet activation, the main targets of antiplatelet aggregation, and the antiplatelet aggregation components of natural drugs and their mechanisms of action to provide new research ideas for the development and application of antiplatelet drugs.
In this review, we systematically searched the PubMed, Google Scholar, Web of Science, and CNKI databases and selected studies based on predefined eligibility criteria. We then assessed their quality and extracted data.
ADP, AA, THR, AF, collagen, SDF-1α, and Ca²⁺ can induce platelet aggregation and trigger thrombosis. Natural drugs have a good inhibitory effect on platelet activation. More than 50 kinds of natural drugs and over 120 kinds of chemical compounds, including flavonoids, alkaloids, saponins, terpenoids, coumarins, and organic acids, have significantly inhibited platelet activation activity. The MAPK pathway, cGMP-PKG pathway, cAMP-PKA pathway, PI3K-AKT pathway, PTK pathway, PLC pathway, and AA pathway are the main mechanisms and pathways of platelet activation.
Natural drugs and their active ingredients have shown good activity and application prospects in anti-platelet aggregation. We hope that this review provides new research ideas for the development and application of antiplatelet drugs.
Development of a LC–MS/MS method for the determination of CKD-712 in rat plasma: Application to a pharmacokinetic study in rats
2017, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Citation Excerpt :
CKD-712 [(S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydrosioquinoline], a derivative of higenamine isolated from Aconitum japonicum [2], is a drug candidate on stage of clinical trial for the treatment of sepsis [3,4], as it has anti-inflammatory effects by suppressing nuclear factor-kB (NF-kB) in normal cells [5]. CKD-712 exhibits protective effects against lipopolysaccharide (LPS)-mediated platelet aggregation, inducible nitric oxide synthase (iNOS) expression, and cecum-ligation puncture (CLP)-induced septic mortality in mice [4,6–8]. Three major peaks corresponding to CKD-712 were detected in GC/MS spectra of rat urine sample after oral administration of CKD-712 based on the conference proceedings [9].
CKD-712 is a potential treatment for sepsis, as it exhibits protective effects against lipopolysaccharide-mediated platelet aggregation, inducible nitric oxide synthase expression, and cecum-ligation puncture-induced septic mortality in mice. In this study, we develop a rapid and sensitive LC–MS/MS method for determining CKD-712 in rat plasma. CKD-712 and papaverine hydrochloride (an internal standard) were analyzed using an LC–MS/MS system consisting of an Agilent HPLC system (HP-1100) equipped with an Atlantis HILIC Silica (2.1 × 50 mm, 3 μm) column and a API 4000 (Applied Biosystems/MDS Sciex, USA) in a positive ESI mode. We utilized multiple reaction monitoring (MRM) at m/z transitions of 306.2–164.0 to analyze CKD-712, and 340.3–202.1 m/z for IS, with a mobile phase of acetonitrile (0.025% trifluoroacetic acid):20 mM ammonium acetate (94:6, v/v) at a flow rate of 0.25 mL/min. The lower limit of quantification (LLOQ) was 5 ng/mL, with a linearity ranging from 5 to 1000 ng/mL (r > 0.999). Validation parameters including specificity, precision, accuracy, matrix effect, recovery, dilution effect and stability results were well within acceptance criteria, and applied successfully on a pharmacokinetic study in rats.
Applications of Higenamine in pharmacology and medicine
2017, Journal of Ethnopharmacology
Citation Excerpt :
Furthermore, higenamine could cause a slight up-regulation the amount of myocardial β adrenoceptors whose mechanisms need to be investigated further (Xiang- Rong et al., 1995). Apart from its interaction with β adrenergic receptor, some researchers suggest that higenamine may also be a α2-adrenergic receptor antagonist (Yun-Choi et al., 2001a, 2001b). On the one hand, higenamine has a catechol moiety in its structure, which is usually considered as a critical component for the α2-adrenergic receptor antagonist.
Aconitum has been used as local and traditional medicines in many asian regions for the treatment of various diseases such as collapse, syncope, painful joints, oedema, bronchial asthma et al. Higenamine, a plant-based alkaloid, was initially isolated from Aconitum and identified as the active cardiotonic component of Aconitum. It has been tested as a candidate of pharmacologic stress agent in the detection of coronary artery diseases (CADs) and now researchers have just accomplished the phase III clinical studies successfully in China. Besides, a large number of studies have revealed the various pharmacological properties and potentially multi-spectral medical applications of higenamine. However, to date, no comprehensive review on higenamine has been published.
This present paper aims to compile a comprehensive update regarding the biochemistry, pharmacokinetic features, pharmacological activities, clinical and potential clinical uses and toxicities on higenamine with the ultimate objective of providing a guide for future research on this drug.
The selection of relevant data was made through a search using the keyword “higenamine” in “Web of science”, “Pubmed”, and “China Knowledge Resource Integrated (CNKI)”. Information was also acquired from local classic herbal literature, government reports and conference papers.
In addition to Aconitum, higenamine also exists in many other plants including Tinospora crispa, Nandina domestica T_HUNBERG, Gnetum Parvifolium C.Y. Cheng, sarum Heterotropoides_,Nelumbo nucifera_,N.nucifera. The pharmacokinetic studies conducted in animals and humans showed that higenamine conformed to a two-compartment pharmacokinetic model. Studies over the last four decades on higenamine have revealed its various pharmacological properties such as positive inotropic and chronotropic effect, activating slow channel effect, vascular and tracheal relaxation effect, anti-thrombotic, anti-apoptotic and anti-oxidative effect, anti-inflammatory and immunomodulatory effect. This phytochemical constituent has shown its potential therapeutic effects for diseases like heart failure, disseminated intravascular coagulation (DIC), shock, arthritis, asthma, ischemia/reperfusion (I/R) injuries and erectile dysfunction.
Extensive basic and clinical studies on higenamine showed valuable therapeutic effects on different disorders. However, the underlying mechanisms of higenamine have not been established. Therefore, the safety, tolerability and efficacy of higenamine are as yet, not fully understood. Additionally, some of the studies were small sample-sized and unreliable. To sum up, there is a need for deeper investigation in the mechanisms of higenamine action, as well as well-designed preclinical and clinical trials studies to test the safety and clinical value of the drug.
PH-Dependent nanostructure based on isoquinoline-cyclodextrin conjugate for thrombosis therapy
2012, Nanomedicine: Nanotechnology, Biology, and Medicine
The modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with β-cyclodextrin (β-CD) provides an oral antithrombotic agent, 6-(3′S-isoquinoline-3′-carboxylaminoethylamino)-6-deoxy-β-CD (THIQA-β-CD). In aqueous solution THIQA-β-CD undergoes intermolecular inclusion complexation and forms pH-dependent nanostructures. The morphological feature of THIQA-β-CD is a nanocloud consisting of numerous particles that are 5 nm–6 nm in diameter at pH 3.0. The nanocloud switches to a nanorod ranging from 100 nm to 385 nm in length at pH 7.2, then to nanowires of 50 nm to 530 nm in length at pH 10.1. THIQA-β-CD, which has unusual nanostructures, offers enhanced stability in blood. Inhibition of thrombin-induced platelet aggregation in vitro and demonstrated antithrombotic efficacy in vivo. This investigation demonstrated that the modification of THIQA with β-CD is a promising approach for clinical therapy of thrombus disease. The pH-dependent nanostructures of conjugate provide the desired in vivo antithrombotic activity and in vitro stability in blood.
This study a demonstrates that the modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with beta-cyclodextrin, which leads to pH dependent nanostructure formation, is a promising approach for clinical therapy of thrombotic disease.
Pharmacological effects of Chinese herb aconite (Fuzi) on cardiovascular system
2012, Journal of Traditional Chinese Medicine
Fuzi (aconite, Radix Aconiti praeparata), a widely used Chinese herb, plays a significant role in the cardiovascular system. This is mainly reflected by Fuzi's cardiotonic effect, its protective effect on myocardial cells, and its effect on heart rate and rhythm, blood pressure, and hemodynamics. In this article, the pharmacological effects and the corresponding mechanisms of Fuzi (aconite) and its active components on cardiovascular system are reviewed.
CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline, inhibits the lipopolysaccharide-stimulated secretion of HMGB1 by inhibiting PI3K and classical protein kinase C
2011, International Immunopharmacology
Citation Excerpt :
CKD712, a synthetic tetrahydroisoquinoline alkaloid of (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, is an (s)-form of the YS-49 enantiomer, a derivative of higenamine. CKD712 shows protective effects against LPS-mediated platelet aggregation, iNOS expression, and cecum-ligation puncture (CLP)-induced septic mortality in mice [18–21]. CKD712 is a candidate molecule for the treatment of sepsis [18], and, here, we demonstrate the effects of CKD712 on HMGB1 secretion and the activity of its effector enzyme, cPKC, on HMGB1 phosphorylation.
CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, was considered as a new effective drug candidate to sepsis, based on its anti-inflammatory activity. It was reported that CKD712 inhibited various signal pathways which play a key role in production of proinflammatory cytokines. Here, we examined the effect of CKD712 on the secretion of high mobility group box 1 (HMGB1), which is one of the proinflammatory cytokines. CKD712 can reduce Gram-negative lipopolysaccharide (LPS)- and Gram-positive lipoteichoic acid (LTA)-stimulated HMGB1 secretion in RAW264.7 and human peripheral blood monocytes (PBMo), and also reduce LPS-induced nucleocytoplasmic translocation of HMGB1 1 h before or after LPS treatment. CKD712 could dose-dependently inhibit the activation of PI3K and PI3K-dependent kinase 1 (PDK1), which are involved in HMGB1 secretion signaling pathway. In addition, CKD712 inhibited classical protein kinase C (cPKC), the effective kinase for phosphorylation of HMGB1 for secretion, however, had no effect on histone acetyl-transferase activity, which is another mechanism known for HMGB1 secretion. Thus, we suggest that CKD712 could inhibit LPS- and LTA-stimulated HMGB1 secretion through the inhibition of HMGB1 phosphorylation by inhibiting PI3K-PKC signaling pathway.

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Thrombosis Research

Abstract

Section snippets

Materials and Animals

Antiaggregating Activities of YS-49 and YS-51 on Human and Rat Platelets

Discussion

Acknowledgements

References (21)

Pharmacological evaluation of GS-389, a novel tetrahydroisoquinoline analog related to higenamine, on vascular smooth muscle

Life Sci

Cardiovascular effect of a naphtylmethyl substituted tetrahydroisoquinoline, YS 49, in rat and rabbit

Life Sci

Epinephrine induced platelet aggregation in platelet rich plasma

Thromb Res

Antiplatelet and antithrombotic effects of a combination of ticlopidine and Ginkgo biloba Ext (Egb 761)

Thromb Res

Normal platelet function and antiplatelet drugs

ACC Curr J Rev

Platelet-dependent and procoagulant mechanisms in arterial thrombosis

Int J Cardiol

Studies on cardiac principle in Aconite roots: I. Isolation and structure determination of higenamine

Yakugaku Zasshi

Anti-thrombotic effects of higenamine

Planta Med

Higenamine reduced mortalities in the mouse models of thrombosis and endotoxic shock

Yakhak Hoeji

Platelet anti-aggregating activities of higenamine analogs

Yakhak Hoeji

Cited by (29)

Mechanism of platelet activation and potential therapeutic effects of natural drugs

Development of a LC–MS/MS method for the determination of CKD-712 in rat plasma: Application to a pharmacokinetic study in rats

Applications of Higenamine in pharmacology and medicine

PH-Dependent nanostructure based on isoquinoline-cyclodextrin conjugate for thrombosis therapy

Pharmacological effects of Chinese herb aconite (Fuzi) on cardiovascular system

CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline, inhibits the lipopolysaccharide-stimulated secretion of HMGB1 by inhibiting PI3K and classical protein kinase C

REGULAR ARTICLEAntithrombotic Effects of YS-49 and YS-51—1-Naphthylmethyl Analogs of Higenamine

Abstract

Section snippets

Materials and Animals

Antiaggregating Activities of YS-49 and YS-51 on Human and Rat Platelets

Discussion

Acknowledgements

Life Sci

Life Sci

Thromb Res

Thromb Res

ACC Curr J Rev

Int J Cardiol

Studies on cardiac principle in Aconite roots: I. Isolation and structure determination of higenamine

Yakugaku Zasshi

Anti-thrombotic effects of higenamine

Planta Med

Higenamine reduced mortalities in the mouse models of thrombosis and endotoxic shock

Yakhak Hoeji

Platelet anti-aggregating activities of higenamine analogs

Yakhak Hoeji

REGULAR ARTICLE
Antithrombotic Effects of YS-49 and YS-51—1-Naphthylmethyl Analogs of Higenamine