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The Potential of Plants as Treatments for Venous Thromboembolism
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Lilitha L. Denga, Namrita Lall
Coumarin derivatives have attractive anticoagulant Vitamin K antagonist activity (Lei et al. 2015). Dicoumarol is a Vitamin K antagonist produced by fungal species such as Penicillium nigricans and Penicillium jensi on Melilotus alba Medik. and Melilotus officinalis (L.) Pall. (sweet clover) (Madari et al. 2003). Dicoumarol is the building block for modern-day Vitamin K antagonists, and its derivatives are hydroxylated in position 4 and have a substitution in position 3 (Lei et al. 2015). These are the minimum requirements for the anticoagulant activity of coumarins. Warfarin is a synthetic derivative of dicoumarol synthesized by the Michael addition of 4-hydroxycoumarin and benzolactone (Jain and Joshi 2012).
Rodenticides
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
The warfarins (the carbon-3-substituted 4-hydroxycoumarin derivatives) and “superwarfarins” (brodifacoum, indanediones) (Figure 30.1) are popular rodenticides, whose properties were originally isolated from the sweet clover plant.† By 1950, the warfarins had achieved international notoriety as the most useful rodenticides. The clinical feasibility of oral anticoagulants in humans became known soon after with the realization of their relatively low toxicity. Rodent resistance to warfarin, however, became prevalent in the 1960s via autosomal dominant gene transmittance. By the 1970s, novel second-generation, very long-acting anticoagulants (superwarfarins) were synthesized to combat rodent resistance. Structures of 4-hydroxycoumarin (parent molecule), brodifacoum (long-acting coumarin derivative, with the parent molecule in blue), and 1,2-indandione.
Effects of Antithrombotic and Results of Drug Screening
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
Besides indandione derivatives, only 4-hydroxycoumarin derivatives are effective as anticoagulants. Coumarin, referred to in another section as one of the most effective benzopyrones, is therefore not effective as an anticoagulant. But is also the opposite true? That is, do oral anticoagulants show vasotropic or endotheloprotective activity typical of benzopyrones? In fact, they do exert such an effect which is practically immediate and should probably always be present even under clinical conditions (Figure 21 in Chapter 3).385 On the other hand, the curve shows a typical optimum and the effective anticoagulant dose (as documented by ex vivo tests) already coincides with the ascending limb of the dose-to-effect curve, i.e., with an already endothelemia-increasing dose. This potentially unfavorable effect is particularly marked after repeated administration, i.e., has a cumulative nature (Figure 64). It can be remembered that an endothelial damage after therapeutic doses of warfarin was described by Kahn et al.671 The endothelemia-increasing effect may be blocked by the concomitant administration of other endotheloprotective drugs, especially those possessing no marked optimum dose. Thus, prenylamine (0.5 mg/kg p.o.) completely inhibited the endothelemia-increasing effect of warfarin without influencing one-stage prothrombin time (Figures 65, 66). The favorable effect of added prenylamine was manifested also by the significant prevention of a hematocrit decrease after warfarin in rats, i.e., prenylamine may have a protective effect against capillary bleeding after coumarin anticoagulants.
A novel anticancer chromeno-pyrimidine analogue inhibits epithelial-mesenchymal transition in lung adenocarcinoma cells
Published in Toxicology Mechanisms and Methods, 2021
Venkateswarareddy Nallajennugari, Sankar Pajaniradje, Srividya Subramanian, Suhail Ahmad Bhat, Parthasarathi D, Savitha Bhaskaran, Syed Ali Padusha M, Rukkumani Rajagopalan
While coumarin itself was found to be exhibiting cytotoxic effects against Hep2 cells in a dose-dependent manner (Mirunalini et al. 2014), a study revealed that 4-hydroxycoumarin inhibited cell proliferation in a gastric carcinoma cell line (Budzisz et al. 2003). Interestingly, fused coumarin scaffolds demonstrate a wide variety of biologically relevant actions such as antibacterial (Penta 2016), antifungal (Khan et al. 2004), antiviral (Neyts et al. 2009), antimutagenic (Matsumoto et al. 2017), antitubercular (Keri et al. 2015), antioxidant (Bubols et al. 2013), scavenging of reactive oxygen species (ROS) (Al-Majedy et al. 2016), anticoagulant (Abdelhafez et al. 2010), anti-inflammatory (Kontogiorgis and Hadjipavlou-Litina 2005), antithrombotic (Jain et al. 2013), and anticancer activities (Sashidhara et al. 2010). They also exhibit cyclooxygenase (Nargotra et al. 2011), lipoxygenase (Kwon et al. 2011), cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities, Central nervous system stimulant (Patil et al. 2013), a vasodilator (Najmanová et al. 2015), and cytotoxic effects (Kostova 2005). Studies have also shown strong antitumor activity of a series of 6-methyl-4-substituted coumarin and 4-substituted benzo coumarin against MCF-7 and HepG-2 cell lines (Morsy et al. 2017).
Effects of CYP2C11 gene knockout on the pharmacokinetics and pharmacodynamics of warfarin in rats
Published in Xenobiotica, 2019
Huanying Ye, Danjuan Sui, Wei Liu, Yuannan Yuan, Zhen Ouyang, Yuan Wei
Warfarin (3-alpha-phenylpropanone-4-hydroxycoumarin) is a vitamin K antagonist and is used as a long-term oral coumadin anticoagulant. It is commonly used for preventing and treating thrombosis in patients with venous thromboembolism (VTE), pulmonary embolism, heart valve replacement and atrial fibrillation, as well as to reduce the risk of myocardial infarction recurrence and thromboembolic death after myocardial infarction (Ansell et al., 2004). Its anticoagulant mechanism is mainly mediated by the obstruction of the cyclic interconversion between vitamin K and the epoxides. This process interferes with the activation of vitamin K-dependent coagulation factors (factor II, VII and IX), and the synthesis of anticoagulant proteins C and S (Hirsh et al., 2003; Redman, 2001). With high bioavailability, oral warfarin is rapidly absorbed from the human gastrointestinal tract and reaches its peak concentration (Cmax) 90 min after oral administration (Breckenridge, 1978; Kelly & O’Malley, 1979; O’Reilly, 1976). Warfarin circularly binds to plasma proteins (albumin) and accumulates in the livers of animals (O’Reilly, 1987), where the two enantiomers are metabolized in vivo by different cytochrome P450s (CYPs) into inactive products that are excreted in the urine. The major enzyme involved in metabolizing S-warfarin in humans is CYP2C9, which converts it into the inactive 6- and 7-hydroxylated products (Hermida et al., 2002; Miners & Birkett, 1998), while R-warfarin is mainly metabolized by CYP3A4, 1A1, and 1A2 (Kaminsky & Zhang, 1997).