Drugs and Therapeutics
James Sherifi in General Practice Under the NHS, 2023
As a group, side effects are few and minor, the most common being oedema, facial flushing, and headache. Warfarin—1940sAnticoagulant Dicoumarols were first identified in the 1940s in decomposing sweet clover, following a serendipitous observation by a vet who noted cattle dying of a haemorrhagic illness after ingesting rotting silage. Coumarin was subsequently found in many sweet-smelling plants, such as liquorice and lavender. Warfarin, a more potent form of dicoumarol, was introduced as a rodenticide before finding a more humane use, in the 1950s, as an anticoagulant agent in man.8
Plant Source Foods
Chuong Pham-Huy, Bruno Pham Huy in Food and Lifestyle in Health and Disease, 2022
Due to its exotic flavor and hot taste, cinnamon is used as a culinary spice and also a traditional medicine since antiquity. In traditional medicine, cinnamon is used in the treatment of respiratory and digestive ailments, as a stimulant, and as an anointment since antiquity (246). Recently, many experimental and clinical trials have explored its antimicrobial, anti-inflammatory, antidiabetic, antioxidant, antilipemic, and cognition enhancer effects for the treatment of infection, diabetes, depression, hypercholesterolemia, and Parkinson’s disease (246–248). However, Cassia cinnamon (Chinese cinnamon) contains high levels of coumarins, about ten times more than Ceylon cinnamon. Coumarin is toxic to the liver in high doses. Therefore, its addition into food products is prohibited. Due to a lack of awareness regarding the standard limits of cinnamon in these products, it is advisable for patients of hepatic disorders to avoid cinnamon (246). In addition, a daily intake of coumarin more than 0.1 mg/kg body weight can lead to conspicuous effect on the blood coagulation profile if the patient is simultaneously on drugs such as warfarin. However, these results are still contradictory (246). So, it is recommended not to take a lot of pure cinnamon product or supplement. High intake of cinnamon can cause liver damage, mouth sore, cancer, hemorrhage, and breathing problems.
Pharmacological actions of chemical constituents
C. P. Khare in Evidence-based Ayurveda, 2019
Most coumarins occur in higher plants, with the richest sources being the Rutaceae and Umbelliferone. Although distributed throughout all parts of the plant, the coumarins occur at the highest levels in the fruits (Bael fruits (Aegle marmelos), Tetrapleura tetraptera TAUB, bilberry, and cloudberry), followed by the roots, stems and leaves. They are also found at high levels in some essential oils, particularly cinnamon bark oil (7,000 ppm), cassia leaf oil (up to 87,300 ppm) and lavender oil. Coumarin is also found in fruits (e.g., bilberry, cloudberry), green tea and other foods such as chicory. Environmental conditions and seasonal changes can influence the occurrence in diverse parts discovered in microorganisms. Some important coumarin members have been isolated from microbial sources, e.g., novobiocin and coumermycin from Streptomyces, and aflatoxins from Aspergillus species.
Intestinal epithelial damage due to herbal compounds – an in vitro study
Published in Drug and Chemical Toxicology, 2023
Susan M. Britza, Ian F. Musgrave, Rachael Farrington, Roger W. Byard
Coumarin is an aromatic organic compound found in hundreds of plant species and herbal products, most commonly in Apiaceae, Asteraceae, Clusiaceae, Lamiaceae, Oleaceae, Rutaceae and Thymelaeaceae families. Of particular note are common traditional and modern herbal medicines which contain high concentrations of coumarin compounds including Uncaria tomentosa (Willd.) DC (Cat’s Claw), Lawsonia inermis L. (Henna), Aeasculus hippocastanum L. (Horse-chestnut), and controversial Hypericum perforatum L. (Saint John’s Wort) (Matos et al.2015). Due to an abundance of coumarin compounds in nature and a high likelihood of dietary exposure, extensive research has been carried out into its toxicological properties (Fentem et al.1992, Loprinzi et al.1997, Lacy and O’Kennedy 2004, Tanaka et al.2016), and though human toxicity is rare, clinical presentations are often associated with hepatotoxic effects (Cox et al.1989, Egan et al.1990). This is largely due to the coumarin toxic metabolite o-hydroxyphenylacetaldehyde (o-HPA). Metabolism of coumarin is predominantly through cytochrome P450 enzymes, particularly CYP2A6 and CYP3A4, to form nontoxic 7-hydroxycoumarin and 3-hydroycoumarin respectively, and CYP2E1 and CYP1A1–2 forming non-reactive 3, 4-epoxide; o-HPA is formed from the intermediate metabolite, 3, 4-epoxide (Born et al.2000). Hence, the metabolism of coumarin is key to associated cases of toxicity.
Implications for herbal polypharmacy: coumarin-induced hepatotoxicity increased through common herbal phytochemicals astragaloside IV and atractylenolide I
Published in Toxicology Mechanisms and Methods, 2022
Susan M. Britza, Ian F. Musgrave, Roger W. Byard
Coumarin-induced hepatotoxicity has been investigated previously in animal models and humans (Fetner et al. 1992; Loprinzi et al. 1997; Tanaka et al. 2016). Of note are several papers indicating that coumarin cytotoxic effects are metabolism dependent (Vassallo et al. 2004; Tanaka et al. 2016). In 2000, an in vitro study investigating the formation of o-hydroxyphenylacetaldehyde (o-HPA), it was shown that coumarin is metabolized by CYP enzymes, specifically CYP3A4 and CYP2E1/1A1-2, to produce toxicologically reactive metabolites 3-hydroxycoumarin and o-HPA, respectively, which are detoxified through glutathione conjugation. Nevertheless, substantial quantities of coumarin are required for toxic levels and it was suggested that toxicity would be rare in humans (Born et al. 2000). However, coumarins are common in many dietary and herbal supplements but are also found abundantly in many fruits, vegetables, nuts, seeds, wine, coffee, and teas (Stefanachi et al. 2018). Hence, more recent reviews of hepatotoxicity in patients treated with coumarin and hepatotoxicity from dietary intake suggested a reasonable level of risk and resulted in the definition of a lower tolerable dose of coumarin (0.1 mg/kg) (EFSA 2008).
In vivo evaluation of pharmacokinetic drug–drug interactions between fluorinated pyrimidine anticancer drugs, 5-fluorouracil and capecitabin, and an anticoagulant, warfarin
Published in Xenobiotica, 2022
Ai Hasegawa, Yoshie Tsujiya, Ayaka Ueda, Motohiro Yamamori, Noboru Okamura
Warfarin is a coumarin derivative whose molecular structure is similar to that of reduced vitamin K and is an anticoagulant for preventing and treating thromboembolism. It suppresses thrombin production by suppressing the synthesis of a vitamin K-dependent coagulation factor and exhibits an anticoagulation effect. In clinical practice, the dose is adjusted using prothrombin time (PT). Warfarin is extremely well absorbed from the upper gastrointestinal tract (stomach and upper small intestine), with an approximately 100% oral bioavailability. Also known as an optical isomer, (S)-warfarin, which is mainly metabolised by cytochrome P450 (CYP) 2C9 (CYP2C9), has five times the anticoagulant activity of (R)-warfarin, which is metabolised by CYP1A2, 2C19, and 3A4 (O'Reilly 1974).
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