ABSTRACT
Drug-induced bleeding disorders contribute to substantial morbidity and mortality. Antithrombotic agents that cause unintended bleeding of obvious cause are relatively easy to control. However, the mechanisms of most drug-induced bleeding disorders are poorly understood, which makes intervention more difficult. As most bleeding disorders are associated with the dysfunction of coagulation factors, we adapted our recently established cell-based assay to identify drugs that affect the biosynthesis of active vitamin K-dependent (VKD) coagulation factors with possible adverse off-target results. The National Institutes of Health (NIH) Clinical Collection (NCC) library containing 727 drugs was screened, and 9 drugs were identified, including the most commonly prescribed anticoagulant warfarin. Bleeding complications associated with most of these drugs have been clinically reported, but the pathogenic mechanisms remain unclear. Further characterization of the 9 top-hit drugs on the inhibition of VKD carboxylation suggests that warfarin, lansoprazole, and nitazoxanide mainly target vitamin K epoxide reductase (VKOR), whereas idebenone, clofazimine, and AM404 mainly target vitamin K reductase (VKR) in vitamin K redox cycling. The other 3 drugs mainly affect vitamin K availability within the cells. The molecular mechanisms underlying the inactivation of VKOR and VKR by these drugs are clarified. Results from both cell-based and animal model studies suggest that the anticoagulation effect of drugs that target VKOR, but not VKR, can be rescued by the administration of vitamin K. These findings provide insights into the prevention and management of drug-induced bleeding disorders. The established cell-based, high-throughput screening approach provides a powerful tool for identifying new vitamin K antagonists that function as anticoagulants.
Subject(s)
Anticoagulants/isolation & purification , Anticoagulants/pharmacology , Hemorrhagic Disorders/chemically induced , High-Throughput Screening Assays/methods , Vitamin K/metabolism , 4-Hydroxycoumarins/adverse effects , 4-Hydroxycoumarins/isolation & purification , 4-Hydroxycoumarins/pharmacology , Animals , Anticoagulants/adverse effects , Blood Coagulation/drug effects , Cell Culture Techniques/methods , Drug Evaluation, Preclinical/methods , HEK293 Cells , Hep G2 Cells , Humans , Indenes/adverse effects , Indenes/isolation & purification , Indenes/pharmacology , Male , Metabolic Networks and Pathways/drug effects , Mice , Mice, Inbred BALB C , Off-Label Use , Vitamin K/adverse effects , Vitamin K/antagonists & inhibitors , Vitamin K/isolation & purification , Vitamin K/pharmacology , Vitamin K Epoxide Reductases/antagonists & inhibitors , Vitamin K Epoxide Reductases/metabolismABSTRACT
Ferula communis is an ombelliferous plant of the Mediterranean regions. It is represented in Morocco by two varieties: brevifolia and genuina. The later is very rich in a soap or resinous gum. This product, collected from the roots, is largely used in traditional medicine. It is know as fessoukh in Morocco and other Arab countries. This plant is also well known for its toxicity and its anticoagulant activity. In the present review, are discussed: (1) the ethnobotany of the plant, especially medicinal uses of fessoukh in traditional medicine as well as alimentary use of young stems as legumes; (2) clinical and biochemical data of intoxication by this plant, which are dominated by haemorrhage as a consequence of blood coagulation disturbance; (3) 4-hydroxycoumarins isolated from Ferula communis L. and their anticoagulant activity; (4) the role of vitamin K1 in the treatment of poisoning by this plant.
Subject(s)
4-Hydroxycoumarins/pharmacology , Anticoagulants/pharmacology , Ferula/chemistry , Plants, Medicinal , Plants, Toxic , 4-Hydroxycoumarins/adverse effects , 4-Hydroxycoumarins/isolation & purification , 4-Hydroxycoumarins/poisoning , Animals , Anticoagulants/adverse effects , Anticoagulants/isolation & purification , Anticoagulants/poisoning , Blood Coagulation Factors/physiology , Ferula/poisoning , Hemorrhage/chemically induced , Humans , Italy , Morocco , Plant Poisoning/drug therapy , Plant Poisoning/veterinary , Sheep , Sheep Diseases/chemically induced , Vitamin K 1/physiology , Vitamin K 1/therapeutic useABSTRACT
Thirteen compounds have been isolated from Gerbera anandria (L.) Sch Bip. Among them, three new compounds were elucidated by chemical correlations and spectral analyses. They are 3.8-dihydroxy-4-methoxy-coumarin (XIX), 3,8-dihydroxy-4-methoxy-2-oxo-2H-1-benzopyran-5-carboxylic acid (XVII), and 5,8-dihydroxy-7-(4-hydroxy-5-methyl-coumarin-3-)coumarin (XXI).