Cultures treated with GSE exhibited significant downregulation of CCR2b message compared to that of the control cultures. The percent inhibitions are GSE at 0. Cultures treated with GSE at 5,1,0. Cells treated with GSE 0. GSE at lower concentrations of 0.
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Fig 2. Cytoplasmic RNA was extracted from these cultured cells and subjected to reverse transcription. The PCR products were separated by 1.
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Quantitation of changes in CCR2b gene expression. Percent change in laser densitometry reading of the photogarphic negatives of experimental values after normalization with respective G3PDH values was determined and then compared with control values. Quantitation of changes in CCR-3 gene expression. Isotype control monoclonal antibody IgG 1 k was used as a negative control to set quadrant as described by the manufacturer data not shown.
Flavonoids can mediate potential beneficial effects by intricately influencing cell surface receptors. GSE flavonoids display intriguing pharmacologic actions and are promising prophylactic agents To glean insight into the mechanism of their action, we have evaluated the capacity of GSE flavonoids to regulate the expression of HIV-1 entry coreceptors by immunocompetent mononuclear leukocytes.
Our findings indicate for the first time, as far as we are aware, that GSE flavonoid components can intercept processes culminating in the expression of HIV-1 entry coreceptors. Not much information is available concerning the plasma concentrations of flavonoids following the consumption of products such as GSE. Recent work, however, prompts us to infer significant bioavailability of phenolics after consumption of a dealcolized polyphenol extract from red wine, rich in oligomeric procyanidins, by human subjects 3 , Manifestation of appreciable pharmacological activity after consumption of mg of GSE by human subjects indirectly indicated substantial absorption 40 , On the basis of above studies, microgram or above concentrations of polyphenols can be expected in vivo.
Several studies propose that the pharmacologic effects displayed by procyanidin mixtures are due to the oligomers present therein 4 , 6 , 15 , 38 , Laparra et al. Assuming that the preparation was free of monomers, and that no degradation of the dimers occurred in the acid conditions prevailing in the stomach, this reflects facile absorption of the intact dimers. Harmund and Blanquet 10 documented similar results on the absorption of radioactive grape procyanidin oligomers and reported that the amount of radioactivity excreted into the feces increased with the dose.
Yamakoshi et al. In a subsequent study 15 , these authors reported a rapid appearance of procyanidins in the plasma of grape seed extract-fed rats and contended that the compounds present in the plasma represented shorter oligomers. One might expect that procyanidin oligomers conforming to certain size range would attach to proteins in as much as binding to proteins and carbohydrates is one of the intrinsic characteristics of long chain procyanidins. While examining the effect of feeding of grape seed extracts, predominantly containing longer procyanidins, to rats, Saito et al.
Recent studies showed that human subjects who consumed red wine excreted intact procyanidins 36 , In this context, it is interesting to note that procyanidins and anthocyanidins are the major polyphenol constitutents of red wine and red grapes. Lapidot et al. Anthocyanidins are stable only at very low pH. The authors deduced that proanthocyanidins entering the body from the administered red wine in this instance would have degraded to anthocyanidins in the urine under its acidic conditions , upon storage. Only a few natural products from plants have received scrutiny for their potential anti -HIV effects 17 , Discovery of very specific and less toxic antiviral agents is a current high priority in the search for more effective therapies against HIV This suggests that flavonoid components of the extract can interfere with the binding of the virus to the cell receptor and, thus can prevent HIV entry into the normal lymphocyte.
Furthermore, these studies may provide new information and impetus for developing a potential clinical trial of grape proanthocyanidins as an adjunct nutritional supplement, along with the existing conventional therapeutic regimens, in the treatment of HIV infection. We wish to thank Mr. Richard Keeley for the provision of grape seed extracts, and for his support and encouragement.
Postepy Hig Med Dosw. Nair Ph. Email: mnair acsu. Tel : Fax: Received: July 23, In revised form: September 19, F: the interacting herb should be administered simultaneously with warfarin in two or more separate courses, with similar results for each course. G: similar outcome should be found for the patient cousing the interacting herb with warfarin at a time prior to that reported.
Mechanisms of herb-warfarin interaction are divided into two categories: those involving pharmacokinetics PK of warfarin and those involving pharmacodynamics PD. In addition, we attempted to identify the possible corresponding mechanisms of interactions for relevant herbs. Pharmacokinetic interactions are those that can affect the process by which warfarin is absorbed, metabolized, and distributed as summarized below.
Among these, cytochrome Ps for the metabolism of warfarin is main focus. Other enzymes like UDP-glucuronyltransferase UGT may also be involved in herb-warfarin interaction, but little information or literature is available to confirm their effects. Passive diffusion is known as the primary means for warfarin to cross biological membranes.
Until now, no transporters have been identified for warfarin absorption in gastrointestinal GI environment [ 17 ]. Some herbs including Aloe, Jalap, Cascara, and Rhubarb are found to be able to bind with warfarin to affect its absorption [ 18 ]. Some herbs may directly cause gastrointestinal membrane erosions leading to risk of hemorrhage after their coadministration with warfarin [ 19 ].
Warfarin is metabolized mainly by cytochrome Ps CYPs , a very large family of related isoenzymes [ 20 ].
Updates on the Clinical Evidenced Herb-Warfarin Interactions
Of all those isoenzymes, CYP2C9 accounts for the greatest proportion for metabolism of S -warfarin, which is much more potent than R -enantiomer clinically. Herbs competitively bound to albumin will affect the plasma concentration of warfarin, which may also be one of the reasons for herb-warfarin interaction [ 22 ].
This, however, is not regarded as the main cause of herb-warfarin interaction [ 23 ]. Most of above PK mechanisms for warfarin related interaction were direct interaction such as alteration on CYP enzyme activities and inhibition on protein binding of warfarin. However, there was indeed indirect interaction, for example, when gastrointestinal membrane was damaged. Pharmacodynamic interactions are those where the effects of one drug are changed by the presence of another drug at its site of action. Sometimes the drugs directly compete for particular receptors, specifically VKOR, but often the reaction is more indirect and involves interference with physiological mechanisms.
Therefore, pharmacodynamic interactions are more complicated to be classified neatly than pharmacokinetic interactions. Figure 1 illustrates the process of blood coagulation, pharmacodynamics effects of warfarin, and how herbal components would affect it. It has been shown that pharmacodynamics related mechanisms comprised Schematic illustration of the potential pharmacodynamics mechanism for the interaction between warfarin and herbs.
Platelet aggregation is the first step of coagulation, and a cascade of further platelet activation initiates the formation of blood clot. Reduced platelet aggregation may inhibit thromboxane synthesis [ 24 ], thus interfering with clotting mechanisms, decreasing blood coagulation, and prolonging bleeding time [ 25 ]. Some antiplatelet herbs, for instance, Ginkgo particularly ginkgolide B , have been shown to inhibit the binding of platelet activating factor to their receptors on platelet membranes, resulting in reduced platelet aggregation [ 26 , 27 ].
It can be inferred that the concurrent administration of warfarin with ginkgo may present an additional risk of bleeding.
In vivo, vitamin K can be obtained from two main pathways: being taken from food and being synthesized by vitamin K cycle. Some herbs may stop intestinal flora from synthesizing vitamin K, such as Thymus vulgaris and Allium sativum [ 29 ], thereby enhancing the effect of warfarin. Several herbs such as green tea may contain large amount of vitamin K, which may also result in interaction with warfarin [ 30 ]. Besides, synthetized by intestinal flora and taken from food, the primary way for reduced vitamin K synthesis is vitamin K cycle [ 31 ]. Some herbs, such as Lapachol [ 32 ], affect key enzymes in this circle such as vitamin K epoxide reductase VKOR , regulating the amount of vitamin K in vivo , thereby interacting with warfarin.
Warfarin is a synthetic derivative of dicoumarol. Dicoumarol, in turn, is derived from coumarin [ 33 ]. Although coumarin itself has no anticoagulant properties, it is transformed into the natural anticoagulant dicoumarol by a number of species of fungi [ 33 ]. Therefore, herbs containing coumarin or its derivatives may display similar anticoagulative effects as warfarin. Concurrent administration of warfarin with these herbs may present an additional risk of bleeding.
Some herbs, for instance, Danshen Salvia miltiorrhiza , may affect the expression of thrombomodulin [ 34 ], changing blood coagulation in vivo , thereby interacting with warfarin. Thirty-eight herbs were listed in the current review, including herbs clinically evidenced to interact with warfarin; herbs preclinical evidenced to affect PK or PD of warfarin; herbs containing vitamin K or coumarin; and herbs with similar or opposite pharmacological actions to those of warfarin.
On basis of this overview, effects and severity of each proposed herb-warfarin interaction, as well as the possibility and potential mechanism for those interactions, were abstracted and compiled in Table 3.
PK factors including the following: E: interference with warfarin absorption; F: interference with metabolizing enzymes of warfarin; G: interference with protein binding of warfarin. Boldo was traditionally used for dyspepsia, digestive disturbances, constipation, and rheumatism. Recent research has shown boldine, one of the major active components from Boldo, to be a potent antioxidant [ 35 ].
Boldo also contained amount of natural coumarins. But it is unclear whether they have any anticoagulant activity [ 36 ]. No relevant pharmacokinetic data of Boldo have been found yet.
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One case report suggested that it might interact with warfarin. A woman taking warfarin together with 10 drops of Boldo and one capsule of Fenugreek showed a modest rise in her INR from 2 to 3. A week after stopping Boldo, her INR had fallen to 2. The mechanism of this interaction remains unknown.
Interaction between Boldo and warfarin was defined as doubtful. Cannabinoids are the major active compounds in Cannabis. Medicinal Cannabis is used to treat chronic conditions, including adjunct and neuropathic pain. There is no experimental evidence for interaction between warfarin and Cannabis [ 37 ]. However, a clinical case report described a raised INR and bleeding in a patient who smoked Cannabis 2. This would be expected to increase the metabolism of warfarin effects, which is in contrast to the case report. Because of the existence of other factors, it is not reasonable to ascribe the INR change specifically to herb-drug interaction by a single case report.
Interaction between Cannabis and warfarin was defined as possible. Chamomile is used for dyspepsia, flatulence, and nasal catarrh [ 40 ]. However, the effects were weak when compared with the known potent CYP3A4 inhibitor ketoconazole [ 42 ]. An isolated case of bleeding in a patient taking warfarin with Chamomile products drinking 4 to 5 cups of Chamomile tea daily for chest congestion, and using a chamomile-based skin lotion 4 to 5 times daily for foot oedema had been reported [ 44 ].
Because of many other factors influencing anticoagulant control, it is unreasonable to identify a drug interaction in a single case report without other supporting evidence. Interaction between Chamomile and warfarin was defined as possible. Chitosan is used as a dietary supplement for obesity and hypercholesterolemia [ 40 ]. Chitosan is an absorption enhancer and increased the permeability of hydrophilic drugs across intestinal and mucosal epithelia [ 45 ].
One case report suggested that Chitosan might increase the effects of warfarin.