Herbal remedies: adverse effects and drug interactions.
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A growing number of Americans are using herbal products for preventive and therapeutic purposes. The manufacturers of these products are not required to submit proof of safety and efficacy to the U.S. Food and Drug Administration before marketing. For this reason, the adverse effects and drug interactions associated with herbal remedies are largely unknown. Ginkgo biloba extract, advertised as improving cognitive functioning, has been reported to cause spontaneous bleeding, and it may interact with anticoagulants and antiplatelet agents. St. John's wort, promoted as a treatment for depression, may have monoamine oxidase-inhibiting effects or may cause increased levels of serotonin, dopamine and norepinephrine. Although St. John's wort probably does not interact with foods that contain tyramine, it should not be used with prescription antidepressants. Ephedrine-containing herbal products have been associated with adverse cardiovascular events, seizures and even death. Ginseng, widely used for its purported physical and mental effects, is generally well tolerated, but it has been implicated as a cause of decreased response to warfarin. Physicians must be alert for adverse effects and drug interactions associated with herbal remedies, and they should ask all patients about the use of these products. (+info)
Interactions of 6-gingerol and ellagic acid with the cardiac sarcoplasmic reticulum Ca2+-ATPase.
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The inotropic/lusitropic effects of beta-adrenergic agonists on the heart are mediated largely by protein kinase A (PKA)-catalyzed phosphorylation of phospholamban, the natural protein regulator of the Ca2+ pump present in sarcoplasmic reticulum (SR) membranes. Gingerol, a plant derivative, is known to produce similar effects when tested in isolated cardiac muscle. The purpose of the present study was to compare the effects of gingerol and another plant derivative, ellagic acid, on the kinetics of the SR Ca2+ pump with those of PKA-catalyzed phospholamban phosphorylation to elucidate their mechanisms of Ca2+ pump regulation. As previously demonstrated for PKA, 50 microM gingerol or ellagic acid increased Vmax(Ca) of Ca2+ uptake and Ca2+-ATPase activity assayed at millimolar ATP concentrations in light cardiac SR vesicles. Unlike PKA, which decreases Km(Ca), neither compound had a significant effect on Km(Ca) in unphosphorylated vesicles. However, gingerol increased Km(Ca) in phosphorylated vesicles, in which Ca2+ uptake was significantly increased further at saturating Ca2+ and remained unchanged at subsaturating Ca2+. An inhibition of Ca2+ uptake by gingerol at micromolar MgATP concentrations was overcome with increasing MgATP concentrations. The stimulation of Ca2+ uptake attributable to gingerol in unphosphorylated microsomes at saturating Ca2+ was 30% to 40% when assayed at 0.05 to 2 mM MgATP and only about 12% in phosphorylated microsomes as well as in rabbit fast skeletal muscle light SR. The present results support the view that an ATP-dependent increase in Vmax(Ca) of the SR Ca2+ pump plays an important role in mediating cardiac contractile responses to gingerol and phospholamban-dependent beta-adrenergic stimulation. (+info)
Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro.
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Estrogenic isoflavones, such as genistein and daidzein, are present in virtually all natural-ingredient rodent diets that use soy as a source of protein. Since these compounds are endocrine-active, it is important to determine whether the amounts present in rodent diets are sufficient to affect sexual development. The present study consisted of in vitro and in vivo parts. In the in vitro portion, human hepatoma cells were transfected with either rat estrogen receptor (ER) alpha or beta plus an estrogen-responsive luciferase reporter gene. Genistein and daidzein were complete agonists at both ERs, genistein being more potent than daidzein, and both compounds were more potent at ER beta than ER alpha. In combined studies with estradiol, genistein exerted additive effects with estradiol in vitro. In the in vivo portion of the study, groups of six pregnant Sprague-Dawley females were fed one of the following four diets, and the pups were maintained on the same diets until puberty: (1) a natural-ingredient, open-formula rodent diet (NIH-07) containing 16 mg genistein and 14 mg daidzein per 100 g of feed; (2) a soy- and alfalfa-free diet (SAFD) in which casein and corn oil were substituted for soy and alfalfa meal and soy oil, respectively, that contained no detectable isoflavones; (3) SAFD containing 0.02% genistein (GE.02); or (4) SAFD containing 0.1% genistein (GE.1). In the GE.1 group, effects of dietary genistein included a decreased rate of body-weight gain, a markedly increased (2.3-fold) uterine/body weight (U/BW) ratio on postnatal day (pnd) 21, a significant acceleration of puberty among females, and a marginal decrease in the ventral prostate weight on postnatal day (pnd) 56. However, developmental differences among the groups fed SAFD, GE.02, or NIH-07 were small and suggested minimal effects of phytoestrogens at normal dietary levels. In particular, on pnd 21, the U/BW ratio of the GE.02 and NIH-07 groups did not differ significantly from that of the SAFD group. Only one statistically significant difference was detected between groups fed SAFD and NIH-07: the anogenital distance (AGD) of female neonates on pnd 1 whose dams were fed NIH-07 was 12% larger than that of neonates whose dams were fed SAFD. The results suggest that normal amounts of phytoestrogens in natural-ingredient rodent diets may affect one developmental parameter, the female AGD, and that higher doses can affect several other parameters in both males and females. Based on these findings, we do not suggest replacing soy- and alfalfa-based rodent diets with phytoestrogen-free diets in most developmental toxicology studies. However, phytoestrogen-free diets are recommended for endocrine toxicology studies at low doses, to determine whether interactive effects may occur between dietary phytoestrogens and man-made chemicals. (+info)
Herb-drug interactions: review and assessment of report reliability.
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AIMS: The aim of this systematic review was to assess the published clinical evidence on interactions between herbal and conventional drugs. METHODS: Four electronic databases were searched for case reports, case series or clinical trials of such interactions. The data were extracted and validated using a scoring system for interaction probability. RESULTS: One hundred and eight cases of suspected interactions were found. 68.5% were classified as 'unable to be evaluated', 13% as 'well-documented' and 18.5% as 'possible' interactions. Warfarin was the most common drug (18 cases) and St John's wort the most common herb (54 cases) involved. CONCLUSION: Herb-drug interactions undoubtedly do occur and may put individuals at risk. However our present knowledge is incomplete and more research is urgently needed. (+info)
NMR investigations of protein-carbohydrate interactions: insights into the topology of the bound conformation of a lactose isomer and beta-galactosyl xyloses to mistletoe lectin and galectin-1.
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A hallmark of oligosaccharides is their often limited spatial flexibility, allowing them to access a distinct set of conformers in solution. Viewing each individual or even the complete ensemble of conformations as potential binding partner(s) for lectins in protein-carbohydrate interactions, it is pertinent to address the question on the characteristics of bound state conformation(s) in solution. Also, it is possible that entering the lectin's binding site distorts the low-energy topology of a glycosidic linkage. As a step to delineate the strategy of ligand selection for galactosides, a common physiological docking point, we have performed a NMR study on two non-homologous lectins showing identical monosaccharide specificity. Thus, the conformation of lactose analogues bound to bovine heart galectin-1 and to mistletoe lectin in solution has been determined by transferred nuclear Overhauser effect measurements. It is demonstrated that the lectins select the syn conformation of lactose and various structural analogues (Galbeta(1-->4)Xyl, Galbeta(1-->3)Xyl, Galbeta(1-->2)Xyl, and Galbeta(1-->3)Glc) from the ensemble of presented conformations. No evidence for conformational distortion was obtained. Docking of the analogues to the modeled binding sites furnishes explanations, in structural terms, for exclusive recognition of the syn conformer despite the non-homologous design of the binding sites. (+info)
St Johns wort increases expression of P-glycoprotein: implications for drug interactions.
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AIMS: St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in significant reductions in trough plasma concentrations of indinavir and cyclosporin [1, 2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug-drug interactions. METHODS: Healthy volunteers were randomized to either SJW (0.15%) 600 mg three times daily for 16 days (n = 15) or placebo (n = 7). Blood samples were obtained for P-glycoprotein expression and function at baseline, 16 and 32 days post treatment. Peripheral blood lymphocytes (PBMCs) were isolated by Ficoll density gradient centrifugation, fixed and permeabilized. Cells were stained with a P-glycoprotein specific antibody, quantified by flow cytometry and median fluorescence intensity (MFI) values obtained. Vimentin and IE (nonsense antibody) were used as controls. The presence of the MDR 1 gene product was confirmed by RT-PCR. P-glycoprotein mediated drug efflux was determined as a function of rhodamine efflux in the absence and presence of ritonavir. Data are expressed as mean +/- s.d. and were subjected to nonparametric analysis. RESULTS: P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW (7.0 +/- 1.9 vs 29.5 +/- 14.3 (MFI); P < 0.05). There was no effect with placebo (5.1 +/- 1.3 vs 6.0 +/- 1.9 MFI). SJW increased P-glycoprotein mediated rhodamine efflux (reduced ratio) compared with baseline (0.12 +/- 0.04 vs 0.24 +/- 0.18 P < 0.05). There was no change with placebo. Ritonavir (5 microm) inhibited P-glycoprotein mediated efflux in both groups producing greater intracellular accumulation of rhodamine. However, this effect was attenuated following treatment with SJW (23.9 +/- 15.3% vs 75.4 +/- 16.4% P < 0.05). CONCLUSIONS: SJW increased expression and enhanced the drug efflux function of the multi drug transporter P-glycoprotein in PBMCs of healthy volunteers. This may represent a second mechanism for the drug-herb interactions seen in clinical practice and account for the discrepancies between in vitro and in vivo data. Since P-glycoprotein and CYP3A4 have distinct though overlapping substrates, patients receiving drugs, which are P-glycoprotein substrates should be warned against self-medication with SJW as clinically significant drug interactions may occur. (+info)
Pharmacokinetic interactions between carbamazepine and the traditional Chinese medicine Paeoniae Radix.
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The present study was conducted to evaluate the effects of Paeoniae Radix (PR), one of the most famous tonic traditional Chinese medicines, on the pharmacokinetics of carbamazepine (CBZ) in rats and to determine the possible interactions between PR and CBZ. The significant decrease in Tmax indicated that simultaneous oral administration of PR contributed to more rapid absorption of CBZ. It is suggested that the faster absorption of CBZ might lead to the rapid onset of its clinical effect. There were no significant differences in maximum concentration (Cmax), area under the plasma concentration-time curve (AUC), half-life (t1/2), mean residence time (MRT), clearance/bioavailability (CL/F), and apparent volume of distribution/bioavailability (Vd/F) of CBZ between the two groups, showing that PR did not significantly affect the absorption extent, distribution, metabolism, and elimination of CBZ. A significant decrease in protein binding rate was found when CBZ was coadministered with PR. Further studies are in progress to clarify the clinical significance and the mechanism underlying the effects of PR on the protein binding of CBZ observed in the present study. (+info)
St John's wort (Hypericum perforatum): drug interactions and clinical outcomes.
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AIMS: The aim of this work is to identify the medicines which interact with the herbal remedy St John's wort (SJW), and the mechanisms responsible. METHODS: A systematic review of all the available evidence, including worldwide published literature and spontaneous case reports provided by healthcare professionals and regulatory authorities within Europe has been undertaken. RESULTS: A number of clinically significant interactions have been identified with prescribed medicines including warfarin, phenprocoumon, cyclosporin, HIV protease inhibitors, theophylline, digoxin and oral contraceptives resulting in a decrease in concentration or effect of the medicines. These interactions are probably due to the induction of cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP1A2 and the transport protein P-glycoprotein by constituent(s) in SJW. The degree of induction is unpredictable due to factors such as the variable quality and quantity of constituent(s) in SJW preparations. In addition, possible pharmacodynamic interactions with selective serotonin re-uptake inhibitors and serotonin (5-HT(1d)) receptor-agonists such as triptans used to treat migraine were identified. These interactions are associated with an increased risk of adverse reactions. CONCLUSIONS: In Sweden and the UK the potential risks to patients were judged to be significant and therefore information about the interactions was provided to health care professionals and patients. The product information of the licensed medicines involved has been amended to reflect these newly identified interactions and SJW preparations have been voluntarily labelled with appropriate warnings. (+info)