Data indicate that extracts of Uncaria tomentosa inhibit the most important drug metabolizing enzyme cytochrome P 3A4 CYP3A4 [ 13 ], possibly explaining the published case report describing an interaction between this compound and the HIV protease inhibitors atazanavir, ritonavir, and saquinavir [ 14 ]. Beyond this, no data exist on possible influences of Uncaria tomentosa and Otoba parvifolia on drug metabolizing enzymes or drug transporters being important for drug—drug or herb—drug interactions.
Thus, this in vitro study evaluated the effects of Samento and Banderol on the expression and activity of a broad set of drug transporting or metabolizing proteins.
Neither Samento nor Banderol increased intracellular calcein fluorescence in L-MDR1 cells over-expressing human P-glycoprotein P-gp , indicating lack of P-gp inhibition data not shown. However, also in this cell system, no significant increase in intracellular calcein fluorescence by Samento or Banderol was observed, verifying the lack of P-gp inhibition by these extracts data not shown.
Samento also inhibited both transporters, but with lower potency disabling a calculation of IC 50 values Figure 1 B.
Each curve depicts the results of 3—4 experiments with each concentration tested in octuplet. Induction of several drug metabolizing enzymes and drug transporters was tested by incubation of LS cells with Samento, Banderol, or the positive controls for four days. Figure 3 depicts the influence of Samento on the mRNA expression of several important drug metabolizing enzymes and drug transporters.
The lowest concentration of Samento tested 0. Influence of Samento on the mRNA expression of several drug metabolizing enzymes and drug transporters in LS cells. Cells were incubated for four days with different concentrations 0. Expression data were normalized to the housekeeping gene GU and to the negative control.
In contrast, Banderol had no significant effect on the mRNA expression of any of the genes investigated data not shown. We therefore investigated by means of reporter gene assay, whether this extract can activate PXR. To demonstrate possible influences on aryl hydrocarbon receptor AhR , another important transcription factor regulating e. Results of the reporter gene assays.
Each curve depicts the results of three experiments with each concentration tested in triplicate. Effects of Samento 0. Exemplarily, 1 blot of a series of 5 is depicted. Cells were pre-treated with Samento 0. So far, Samento a TOA-free extract from Uncaria tomentosa and Banderol an extract from Otoba parvifolia often used alternately or in addition to antibiotics by chronic borreliosis patients have not been characterized for their potential to act as perpetrators in herb—drug interactions.
However, for safe application, it is crucial to know whether the pharmacokinetics of concomitantly used drugs can be altered by these herbal extracts. This study, therefore, scrutinized in vitro whether Samento and Banderol can inhibit the activity or induce the expression of important drug metabolizing enzymes and drug transporters.
Whether this inhibition is clinically relevant cannot be estimated, because it is completely unknown which ingredients at what concentrations reach the systemic circulation after ingestion of these herbal drugs. Inhibition of the CYPs tested was mostly weak or absent up to the maximum concentration tested Figure 2.
Again, the clinical relevance is unclear due to the lack of pharmacokinetic data of Samento. However, at the highest recommended dose, the concentration of Samento in the gut is about 0. This might explain the observed interaction of Uncaria tomentosa with HIV protease inhibitors [ 14 ] and might also lead to further interactions with concomitantly used drugs in borreliosis therapy, like clarithromycin, a CYP3A4 substrate [ 15 ]. Since CYP3A4 is the most important drug-metabolizing enzyme and its inhibition might lead to increased systemic exposure to every second licensed drug, this CYP3A4 inhibitory potential of Samento should be further evaluated in a clinical trial.
Not only inhibition, but also induction of pharmacokinetically relevant enzymes and transporters can lead to drug—drug or herb—drug interactions [ 16 ]. PXR activating drugs e.
Whereas Banderol had no effect on any gene expression investigated, Samento turned out to clearly activate PXR in a similar range as the positive control rifampicin. In contrast, AhR was not profoundly affected Figure 4.
Possibly, induction provoked by one ingredient is superimposed by a repressive effect of another ingredient, leading to a net repressive effect at lower concentrations of Samento and a zero net effect at higher concentrations. This induction was not observed at the protein level. However, this might be attributed to the much lower sensitivity of western blot semi-quantification compared to quantitative RT-PCR.
So far, only few data exist on the regulation of CYP2J2 expression. Other studies suggest that activator protein-1 AP-1 and an APlike element play a role in inducing CYP2J2 expression in human liver-derived cells [ 18 ], which might also be the case in our cell system.
CYP2J2 is mainly expressed in the heart and plays an important role in arachidonic acid metabolism and thus in cardiovascular physiology [ 18 ]. In contrast, its involvement in induction-mediated drug—drug interactions is unknown so far, although several drug substrates have been described e.
Besides such drug-metabolizing enzymes, induction of ABCB1 by Samento could also lead to reduced bioavailability of some of the frequently used antibiotics in borreliosis therapy, which are P-gp substrates: tetracycline [ 19 ], minocycline [ 20 ], azithromycin [ 21 ], and clarithromycin [ 21 ].
The maximum concentration used for both extracts was set to a dilution of due to several reasons: 1 this dilution contains 0. Toxic effects on cells can negatively influence transporter inhibition assays. Possible P-gp inhibition by Samento and Banderol was assessed in a calcein assay using calcein acetoxymethylester as a fluorogenic substrate as validated and described previously [ 22 , 23 ].
Cell lines were cultured and treated as published previously as were the results for the positive controls verapamil and quinidine [ 22 , 23 ], which are not depicted in this publication, because the potency of a small molecule given in molar cannot be compared to that of an extract given as a dilution.
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We never dilute our funds, because we want to maintain the maximum quality. Also, our extracts and herbal teas are not blended with cheap goods from abroad.
Why are we emphasizing this so emphatically? Unfortunately, it has been happening again and again lately that other suppliers dilute high-quality tinctures in their own filling with water. We don't think this is fair, so we only have original packaged goods with seals. We mainly use plants and basic materials produced in Italy.
There is a proof of origin on each package, and on our website we inform users where which plant is grown. Even in the case of quite exotic plants, such as. These plants will be available to us directly in the coming years. Almost all products of the Revitalconcept come from organic farming or approved game collection in nature reserves and are vegan.
Non-vegan products based on honey, wax, propolis or milk. B are shown separately. As a Revitalconcept, we do not do any animal testing with our products. Special veterinary clinics use our exclusive products for research purposes: e. It is very important to us that agriculture is environmentally sustainable and that we treat our farmers responsibly and fairly. So we only manage small areas and provide for a 7-field economy. We stay away from monocultures and appreciate that nature - especially on the Italian Islands - gives us so many medicinal plants from game collection.
We harvest only the young shoots in these plants in meticulous manual work and thus promote sustainable growth. This is also the reason why our herbal teas with cistrose taste so particularly good. With our uniquely high quality, we stand out from cheap goods from abroad. We also deal with packaging sustainably.
We largely dispense with plastic packaging and use packaging and cartons as best we can. There is certainly a good reason why our products are recommended by renowned therapists and physicians such as Dr. Klinghardt and Dr.
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