St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Parametric Imaging of P-Glycoprotein Function at the Blood-Brain Barrier Using kE,brain-maps Generated from [11C]Metoclopramide PET Data in Rats, Nonhuman Primates and Humans.

PURPOSE: PET imaging using [11C]metoclopramide revealed the importance of P-glycoprotein (P-gp, ABCB1) in mediating the brain-to-blood efflux of substrates across the blood-brain barrier (BBB). In this work, the elimination rate constant from the brain (kE,brain), calculated from dynamic PET images without the need for arterial blood sampling, was evaluated as an outcome parameter for the interpretation of [11C]metoclopramide PET data. PROCEDURES: kE,brain parameter was obtained by linear regression of log-transformed brain time-activity curves (TACs). kE,brain values (h-1) obtained under baseline conditions were compared with values obtained after complete P-gp inhibition using tariquidar in rats (n = 4) and baboons (n = 4) or after partial inhibition using cyclosporine A in humans (n = 10). In baboons, the sensitivity of kE,brain to measure complete P-gp inhibition was compared with outcome parameters derived from kinetic modeling using a 1-tissue compartment model (1-TCM). Finally, kE,brain-maps were generated in each species using PMOD software. RESULTS: The linear part of the log-transformed brain TACs occurred from 10 to 30 min after radiotracer injection in rats, from 15 to 60 min in baboons, and from 20 to 60 min in humans. P-gp inhibition significantly decreased kE,brain values by 39 ± 12% in rats (p < 0.01), by 32 ± 6% in baboons (p < 0.001), and by 37 ± 22% in humans (p < 0.001). In baboons, P-gp inhibition consistently decreased the brain-to-plasma efflux rate constant k2 (36 ± 9%, p < 0.01) leading to an increase in the total brain volume of distribution (VT, 101 ± 12%, p < 0.001). In all studied species, brain kE,brain-maps displayed decreased P-gp-mediated efflux across the BBB. CONCLUSIONS: kE,brain of [11C]metoclopramide provides a simple outcome parameter to describe P-gp function in the living brain when arterial input function data are unavailable, although less sensitive than VT. kE,brain-maps represent easy to compute parametric images reflecting the effect of P-gp on [11C]metoclopramide elimination from the brain.

Impact of Cytochrome Induction or Inhibition on the Plasma and Brain Kinetics of [11C]metoclopramide, a PET Probe for P-Glycoprotein Function at the Blood-Brain Barrier.

[11C]metoclopramide PET imaging provides a sensitive and translational tool to explore P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Patients with neurological diseases are often treated with cytochrome (CYP) modulators which may impact the plasma and brain kinetics of [11C]metoclopramide. The impact of the CYP inducer carbamazepine or the CYP inhibitor ritonavir on the brain and plasma kinetics of [11C]metoclopramide was investigated in rats. Data obtained in a control group were compared with groups that were either orally pretreated with carbamazepine (45 mg/kg twice a day for 7 days before PET) or ritonavir (20 mg/kg, 3 h before PET) (n = 4 per condition). Kinetic modelling was performed to estimate the brain penetration (VT) of [11C]metoclopramide. CYP induction or inhibition had negligible impact on the plasma kinetics and metabolism of [11C]metoclopramide. Moreover, carbamazepine neither impacted the brain kinetics nor VT of [11C]metoclopramide (p > 0.05). However, ritonavir significantly increased VT (p < 0.001), apparently behaving as an inhibitor of P-gp at the BBB. Our data suggest that treatment with potent CYP inducers such as carbamazepine does not bias the estimation of P-gp function at the BBB with [11C]metoclopramide PET. This supports further use of [11C]metoclopramide for studies in animals and patients treated with CYP inducers.

ABCB1 and ABCG2 Together Limit the Distribution of ABCB1/ABCG2 Substrates to the Human Retina and the ABCG2 Single Nucleotide Polymorphism Q141K (c.421C> A) May Lead to Increased Drug Exposure.

The widely expressed and poly-specific ABC transporters breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) are co-localized at the blood-brain barrier (BBB) and have shown to limit the brain distribution of several clinically used ABCB1/ABCG2 substrate drugs. It is currently not known to which extent these transporters, which are also expressed at the blood-retinal barrier (BRB), may limit drug distribution to the human eye and whether the ABCG2 reduced-function single-nucleotide polymorphism (SNP) Q141K (c.421C > A) has an impact on retinal drug distribution. Ten healthy male volunteers (five subjects with the c.421CC and c.421CA genotype, respectively) underwent two consecutive positron emission tomography (PET) scans after intravenous injection of the model ABCB1/ABCG2 substrate [11C]tariquidar. The second PET scan was performed with concurrent intravenous infusion of unlabelled tariquidar to inhibit ABCB1 in order to specifically reveal ABCG2 function.In response to ABCB1 inhibition with unlabelled tariquidar, ABCG2 c.421C > A genotype carriers showed significant increases (as compared to the baseline scan) in retinal radiotracer influx K 1 (+62 ± 57%, p = 0.043) and volume of distribution V T (+86 ± 131%, p = 0.043), but no significant changes were observed in subjects with the c.421C > C genotype. Our results provide the first evidence that ABCB1 and ABCG2 may together limit the distribution of systemically administered ABCB1/ABCG2 substrate drugs to the human retina. Functional redundancy between ABCB1 and ABCG2 appears to be compromised in carriers of the c.421C > A SNP who may therefore be more susceptible to transporter-mediated drug-drug interactions at the BRB than non-carriers.

[Why using antidepressants in chronic pain†? Practical prescription recommendations]. / Antidépresseurs dans la douleur chronique†: pourquoi les utiliser, comment les prescrire en pratique†?

The use over the last 50 years of antidepressants having both serotonergic and noradrenergic properties, as the first line for the management of neuropathic pain or chronic pain syndromes, is based on a twofold rationale: on the one hand, a plausible analgesic mechanism of action independent of the effect on mood, on the other hand, efficacy data in humans and animals. Their prescription should be part of a multimodal approach to pain. The dose to reach the analgesic effect, which on average occurs within four weeks after the initiation of treatment, is sometimes lower than the dose required to achieve the antidepressant effect. The choice of antidepressant will rely on the profile of adverse effects and other expected secondary benefits in the case of comorbidities.

L'utilisation depuis 50 ans d'antidépresseurs ayant à la fois une action sérotoninergique et noradrénergique comme première ligne pour la prise en charge de douleurs neuropathiques ou de syndromes douloureux chroniques est basée sur les deux raisons suivantes : d'une part, un mécanisme d'action antalgique plausible et indépendant de l'effet thymique, d'autre part, des données d'efficacité chez l'humain et l'animal. Leur prescription doit s'inscrire dans une approche multimodale de la douleur. La dose nécessaire pour atteindre l'effet antalgique, qui survient en moyenne dans les 4 semaines après l'introduction du traitement, est parfois moins importante que celle qui permet d'obtenir l'effet antidépresseur. Le choix de la molécule se fera en fonction du profil d'effets indésirables et d'autres bénéfices secondaires éventuels attendus.

Cannabinoids and COVID-19.

Since the endocannabinoid system is involved in immune function, the effect of cannabinoid intake on infectious conditions is questioned for several years and is of particular interest in the COVID 19 pandemia. Some data suggest that the immunomodulatory effect of cannabinoids may affect the course and severity of SARS-CoV-2 infection. Given the large number of cannabinoids consumers in the community, this commentary presents the current knowledge on the potential impact of cannabinoids and endocannabinoids on bacterial and viral infection courses namely SARS-CoV-2 disease. Practical recommendations, which can be drawn from the literature, are given.

Snapshot of proton pump inhibitors prescriptions in a tertiary care hospital in Switzerland: less is more?

Background Proton pump inhibitors are among the most widely prescribed drugs in the world, but more than half of the indications for prescription are unjustified. The misuse of this therapeutic class has heavy consequences such as additional health costs, adverse drug reactions following long-term use and gastric acid rebound when the proton pump inhibitor is discontinued. Objective The overprescription of proton pump inhibitors is therefore becoming a public health problem, which led us to evaluate their use within the Geneva University Hospitals. Setting Patients hospitalized in two divisions of the department of internal medicine of the Geneva University Hospitals on a single day. Methods This is a register-based cross-sectional study and it collected data about the prescription pattern of proton pump inhibitors by consulting the electronic records of patients included. Main outcome measure To determine if the proton pump inhibitors prescription is made according to the market authorization and the available guidelines. Results Hundred-eighty patients were included. 54% of patients were on proton pump inhibitors, 29% of whom had their treatment initiated at hospital. Of the indications for treatment, 72% were not justified and 63% of the justified indications did not have an adequate dosage. Therefore, in all patients with a proton pump inhibitor at hospital, only 11% had a justified indication with an adequate dose. Finally, 87% of known home prescriptions were renewed on admission and among them, 71% did not have a justified or possibly justified indication according to the guidelines. Conclusion Indication for treatment inside the hospital was not justified in 72% of patients and only 11% had a justified indication with an adequate dosage. Precise guidelines with evidence-based indications and adequate daily doses would help to correctly prescribe proton pump inhibitors. Moreover, patients should benefit from a thorough evaluation of their treatment.