Anti-Inflammatory and Antimicrobial Activities of Portuguese Prunus avium L. (Sweet Cherry) By-Products Extracts.

The bioactivity of natural by-products in food and pharmaceutical applications is the subject of numerous studies. Cherry production and processing generates large amounts of biowaste, most of which is not used. The recovery of these by-products is essential for promoting the circular economy and to improving sustainability in the food industry. In this work, we explored the anti-inflammatory and antimicrobial potential of two different extracts from stems, leaves, and flowers of Portuguese cherries. The anti-inflammatory potential was studied on lipopolysaccharide (LPS)-stimulated mouse macrophages (RAW 264.7) by evaluating the effect of by-products on cellular viability and nitric oxide (NO) production. Disc diffusion and minimum inhibitory concentration (MIC) were used to determine antimicrobial activity. The cherry by-products had no cytotoxic effect on RAW 264.7 cells, and were able to inhibit nitrite production in a dose-dependent manner. Moreover, all aqueous infusions showed good antioxidant activity against NO radicals. Moreover, leaf extracts showed the best activity against most of the strains studied. The results revealed, for the first time, interesting anti-inflammatory and antimicrobial properties of cherry by-products. This could potentially be of interest for their therapeutic use in the treatment of inflammation-related diseases or in controlling the growth of microorganisms.

Effects of Functional Phenolics Dietary Supplementation on Athletes' Performance and Recovery: A Review.

In recent years, many efforts have been made to identify micronutrients or nutritional strategies capable of preventing, or at least, attenuating, exercise-induced muscle damage and oxidative stress, and improving athlete performance. The reason is that most exercises induce various changes in mitochondria and cellular cytosol that lead to the generation of reactive species and free radicals whose accumulation can be harmful to human health. Among them, supplementation with phenolic compounds seems to be a promising approach since their chemical structure, composed of catechol, pyrogallol, and methoxy groups, gives them remarkable health-promoting properties, such as the ability to suppress inflammatory processes, counteract oxidative damage, boost the immune system, and thus, reduce muscle soreness and accelerate recovery. Phenolic compounds have also already been shown to be effective in improving temporal performance and reducing psychological stress and fatigue. Therefore, the aim of this review is to summarize and discuss the current knowledge on the effects of dietary phenolics on physical performance and recovery in athletes and sports practitioners. Overall, the reports show that phenolics exert important benefits on exercise-induced muscle damage as well as play a biological/physiological role in improving physical performance.

Anti-Inflammatory and Antiproliferative Properties of Sweet Cherry Phenolic-Rich Extracts.

Cherries have largely been investigated due to their high content in phenolics in order to fully explore their health-promoting properties. Therefore, this work aimed to assess, for the first time, the anti-inflammatory potential of phenolic-targeted fractions of the Saco cherry, using RAW 264.7 macrophages stimulated with lipopolysaccharide. Additionally, the cytotoxic effects on gastric adenocarcinoma (AGS), neuroblastoma (SH-SY5Y) and normal human dermal fibroblast (NHDF) cells were evaluated, as well as the ability to protect these cellular models against induced oxidative stress. The obtained data revealed that cherry fractions can interfere with cellular nitric oxide (NO) levels by capturing NO radicals and decreasing inducible nitric oxide synthase and cyclooxygenase-2 expression. Furthermore, it was observed that all cherry fractions exhibited dose-dependent cytotoxicity against AGS cells, presenting cytotoxic selectivity for these cancer cells when compared to SH-SY5Y and NHDF cells. Regarding their capacity to protect cancer cells against oxidative injury, in most assays, the total cherry extract was the most effective. Overall, this study reinforces the idea that sweet cherries can be incorporated into new pharmaceutical products, smart foods and nutraceuticals.

Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression.

Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although several antidepressant drugs are clinically available, less than 50% of depressed patients respond to first-line pharmacological treatments. Chronotherapeutic approaches to enhance the effectiveness of antidepressants are not completely known. Even so, experimental results found until this day suggest a positive influence of drug dosing-time on the efficacy of depression therapy. On the other hand, antidepressants have also demonstrated to modulate circadian rhythmicity and sleep-wake cycles. This review aims to evidence the potential of chronotherapy to improve the efficacy and/or safety of antidepressants. It includes pre-clinical and clinical studies that demonstrate the relevance of determining the most appropriate time of administration for antidepressant drugs. In parallel, their positive influence on the resynchronization of disrupted circadian rhythms is also herein discussed. It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics.

Valorisation of Prunus avium L. By-Products: Phenolic Composition and Effect on Caco-2 Cells Viability.

Prunus avium L. by-products, such as stems, leaves, and flowers, are used in folk medicine to prevent and treat some diseases. However, their phenolic composition and in vitro bioactivities against tumor cells are poorly known. In this work, we compared the phenolic profile and the biological potential of aqueous infusions and hydroethanolic extracts of P. avium leaves, stems, and flowers from Saco cultivar, collected from the Fundão region (Portugal). Among the fifty-two phenolic compounds tentatively identified by HPLC-DAD-ESI/MSn, the hydroxycinnamic acids were the most abundant. Both extracts of stems revealed a higher activity against DPPH•. Meanwhile, hydroethanolic extracts from stems and flowers and aqueous infusions of flowers were the most effective in inhibiting the growth of the human epithelial colorectal adenocarcinoma (Caco-2) cells at concentrations above 200 µg/mL. More detailed knowledge about the phenolic composition and health-promoting properties of Portuguese P. avium by-products allows for increasing the biological and commercial value of these bio-wastes, which may have a positive impact on food and pharmaceutical industries, as on the valorization of the local economy.

Peptide-lipid nanoconstructs act site-specifically towards glioblastoma growth impairment.

Ultra-small nanostructured lipid carriers (usNLCs) have been hypothesized to promote site-specific glioblastoma (GB) drug delivery. Envisioning a multitarget purpose towards tumor cells and microenvironment, a surface-bioconjugated usNLC prototype is herein presented. The comeback of co-delivery by repurposing atorvastatin and curcumin, as complementary therapy, was unveiled and characterized, considering colloidal properties, stability, and drug release behavior. Specifically, the impact of the surface modification of usNLCs with hyaluronic acid (HA) conjugates bearing the cRGDfK and H7k(R2)2 peptides, and folic acid (FA) on GB cells was sequentially evaluated, in terms of cytotoxicity, internalization, uptake mechanism and hemolytic character. As proof-of-principle, the biodistribution, tolerability, and efficacy of the nanocarriers were assessed, the latter in GB-bearing mice through magnetic resonance imaging and spectroscopy. The hierarchical modification of the usNLCs promotes a preferential targeting behavior to the brain, while simultaneously sparing the elimination by clearance organs. Moreover, usNLCs were found to be well tolerated by mice and able to impair tumor growth in an orthotopic xenograft model, whereas for mice administered with the non-encapsulated therapeutic compounds, tumor growth exceeded 181% in the same period. Relevant biomarkers extracted from metabolic spectroscopy were ultimately identified as a potential tumor signature.

Improving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin A.

Neolignan licarin A (1) was isolated from leaves of Nectandra oppositifolia (Lauraceae) and displayed activity against trypomastigote forms of the etiologic agent of American trypanosomiasis, Trypanosoma cruzi. Aiming for the establishment of SAR, five different compounds (1a - 1e) were prepared and tested against T. cruzi. The 2-allyl derivative of licarin A (1d) exhibited higher activity against trypomastigotes of T. cruzi (IC50 = 5.0 µM and SI = 9.0), while its heterocyclic derivative 1e displayed IC50 of 10.5 µM and reduced toxicity against NCTC cells (SI > 19.0). However, these compounds presented limited oral bioavailability estimation (<85%, Papp <1.0 × 10-6 cm/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (2), vanillyl alcohol (3), isoeugenol (4), and eugenol (5), as well as its corresponding methyl (a), acetyl (b), O-allyl (c), and C-allyl (d) analogues. Vanillin (2) and its acetyl derivative (2b) displayed expressive activity against intracellular amastigotes of T. cruzi with IC50 values of 5.5 and 5.6 µM, respectively, and reduced toxicity against NCTC cells (CC50 > 200 µM). In addition, these simplified analogues showed a better permeability profile (Papp > 1.0 × 10-6 cm/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (3b) and isoeugenol methyl derivative (4a) displayed activity against the extracellular forms of T. cruzi (trypomastigotes) with IC50 values of 5.1 and 8.8 µM respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (1d, 1e, 3d, and 4a) were selected for a mechanism of action study. After a short incubation period (1 h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound 4a, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of T. cruzi and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease.

Nose-to-brain Delivery of Natural Compounds for the Treatment of Central Nervous System Disorders.

BACKGROUND: Several natural compounds have demonstrated potential for the treatment of central nervous system disorders such as ischemic cerebrovascular disease, glioblastoma, neuropathic pain, neurodegenerative diseases, multiple sclerosis and migraine. This is due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. Nevertheless, many of these molecules have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations. Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration, by enabling a direct transport into the brain through the olfactory and trigeminal nerves. With this approach, the blood-brain barrier is circumvented and peripheral exposure is reduced, thereby minimizing possible adverse effects. OBJECTIVE: Herein, brain-targeting strategies for nose-to-brain delivery of natural compounds, including flavonoids, cannabinoids, essential oils and terpenes, will be reviewed and discussed. Brain and plasma pharmacokinetics of these molecules will be analyzed and related to their physicochemical characteristics and formulation properties. CONCLUSION: Natural compounds constitute relevant alternatives for the treatment of brain diseases but often require loading into nanocarrier systems to reach the central nervous system in sufficient concentrations. Future challenges lie in a deeper characterization of their therapeutic mechanisms and in the development of effective, safe and brain-targeted delivery systems for their intranasal administration.

Safety evidence on the administration of Fucus vesiculosus L. (bladderwrack) extract and lamotrigine: data from pharmacokinetic studies in the rat.

Fucus vesiculosus is often incorporated in weight loss dietary supplements to improve weight loss in overweight adults. Obesity is a common condition in epilepsy patients and is indeed increasing in refractory epilepsy and in patients under polytherapy. Since lamotrigine (LTG) is a first-line antiepileptic drug, used in monotherapy or adjunctive therapy, the main objective of this work was to investigate the potential pharmacokinetic-based interactions between F. vesiculosus and LTG in rats. In a first pharmacokinetic study, a single oral dose of F. vesiculosus extract (575 mg/kg, p.o.) was co-administered with a single-dose of LTG (10 mg/kg, p.o.). In a second study, rats were orally pretreated with F. vesiculosus extract (575 mg/kg/day, p.o.) for 14 days and received LTG (10 mg/kg, p.o.) on the 15th day. In the control groups, rats received water instead of the extract. After LTG administration, blood samples were taken until 96 h post-dose, and LTG concentrations measured in plasma were submitted to a non-compartmental pharmacokinetic analysis. The co-administration of F. vesiculosus extract and LTG caused no significant changes in the drug kinetics. However, the repeated pretreatment with F. vesiculosus extract significantly reduced the peak concentrations of LTG and caused a slightly decrease in the extent of systemic drug exposure. Overall, based on these results, no significant clinical impact is expected from the administration of F. vesiculosus dietary supplements and LTG.

Short-term effects of Garcinia cambogia extract on the pharmacokinetics of lamotrigine given as a single-dose in Wistar rats.

Garcinia cambogia supplements are widely used for weight loss. Knowing that epilepsy patients are at greater risk of developing overweight/obesity, the investigation of herb-drug interactions involving antiepileptic drugs of narrow therapeutic index is fully justified. This work was planned to assess potential pharmacokinetic-based interactions between G. cambogia extract and lamotrigine (LTG) through two independent pharmacokinetic studies. In the first study (co-administration study), rats were orally co-administered with a single-dose of G. cambogia extract (821 mg/kg) and LTG (10 mg/kg). In the second study (pre-treatment study), rats were orally pre-treated for 14 days with G. cambogia extract (821 mg/kg/day), being LTG administered (10 mg/kg) on the 15th day. Rats of the control groups received water instead of the extract. Following LTG administration, blood samples were collected until 96 h post-dose, and plasma LTG concentrations were determined and submitted to a non-compartmental analysis. Globally, no statistically significant effects were identified in the co-administration study of G. cambogia extract and LTG. In the 14-day pre-treatment study, a statistically significant decrease in the rate of systemic exposure to LTG and an increase of apparent volume of distribution were found. Even so, a minor or no clinical impact is expected from the administration of G. cambogia dietary supplements and LTG.

Evaluation of the effects of Citrus aurantium (bitter orange) extract on lamotrigine pharmacokinetics: Insights from in vivo studies in rats.

Citrus aurantium extracts have thermogenic and lipolytic activities and are largely used for weight loss/management. Once epilepsy and obesity are prevalent comorbid conditions and herb-drug interactions can compromise antiepileptic drugs safety, we aimed to evaluate the effects of C. aurantium extract on the pharmacokinetics of lamotrigine (LTG) in rats. In the first pharmacokinetic study, a single oral dose of C. aurantium extract (164 mg/kg; p.o.) was administered with a single oral dose of LTG (10 mg/kg; p.o.). In the following study, the C. aurantium extract was daily administered (164 mg/kg; p.o.) during 14 days followed by a single dose of LTG (10 mg/kg; p.o.) on the 15th day. From the pharmacokinetic analysis, no significant effects were observed after the co-administration of C. aurantium extract and LTG. After the 14-day pre-treatment period, the main effects of the extract were limited to a significantly decrease in the time to reach peak drug concentration (tmax;p < 0.05). Considering the minor effects induced by C. aurantium extract on the pharmacokinetics of LTG in rats, no relevant interactions are expected to occur in the clinical practice. Notwithstanding, C. aurantium safety in patients under LTG therapy should be further assessed in controlled clinical trials.

Effects of Paullinia cupana extract on lamotrigine pharmacokinetics in rats: A herb-drug interaction on the gastrointestinal tract with potential clinical impact.

Paullinia cupana-containing preparations are being consumed worldwide for weight reduction. As obesity and epilepsy are common comorbidities and lamotrigine (LTG) is a broad-spectrum antiepileptic drug, it is likely to find epilepsy patients taking P. cupana and LTG simultaneously. Thus, this work aimed to investigate the potential interaction between P. cupana extract and LTG in rats. In a study, rats were orally co-administered with a single-dose of P. cupana extract (821 mg/kg) and LTG (10 mg/kg). In another study, rats were orally pre-treated for 14 days with P. cupana extract (821 mg/kg/day) receiving LTG (10 mg/kg, p.o.) on the 15th day. Rats of the respective control groups received the corresponding volume of the extract vehicle. LTG concentrations were determined at several post-dose time-points and submitted to a non-compartmental pharmacokinetic analysis. The co-administration of P. cupana and LTG induced a significant reduction of LTG Cmax and AUC0-24 and prolonged the mean residence time. However, no significant effects were observed on LTG pharmacokinetics following a 14-day pre-treatment period with the extract. In this study changes in the body weight of rats and in some biochemical parameters were also evaluated. Overall, the results revealed a pharmacokinetic-based herb-drug interaction between P. cupana extract and LTG, mainly after their co-administration.

Flavonoid compounds as reversing agents of the P-glycoprotein-mediated multidrug resistance: An in vitro evaluation with focus on antiepileptic drugs.

The pharmacoresistance to antiepileptic drugs (AEDs) remains a major unsolved therapeutic need. The overexpression of multidrug transporters, as the P-glycoprotein (P-gp), at the level of the blood-brain barrier of epileptic patients has been suggested as a key mechanism underlying the refractory epilepsy. Thus, efforts have been made to search for therapeutically useful P-gp inhibitors. Herein, the strategy of flavonoid/AED combined therapy was exploited as a possible approach to overcome the P-gp-mediated pharmacoresistance. For this purpose, several in vitro studies were performed using Madin-Darby canine kidney II (MDCK II) cells and those transfected with the human multidrug resistance-1 (MDR1) gene, overexpressing the P-gp (MDCK-MDR1). Overall, the results showed that baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin, at 200µM, produced a marked increase on the intracellular accumulation of rhodamine 123 in MDCK-MDR1 cells, potentially through inhibiting the P-gp activity. In addition, with the exception of lamotrigine, all other AEDs tested (phenytoin, carbamazepine and oxcarbazepine) and their active metabolites (carbamazepine-10,11-epoxide and licarbazepine) demonstrated to be P-gp substrates. Furthermore, the most promising flavonoids as P-gp inhibitors promoted a significant increase on the intracellular accumulation of the AEDs (excluding lamotrigine) and their active metabolites in MDCK-MDR1 cells, evidencing to be important drug candidates to reverse the AED-resistance. Thus, the co-administration of AEDs with baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin should continue to be explored as adjuvant therapy for refractory epilepsy. List of chemical compounds studied in this article: Baicalein (PubChem CID: 5,281,605); Carbamazepine (PubChem CID: 2554); Carbamazepine 10,11-epoxide (PubChem CID: 2555); (-)-Epigallocatechin gallate (PubChem CID: 65064); Kaempferol (PubChem CID: 5280863); Lamotrigine (PubChem CID: 3878); Licarbazepine (PubChem CID: 114709); Oxcarbazepine (PubChem CID: 34312); Phenytoin (PubChem CID: 1775); Silymarin (PubChem CID: 7073228); Quercetin (PubChem CID: 5280343); Verapamil (PubChem CID: 2520).

A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT inhibitor, in rat.

Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor that emerged to fulfil the need of a safer and more efficacious COMT inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9-1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing.

Gastrodia elata and epilepsy: Rationale and therapeutic potential.

BACKGROUND: Gastrodia elata Blume (G. elata) is a traditional Chinese herb used for centuries in folk medicine. Due to the claimed anticonvulsant properties of G. elata, it is expected that this herb continues to be a target of research, aiming to deepen the available knowledge on its biological activity and safety. PURPOSE: The current review aims to discuss the most recent advances on the elucidation of the phytochemical composition and anticonvulsant potential of G. elata. METHODS: Available literature was reviewed from PubMed, ISI Web of Knowledge and Science Direct, using combinations of the following keywords: Gastrodia elata, tianma, epilepsy, anticonvulsant and pharmacokinetics. Abstracts and full texts were evaluated for their clarity and scientific merit. RESULTS: G. elata rhizome, as well as specific phenolic compounds isolated from this herb, have demonstrated anticonvulsant potential in a variety of in vitro and in vivo models. The pharmacological mechanisms potentially involved in the anticonvulsant activity have been extensively studied, being similar to the known mechanisms claimed for the available antiepileptic drugs. In addition, the pharmacokinetics of the main bioactive component of G. elata (gastrodin) has also been studied. CONCLUSION: Due to its recognised therapeutic properties, G. elata has gained an increasing interest within the scientific community and, therefore, new medicinal preparations containing G. elata rhizome itself or its bioactive components are expected to be developed in the coming years. Moreover, specific phytochemical constituents isolated from G. elata may also be considered to integrate programs of discovery and development of new anticonvulsant drug candidates.

Herb-drug pharmacokinetic interaction between carica papaya extract and amiodarone in rats.

PURPOSE: Carica papaya has been traditionally used worldwide in folk medicine to treat a wide range of ailments in humans, including the management of obesity and digestive disorders. However, scientific information about its potential to interact with conventional drugs is lacking. Thus, this work aimed to investigate the interference of a standardized C. papaya extract (GMP certificate) on the systemic exposure to amiodarone (a narrow therapeutic index drug) in rats. METHODS: In the first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of C. papaya (1230 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in the second study, rats were pre-treated for 14 days with C. papaya (1230 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the herbal extract vehicle. Blood samples were collected before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h following amiodarone administration; in addition, at 24 h post-dose, blood and tissues (heart, liver, kidneys and lungs) were also harvested. Thereafter, the concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were determined in plasma and tissue samples employing a high-performance liquid chromatography-diode array detection method previously developed and validated. RESULTS: In both studies was observed a delay in attaining the maximum plasma concentrations of amiodarone (tmax) in the rats treated with the extract. Nevertheless, it must be highlighted the marked increase (60-70%) of the extent of amiodarone systemic exposure (as assessed by AUC0-t and AUC0-∞) in the rats pre-treated with C. papaya comparatively with the control (vehicle) group. CONCLUSIONS: The results herein found suggest an herb-drug interaction between C. papaya extract and amiodarone, which clearly increase the drug bioavailability. To reliably assess the clinical impact of these findings appropriate human studies should be conducted.

Investigating herb-drug interactions: the effect of Citrus aurantium fruit extract on the pharmacokinetics of amiodarone in rats.

Citrus aurantium extract has been largely used in weight loss and sports performance dietary supplements. However, the safety of C. aurantium-containing products has been questioned mainly due to the association of its use with adverse events in the cardiovascular system. Therefore, this work aimed to assess the potential for herb-drug interactions among a standardized C. aurantium extract (GMP certificate) and amiodarone (narrow therapeutic index drug) in rats. In a first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of C. aurantium (164 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in a second study, rats were pre-treated during 14 days with C. aurantium (164 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. Overall, after analysis of the pharmacokinetic data, it deserves to be highlighted the significant increase of the peak plasma concentration of amiodarone in rats pre-treated with C. aurantium extract, while the extent of systemic exposure was comparable between both groups. This paper reports, for the first time, data on the potential of herb-drug interaction between C. aurantium extract and amiodarone. However, specific clinical trials should be performed to confirm these results in humans.

Herb-drug interaction of Fucus vesiculosus extract and amiodarone in rats: a potential risk for reduced bioavailability of amiodarone in clinical practice.

Fucus vesiculosus is a seaweed claimed to be useful for obesity management. Therefore, considering the relationship between obesity and cardiovascular diseases, this work aimed to assess the potential for an herb-drug interaction among a standardized F. vesiculosus extract (GMP certificate) and amiodarone (a narrow therapeutic index drug) in rats. In a first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of F. vesiculosus (575 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in a second study, rats were pre-treated during 14 days with F. vesiculosus (575 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. After analysis of the pharmacokinetic data it deserves to be highlighted the significant decrease in the peak plasma concentration of amiodarone (55.4%) as well as the reduction of systemic exposure to the parent drug (~30%) following the simultaneous co-administration of F. vesiculosus extract and amiodarone. This paper reports, for the first time, the herb-drug interaction between F. vesiculosus and amiodarone, which determined a considerable decrease on amiodarone bioavailability in rats. Therefore, the therapeutic efficacy of amiodarone may be compromised by the concurrent administration of herbal slimming medicines/dietary supplements containing F. vesiculosus.

Evaluation of the permeability and P-glycoprotein efflux of carbamazepine and several derivatives across mouse small intestine by the Ussing chamber technique.

PURPOSE: The rational discovery and development of new antiepileptic drugs (AEDs) with safer therapeutic index and better pharmacokinetic properties is still warranted nowadays. Because the long-term management of epilepsy is attained by means of orally administered AEDs, investigation of their potential to be well absorbed at the intestinal level is mandatory. Moreover, involvement of the efflux transport mediated by P-glycoprotein (P-gp) may compromise the systemic and central nervous system disposition of AEDs. Therefore, this study aimed at characterizing mouse jejunal passive transport and the possible active efflux mediated by P-gp of a series of dibenz[b,f]azepine-5-carboxamide derivatives (carbamazepine [CBZ], oxcarbazepine [OXC], S-licarbazepine [S-Lic], R-licarbazepine [R-Lic], carbamazepine-10,11-epoxide [CBZ-E], 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine [trans-diol], and BIA 2-024), which comprise some AEDs and metabolites. METHODS: Permeation studies were performed with freshly excised mouse jejunum segments mounted in Ussing chambers. Absorptive (M-S) and secretive (S-M) transports were analyzed with and without verapamil, which is a P-gp inhibitor widely recognized. Apparent permeability coefficients (P(app) ) in both directions and in absence or presence of verapamil were determined for each test compound. The in vitro method was validated using five controls that included high and low permeable markers with known absorption fraction (Fa) and also well-known P-gp substrates. The integrity of intestinal membrane was guaranteed during the assay by measuring the transepithelial electrical resistance. KEY FINDINGS: The correlation obtained between P(app) (M-S) and Fa of references was high (r(2) = 0.9945), and could be used to classify the derivatives according to Biopharmaceutical Classification System: CBZ and OXC were the only classified as highly permeable. The P(app) (S-M) of OXC, CBZ-E, R-Lic, and BIA 2-024 were significantly higher than their P(app) (M-S). After verapamil addition, their P(app) (S-M) lowered while P(app) (S-M) increased, suggesting the involvement of P-gp on the transport of those compounds across mouse jejunum segments. In opposition, CBZ, S-Lic, and trans-diol presented no statistical differences between the P(app) values reported in both directions, with or without verapamil. The results reported herein suggest that differences in biodisposition of S-Lic and R-Lic might result from their distinct interaction with P-gp. SIGNIFICANCE: The Ussing chamber model used herein showed to be useful for predicting Fa of AEDs and the involvement of efflux transport, namely P-gp, on their absorption. This is an important achievement as compounds that are not transported by P-gp may offer advantages when used in patients with pharmacoresistant epilepsy.

Herb-Drug Interaction of Paullinia cupana (Guarana) Seed Extract on the Pharmacokinetics of Amiodarone in Rats.

Paullinia cupana is used in weight-loss programs as a constituent of medicinal/dietary supplements. This study aimed to assess a potential herb-drug interaction among a standardized (certified) Paullinia cupana extract and amiodarone (narrow therapeutic index drug) in rats. In a first pharmacokinetic study rats were simultaneously coadministered with a single dose of Paullinia cupana (821 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.), and in a second study rats were pretreated during 14 days with Paullinia cupana (821 mg/kg/day, p.o.) receiving amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. Blood samples were collected at several time points after amiodarone dosing, and several tissues were harvested at the end of the experiments (24 h after dose). Plasma and tissue concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were measured and analysed. A significant reduction in the peak plasma concentration (73.2%) and in the extent of systemic exposure (57.8%) to amiodarone was found in rats simultaneously treated with Paullinia cupana and amiodarone; a decrease in tissue concentrations was also observed. This paper reports for the first time an herb-drug interaction between Paullinia cupana extract and amiodarone, which determined a great decrease on amiodarone bioavailability in rats.