Flavonoid-statin interactions causing myopathy and the possible significance of OATP transport, CYP450 metabolism and mevalonate synthesis.

3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary treatment for hyperlipidemic cardiovascular diseases which are a leading global cause of death. Statin therapy is life saving and discontinuation due to adverse events such as myotoxicity may lead to unfavourable outcomes. There is no known mechanism for statin-induced myotoxicity although it is theorized that it is due to inhibition of downstream products of the HMG-CoA pathway. It is known that drug-drug interactions with conventional medicines exacerbate the risk of statin-induced myotoxicity, though little attention has been paid to herb-drug interactions with complementary medicines. Flavonoids are a class of phytochemicals which can be purchased as high dose supplements. There is evidence that flavonoids can raise statin plasma levels, increasing the risk of statin-induced myopathy. This could be due to pharmacokinetic interactions involving hepatic cytochrome 450 (CYP450) metabolism and organic anion transporter (OATP) absorption. There is also the potential for flavonoids to directly and indirectly inhibit HMG-CoA reductase which could contraindicate statin-therapy. This review aims to discuss what is currently known about the potential for high dose flavonoids to interact with the hepatic CYP450 metabolism, OATP uptake of statins or their ability to interact with HMG-CoA reductase. Flavonoids of particular interest will be covered and the difficulties of examining herbal products will be discussed throughout.

Prevalence, beliefs and impact of drug-drug interactions between antiretroviral therapy and illicit drugs among people living with HIV in Spain.

Drug use implies important challenges related to HIV management, particularly due to an increased risk of potential interactions between antiretroviral therapy (ART) and illicit drugs (pDDIs). This study analyses the prevalence and severity of pDDIs among people living with HIV (PLHIV). It also explores their awareness of pDDIs and their beliefs about the toxicity that they may cause, as well as the impact of pDDIs on selected health variables. We conducted an on-line cross-sectional survey across 33 Spanish hospitals and NGOs to collect demographics and clinical data. pDDIs were checked against the Interaction Checker developed by Liverpool University. The sample of the present study was composed of 694 PLHIV who used illicit drugs. They represented 49.5% of the 1,401 PLHIV that participated in the survey. After excluding 38 participants due to lack of information on their ART or illicit drug use, 335 (51.1%) participants consuming drugs presented with some potentially significant pDDIs between their ART and illicit drugs, with a mean of 2.1±1.7 (1-10) pDDIs per patient. The drugs most frequently involved in pDDIs were cocaine, cannabis, MDMA and nitrates ("poppers"). The prevalence of pDDIs across ART regimens was: protease inhibitors (41.7%); integrase inhibitor-boosted regimens (32.1%), and non-nucleoside reverse transcriptase inhibitors (26.3%). An awareness of pDDIs and beliefs about their potential toxicity correlated positively with intentional non-adherence (p<0.0001). Participants with pDDIs exhibited a higher prevalence of intentional non-adherence (2.19±1.04 vs. 1.93±0.94; p = 0.001). The presence of pDDIs was not associated with poorer results in the clinical variables analysed. A significant proportion of PLHIV who use drugs experience pDDIs, thereby requiring close monitoring. pDDIs should be considered in the clinical management of HIV patients. Adequate information about pDDIs and indicators about how to manage ART when PLHIV use drugs could improve ART non-adherence.

Pharmacokinetics of gallic acid and protocatechuic acid in humans after dosing with Relinqing (RLQ) and the potential for RLQ-perpetrated drug-drug interactions on organic anion transporter (OAT) 1/3.

CONTEXT: Relinqing granules (RLQ) are being used alone or in combination with antibacterial drugs to treat urological disorders. OBJECTIVE: This study investigates the pharmacokinetics of RLQ in humans and the potential for RLQ-perpetrated interactions on transporters. MATERIALS AND METHODS: Twelve healthy subjects (six women and six men) participated to compare single- and multiple-dose pharmacokinetics of RLQ. In the single-dose study, all 12 subjects received 8 g of RLQ orally. After a 7-d washout period, the subjects received 8 g of RLQ for seven consecutive days (t.i.d.) and then a single dose. Gallic acid (GA) and protocatechuic acid (PCA) in plasma and urine samples were analysed using LC-MS/MS. The transfected cells were used to study the inhibitory effect of GA (50-5000 µg/L) and PCA (10-1000 µg/L) on transporters OAT1, OAT3, OCT2, OATP1B1, P-gp and BCRP. RESULTS: GA and PCA were absorbed into the blood within 1 h after administration and rapidly eliminated with a half-life of less than 2 h. The mean peak concentrations of GA (102 and 176 µg/L) and PCA (4.54 and 7.58 µg/L) were lower in males than females, respectively. The 24 h urine recovery rates of GA and PCA were about 10% and 5%, respectively. The steady-state was reached in 7 d without accumulation. GA was a potent inhibitor of OAT1 (IC50 = 3.73 µM) and OAT3 (IC50 = 29.41 µM), but not OCT2, OATP1B1, P-gp or BCRP. DISCUSSION AND CONCLUSIONS: GA and PCA are recommended as PK-markers in RLQ-related pharmacokinetic and drug interaction studies. We should pay more attention to the potential for RLQ-perpetrated interactions on transporters.

Interaction of silymarin components and their sulfate metabolites with human serum albumin and cytochrome P450 (2C9, 2C19, 2D6, and 3A4) enzymes.

Silymarin is a mixture of flavonolignans isolated from the fruit of milk thistle (Silybum marianum (L.) Gaertner). Milk thistle extract is the active ingredient of several medications and dietary supplements to treat liver injury/diseases. After the oral administration, flavonolignans are extensively biotransformed, resulting in the formation of sulfate and/or glucuronide metabolites. Previous studies demonstrated that silymarin components form stable complexes with serum albumin and can inhibit certain cytochrome P450 (CYP) enzymes. Nevertheless, in most of these investigations, silybin was tested; while no or only limited information is available regarding other silymarin components and metabolites. In this study, the interactions of five silymarin components (silybin A, silybin B, isosilybin A, silychristin, and 2,3-dehydrosilychristin) and their sulfate metabolites were examined with human serum albumin and CYP (2C9, 2C19, 2D6, and 3A4) enzymes. Our results demonstrate that each compound tested forms stable complexes with albumin, and certain silymarin components/metabolites can inhibit CYP enzymes. Most of the sulfate conjugates were less potent inhibitors of CYP enzymes, but 2,3-dehydrosilychristin-19-O-sulfate showed the strongest inhibitory effect on CYP3A4. Based on these observations, the simultaneous administration of high dose silymarin with medications should be carefully considered, because milk thistle flavonolignans and/or their sulfate metabolites may interfere with drug therapy.

Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination.

The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intestine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signaling molecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for maintaining systemic homeostasis. Alterations in the expression and function of OATs contribute to the intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs, and to many pathophysiological conditions. Consequently, the activity of these transporters must be highly regulated to carry out their normal functions. This review will present an update on the recent advance in understanding the cellular and molecular mechanisms underlying the regulation of renal OATs, emphasizing on the post-translational modification (PTM), the crosstalk among these PTMs, and the remote sensing and signaling network of OATs. Such knowledge will provide significant insights into the roles of these transporters in health and disease.

Cannabidiol in the treatment of epilepsy: Current evidence and perspectives for further research.

The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam. This article is part of the special issue on 'Cannabinoids'.

Herb-drug interaction of gastrodiae rhizoma on carbamazepine: A pharmacokinetic study in rats.

OBJECTIVE: Gastrodiae Rhizoma (GR), is a traditional Chinese Medicine that has been used for neurological disorders, including epilepsy. Epilepsy patients may be treated with adjunctive therapy of GR with antiepileptic drugs (AEDs). In particular, carbamazepine (CBZ) is of high potential to interact with concurrent treatment of Chinese Medicine. This study was to investigate the herb-drug interactions of GR and CBZ, an AED, through pharmacokinetic approach in rats. METHODS: We adopted a high-performance liquid chromatography (HPLC) system to quantify the plasma level of CBZ and its metabolite (carbamazepine-10, 11-epoxide, CBZE). The method was validated as per instructions under United States Food and Drug Administration (USFDA) guidance. For the herb-drug interaction study, rats were randomly divided into four different treatment groups: single-dose CBZ treatment, single-dose CBZ/GR treatment, 2-week course of CBZ treatment and 2-week course of CBZ/GR treatment. RESULTS: Our results demonstrated the auto-induction of CBZ metabolization when comparing single-dose with 2-week course of CBZ treatment. Pharmacokinetic interactions were noted in concomitant use of GR with CBZ by comparing two single-dose treatments (CBZ versus CBZ/GR). Our data showed that GR increased the mean residence time (MRT0-t) and the time taken to reach the maximum concentration (Tmax) of CBZ in single-dose of CBZ/GR treatment. The maximum drug concentration (Cmax) of CBZ was reduced in single-dose CBZ/GR treatment. When comparing the 2-week course of CBZ treatment with the 2-week course of CBZ/GR treatment, the MRT0-t and half-life of CBZ were increased. The AUC0-t, the Cmax and the half-life of CBZE were increased. CONCLUSION: CBZ/GR treatment may reduce the auto-induction of CBZ over 2 weeks. While the reduction of auto-induction could enhance the therapeutic effects of CBZ, it could also lead to an increase in neurological side effects and non-neurological adverse effects. Our results provided preclinical evidence of herb-drug interaction, which may have implications for epilepsy patients treated with GR.

Nanomedicine: a new paradigm to overcome drug incompatibilities.

OBJECTIVES: Drug incompatibilities may compromise the safety and effectiveness of combined drugs and result in mild-to-serious clinical complications, such as catheter obstruction, loss of drug efficacy, formation of toxic derivatives and embolism. Various preventive strategies have been implemented to overcome drug incompatibilities with limited success. This review presents an innovative approach to prevent drug incompatibilities via isolating the incompatible drugs into nanostructures. KEY FINDINGS: Several examples of incompatible drugs may be loaded separately into nanostructures of various types. Physicochemical characteristics and biocompatibility of the nanomaterials that are being utilized to prevent physicochemical incompatibilities should be carefully considered. CONCLUSIONS: There is a new era of exploiting nanomaterials in overcoming various types of physicochemical incompatibilities, with additional benefits of further improvements in pharmacokinetic profiles and pharmacological actions of the administered drugs.

Effects of puerarin on the pharmacokinetics of astragaloside IV in rats and its potential mechanism.

Context: Puerarin and astragaloside IV (AS-IV) are sometimes used together for the treatment of disease in Chinese clinics, however, the drug-drug interaction between puerarin and AS-IV is still unknown.Objective: This study investigates the effects of puerarin on the pharmacokinetics of astragaloside IV in rats and clarifies its main mechanism.Materials and methods: The pharmacokinetic profiles of oral administration of astragaloside IV (20 mg/kg) in Sprague-Dawley rats, with or without pre-treatment of puerarin (100 mg/kg/day for 7 days) were investigated. The effects of puerarin on the transport and metabolic stability of AS-IV were also investigated using Caco-2 cell transwell model and rat liver microsomes.Results: The results showed that puerarin could significantly increase the peak plasma concentration (from 48.58 ± 7.26 to 72.71 ± 0.62 ng/mL), and decrease the oral clearance (from 47.5 ± 8.91 to 27.15 ± 9.27 L/h/kg) of AS-IV. The Caco-2 cell transwell experiments indicated that puerarin could decrease the efflux ratio of astragaloside IV from 1.89 to 1.26, and the intrinsic clearance rate of astragaloside IV was decreased by the pre-treatment with puerarin (34.8 ± 2.9 vs. 41.5 ± 3.8 µL/min/mg protein).Discussion and conclusions: These results indicated that puerarin could significantly change the pharmacokinetic profiles of astragaloside IV, via increasing the absorption of astragaloside IV or inhibiting the metabolism of astragaloside IV in rats.

Pharmacodynamic interactions of antiepileptic drugs: From bench to clinical practice.

BACKGROUND: Approximately 50% of patients do not achieve seizure control with antiepileptic drug (AED) monotherapy, and polytherapy, with more than one AED, is often required. To date, no evidence-based criteria on how to combine AEDs exist. OBJECTIVE: This narrative review aimed to provide critical findings of the available literature about the role of pharmacodynamic AEDs' interactions in patients whose epilepsies were treated with polytherapy. METHODS: Electronic databases, Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE), were systematically searched to identify relevant studies on pharmacodynamic AEDs' interactions in patients with epilepsy. RESULTS AND CONCLUSION: Most data on AED combinations are coming from animal models and preclinical studies. Combining AEDs with different mechanisms of actions seems to have greater effectiveness and lower risk of adverse event development. Conversely, the combination of AEDs may cause pharmacodynamic synergistic effects that may result in not only increased efficacy but also more adverse effects. Despite some AED associations that have been proven to be effective in specific epilepsy/seizure type (e.g., phenobarbital+/phenytoin for tonic seizures and ethosiximide + valproate for absences; lamotrigine + valproate for various epilepsy/seizure types), no clear and definitive evidence exists about AED combinations in humans. Examples of pharmacodynamic interactions that possibly explain the synergistic effects on efficacy or adverse effects include the combination between vigabatrin or pregabalin and sodium channel blockers (supra-additive antiseizure effect) and lacosamide combined with other sodium channel blockers (infra-additive antiseizure effect and neurotoxicity synergistic). The pharmacodynamic lamotrigine-valproate interaction is also supported by synergistic adverse events. Therefore, well-designed double-blind prospective studies recruiting a sufficient number of patients possibly with a crossover design and carefully ascertain the role of pharmacokinetic interactions and variations of AEDs' levels in the blood are needed.

Central nervous system evaluation of an ethanol extract of Bidens odorata Cav (Asteraceae) leaves, and its antinociceptive interaction with paracetamol and naproxen.

INTRODUCTION: Bidens odorata Cav (Asteraceae) is a medicinal plant employed for the treatment of pain, anxiety, and depression. This study aimed to evaluate some neuropharmacological effects of an ethanol extract of B. odorata (BOE) and assess its antinociceptive interaction with naproxen and paracetamol. MATERIALS AND METHODS: The following neuropharmacological effects were evaluated with the ethanolic extract of B. odorata leaves (BOE) (10-200 mg/kg p.o.): the strychnine-induced-convulsion assay (anticonvulsant effect), rotarod test (locomotor activity), tail suspension test (anti-depressant-like activity), cylinder exploratory test (anxiolytic-like actions), and pentobarbital-induced sleep test (sedative effect). The interaction of the BOE-paracetamol and BOE-naproxen combinations were evaluated with the acetic acid-induced writhing test. The ED50 value of each drug was estimated and the combinations of paracetamol and naproxen with BOE were calculated. RESULTS: BOE (100-200 mg/kg) showed anti-convulsant activity by increasing the latency to occurrence of strychnine-induced convulsions, antidepressant-like effects by 28% and 33%, respectively, exerted anxiolytic actions (ED50 = 125 mg/kg), but did not affect motor locomotion. The pre-treatment with 2 mg/kg flumazenil or 20 mg/kg pentylenetetrazol partially reverted the anxiolytic activity shown by BOE alone. BOE (200 mg/kg) prolonged the duration of sleep with similar effect in comparison to clonazepam (1.5 mg/kg). The combinations of BOE-paracetamol (1:1) and BOE-naproxen (1:1) showed antinociceptive synergism. CONCLUSION: BOE induces sedative and anticonvulsant effects. The anxiolytic actions shown by BOE are probably induced by the participation of the GABAergic system. BOE exerts antinociceptive synergistic interaction with paracetamol and naproxen probably by the participation of nitric oxide and ATP-sensitive K+ channels, respectively.

Clinically Significant Drug-Drug Interactions with Agents for Attention-Deficit/Hyperactivity Disorder.

This article provides an overview of the pharmacokinetic drug-drug interactions (DDIs) for agents prescribed for attention-deficit/hyperactivity disorder (ADHD). Polypharmacy in the treatment of patients with ADHD leads to high exposures to DDIs and possibly adverse safety outcomes. We performed a systematic search of DDI reports for ADHD agents in Embase and Medline. We also searched for agents in the pharmacological pipeline, which include (1) mazindol, molindone and viloxazine, which were previously prescribed for other indications; (2) centanafadine and AR-08, never before approved; and (3) two extracts (Polygala tenuifolia extract and the French maritime pine bark extracts). The identified literature included case reports, cross-sectional, cross-over and placebo-controlled studies of patient cohorts and healthy volunteers. The DDIs were classified as follows: ADHD agents acting as perpetrators, i.e., affecting the clearance of co-prescribed agents (victim drugs), or ADHD agents being the victim drugs, being affected by other agents. Ratios for changes in pharmacokinetic parameters before and after the DDI were used as a rough estimate of the extent of the DDI. Alcohol may increase plasma dextroamphetamine concentrations by presystemic effects. Until studies are done to orient clinicians regarding dosing changes, clinicians need to be aware of the potential for cytochrome P450 (CYP) 2D6 inhibitors to increase amphetamine levels, which is equivalent to increasing dosages. Atomoxetine is a wide therapeutic window drug. The CYP2D6 poor metabolizers who do not have CYP2D6 activity had better atomoxetine response, but also an increased risk of adverse effects. CYP2D6 inhibitors have been used to increase atomoxetine response in CYP2D6 extensive metabolizers. Guanfacine is mainly metabolized by CYP3A4, which can be induced and inhibited. The package insert recommends that in guanfacine-treated patients, after adding potent CYP3A4 inducers, the guanfacine dose should be doubled; after adding potent CYP3A4 inhibitors the guanfacine dose should be halved. Based on a phenobarbital case report and our experience with CYP3A4-metabolized antipsychotics, these correction factors may be too low. According to two case reports, carbamazepine is a clinically relevant inducer of methylphenidate (MPH). A case series study suggested that MPH may be associated with important elevations in imipramine concentrations. Due to the absence of or limitations in the data, no comments for clinicians can be provided on the pharmacokinetic DDIs for clonidine, centanafadine, mazindol, molindone, AR-08, P. tenuifolia extract and the French maritime pine bark extracts. According to currently available data, clinicians should not expect that ADHD drugs modify each other's serum concentrations. A summary table for clinicians provides our current recommendations on pharmacokinetic DDIs of ADHD agents based on our literature review and the package inserts; whenever it was possible, we provide information on serum concentrations and dose correction factors. There will be a need to periodically update these recommendations and these correction factors as new knowledge becomes available.

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.

OBJECTIVE: Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. METHODS: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a+/- mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a+/- mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA)A receptors to investigate the activity of GABAA receptors when treated with CBD and clobazam together. RESULTS: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation. SIGNIFICANCE: Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.

Use of dietary and herbal supplements in adult patients with epilepsy.

PURPOSE: To study the extent and characteristics of dietary and herbal supplements use in a large cohort of adult patients with epilepsy. METHODS: This prospective study included 490 patients receiving care at a university epilepsy clinic. A number of variables, including demographics, characteristics of epilepsy and its treatment, comedication as well as data related to supplements intake were collected from medical records and a dedicated questionnaire. RESULTS: Overall 247 patients (50.4%) took at least one dietary supplement; nearly half (111, 44.9%) of this group took >1 products. Multivitamins and magnesium were the most prevalent supplements. Most of the patients used supplements for general health rather than their epilepsy condition. The average number of supplements and prescription medications used per person was 5.4. Ten percent (25 of 247) of subjects used dietary supplements which could have proconvulsive effect or potential for interaction with prescription medications. Multivariate analysis revealed two independent variables associated with supplements intake, younger age and female sex. CONCLUSION: Dietary and herbal supplements use is common in patients with epilepsy, adding to the burden of overmedication. Concurrent use of supplements may potentially lead to interactions with prescription medications or loss of seizure control. Health care providers should routinely check for dietary supplements use to limit potential harm related to their intake.

Effectiveness of three-dimensional visualisation on undergraduate nursing and midwifery students' knowledge and achievement in pharmacology: A mixed methods study.

BACKGROUND: Historically nursing and midwifery students have reported difficulty understanding the concept-based science underpinning the interactions between drugs and their targets. This knowledge is crucial for the administration and monitoring of the therapeutic and adverse effects of medications. Immersive three-dimensional technology is reported to enhance understanding of complex scientific concepts but the physical effects of motion sickness may limit its use. OBJECTIVES: This project compared the effectiveness of three-dimensional immersive visualisation technology with two-dimensional visualisation technology as a teaching method to improve student understanding of a pharmacological concept, and to assess levels of student discomfort and satisfaction associated with the experience. DESIGN: Traditional lecture content and presentation about drug-receptor binding was followed by exposure to either a two- or three-dimensional artifact visualising ß-adrenoceptor binding. Two student groups were compared by type of exposure: Group 1 watched the artifact via a three-dimensional immersive facility and Group 2 on a wide, two-dimensional screen. SETTINGS: School of Nursing and Midwifery in a regional university in Southeast Queensland, Australia. PARTICIPANTS: Two hundred and two second year undergraduate nursing and midwifery students. METHODS: The study used mixed methods methodology. Pre- and post- testing of student knowledge was collected using five multiple-choice questions. A post-intervention survey elicited students' self-assessed perceptions of discomfort and satisfaction with the learning experience. RESULTS: The three-dimensional immersive learning experience was comparable to the two-dimensional experience in terms of satisfaction and comfort but resulted in statistically significant improvements in post-test scores. CONCLUSIONS: The three-dimensional experience improved understanding when compared to two-dimensional viewing, satisfied students leaning needs, and caused minimal discomfort. The results are encouraging in terms of using three-dimensional technology to enhance student knowledge of pharmacological concepts necessary for competency in medication management.

Pharmacodynamic Drug-Drug Interactions.

Pharmacodynamic drug-drug interactions (DDIs) occur when the pharmacological effect of one drug is altered by that of another drug in a combination regimen. DDIs often are classified as synergistic, additive, or antagonistic in nature, albeit these terms are frequently misused. Within a complex pathophysiological system, the mechanism of interaction may occur at the same target or through alternate pathways. Quantitative evaluation of pharmacodynamic DDIs by employing modeling and simulation approaches is needed to identify and optimize safe and effective combination therapy regimens. This review investigates the opportunities and challenges in pharmacodynamic DDI studies and highlights examples of quantitative methods for evaluating pharmacodynamic DDIs, with a particular emphasis on the use of mechanism-based modeling and simulation in DDI studies. Advancements in both experimental and computational techniques will enable the application of better, model-informed assessments of pharmacodynamic DDIs in drug discovery, development, and therapeutics.

Interaction between carboxymethyl pachyman and lotus seedpod oligomeric procyanidins with superior synergistic antibacterial activity.

The inhibitory effect of carboxymethyl pachyman (CMP) mixed with lotus seedpod oligomeric procyanidins (LSPC) in certain ratios against E. coli 10899 was determined. Added low concentration of LSPC could improve the antibacterial activity of CMP, and a significant synergistic effect could be observed between them, especially when the concentration of CMP was below its critical concentration (1.35 mg/mL). Then, the interaction between CMP and LSPC was characterized after mixing; the changes in spectral characteristics, thermal properties, crystallinity pattern, molecular weight, chain morphology and microrheological behaviour explained the influence of interaction on the structure of CMP and LSPC. The smaller molecular size, electrostatic interaction and stronger hydrophobic interaction might play important roles in improving the antibacterial activity of mixture. The dissociation constant (Kd) was determined to be 0.102±0.0008 mg/mL using MicroScale Thermophoresis (MST), and the micromorphology was observed by SEM. Therefore, this mixture might be an effective natural bacteriostat.

Physical compatibility of pentoxifylline and intravenous medications.

OBJECTIVE: To investigate the physical and chemical compatibility of pentoxifylline (PTX) with a wide range of parenteral medications used in the neonatal intensive care setting. DESIGN: PTX and drug solutions were combined in glass phials and inspected visually for physical incompatibility. The chemical compatibility was evaluated on the basis of PTX concentrations. RESULTS: Precipitation, colour change or turbidity was not visible in any of the test mixtures, indicating no observed physical incompatibility or apparent risk of blockage in narrow-bore intravenous tubing. The PTX concentration was approximately 2.5% and 4.5% lower when combined with dopamine and amoxicillin, respectively. The PTX concentration ratios for all other combinations were in the range of 99%-102%. CONCLUSION: In simulated Y-site conditions, physical compatibility testing of PTX and 30 parenteral medications revealed no evidence of precipitation. Based on PTX concentration tests, it could be prudent to avoid mixing PTX with dopamine or amoxicillin.

Prevalence of drug-herb and drug-supplement interactions in older adults: a cross-sectional survey.

BACKGROUND: Polypharmacy is common among older adults, with increasing numbers also using prescription drugs with herbal medicinal products (HMPs) and dietary supplements. There is no reliable evidence from the UK on concurrent use of HMPs and dietary supplements with prescription drugs in older adults. AIM: To establish prevalence of concurrent prescription drugs, HMPs, and dietary supplements among UK community-dwelling older adults and identify potential interactions. DESIGN AND SETTING: Cross-sectional survey of older adults registered at two general practices in South East England. METHOD: A questionnaire asking about prescription medications, HMPs, and sociodemographic information was posted to 400 older adults aged ≥65 years, identified as taking ≥1 prescription drug. RESULTS: In total 155 questionnaires were returned (response rate = 38.8%) and the prevalence of concurrent HMPs and dietary supplements with prescriptions was 33.6%. Females were more likely than males to be concurrent users (43.4% versus 22.5%; P = 0.009). The number of HMPs and dietary supplements ranged from 1 to 8, (mean = 3, median = 1; standard deviation = 1.65). The majority of concurrent users (78.0%) used dietary supplements with prescription drugs. The most commonly used dietary supplements were cod liver oil, glucosamine, multivitamins, and vitamin D. Others (20.0%) used only HMPs with prescription drugs. Common HMPs were evening primrose oil, valerian, and Nytol Herbal® (a combination of hops, gentian, and passion flower). Sixteen participants (32.6%) were at risk of potential adverse drug interactions. CONCLUSION: GPs should routinely ask questions regarding herbal and supplement use, to identify and manage older adults at potential risk of adverse drug interactions.