Potential Pharmacodynamic Interactions Research Articles

Potential Implications of Multi-Drug Exposure with Synthetic Cannabinoids: A Scoping Review of Human Case Studies

Synthetic cannabinoids are a rapidly evolving, diverse class of new psychoactive substances. Synthetic cannabinoid use results in a higher likelihood of adverse events and hospitalization when compared to cannabis use. The mechanisms behind synthetic cannabinoid toxicity remain elusive. Furthermore, poly-substance use may be a significant contributing factor in many cases. This scoping review aimed to identify the key characteristics of synthetic cannabinoid co-exposure cases and discuss the potential implications of poly-substance use in humans. There were 278 human cases involving 64 different synthetic cannabinoids extracted from the databases. Cases involved a total of 840 individual co-exposures, with an average of four substances involved in each case. The most common co-exposures were alcohol (11.4%), opioids (11.2%), and cannabis (11.1%). When analyzed by case outcome, co-exposure to either antipsychotics/antidepressants, alcohol, or tobacco were significantly associated with mortality as an outcome (p < 0.05). Drug-use history (63.4%), mental illness (23.7%), and hypertensive and atherosclerotic cardiovascular disease (20.1%) were prevalent patient histories in the case cohort. There are several potential pharmacodynamic and pharmacokinetic interactions between co-exposure drugs and synthetic cannabinoids that could worsen clinical presentation and toxicity in synthetic cannabinoid users. Individuals with substance-use disorders or psychiatric illness would be especially vulnerable to these multi-drug interactions. Further research into these complex exposures is needed for the successful prevention and treatment of synthetic cannabinoid-related harms.

Interconnection between injectable omeprazole and clopidogrel tablet: a comprehensive analysis of clinical and pharmacological implications

Therapeutic synergy is a sought-after goal in contemporary medical practice, aiming to maximize therapeutic benefits while minimizing pharmacological adverse effects (Chowdhury et al., 2020). However, the drug interaction between injectable omeprazole and clopidogrel tablet emerges as a crucial clinical and pharmacological concern. Clopidogrel, a widely used antiplatelet agent in cardiovascular event prevention, and omeprazole, a proton pump inhibitor often prescribed for gastrointestinal disorders, are frequently co-administered in patients with elevated cardiovascular risk (Bhurke et al., 2018). Nevertheless, recent studies suggest that this combination might compromise the antiplatelet efficacy of clopidogrel due to potential pharmacokinetic and pharmacodynamic interactions.

Innovative LC-MS/MS method for therapeutic drug monitoring of fenfluramine and cannabidiol in the plasma of pediatric patients with epilepsy

We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying fenfluramine (FFA), its active metabolite norfenfluramine (norFFA), and Epidyolex®, a pure cannabidiol (CBD) oral solution in plasma. Recently approved by the EMA for the adjunctive treatment of refractory seizures in patients with Dravet and Lennox-Gastaut syndromes aged above 2 years, FFA and CBD still do not have established therapeutic blood ranges, and thus need careful drug monitoring to manage potential pharmacokinetic and pharmacodynamic interactions. Our method, validated by ICH guidelines M10, utilizes a rapid extraction protocol from 100 µL of human plasma and a reversed-phase C-18 HPLC column, with deuterated internal standards. The Thermofisher Quantiva triple-quadrupole MS coupled with an Ultimate 3000 UHPLC allowed multiple reaction monitoring detection, ensuring precise analyte quantification. The assay exhibited linear responses across a broad spectrum of concentrations: ranging from 1.64 to 1000 ng/mL for both FFA and CBD, and from 0.82 to 500 ng/mL for norFFA. The method proves accurate and reproducible, free from matrix effect. Additionally, FFA stability in plasma at 4 °C and −20 °C for up to 7 days bolsters its clinical applicability. Plasma concentrations detected in patients samples, expressed as mean ± standard deviation, were 0.36 ± 0.09 ng/mL for FFA, 19.67 ± 1.22 ng/mL for norFFA. This method stands as a robust tool for therapeutic drug monitoring (TDM) of FFA and CBD, offering significant utility in assessing drug-drug interactions in co-treated patients, thus contributing to optimized patient care in complex therapeutic scenarios.

The use of potentially interacting supplement–drug pairs in adults with type 2 diabetes: A large population-based cohort study in the UK Biobank

AimsTo examine the patterns of use of potentially interacting supplement–drug pairs in adults with type 2 diabetes (T2D) in real-world settings, and to explore the impact of potentially interacting supplement–drug pairs on downstream outcomes. MethodsPotentially interacting supplement–drug pairs were identified from four tertiary databases. We categorized the potential pharmacodynamic interactions into different clinical types according to their related outcomes and explored their associations with incident outcomes using Cox models. Results26,394 participants with T2D in the UK Biobank were included. Half (48.5 %) were supplement users, of whom 85.0 % were taking potentially interacting supplement–drug pairs. The potential pharmacodynamic interactions were related to various clinical outcomes, including reducing the effects of glucose-lowering drugs (50.7 %), hypotension (49.8 %), bleeding (50.4 %) and hepatotoxicity (34.8 %). Exploratory analyses found that the use of potentially interacting supplement–drug pairs was associated with incident hepatic diseases (hazard ratio = 1.26, 95 % confidence interval 1.10–1.44, P < 0.001). ConclusionsReal-world data suggests that most adults with T2D who concurrently used supplements and drugs were on potentially interacting supplement-drug combinations, with the potential of causing adverse outcomes such as incident hepatic diseases. Clinicians should communicate with patients and assess the potential risk of supplement–drug interactions in clinical settings.

Toenail Onychomycosis with or without Diabetes in Canada: Patient Treatment Preferences and Health State Utilities.

Toenail onychomycosis affects approximately 6.7% of Canadians. Symptoms include nail discolouration/disfiguration and pain; psychosocial impacts contribute to reduced health-related quality-of-life. Comorbid diabetes increases the risk of complications and exacerbates burden. Treatment may include topical therapy and/or oral agents. To understand toenail onychomycosis treatment preferences, and to quantify the impact of toenail onychomycosis, with or without diabetes, on patient well-being. Adults living in Canada with self-reported, physician-diagnosed, toenail onychomycosis were recruited online. A discrete choice experiment was used to quantify treatment preferences. Scenarios were randomized; data were analyzed using conditional logit regression. Health state utilities were estimated using the Health Utilities Index Mark 3®. Results were stratified by diabetes status and toenail onychomycosis severity; the Wilcoxon Rank Sum test was used to assess between-group utility differences. Three-hundred thirteen participants with toenail onychomycosis were included (161 had comorbid diabetes; 61.3%, severe onychomycosis). The mean age was 57.7 years; 55.9% were male. Treatment attributes with statistically significant impacts on patient preferences were efficacy (odds ratio [OR],1.04; 95% confidence interval [CI], 1.02-1.05 per 1% increased treatment success), administration method (one pill versus topical nail lacquer reference, 1.14; 1.04-1.26; topical solution applicator versus reference: 1.15; 1.03-1.29), severe adverse events (0.85; 0.80-0.90 per 1% increased risk), and risk of potential pharmacodynamic (0.80; 0.76-0.85) and alcohol (0.93; 0.88-0.98) interactions; preferences were more pronounced for efficacy and avoiding severe adverse events among toenail onychomycosis patients with comorbid diabetes. The mean (95% CI) utility value was 0.73 (0.70-0.75) overall, and statistically significantly lower (p=0.02) for toenail onychomycosis patients with diabetes (0.70; CI, 0.66-0.73) than those without (0.76; CI, 0.72-0.79). Among patients with toenail onychomycosis, the presence of diabetes was associated with differing treatment-related preferences. Utility values for patients with toenail onychomycosis represent a significant decline from full health that is exacerbated by comorbid diabetes.

Development of a Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method for Characterizing Linalool Oral Pharmacokinetics in Humans.

Lavender (Lavandula angustifolia Miller or Lavandula officinalis Chaix) is an ethnopharmacological plant commonly known as English lavender. Linalool and linalyl acetate are putative phytoactives in lavender essential oil (LEO) derived from the flower heads. LEO has been used in aroma or massage therapy to reduce sleep disturbance and to mitigate anxiety. Recently, an oral LEO formulation was administered in human clinical trials designed to ascertain its anxiolytic effect. However, human pharmacokinetics and an LC-MS/MS method for the measurement of linalool are lacking. To address this deficiency, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the analysis of linalool in human serum. Prior to the analysis, a simple sample preparation protocol including protein precipitation and liquid-liquid extraction of serum samples was created. The prepared samples were analyzed using a C18 reversed-phase column and gradient elution (acetonitrile and water, both containing 0.1% formic acid). A Waters Xevo TQ-S tandem mass spectrometer (positive mode) was used to quantitatively determine linalool and IS according to transitions of m/z 137.1→95.1 (tR 0.79 min) and 205.2→149.1 (tR 1.56 min), respectively. The method was validated for precision, accuracy, selectivity, linearity, sensitivity, matrix effects, and stability, and it was successfully applied to characterize the oral pharmacokinetics of linalool in humans. The newly developed LC-MS/MS-based method and its application in clinical trial serum samples are essential for the characterization of potential pharmacokinetic and pharmacodynamic interactions.

Potential Drug-Drug Interactions Among Hospitalised Elderly Patients in Northern Sri Lanka, A Lower Middle-Income Country: A Retrospective Analysis.

Elderly individuals are more vulnerable to potential drug-drug interactions (pDDIs) as age-related physiological changes, polypharmacy and hospitalisations are known to increase the risk of pDDIs. The aims of this study were to assess the impact of hospitalisation and other associated factors on pDDIs in elderly patients, in a resource-limited setting. This is a retrospective analysis of data of elderly patients (aged ≥ 65 years) admitted to the medical units of Jaffna Teaching Hospital. Preadmission and post-admission data were collected from clinic and hospital records, respectively. The British National Formulary was used to identify and categorise pDDIs. Point prevalence of pDDIs in elderly patients and the total number of pDDIs before and after hospitalisation were estimated. Factors contributing to pDDIs were determined by univariate and multivariable logistic regression. Two hundred and eighty-eight hospitalised elderly patients with a median age of 71 years (interquartile range 67-76 years) showed a significant increase in the prevalence of pDDIs post-admission compared with the preadmission values (77.1% vs 61.5%; p < 0.001) associated with an increase in total pDDIs (377 vs 488; p < 0.001) where the majority (> 75%) were potential pharmacodynamic interactions. An unadjusted analysis showed a significant association between pDDI and polypharmacy [taking five or more medications] (odds ratio [OR] = 14.17; 95% confidence interval [CI] 7.41-27.10), the presence of more than three underlying medical conditions (OR 4.14; 95% CI 1.70-10.06), ischaemic heart disease (OR 3.25; 95% CI 1.78-5.94) and asthma (OR 8.14; 95% CI 2.46-26.88). However, when adjusted for confounders only polypharmacy (OR 14.10; 95% CI 6.50-30.60) and the presence of underlying asthma (OR 11.61; 95% CI 2.82-47.85) were associated with pDDIs. The prevalence of pDDIs among elderly patients was high and increased with hospital admissions. Polypharmacy and relevant comorbidities were contributory factors. Increased awareness of the potential for pDDIs through appropriate training and simple measures including a proper drug history, creating a bespoke pDDI list and frequent medication reviews by healthcare professionals would help to mitigate pDDIs in resource-limited and technology-limited settings.

FOLFIRINOX Pharmacodynamic Interactions in 2D and 3D Pancreatic Cancer Cell Cultures

The multi-drug combination regime, FOLFIRINOX, is a standard of care chemotherapeutic therapy for pancreatic cancer patients. However, systematic evaluation of potential pharmacodynamic interactions among multi-drug therapy has not been reported previously. Here, pharmacodynamic interactions of the FOLFIRINOX agents (5-fluorouracil (5-FU), oxaliplatin (Oxa) and SN-38, the active metabolite of irinotecan) were assessed across a panel of primary and established pancreatic cancer cells. Inhibition of cell proliferation was quantified for each drug, alone and in combination, to obtain quantitative, drug-specific interaction parameters and assess the nature of drug interactions. The experimental data were analysed assuming Bliss independent interactions, and nonlinear regression model fitting was conducted in SAS. Estimates of the drug interaction term, psi (ψ), revealed that the Oxa/SN-38 combination appeared synergistic in PANC-1 (ψ = 0.6, 95% CI = 0.4, 0.9) and modestly synergistic, close to additive, in MIAPaCa-2 (ψ = 0.8, 95% CI = 0.6, 1.0) in 2D assays. The triple combination was strongly synergistic in MIAPaCa-2 (ψ = 0.2, 95% CI = 0.1, 0.3) and modestly synergistic/borderline additive in PANC-1 2D (ψ = 0.8, 95% CI = 0.6, 1.0). The triple combination showed antagonistic interactions in the primary PIN-127 and 3D PANC-1 model (ψ > 1). Quantitative pharmacodynamic interactions have not been described for the FOLFIRINOX regimen; this analysis suggests a complex interplay among the three chemotherapeutic agents. Extension of this pharmacodynamic analysis approach to clinical/translational studies of the FOLFIRINOX combination could reveal additional pharmacodynamic interactions and guide further refinement of this regimen to achieve optimal clinical responses.Graphical abstract

Potential pharmacokinetic and pharmacodynamic herb-drug interactions of Andrographis paniculata (Burm. f.) and andrographolide: A systematic review

Introduction: Herb–drug interactions (HDIs) in pharmacokinetics and pharmacodynamics can occur when natural compounds are used in combination with drugs. This study aimed to review the potential interaction of Andrographis paniculata (Burm. f.) extract (APE) and its primary compound andrographolide (AND) with several drugs exhibiting various pharmacological activities.Methods: In this systematic review, articles were collected from international databases such as PubMed, Science Direct, Springer Link, and Scopus until August 2021. The following keywords were used: Andrographis paniculata, andrographolide, HDI, drug interaction, pharmacokinetics, and pharmacology. This review was written in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), SYRCLE’s risk of bias (RoB) tool for animal intervention studies, and Cochrane RoB 2 tool to analyze the RoB for qualitative assessment.Results: Twelve articles were included in accordance with the inclusion and exclusion criteria of this study. Five studies explored the potential of HDIs for combining APE with drugs and AND with theophylline, etoricoxib, nabumetone, naproxen, and tolbutamide. Five studies focused on AND in combination with aminophylline and doxofylline, meloxicam, glyburide, glimepiride, metformin, and warfarin. Two studies tested the combination of APE with gliclazide and midazolam. The HDI mechanism involving the inhibition or induction of cytochrome P450 enzyme expression was dominant in influencing the drug’s pharmacokinetic profile. Pharmacological studies on the combination of several drugs, particularly anti-inflammatory and antidiabetic drugs, showed a synergistic activity.Conclusion: APE and AND have potential pharmacokinetic and pharmacodynamic HDIs with various drugs. This study can be used as a therapeutic consideration in clinical aspects related to the possibility of HDIs of A. paniculata (Burm. f.).

IDF21-0212 Interactions between herbs and antidiabetic drugs and their effects on glycemia: A simple tool for a fast identification

Background: Many studies conducted in Algeria have found that approximately 39% (Boutebba M et al) to 43% (Sadoun et al) of diabetics use the plants concomitantly with their conventional drugs with 22% describing adverse reactions (hypoglycemia or hyperglycemia).This notion is not taken in consideration by many clinicians due to the lack of information and the absence of trainings in the field of phytotherapy, NHP and their potential interactions with drugs. Aim: Our aim is to help health professional identifying potential herbs-antidiabetic drugs interaction by creating a simple tool by reviewing the literature. Method: Databases (MEDLINE, Google scholar, science direct, NCBI) and books (as Medi-herb, WHO monographs on selected medicinal plants…) were consulted searching for the clinical studies, case reports and studies published in term of herb-antidiabetic drugs interaction. The most commonly used plants by the Algerian diabetics were selected using the previous ethnopharmacological surveys and the antidiabetic effect of these plants to deduct the potential pharmacodynamic interactions were searched. The interactions were classified into four groups each group corresponds to a level of evidence:1.Probable interactions with high chances to produce: include interactions supported by clinical evidence and case studies.2.Possible interactions with medium chances to produce: include interactions based on animal or in vitro data.3.Theoretical interactions: include theoretical interactions extrapolated from pharmacodynamic and pharmacokinetic data.4.No reported interactions or theoretical interactions identified from the literature. Results: Thirty-one plants and six antidiabetic drugs were retained to create the tool. More than 200 references were reviewed. A grid was established with color keys that were used to simplify the detection of the interaction and its level of evidence by the user. Discussion: The tool that we developed can help health professionals who take care of diabetics to determine the risk of hyperglycemia or hypoglycemia and avoiding them which contributes to a better control of glucose level and an improvement of the diabetes management.

Dietary Supplement Use and Interactions with Tamoxifen and Aromatase Inhibitors in Breast Cancer Survivors Enrolled in Lifestyle Interventions.

The use of dietary supplements is common in the general population and even more prevalent among cancer survivors. The World Cancer Research Fund/American Institute for Cancer Research specifies that dietary supplements should not be used for cancer prevention. Several dietary supplements have potential pharmacokinetic and pharmacodynamic interactions that may change their clinical efficacy or potentiate adverse effects of the adjuvant endocrine therapy prescribed for breast cancer treatment. This analysis examined the prevalence of self-reported dietary supplement use and the potential interactions with tamoxifen and aromatase inhibitors (AIs) among breast cancer survivors enrolled in three randomized controlled trials of lifestyle interventions conducted between 2010 and 2017. The potential interactions with tamoxifen and AIs were identified using the Natural Medicine Database. Among 475 breast cancer survivors (2.9 (mean) or 2.5 (standard deviation) years from diagnosis), 393 (83%) reported using dietary supplements. A total of 108 different types of dietary supplements were reported and 36 potential adverse interactions with tamoxifen or AIs were identified. Among the 353 women taking tamoxifen or AIs, 38% were taking dietary supplements with a potential risk of interactions. We observed a high prevalence of dietary supplement use among breast cancer survivors and the potential for adverse interactions between the prescribed endocrine therapy and dietary supplements was common.

Is ketamine and lamotrigine interactions responsible for the sub-therapeutic effect of ketamine?

IntroductionThe immediate antidepressant effect of Ketamine has become a breakthrough in the treatment of depression. Cytochrome CYP3A4 and 2B6 primarily metabolize Ketamine.ObjectivesThe present study explores potential pharmacokinetic and pharmacodynamic interactions of Lamotrigine and Ketamine.MethodsA literature search was conducted using (“ketamine” OR “Lamotrigine” AND Interactions in PubMed, Embase, and PsycINFO. Our literature search resulted in 72 hits and result in qualified five studies.ResultsWe found five studies: one RCT study, a RCT, a crossover design, Two case reports, and one murine model study. In the first RCT conducted on 16 healthy normal volunteer subjects. lamotrigine significantly decreased ketamine-induced perceptual abnormalities (P &lt; 0.001), positive (P &lt; 0.001) and negative symptoms (P &lt; 0.05), and learning and memory impairment (P &lt; 0.05) which shows the counter effect of ketamine. Another study revealed Ketamine evoked increases in all the BPRS subscale scores, and all scores were lower after lamotrigine pretreatment. A case report from 2014 reports the failure of ketamine anesthesia in a patient with lamotrigine overdose. Another case report mentions that Lamotrigine reduced the craving in a patient with ketamine use disorder. A murine model study with lamotrigine showed improved PPI (Prepulse inhibition) ketamine-induced disruption. These results suggest that Lamotrigine may exert this effect via a glutamatergic system.ConclusionsThe literature review suggests that Lamotrigine interferes with glutamatergic neurotransmission reducing the effect of Ketamine. It is not clear how this may impact Ketamine’s antidepressant action. Future large scale and well-designed RCTs are required to confirm these findings.Conflict of interestNo significant relationships.

Development of a liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for characterizing caffeine, methylliberine, and theacrine pharmacokinetics in humans

Coffea liberica possesses stimulant properties without accumulating the methylxanthine caffeine. The basis for this peculiar observation is that methylurates (e.g., theacrine and methylliberine) have replaced caffeine. The stimulant properties of methylurates, alone and in combination with caffeine, have recently been investigated. However, human pharmacokinetics and LC-MS/MS methods for simultaneous measurement of methylxanthines and methylurates are lacking. To address this deficiency, we conducted a pharmacokinetic study in which subjects (n = 12) were orally administered caffeine (150 mg), methylliberine (Dynamine™, 100 mg), and theacrine (TeaCrine®, 50 mg) followed by blood sampling over 24 h. Liquid-liquid extraction of plasma samples containing purine alkaloids and internal standard (13C-Caffeine) were analyzed using a C18 reversed-phase column and gradient elution (acetonitrile and water, both containing 0.1% formic acid). A Waters Xevo TQ-S tandem mass spectrometer (positive mode) was used to detect caffeine, methylliberine, theacrine, and IS transitions of m/z 195.11 → 138.01, 225.12 → 168.02, 225.12 → 167.95, and 198.1 → 140.07, respectively. The method was validated for precision, accuracy, selectivity, and linearity and was successfully applied to characterize the oral pharmacokinetics of caffeine, methylliberine, and theacrine in human plasma. Successful development and application of LC-MS/MS-based methods such as ours for the simultaneous measurement of methylxanthines and methylurates are essential for the characterization of potential pharmacokinetic and pharmacodynamic interactions.

Real-World Analysis of Potential Pharmacokinetic and Pharmacodynamic Drug Interactions with Apixaban in Patients with Non-Valvular Atrial Fibrillation.

PurposeWe conducted this study to assess the real-world prevalence, nature, predictors, and clinical necessity of apixaban pharmacokinetic (PK) and pharmacodynamic (PD) drug interactions in patients with non-valvular atrial fibrillation (NVAF) at a tertiary medical institution in Saudi Arabia.Patients and MethodsAn observational retrospective cohort analysis was conducted in adult patients diagnosed with NVAF receiving apixaban for stroke prevention from the period of June 2015 to May 2019.ResultsOf the 1271 patients included in the analysis, 611 (48.1%) patients had potential PD– or PK–drug interactions with apixaban. Of those, 490 (38.6%) patients had potential PD drug–drug interactions (DDIs) and 121 (9.5%) patients had potential PK-DDIs. PD-DDIs with apixaban were mainly with antiplatelet therapy followed by non-steroidal anti-inflammatory drugs and antidepressants. PK-DDIs with apixaban were mainly with combined P-gp/CYP3A4 inhibitors or inducers. History of minor bleeding was positively correlated with PD-DDIs with apixaban, ß coefficient = 0.455 (OR 1.58; 95% CI 1.01–2.45); p<0.05. History of acute coronary syndrome was positively correlated with PD-DDIs with apixaban, ß coefficient = 0.515 (OR 1.60; 95% CI 1.36–1.99); p<0.05. History of heart failure was positively correlated with PK-DDIs with apixaban, ß coefficient = 0.459 (OR 1.58; 95% CI 1.07–2.35); p<0.05. Almost 15% of the included patients had no clinical indication to receive the potential interacting drug with apixaban and about 20% of them were assuming an inappropriate apixaban dose according to the product package insert.ConclusionPharmacodynamics and pharmacokinetics interactions are common in more than half of the patients with NVAF receiving apixaban for stroke prevention in this real-world analysis. Some of these interacting medications are not indicated. Drug–drug interactions should always be considered and monitored with apixaban with a regular assessment of the need for any interacting medication.

Potential pharmacodynamic and pharmacokinetic interactions of Nigella Sativa and Trigonella Foenum-graecum with losartan in L-NAME induced hypertensive rats.

The objective of this investigation was to study whether Nigella Sativa and Trigonella Foenum-graecum, could modulate the losartan pharmacodynamic (PD) and pharmacokinetic (PK) in experimental L-NAME induced hypertensive rats. For in vivo study, the systolic blood pressure (SBP) of rats was measured by the “tail-cuff system” after the treatment of rats with herb alone and herb + losartan in hypertensive rats. The SBP of rats treated with L-NAME + losartan also recorded. For the PK study, blood samples were obtained for up to 12 h to determine the concentrations of the drug, and various PK parameters were calculated. The data displayed that the SBP was significantly (p < 0.05) decreased in the rats when administered with L-NAME + N. Sativa or L-NAME + T. Foenum-graecum in contrast to the rats administered with L-NAME alone. A more prominent decline (p < 0.05) in SBP was detected in rats administered with L-NAME + N. Sativa + losartan and L-NAME + T. Foenum-graecum + losartan. In a PK study, higher losartan Cmax and AUC0-t were noted in rats treated with N. Sativa + losartan and T. Foenum-graecum + losartan, although the difference was not significant in contrast to the control group. This study proposed that the interaction between N. Sativa & losartan and T. Foenum-graecum & losartan could take place on concurrent administration; consequently, the dose of losartan may need to be accustomed when they are utilized simultaneously.

Assessment of Potential Pharmacokinetic and Pharmacodynamic Interactions between XEN901 (a Novel NaV1.6 Selective Sodium Channel Blocker) and Phenytoin (a non-selective NaV Blocker) in Adult Healthy Subjects (4682)

Assessment of Potential Pharmacokinetic and Pharmacodynamic Interactions between XEN901 (a Novel NaV1.6 Selective Sodium Channel Blocker) and Phenytoin (a non-selective NaV Blocker) in Adult Healthy Subjects (4682)

Model-Informed Drug Discovery and Development Strategy for the Rapid Development of Anti-Tuberculosis Drug Combinations

The increasing emergence of drug-resistant tuberculosis requires new effective and safe drug regimens. However, drug discovery and development are challenging, lengthy and costly. The framework of model-informed drug discovery and development (MID3) is proposed to be applied throughout the preclinical to clinical phases to provide an informative prediction of drug exposure and efficacy in humans in order to select novel anti-tuberculosis drug combinations. The MID3 includes pharmacokinetic-pharmacodynamic and quantitative systems pharmacology models, machine learning and artificial intelligence, which integrates all the available knowledge related to disease and the compounds. A translational in vitro-in vivo link throughout modeling and simulation is crucial to optimize the selection of regimens with the highest probability of receiving approval from regulatory authorities. In vitro-in vivo correlation (IVIVC) and physiologically-based pharmacokinetic modeling provide powerful tools to predict pharmacokinetic drug-drug interactions based on preclinical information. Mechanistic or semi-mechanistic pharmacokinetic-pharmacodynamic models have been successfully applied to predict the clinical exposure-response profile for anti-tuberculosis drugs using preclinical data. Potential pharmacodynamic drug-drug interactions can be predicted from in vitro data through IVIVC and pharmacokinetic-pharmacodynamic modeling accounting for translational factors. It is essential for academic and industrial drug developers to collaborate across disciplines to realize the huge potential of MID3.

Synthetic Cathinones and Their Potential Interactions with Prescription Drugs.

Substance use disorder often coexists with other psychiatric disorders, resulting in the simultaneous use of recreational and prescription drugs. The authors aimed to identify potential pharmacokinetic and pharmacodynamic interactions between new psychoactive substances of the cathinone class and specific prescription drugs. The authors performed a systematic literature review on interactions between synthetic cathinones (mephedrone, methylone, methylenedioxypyrovalerone, and alpha-pyrrolidinopentiophenone) and antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine), attention deficit hyperactivity disorder (ADHD) medications (atomoxetine, dexamphetamine, methylphenidate, modafinil) or HIV medications. Although no pharmacokinetic interactions have been reported in previous literatures, such interactions are likely to occur. Metabolic pathways of cathinones, antidepressants, and ADHD medications have been shown to overlap, including metabolism via cytochrome P450 enzymes and their inhibition. Consistent with this finding, interactions of bupropion (a cathinone) with antidepressants and ADHD medications have been found to increase their serum concentrations and half-lives. Additionally, limited pharmacodynamic interactions have been reported. However, as cathinones, antidepressants, and ADHD medications have been reported to increase the extracellular monoamine concentration by affecting reuptake transporters, interactions among these compounds are likely. Presumably, even higher monoamine concentrations could be observed when cathinones are combined with prescription drugs with a similar mode of action, as has been reported in animals exposed to duloxetine and bupropion. HIV medications have a different mode of action; thus, they have been reported to be less likely to have pharmacodynamic interactions with cathinones. Clinicians should be aware of possible interactions between synthetic cathinones and prescription drugs, which may increase the risk of drug toxicity or reduce the therapeutic efficacy of the drugs. Qualitative drug screening for cathinones using mass spectrometry methods may aid the early detection of these agents.

Pharmacokinetic and pharmacodynamic interactions of Tinospora cordifolia aqueous extract and hypoglycemic drugs in streptozotocin-induced diabetes in rats

Context: Tinospora cordifolia (Willd.) Miers is an antidiabetic herb globally marketed as a single or polyherbal formulation. The pharmacological activities of T. cordifolia suggest its potential to be co-administered with commonly prescribed oral hypoglycemic drugs in the therapeutic management of diabetes mellitus. Aims: The aim of this study was to evaluate the potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions of the aqueous extract of T. cordifolia (TCE) with metformin (MET), sitagliptin (SITA), and glibenclamide (GLI) in streptozotocin (STZ)-induced diabetes in rats. Settings and Design: The aqueous TCE (400 mg/kg, p.o.) was co-administered with MET (90 mg/kg, p. o.), SITA (10 mg/kg, p. o.), and GLI (1 mg/kg, p. o.) for 28 days in STZ-induced diabetes in rats. Materials and Methods: The PK parameters of the three drugs were calculated using Phoenix WinNonlin®, and PD activity was determined by estimating fasting blood glucose, liver and kidney function tests, and lipid parameters. Further, histopathological examination of pancreatic cells and estimation of pancreatic antioxidant enzymes was carried out. Statistical Analysis Used: The pharmacokinetic parameters were estimated using pharmacokinetic program WinNonlin® version 3.0 (Pharmasight corporation, Mountain view, CA). The pharmacodynamic parameters were analysed using Graph Pad prism Version 6.00 applying one-way ANOVA followed by the Tukey–Kramer post test. Results: No significant PK interaction was observed between TCE and the three oral hypoglycemics. However, a significant improvement was observed in glycemic control and the conditions associated with diabetes mellitus. In addition, no incidences of hypoglycemia were observed. Conclusion: The co-administration of TCE with MET, SITA, and GLI helped in better management of diabetes and associated comorbidities than their individual administrations. There were no significant PK interactions observed. Our findings provide insights into the safety and efficacy of the combination therapy of TCE with MET, SITA, and GLI in the management of diabetes and associated conditions.

Evaluation of potential herb-drug interactions between oseltamivir and commonly used anti-influenza Chinese medicinal herbs

Ethnopharmacological relevanceAccording to Traditional Chinese Medicine theory, influenza is categorized as a warm disease or Wen Bing. The Wen Bing formulas, such as Yin-Qiao-San and Sang-Ju-Yin, are still first-line herbal therapies in combating variant influenza virus. To continue our study on the pharmacokinetic and pharmacodynamic interactions between Wen Bing formulas and oseltamivir (OS), the first-line western drug for the treatment of influenza, further interactions between OS and the eight single herbs and their relevant marker components from Wen Bing formulas were investigated in the current study. Aim of studyTo establish an in-vitro screening platform for investigation of the potential anti-influenza herbs/herbal components that may have pharmacokinetic and pharmacodynamic interactions with OS. Materials and methodsTo screen potential inhibition on OS hydrolysis, 1 μg/mL of OS is incubated with herbs/herbal components in diluted rat plasma, microsomes and human recombinant carboxylesterase 1(hCE1) under optimized conditions. MDCK-WT and MDCK-MDR1 cell lines are utilized to identify potential modification on P-gp mediated transport of OS by herbs/herbal components. Caco-2 cells with and without Gly-Sar inhibition are performed to study the uptake of OS via PEPT1 transporters. Modification on OAT3 mediated transport is verified by the uptake of OS on HEK293-MOCK/HEK293-OAT3 cells. Anti-virus effects were evaluated using plaque reduction assay on H1N1 and H3N2 viruses. Potential pharmacokinetic and pharmacodynamic interaction between OS (30 mg/kg) and the selected herb, Radix Scutellariae (RS), at 300–600 mg/kg were carried out on rats. All samples are analyzed by an LC/MS/MS method for the contents of OS and OSA. A mechanistic PK model was developed to interpret the HDI between OS and RS in rats. ResultsOur developed platform was successfully applied to screen the eight herbal extracts and their ten marker components on metabolic inhibition of OS and modification of OS transport mediated by P-gp, OAT3 and PEPT1. Results from six in-vitro experiments were analyzed after converting raw data from each experiment to corresponding fold-change (FC) values, based on which Radix Scutellariae (RS) were selected to have the most HDI potential with OS. By analyzing the plasma and urine pharmacokinetic data after co-administration of OS with a standardized RS extract in rats using an integrated population pharmacokinetics model, it is suggested that RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which leads to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine. Never the less, the anti-virus effects of 2.5 h post-dose rat plasma were not influenced by co-administration of OS with RS. ConclusionA six-dimension in-vitro screening platform has been developed and successfully applied to find RS as a potential herb that would influence the co-administrated OS in rats. Although co-administered RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which lead to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine, the anti-virus effect of OS was not influenced by co-administered RS.