Drug Interactions Research Articles

Impact of medication nonadherence and drug-drug interaction testing on the management of primary care patients with polypharmacy: a randomized controlled trial

Impact of medication nonadherence and drug-drug interaction testing on the management of primary care patients with polypharmacy: a randomized controlled trial

Protein‐protein interaction and conformational change in the alpha‐helical membrane transporter BtuCD‐F in the native cellular envelope

Alpha‐helical membrane proteins perform numerous critical functions essential for the survival of living organisms. Traditionally, these proteins are extracted from membranes using detergent solubilization and reconstitution into liposomes or nanodiscs. However, these processes often obscure the effects of nanoconfinement and the native environment on the structure and conformational heterogeneity of the target protein. We demonstrate that pulsed dipolar electron spin resonance spectroscopy, combined with the Gd³⁺‐nitroxide spin pair, enables the selective observation of the vitamin B12 importer BtuCD‐F in its native cellular envelope. Despite the high levels of non‐specific labeling in the envelope, this orthogonal approach combined with the long phase‐memory time for the Gd³⁺ spin enables the observation of the target protein complex at a few micromolar concentrations with high resolution. In the native envelope, vitamin B12induces a distinct conformational shift at the BtuCD‐BtuF interface, which is not observed in the micelles. This approach offers a general strategy for investigating protein‐protein and protein‐ligand/drug interactions and conformational changes of the alpha‐helical membrane proteins in their native envelope context.

Limited Sampling Strategy for Predicting the Area under Plasma Concentration–Time Curve of Nadolol in Healthy Subjects

AbstractNadolol is a hydrophilic β‐adrenoceptor blocker with a relatively long half‐life and negligible metabolism. It is a substrate of P‐glycoprotein and organic anion transporting polypeptide 1A2, and may serve as an in vivo probe drug for the assessment of drug–drug and food–drug interactions mediated by these transporters. In the present study, we aimed to develop limited sampling strategy (LSS) models for predicting the area under the plasma concentration–time curve (AUC0‐∞) of nadolol. Plasma concentration data (Ct) in healthy volunteers reported in four previous studies were randomly divided into a training dataset for model development (n = 15) and a test dataset for model validation (n = 16). By multiple linear regression analysis, we confirmed that four out of the eight models using two time points and all models using three time points met the acceptable criteria. In particular, the three time point models using (C3, C6, and C24) and (C4, C8, and C24) showed better predictive performances with r2 values of 0.983 and 0.980, respectively. In drug interaction studies of nadolol with itraconazole, rifampicin, grapefruit juice, and green tea extract, both LSS models accurately predicted the AUC0‐∞ with percent mean absolute error ≤11% and percent root mean square error ≤12%. In addition, using digitized pharmacokinetic data of nadolol, both LSS models were further validated by predicting the AUC0‐∞ in different doses. The results suggest that the LSS models using three time points allow a reliable prediction of AUC0‐∞ of nadolol in healthy individuals.

Evaluating the drug-drug interactions of SHR4640 on repaglinide and midazolam in healthy subjects

ABSTRACT Background SHR4640, a highly selective URAT1 inhibitor, was evaluated to investigate its inhibitory effects on CYP2C8 and CYP3A4 in vivo clinical trial. This study assessed the pharmacokinetic (PK) impact of SHR4640 when co-administered with the CYP2C8 probe substrate repaglinide and the CYP3A4 probe substrate midazolam. Research design and methods In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC0-inf, AUC0-t, and Cmax). Results The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%. Conclusions SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile. Clinical trial registration www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).

Complexity of the Therapeutic Regimen in Older Adults with Cancer: Associated Factors

Background/Objectives: Population aging is a worldwide phenomenon and is often associated with multimorbidity and polypharmacy. Complex medication regimens are common among older adults and contribute to the occurrence of harmful health outcomes. Age is one of the main risk factors for cancer. This study aimed to determine and characterize the therapeutic complexity in older patients with cancer, and analyze the factors associated with high complexity and the impact of the oncological context. Methods: A cross-sectional study with patients aged ≥65 years with cancer was conducted in three hospitals in northern Portugal. Data collection was obtained using self-reports. The medication regimen complexity was assessed using the Medication Regimen Complexity Index (MRCI). Descriptive and association statistical analysis were performed. Logistic, linear, simple and multiple regression analysis were conducted, with and without automatic variable selection. Results: A total of 552 patients were included (median age, 71; IQR, 68–76). The mean MRCI before the oncological context was 18.67 (SD 12.60) and 27.39 (SD 16.67) after the oncological context, presenting a statistically significant difference in the values obtained (p < 0.001). An elevated complexity was significantly associated with polypharmacy, chronic diseases and with the administration of high-risk medications (p < 0.05). High MRCI values showed a relationship with the occurrence of potential drug interactions (p < 0.001). There was no relationship with the existence of cardiac risk comorbidity. Conclusions: This study demonstrated the existence of high therapeutic complexity in older patients with cancer, suggesting the need for intervention to prevent medication-related problems in this vulnerable population.

Factors Associated with the Practice of Assessing Drug–Drug Interactions Among Pharmacists in Saudi Arabia

Background: Drug–drug interactions (DDIs) occur when two or more drugs are administered concomitantly, changing the pharmacokinetics or pharmacodynamics of a drug’s characteristics. Despite the advances in health technology, DDIs remain a concern to patient safety. This study aimed to (1) assess the knowledge, attitude, and practice of hospital and community pharmacists toward DDIs in Saudi Arabia and (2) examine factors associated with their practice. Methods: A cross-sectional study was conducted using an online self-administered questionnaire targeting hospital and community pharmacists working in Saudi Arabia. The study questionnaire consisted of five sections: demographics, knowledge, attitude, and practice toward DDIs, as well as pharmacy characteristics. Descriptive statistics were used to summarize the characteristics of participants as count and percentage. Chi-square tests were used to examine associations between practice variables and other independent variables. Results: A total of 131 pharmacists participated in the study. The majority were males (81.7%), aged 26–35 years (64.9%), and worked in community pharmacies (81.7%). Nearly half of the participants reported optimal practice regarding checking drug interactions before dispensing any drug. Factors associated with the practice of checking DDIs were found to be gender, perceived workload, perceived knowledge, and attitude variables. Regarding the practice of asking patients about their prescription and OTC drugs, there were statistically significant differences between hospital and community pharmacists. Conclusions: Our findings on both community and hospital pharmacists in Saudi Arabia reveal that pharmacists’ attitudes and perceived knowledge might influence the practice of pharmacists toward DDIs.

Towards streamlined product information: reporting of transporter-mediated drug interactions.

The purpose of this study is to investigate the reporting of risks associated with transporter-mediated drug-drug interactions (DDIs) in medicinal product information and to identify suitable wording for future standardisation of summaries of product characteristics (SmPCs). The SmPCs of medicinal products approved in the European Union from 2012 to 2023 were screened for warnings on Organic Anion Transporting Polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and Breast Cancer Resistance Protein (BCRP). An in-house search engine for product information was used. Warnings were categorised into different DDI scenarios based on the SmPC texts. A total of 192 out of 859 approved medicinal products had SmPC text pertaining to OATP1B1, 1B3 and/or BCRP. The majority of products had text for all three transporters Most texts were located in SmPC Sect.5.2, followed bySect. 4.5. Numerous interaction-texts either concluded that the interaction lacked clinical relevance or lacked information on the clinical relevance of the finding. The highest number of SmPC texts indicating a clinically relevant interaction with outlined clinical consequences was found for BCRP. The article also presents SmPC texts for each DDI scenario, which the authors consider as examples of explicitwordings with actionable recommendations. A potential for improvement of SmPC text for transporter-mediated DDI was identified: Warnings without clinical relevance could be omitted, and some warnings with clinical relevance could be updated to provide actionable recommendations to the prescribers. A selection of unambiguous texts was identified as starting point to generate standard texts.

Should all people starting urate-lowering therapy for gout receive anti-inflammatory prophylaxis?

Co-prescription of anti-inflammatory prophylaxis with colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), or corticosteroids when initiating urate-lowering therapy (ULT) for gout is recommended in clinical guidelines to prevent ULT-induced flares and optimise adherence to ULT. Colchicine prophylaxis is highly clinically and cost-effective and there has been great interest recently in its cardioprotective effects. However, one in four people initiating ULT without prophylaxis in randomised trials do not have a gout flare within six months of initiation, raising the question of whether all people initiating ULT for gout should receive prophylaxis. Uptake of prophylaxis varies and appears to be common in secondary care settings but less commonly used in primary care, where most people with gout are managed and gout may be less severe. Recent clinical guidelines have highlighted that the patient’s perspective is important and that the pros and cons of prophylaxis should be discussed with people with gout initiating ULT. Uptake of prophylaxis seems likely to be influenced by perception of an individual’s risk of ULT-induced flares, as well as concerns about adverse events, polypharmacy, drug interactions, and cost. We advocate a personalised approach between people with gout and clinicians to reach shared treatment decisions when considering co-prescription of prophylaxis when initiating ULT, empowering people with gout to make decisions about their care.

Gene Polymorphisms Play an Important Role in the Drug Interaction Between Posaconazole and Tacrolimus in Renal Transplant Patients

Gene Polymorphisms Play an Important Role in the Drug Interaction Between Posaconazole and Tacrolimus in Renal Transplant Patients

Opportunities and challenges associated with the launch of nirmatrelvir/ritonavir (Paxlovid) in British Columbia during the COVID-19 pandemic: A qualitative study to explore community pharmacists’ perspectives

Background: In February 2022, a novel antiviral for the treatment of COVID-19, nirmatrelvir/ritonavir (Paxlovid), was approved by Health Canada and made available to patients in British Columbia (BC). BC community pharmacists did not prescribe nirmatrelvir/ritonavir, but dispensing involved a detailed assessment with close attention to drug-drug interactions and patient monitoring. As the nirmatrelvir/ritonavir service was unique in BC, and not all pharmacists participated in the program, it is important to evaluate the perspectives of all the pharmacists who were affected so that lessons learned from the program can inform future pandemic planning and government initiatives. Methods: A qualitative research study using key informant semistructured interviews was conducted. Community pharmacists with varying degrees of experience with nirmatrelvir/ritonavir were recruited using multiple methods of recruitment through e-mail and fax invitations and social media posts. Open-ended questions explored pharmacists’ experiences with the nirmatrelvir/ritonavir program, including barriers and facilitators to dispensing it, and recommendations for future pharmacy initiatives. Results: Forty-three community pharmacists participated in the study. Most participants were between the ages of 30 and 39 years and had practiced for less than 10 years. Thematic analysis yielded 36 codes that were organized into 3 overarching themes related to the following: learning; in-process experiences, supports, difficulties; and perceptions about the expanded scope of practice. Discussion: The following strategies may be helpful to consider including in future initiatives: preprinted forms, a hotline for peer support, slower rollouts, a single source for communicating changes, a patient portal, addressing the divisions between dispensary and clinical work, and having specialized positions to support future rollouts. Conclusion: Lessons learned from the nirmatrelvir/ritonavir service included a slower approach to program initiation with additional training opportunities and more streamlined prescription options. Pharmacists also wished for better communication support and involvement in the planning of future initiatives.

Triterpenoids from Ganoderma lucidum inhibit cytochrome P450 enzymes interfering with the metabolic process of specific clinical drugs

BackgroundGanoderma lucidum (G. lucidum), which possesses various biological effects, has been widely used as traditional medicine and functional food in Asian countries, especially China. In consideration of its various biological effects on human healthcare, G. lucidum was usually used in combination with other drugs. However, the potential drug-drug interaction induced by G. lucidum through cytochrome P450 enzymes (CYPs) remain unknown.MethodsUsing the in vivo activity assay of CYPs, the inhibitory effects of G. lucidum and its constituents could be evaluated. The interference of G. lucidum on the metabolic processes of clinical drugs could be investigated. The chemical constituents of G. lucidum could be identified using LC-MS. The interaction between bioactive compounds and CYPs could be proposed through in silico docking analysis and molecular dynamics.ResultsThe dichloromethane extract of G. lucidum could inhibit various CYP450 subtypes in vitro and interfere with the pharmacokinetics of four drugs in rats. Triterpenoids were identified as the main constituents of the dichloromethane extract by Q-TOF-MSn in preliminary analyses. Then, a triterpenoid library containing 66 compounds was established to evaluate their inhibitory effects against CYP 1A2, 2D6, 3A4, 2A6, 2B6, 2C9, and 2C19. CYP 1A2 was inhibited by most lanostane triterpenoids, indicating a strong affinity for these compounds. Among triterpenoids, compound 25 displayed a broad inhibitory effect against CYPs, except for CYP 3A4, 2D6, 2C9, and 2C19. Finally, compounds 6 and 25 exhibited interference with the metabolism of 16 drugs through the inhibition of CYPs in vitro. In silico molecular docking analyses for assaying the interaction between compound 25 and CYPs indicated that the hydrogen bonds formed between the hydroxyl groups and amino acid residues.ConclusionG. lucidum displayed broad inhibitory effects on CYPs, with triterpenoids as the main bioactive constituents, which may induce potential drug-drug interaction. This information should be helpful for the rational use of G. lucidum in promoting human health.

Design-assisted HPLC-UV method for therapeutic drug monitoring of pholcodine, ephedrine, and guaifenesin in biological fluids.

Drug-drug interactions may amplify or diminish their intended effects, or even produce entirely new effects. Multicomponent mixture HPLC analysis offers a thorough and effective method for comprehending the makeup and behavior of complicated materials, advancing research and development across a range of scientific and industrial domains. A novel experimental design-assisted HPLC methodology for the concurrent investigation of the drug-drug interaction of pholcodine, ephedrine, and guaifenesin in biological fluids has been established. Rather than the routine methodology, the application of the factorial design-HPLC method offers a powerful and efficient tool for the analysis of these compounds. Both mixed and full factorial designs were employed to assess the impact of variable factors on chromatographic results. Utilizing an isocratic elution mode on a C18 column, the chromatographic separation was carried out. 15% Methanol, 5% acetonitrile, and 80% phosphate buffer with 0.1%(v/v) triethylamine set to pH 3 make up the mobile phase flowing at rate 1.0 mL/min. The calibration curves of the drugs show excellent linearity over a concentration ranges: 0.20-13.0µg/mL for PHO, 0.50-20.0µg/mL for EPH and 0.70-20.0µg/mL for GUA with LOQ values of 0.18, 0.38 and 0.50. The fast separation and quantitation in less than 6min is an advantage. Also, the method includes a robust sample preparation protocol for the analysis of complex biological samples, ensuring high selectivity and precision. The ease, speed and cost-effectiveness of the method are ideal for supporting in vitro studies, including drug-drug interaction investigations, especially in bioanalytical labs.

Drug Interactions in People on Cannabidiol: Is There Cause for Concern?

Introduction: Cannabidiol (CBD) exhibits multiple therapeutic properties, but its use in advanced cancer patients raises concerns about potential drug-drug interactions (DDIs) due to polypharmacy. This study aims to look for evidence of DDIs between concomitant medications and CBD oil in a randomized placebo-controlled trial of CBD oil for symptom control (MedCan-1 parent study). Materials and Methods: Surrogate measures were used to identify possible drug interactions: (1) the maximum mL of oil self-selected by patients in CBD or placebo groups in relation to opioids, specific drug groups, or individual agents; (2) the occurrence of any new or worse adverse effect in relation to the study arm and the concomitant medication classes/medications of interest. Results: The dose of CBD self-selected by participants was not related to opioid use or medications, including benzodiazepines and antipsychotics. The likelihood of developing an adverse effect while on study or when taking specific medications was not increased by CBD. Participants on paracetamol tolerated a higher dose of CBD. Discussion: Concerns regarding the development of clinically significant drug interactions when taking CBD in the context of anti-cancer and other concomitant medications at least in the short term may be unfounded.

Preliminary guidelines for the detection and management of drug-related problems in cancer patients with type 2 diabetes mellitus: a practical resource for oncology pharmacists.

The prevalence of type 2 diabetes mellitus (T2DM) in cancer patients is high. During the medication review process, clinical pharmacists could detect and manage drug-related problems (DRP) to optimize pharmacotherapy but there is a need to standardize pharmacists' interventions (PI) especially for T2DM-related DRP. The present study aims to describe DRP in cancer patients with T2DM undergoing anticancer treatment (AT) and to propose related preliminary guidelines to manage T2DM-related DRP. The study was conducted in one oncology outpatient hospital where a clinical pharmacy team performs medication reviews to detect and manage DRP by performing PI in cancer patients undergoing AT. All the data from November 23rd, 2015 to November 23rd, 2019 were extracted and demographic, clinical, oncological, and biological data were collected and analyzed. Based on these results and a literature review, a working group (2 pharmacists and one diabetologist) was constituted to propose a first set of preliminary guidelines clinical pharmacists that were then reviewed using the Delphi method by an expert panel of oncologists and pharmacists. A total of 161 T2DM cancer patients were included in the study (19.7% of all cancer patients screened). Overall, 152 DRP (mean 1.67/patient) were detected (49.3% drug interaction) and 152 PI were performed by clinical pharmacists, mainly drug monitoring (48.0) and drug discontinuation (25.7%). Specifically, there was 24 T2DM-related DRP (including 29.2% drug interactions). Twenty-four DRPs were directly related to T2DM status. The five proposed guidelines reached a consensus after revisions and a sixth has been added. DRPs were frequent among cancer patients with T2DM and we hypothesize that the preliminary guidelines should improve the detection of DRPs directly related to T2DM. The implementation of the preliminary guidelines should now be assessed in clinical practice.

Patiromer Does Not Alter Tacrolimus Pharmacokinetics in Kidney Transplant Recipients When Administered Three Hours Post–Tacrolimus

Background. Hyperkalemia is common in kidney transplant (KTx) recipients. Patiromer, a potassium-binding polymer used to treat acute and chronic hyperkalemia, has the potential to bind charged particles in the gastrointestinal tract and thereby potentially affect the absorption of coadministered drugs. The immunosuppressive drug tacrolimus (Tac) has a narrow therapeutic window, is susceptible to drug-drug interactions (DDIs), and a potential gastrointestinal interaction with patiromer could elevate the risk of allograft rejection. We aimed to investigate the potential DDI between patiromer and Tac pharmacokinetics in KTx with hyperkalemia by sampling capillary blood using volumetric absorptive microsampling (VAMS). Methods. Thirteen KTx recipients on Tac twice daily (BID) with plasma potassium levels of >4.6 mmol/L were included. Two 12 h Tac pharmacokinetic investigations were performed with and without 8.4 mg patiromer/d for 1 wk. Oral Tac dose remained unchanged and patiromer was administered 3 h after Tac dose. Tac sampling was self-conducted using VAMS after mastering the technique. Results. Ten patients provided 2 evaluable pharmacokinetic profiles. The Tac area under the curve (AUC)0–12 ratio (AUCTac+patiromer/AUCTac) was 0.99 (90% confidence interval [CI], 0.86-1.14), and the Cmax ratio was 1.01 (90% CI, 0.86-1.19). Tac C0 and C12 fulfilled the bioequivalence criteria with a ratio of 0.98 (90% CI, 0.90-1.07) and 0.93 (90% CI, 0.83-1.04), respectively. Conclusions. When administered 3 h after the Tac morning dose, patiromer has no clinically relevant impact on Tac pharmacokinetics. We demonstrate that VAMS is a well-suited sampling method to simplify the execution of DDI studies.

The distinctive pharmacokinetic profile of rezafungin, a long-acting echinocandin developed in the era of modern pharmacometrics.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis.

Helicobacter pylori, esophageal precancerous lesions, and proton pump inhibitor overuse

This article reviews the cohort study published in the World Journal of Gastroenterology , which reported low rates of Helicobacter pylori (H. pylori ) infection among esophageal cancer (EC) patients, coupled with proton pump inhibitor (PPI) overuse. These findings suggest a potential protective role of H. pylori against EC and indicate a possible association between PPI use and increased cancer risk. In light of these findings, our article examines the complex relationship between H. pylori and esophageal precancerous lesions, exploring the potential underlying mechanisms. We also address growing concerns regarding PPI overuse, including its potential effects on cancer therapy efficacy and the risk of drug interactions. Ultimately, this article highlights the urgent need for further research to evaluate the safety and efficacy of PPIs in cancer patients and to better understand their broader implications.

Cyclin-dependent kinase 4/6 inhibitors and cardiotoxic events in breast cancer: A pharmacovigilance study based on the FAERS database.

Recent trials have highlighted the cardiotoxicity of ribociclib, a CDK4/6 inhibitor, particularly its association with QT prolongation. However, studies on the link between CDK4/6 inhibitors and cardiotoxic events show inconsistent results, and the factors influencing these events and related drug interactions remain underexplored. To address these uncertainties, our study utilizes the FDA adverse event reporting system database (Q1 2015 to Q1 2024) to examine the cardiotoxic events of CDK4/6 inhibitors in breast cancer patients. We employed a comprehensive analytical framework, applying disproportionality methods including Bayesian confidence propagation neural network, proportional reporting ratio, and reporting odds ratio. Our findings highlight significant variability in cardiotoxic events among different CDK4/6 inhibitors, with ribociclib (IC: 0.26, 95%CI: 0.18-0.34) exhibiting pronounced cardiotoxicity. Notably, ribociclib was associated with serious cardiotoxic events such as torsade de pointes/QT prolongation (IC: 2.11, 95% CI: 1.90-2.29) and conduction defects (IC: 2.07, 95% CI: 1.87-2.23). For the first time, palbociclib has been identified with positive signals for cardiotoxic events at the preferred terms level, including pulmonary oedema, increased blood pressure, myocardial infarction, and cardiac flutter. Moreover, multivariable logistic regression and Bayesian network analyses reveal that age, geographic location, and the number of concomitant medications significantly influence cardiotoxic events. Our study also highlights significant drug interactions that increase the probability of specific cardiotoxic outcomes, notably with drugs like sertraline, lansoprazole, capecitabine, and torasemide. These findings highlight the need for personalized treatment plans to mitigate cardiotoxic events and improve patient safety.

MDRepo-an open data warehouse for community-contributed molecular dynamics simulations of proteins.

Molecular Dynamics (MD) simulation of biomolecules provides important insights into conformational changes and dynamic behavior, revealing critical information about folding and interactions with other molecules. The collection of simulations stored in computers across the world holds immense potential to serve as training data for future Machine Learning models that will transform the prediction of structure, dynamics, drug interactions, and more. Ideally, there should exist an open access repository that enables scientists to submit and store their MD simulations of proteins and protein-drug interactions, and to find, retrieve, analyze, and visualize simulations produced by others. However, despite the ubiquity of MD simulation in structural biology, no such repository exists; as a result, simulations are instead stored in scattered locations without uniform metadata or access protocols. Here, we introduce MDRepo, a robust infrastructure that provides a relatively simple process for standardized community contribution of simulations, activates common downstream analyses on stored data, and enables search, retrieval, and visualization of contributed data. MDRepo is built on top of the open-source CyVerse research cyber-infrastructure, and is capable of storing petabytes of simulations, while providing high bandwidth upload and download capabilities and laying a foundation for cloud-based access to its stored data.

Influence of pharmacotherapy on function of biotransformation of xenobiotics liver in patients with neuropsychiatric disorders

BACKGROUND: The mechanisms of drug interactions of psychotropic drugs are associated with the processes of drug biotransformation by enzymes of microsomal oxidation of cytochrome P-450 in the liver. Various drugs can increase or decrease the activity of enzymes of the cytochrome P450-dependent system. AIM: To evaluate the effect of pharmacotherapy with psychotropic drugs: alprazolam, bromazepam, lithium carbonate on the metabolic rate of the model substrate antipyrine in saliva in patients with neuropsychiatric disorders; the effect of the enzyme-inducing activity of the original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in healthy volunteers. MATERIALS AND METHODS: 34 male patients were divided into three groups according to the nosological forms of diseases according to ICD-10: Group 1 — heading F43.23 and F43.25; 2 — F06.61; 3 — F41.2. Patients in the group 1 were prescribed alprazolam, in the 2 — bromazepam, in the 3 — lithium carbonate, for a course of 21 days. The comparison group consisted of 10 healthy volunteers. The original anticonvulsant was prescribed to the volunteers. Determination of the pharmacokinetics of antipyrine parameters as a test witness of the processes of elimination from the body was carried out in saliva before and after the end of therapy at a dose of 10 mg/kg once. RESULTS: Alprazolam administration by patients of group 1 at a dose of 0.5–1.5 mg/day for 21 days did not significantly affect the pharmacokinetic parameters of antipyrine: T1/2, Clt, AUC. Alprazolam did not change the elimination of antipyrine from the saliva of patients. In patients of the group2, who received bromazepam at a dose of 6–12 mg / day,a background decrease in T1/2, an increase in Clt, a decrease in AUC due to concomitant therapy were noted. Comparison of the pharmacokinetic parameters of antipyrine under the influence of bromazepam with background values not reveal significant differences. Therapy with lithium carbonate at a dose of 500–1000 mg/day in patients of the group 3 did not change the parameters of antipyrine elimination. The obtained data indicate that the drugs do not affect the activity of liver microsomal oxidation in patients. The study of the effect of 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in volunteers revealed a diametrically opposite result: a significant decrease in T1/2 by 2 times, an increase in Clt and a decrease in AUC, which indicates accelerated elimination of antipyrine from the saliva of the subjects and indicates the induction of liver microsomal oxidation. CONCLUSIONS: Pharmacotherapy using the studied psychotropic drugs in patients is not associated with the induction or inhibition of liver enzymes, which indicates the absence of drug pharmacokinetic interference. The original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea stimulated the induction of liver microsomal oxidation in volunteers.