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The interaction between cocaine and anesthetic drugs has been known since 1884, when it was first used for the treatment of morphine addiction and as local anesthetic. Due to the large number of users of the substance, the interaction with anesthetic drugs has been frequent and it has been seen that many drugs have their effects altered in the presence of cocaine. Through bibliographical survey in PubMED and CrossRef, aiming to highlight the risks of this interaction and conduct in cases of elective surgeries in these patients, we conducted this study and verified that so many drugs have to be avoided due to their interaction effects, but in the absence of clinical signs of intoxication, screening becomes ineffective.

One of the approaches adopted, as the first treatment method, in previous pandemic viruses before the production of new vaccines or drugs, is to evaluate the effectiveness of existing drugs. Sometimes, it is known that the combination of drugs provides better treatment by increasing the activity of the drugs due to mutual interactions. In this work, we used quantum theory of atoms in molecules and density functional theory to examine the structure and activity relationship between Favipiravir (FPV), a potential antiviral drug for ribonucleic acid viruses, and an inhibitor of influenza virus, and Ibuprofen (IBP), a nonsteroidal anti-inflammatory drug. The drug-likeness evaluations of IBP horizontal ellipsis FPV were also performed. It was observed that FPV and IBP interact in several ways via hydrogen bonding (HB) leading to changes in the activities of the combined drug and IBP horizontal ellipsis FPV is predicted to be orally bioavailable. It was also found that the highest occupied molecular orbital (HOMO) is located on IBP and the lowest unoccupied molecular orbital (LUMO) is distributed over FPV. The biological activity of the combined drug system is increased because of the small HOMO-LUMO energy gap value, partially covalent and non-covalent HB interactions. Communicated by Ramaswamy H. Sarma

Emvododstat was identified as a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of acute myeloid leukaemia and COVID-19. The objective of this paper is to evaluate the metabolism, pharmacokinetics, and drug interaction potentials of emvododstat.Emvododstat showed high binding to plasma protein with minimal distribution into blood cells in mouse, rat, dog, monkey, and human whole blood.O-Demethylation followed by glucuronidation appeared to be the major metabolic pathway in rat, dog, monkey, and human hepatocytes. CYP2C8, 2C19, 2D6, and 3A4 were involved in O-desmethyl emvododstat metabolite formation. Both emvododstat and O-desmethyl emvododstat inhibited CYP2D6 activity and induced CYP expression to different extents in vitro.Emvododstat and O-desmethyl emvododstat inhibited BCRP transporter activity but did not inhibit bile salt transporters and other efflux or uptake transporters. Neither emvododstat nor O-desmethyl emvododstat was a substrate for common efflux or uptake transporters investigated.Emvododstat is bioavailable in mice, rats, dogs, and monkeys following a single oral dose. The absorption was generally slow with the mean plasma T(max) ranging from 2 to 5 h;plasma exposure of O-desmethyl emvododstat was lower in rodents, but relatively higher in dogs and monkeys.

Stevens-Johnson syndrome (SJS) is a delayed hypersensitivity reaction, lasting approximately two to four weeks. It is a rare disease, with an incidence of 1 to 6 cases per million inhabitants. Despite the low prevalence, it manifests itself as a result of drug interactions resulting from practices that are not so rare as polypharmacy and the use of medications without a professional prescription. The methodology of the present study is based on Scoping Review of virtual search platforms. It is expected, at the end of the work, to have an updated compilation of information, in order to contribute to the dissemination of the state of the art on the subject, since the occurrence of SSJ is directly associated with the knowledge that the community has about it.

Objective Several studies have demonstrated that anti-angiogenic agents (AAs) have the ability to regulate immune-related cells in the tumor microenvironment and may affect the clinical effect of immune checkpoint inhibitors (ICIs). Therefore, we investigated the drug interaction between ICI and AA for advanced non-small cell lung cancer (NSCLC). Materials and methods We systematically searched PubMed-MEDLINE, Embase-Scopus, and ISI Web of Science before August 23, 2021. ICI and AA therapy included the concomitant and sequential use of ICIs and AAs. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of patients who received ICI and AA therapy were evaluated and compared to those of patients who received either monotherapy. Subgroup analyses were performed to clarify the cause of heterogeneity; the timing and sequence of ICI and AA administration were predefined as the subgroups. Results Thirteen studies involving 2414 patients were included in the meta-analysis. ICI and AA therapy had significantly higher ORR than either monotherapy (OR [95% CI]: 0.61 [0.50–0.74]; p Conclusion ICI and AA therapy can provide favorable clinical effects compared to either monotherapy; however, ICI administered immediately after AA may not show survival benefits.

Background: Having various limitations in conventional drug delivery system, it is important to focus on the target-specific drug delivery system where we can deliver the drug without any degradation. Among various challenges that are thrown to a formulation scientist, delivering the drug to its right site, in its right dose, is also an important aim. A focused drug transport aims to extend, localize, target and have a safe drug interaction with the diseased tissue. Objective: The aim of targeted drug delivery is to make the required amount of the drug available at its desired site of action. Drug targeting can be accomplished in a number of ways that include enzyme mediation, pH-dependent release, use of special vehicles, receptor targeting, among other mechanisms. Intelligently designed targeted drug delivery systems also offer the advantages of a low dose of the drug along with reduced side effects which ultimately improves patient compliance. Incidences of dose dumping and dosage form failure are negligible. A focused drug transport aims to have a safe drug interaction with the diseased tissue. Conclusion: This review focuses on the available targeting techniques from experiment to perfection for delivery to the colon, brain, and other sites of interest. Overall, the article should make an excellent read for the researchers in this area. Newer drug targets may be identified and exploited for successful drug targeting.

Interest in antibiotic combination therapy is increasing due to antimicrobial resistance and a slowing antibiotic pipeline. However, aside from specific indications, combination therapy in the clinic is often not administered systematically; instead, it is used at the physician’s discretion as a bet-hedging mechanism to increase the chances of appropriately targeting a pathogen(s) with an unknown antibiotic resistance profile. Some recent clinical trials have been unable to demonstrate superior efficacy of combination therapy over monotherapy. Other trials have shown a benefit of combination therapy in defined circumstances consistent with recent studies indicating that factors including species, strain, resistance profile, and microenvironment affect drug combination efficacy and drug interactions. In this review, we discuss how a careful study design that takes these factors into account, along with the different drug interaction and potency metrics for assessing combination performance, may provide the necessary insight to understand the best clinical use-cases for combination therapy.

Background Zeaxanthin is a carotenoid pigment found in several fruits and vegetables. Belonging to the xanthophyll family, it is widely present in human and some animals skin and eyes, performing important physiological functions due to its antioxidant and anti-inflammatory effects. Several studies have explored its health benefits against important disorders such as neurological diseases, allergies, and cancer. Scope and approach The aim of this study we to explore the sources, health benefits, and biological properties of zeaxanthin and analyzes its drug interaction with β-carotene. Key findings and conclusion Severela vegetable sources in particularly fruits parts contains zeaxanthin. Biological investigations showed that zeaxanthin has been found to exhibit a protective effect against excessive light and oxidative stress side effects, preventing the development of several neurological, skin, and eye disorders. It exhibits also antioxidant, antiparasitic, anthelmintic activity, and antiosteoporosis effects. Zeaxanthin can also play a role in the inflammatory response, contributing to the treatment or prevention of diseases like allergies and AIDS. Additionally, zeaxanthin can exhibit anticancer, anti-osteoporotic, and ophthalmologic effects. These different properties are mediated by diffetent cellular and molecular mechanisms exhibited by zeaxanthin such as its activation and/or blocker of cell receptors, its actions on signaling pathways, and also its effects on gene expression. Moreover, the safety as a dietary supplement has also been confirmed and its interaction with other carotenoids, such as β-carotene, has been studied and validated in pharmacokinetic investigations. However, further investigations are needed to explore the full potential of zeaxanthin and to elucidate more its molecular pharmacodynamic actions behind its effects on human health, and to investigate also its clinical applications.

Background The Interaction between anti-tuberculous and immunosuppressive drugs which may increase the risk of graft rejections is a major challenge in managing transplant recipients with tuberculosis (TB). Instead of rifampicin (RFM), most guidelines recommended the use of rifabutin (RFB) because of its reduced capacity to induce immunosuppressant metabolism while maintaining the same efficacy as RFM against TB. However, there has been no available data directly comparing the outcome of RFB from RFM-based anti-TB regimens in liver transplant patients with TB. This study aimed to compare the effects of RFB from RFM-based treatment in terms of the drug interaction with immunosuppressants, as well as the safety, efficacy and clinical outcomes of living donor liver transplant (LDLT) recipients with active TB. Patients and methods A retrospective study was conducted on all adult LDLT recipients diagnosed with active TB from June 1994 to May 2016 that had concurrently and continuously received either RFB or RFM-based treatment and immunosuppressants. Results Twenty-two patients were included. Twelve (55%) patients were in the RFM group. Ten (45%) patients were in the RFB group. RFB group showed a lesser rate of immunosuppressant trough level reduction (20% vs 50%, p = 0.009) during TB treatment. There was no TB recurrence and no significant change in platelet or leukocyte count in either group. Acute cellular rejection (ACR), rate of TB-treatment completion and overall survival, rates were excellent and statistically similar in both groups. Conclusion The use of RFB in LDLT recipients with active TB, had a lesser drug interaction than when RFM was used. However, RFB did not significantly reduced the rate of ACR. RFB and RFM are both effective and safe to use in LDLT recipients with active TB.

Background: AT1R (Angiotensin II type 1 receptor) is the main component of RAS (renin-angiotensin system) system which activates when ANG II (angiotensin II) binds to it. AT1R helps in maintaining osmotic homeostasis and blood pressure regulation. A huge number of polymorphism is associated with AT1R and few of them were studied and found to be associated with the diseases and drug efficacy. Although it is very important receptor but most of the polymorphisms (SNPs) were not studied for their implications in diseases. Huge number of polymorphisms is reported in the databases for AT1R which provide an avenue to explore these polymorphisms for their implications in protein structure, function and drug efficacy. Methods: In the current study all the SNPs (10234) reported in NCBI were analyzed and SNPs which were important in protein structure and drug interactions were identified. Structures of these polymorphic forms were modeled and in silico drug interaction studies were carried out. Results: Result of the interaction studies with polymorphism was in correlation with the reported case. Two SNP mutated structures of AT1R i.e. rs780860717 (G288T), rs868647200 (A182C) shows considerably less binding affinities in case of all angiotensin receptor blockers (ARBs). As a result these polymorphisms may show less efficacy toward these ARBs. The other mutated structures rs12721226 (A163G), rs749234826 (A292G), rs775810028 (A87G) shows increased binding affinities in case of Eprosartan and most of the mutated structures shows increased binding affinity toward Telmisartan than the wild type AT1R. Similarly, these polymorphisms may show increased efficacy in case of these two ARBs. Conclusion: The outcome of the study will help in designing better drugs in near future with broader spectrum. Furthermore in vitro and in vivo studies can be designed according to current results.

Triple whammy (TW) is a potentially dangerous drug combination that can lead to acute kidney injury (AKI). This drug interaction (DI) occurs when angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are used together with diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). One of the most serious consequences of TW DI is an increased risk of developing pre-renal acute kidney injury (pr-AKI). The term TW, in the context of a DI affecting kidney function, is not very widespread. The aim of this article was to gather information on this interaction. Previous knowledge on the mechanism of TW and how to increase patient awareness of this interaction is described. In addition, the specific nature of the acute kidney injury (AKI) caused by triple whammy (AKITW) is presented. On the basis of the current state of knowledge, recommendations on how to manage the TW DI are also demonstrated.

Introduction Chronic hand eczema (CHE) is a frequent skin disorder affecting up to 10% of the population and strongly reduces Quality of Life (QoL). The first-line therapeutic strategies for the management of CHE include a change of lifestyle, an education program for the skin and the application of specific emollients. Topical corticosteroids or calcineurin inhibitors are the most used anti-inflammatory drugs. However, up to 65% of patients require systemic options. Alitretinoin, a retinoid structurally related to vitamin A, is the first systemic treatment approved in the European Union (EU) for severe CHE refractory to potent topical corticosteroids. Areas covered This review summarizes the available data on the pharmacokinetics, pharmacodynamics, efficacy, and safety profile of oral alitretinoin for the treatment of CHE. Expert opinion Alitretinoin can be considered as a valid therapeutic option for the treatment of CHE in patients not responding to ordinary treatments. Clinical trials and real-life experiences showed that it acts effectively on both objective and subjective clinical signs, resulting in a significant improvement in QoL of patients. As for other retinoids, caution should be taken in patients with certain chronic diseases (hepatopathies, kidney failure, hyperlipidemia, thyroid dysfunction) or childbearing potential women.

What is known and objective Long-acting injectable (LAI) antipsychotics are an integral part of mental health treatment. Modifying an LAI regimen poses several challenges because of the extended half-life of the drug. Case summary An acutely psychotic patient with schizoaffective disorder received aripiprazole lauroxil without resolution of symptoms. She was started on a previously successful regimen of oral fluphenazine. Due to continued psychosis, oral carbamazepine was initiated to expedite the LAI's metabolism allowing subsequent doses of fluphenazine to impart activity. What is new and conclusion Potent cytochrome enzyme inducers may help in transitioning patients from LAI antipsychotics to other therapies.

Background: Linagliptin is prescribed as a dipeptidyl peptidase-4 (DPP-4) inhibitor. Azithromycin is specified as an antibiotic that binds with 23s rRNA of the 50s ribosomal subunit, obstructing the microbial protein synthesis. Our study focuses on the drug-drug interactions of these drugs. Objective: The purpose of the study is to understand the bioavailability and physicochemical approaches of Linagliptin and Azithromycin interaction mediated through the strength and nature of the complexation. Methods: The in vitro assessment of drug interaction was conducted using Ultraviolet-visible spectroscopy (UV/VIS), Ultra-Performance Liquid Chromatography (UPLC), Fourier transform infrared spectroscopy (FT-IR), and Differential scanning calorimetry (DSC), while the Oral Glucose Tolerance Test (OGTT) was performed for the in vivo assessment of drug interaction in a mouse model. Results: Mild variation in interaction was observed at different pH values at a specific temperature by Job's and Ardon's equations. In UPLC, the drug mixture assessment showed that the area of Linagliptin was 2013793, and the area of Azithromycin was 54631 in 50 mg/l. The height of Linagliptin in the drug mixture was 579234, and that of Azithromycin was 11442. For Azithromycin, the wavelength of 731.02 cm-1, 993.34 cm-1, 1379.10 cm-1, and 1718.58 cm-1 decreased in the mixture. Also, for Linagliptin, the wavelength 1363.67 cm-1, 1473.62 cm-1, and 1718.58 cm-1 decreased in the drug mixture. The melting endotherm was 125.55°C, melting normalized energy was -3.0 W/mg, and 225.75°C with melting normalized energy of -5.5 W/mg of the drug mixture as indicated by DSC. In the OGTT test, the blood glucose level of Linagliptin decreased in the drug mixture by 13.58 % and 57.25%. Conclusion: Hence, the concomitant administration of Linagliptin and Azithromycin simultaneously might reduce the therapeutic effect of the drug complex.

Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP‐drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies’ guidance documents about drug‐drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions.

Introduction: Multi-pathological patients are at high risk of drug interactions and side effects. We aimed to assess the usefulness of 3 online drug interaction checkers. Methods: In a cross-sectional study, carried out in the Medicine Department of Hospital General of Castellon, Spain, in February 2020, we assessed drug interaction detection with 3 online electronic checkers, Drugs.com, Lexicomp®, and Medscape, and compared results obtained with the 3 tools. From every hospitalized patient, we obtained the list of drugs he or she had been taking until admission. Bivariable tests were used for analysis. p values Results: We included data from 134 patients; 68 (51%) were male; median (and interquartile range) of their age was 82 (76–88) years. A total of 1,082 substance drugs were entered in the checkers. The number of highest grade interactions found with every program was Drugs.com 85, Lexicomp® 33, and Medscape 67. Positive correlations were found between age and number of drug substances prescribed (p = 0.009) and between number of drug substances prescribed and interactions found with any of the 3 checkers (p < 0.001 in all 3 cases). Regarding highest grade interactions, agreement among all 3 checkers was poor. Conclusions: The 3 online checkers we assessed found a large number of interactions. The 3 programs gave very discrepant results. Impact on Practice Statements: The analyzed programs, Drugs.com, Lexicomp®, and Medscape Interactions, found a large number of drug interactions in the studied patients. The 3 programs gave very discrepant results among them.

Islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor, is in clinical development for the treatment and prevention of HIV-1 infection. Because islatravir may be coadministered with other antiretroviral agents, assessment of potential drug-drug interactions are warranted. This phase 1, open-label, fixed-sequence, 2-period trial in adults without HIV (N = 12) assessed the safety and pharmacokinetic interactions of islatravir administered with dolutegravir and tenofovir disoproxil fumarate (TDF). In period 1, participants received a single oral dose of islatravir (20 mg). In period 2, participants received oral doses of dolutegravir (50 mg) and TDF (300 mg) once daily on days 1 through 11, with a single oral dose of islatravir (20 mg) coadministered on day 8. There were no clinically significant changes in islatravir, dolutegravir, or TDF pharmacokinetics following coadministration. Islatravir was generally well tolerated when administered alone or in combination with dolutegravir and TDF. Coadministration of islatravir, dolutegravir, and TDF is supported, with no clinically meaningful effect on pharmacokinetics, safety, or tolerability in participants without HIV.

Objective: This study was conducted to develop a sensitive and effective LC-MS/MS method for the determination of bencycloquidium bromide (BCQB) and its application in pharmacokinetic drug interaction study between BCQB and paroxetine. Methods: The chromatographic separation was performed on Hedera ODS-2 C18 column with a mobile phase consisted of acetonitrile-10 mmol/l ammonium acetate containing 0.2% acetic acid (33:67, v/v) at 550 μl/min, and the plasma samples were processed using solid-phase extraction. The MS/MS transitions were m/z 330.2 → 142.0 for BCQB and m/z 344.2 → 156.1 for the I. S in positive ESI mode. Results: The validated method was linear over the concentration range of 2-1200 pg/ml with the correlation coefficient r2>0.998. The intra-and inter-batch precisions of the assay were lower than 8.2% and 9.1%, respectively. The lower limit of quantification (LLOQ) was 2 pg/ml. The stability data at different storage conditions of BCQB were within±5% RE. The mean AUC0-36 of BCQB was increased by approximately 33%, after the administration of BCQB alone and upon co-administration with paroxetine during the drug interaction study. Conclusion: The LC-MS/MS method validated in this study was robust, reproducible, accurate, precise and reliable and was successfully applied in the pharmacokinetic drug interaction studies.

Psychiatric signs and symptoms occur frequently in individuals with central nervous system diseases. Inadequately treated, these comorbid conditions affect patient rehabilitation, compliance with treatment and quality of life. Their management poses a major challenge given the variable efficacy and safety profiles of available psychotropic drugs and increased risk of drug interaction. This review aims to summarize the existing literature on the prescription of psychotropic drugs for management of psychiatric disorders among persons with central nervous system's diseases.

Висока захворюваність і смертність від серцево-судинних захворювань призвели до необхідності широкого використання антитромбоцитарних засобів у клінічній практиці. Найбільш перспективною вважається комбінована антиагрегантна терапія з використанням препаратів, що мають різні механізми впливу на тромбоцитарну ланку гемостазу, за рахунок чого можна досягти вираженого синергічного ефекту. У нашій країні переважно призначається комбінація ацетилсаліцилової кислоти і клопідогрелю, яку часто називають подвійною антитромбоцитарною терапією (ПАТ). Для зменшення ризиків розвитку шлунково-кишкових ускладнень при використанні ПАТ рекомендований прийом інгібіторів протонної помпи (ІПП), проте в деяких дослідженнях згадується, що одночасне призначення ІПП та клопідогрелю в перспективі підвищує ризик виникнення несприятливих серцево-судинних подій, до яких відносять інфаркт міо-карда, інсульт, нестабільну стенокардію, необхідність повторних коронарних втручань і коронарну смерть. У зв’язку з цим представляється актуальною проблема розробки підходів диференційованого застосування ІПП у пацієнтів, які отримують ПАТ. Надано огляд літератури з означеної вище проблематики, наведено результати досліджень із вивчення впливу різних ІПП на клінічні наслідки у хворих, які приймають клопі-догрель.

Objective:Comprehensive and supportive therapies of sepsis and septic shock (SSS) cause polypharmacy and increase the risk of drug interactions. This study aimed to evaluate the rate of polypharmacy, potential drug interactions, and clinical pharmacists’ interventions on drug interactions in patients with SSS.Materials and Methods:This prospective, cross-sectional study was conducted in the intensive care unit of a university hospital. Drug interactions and clinical pharmacist’s interventions on these interactions were evaluated in patients with SSS.Results:The mean number of drugs received by 65 patients (67.7% male) was 8.69±2.12, and 161 drug interactions were recorded. After the assessment of these drug interactions according to their clinical significance, interventions were made in 19 (11.8%) patients. Of these drugs, 78.9% were related to antimicrobials (especially clarithromycin, 31.6%). All interventions were accepted and fully implemented by physicians. The number of drug interactions increased with the increasing frequency of drug use (r=0.475; p

Drug interaction in critically ill patient is very common and affecting patients Physically, Mentally and Financially. There are various measures which has been taken to minimize this burden on patient, such as books being prepared which include various drug interaction, maintain websites and database that provides information regarding drug interactions. With the use of these website and databases the drug interaction can be managed. It is common practice that side effects of drug interaction are being managed by additional drugs, the main reason behind it could be non-availability of alternative drugs or costlier alternative. These factors remain the main cause of treatment failure in majority of patients leading to prolong. The current study was performed for the duration of 12 months, from this study it was identified that 113 types of major drug interactions commonly found in total 250 prescriptions which were evaluated and managed accordingly. Suggestions being prescribed by various sites were, avoid concomitant use of drug, use alternative therapy, and monitor closely for any adverse effect. During suggestion made by the Clinical Pharmacist, for the same drug interactions it was identified that more of drug therapy adjustment can be done then provided by the online database. The parameter on which the drug interactions management are being suggested were focused on just type of drug interaction and its effect, it does not include the actual pharmacodynamic and pharmacokinetic changes in therapy. The suggestion made by the clinical pharmacist were includes drug removal, drug dosage changes, alternative therapy, alternative route of administration, change in time interval etc. From this study it was concluded that the drug interaction management can be done at various stages of treatment with proper therapy modification by the clinical pharmacist, and if done properly it will improve the overall outcome of patient health care.

Aripiprazole, an atypical antipsychotic, is a metabolic substrate for cytochrome P450 (CYP)3A4 and 2D6. Terbinafine, an antifungal agent used for onychomycosis, is a CYP2D6 inhibitor and could theoretically reduce the metabolism of aripiprazole. However, there are no published reports describing this interaction. We present 2 female patients hospitalized in a psychiatric unit who were both taking aripiprazole 15 mg daily and terbinafine 250 mg daily prior to admission. The first patient was a 58-year-old female who was prescribed aripiprazole and terbinafine concomitantly for approximately 5 months prior to admission. A commercial pharmacogenetic testing platform classified this patient as a normal metabolizer for CYP3A4 and 2D6. The first patient's serum trough aripiprazole concentration at steady-state concentration (Css) was 207.5 ng/mL. The second patient was a 43-year-old female who was taking aripiprazole and terbinafine concomitantly for approximately 2 weeks prior to admission who had a Css aripiprazole concentration of 278.9 ng/mL. Aripiprazole has a wide therapeutic range (100 to 350 ng/mL) and a reference dose-related drug concentration of 11.7 (mean) ± 5.6 (SD) ng/mL/mg/d. Our patients had Css aripiprazole concentrations 18% and 59% higher than guideline-supported dose-related drug concentrations. Through the use of therapeutic drug monitoring, pharmacogenetic data, electronic pharmaceutical claims data, and the Drug Interaction Probability Scale, we suggest terbinafine possibly increases aripiprazole concentrations 18% to 59%. Further reports are needed to confirm these findings prior to using this information in clinical practice.

INTRODUCTION Catha edulis (Vahl) Forssk. ex Endl. (Celestraceae) is used as a recreational drug on daily basis for its euphoric and psychostimulant effects. It is also chewed by individuals who are on medications, raising the possibility of drug-khat interaction. However, limited data are available in the literature, although clinically significant interactions are expected, as khat contains a complex mixture of pharmacologically active constituents. AREAS COVERED It provides an overview of the phytochemistry, pharmacokinetics, pharmacodynamics, and pharmacogenetics of khat based on the literature mined from PubMed, Google Scholar, and Cochrane databases. It also presents a detailed account of drug-khat interactions with specific examples and their clinical significance. The interactions mainly occur at the pharmacokinetics level and particular attention is paid for the phases of absorption and cytochrome P450 enzyme-mediated metabolism. EXPERT OPINION Despite the increasing trend of khat chewing with medications among the populace and the potential risk for the occurrence of clinically significant interactions, there is paucity of data in the literature demonstrating the magnitude of the risk. The available data, however, clearly demonstrate that the consequence of drug-khat interaction is dependent on genotype. Genotyping, where feasible, could be used to improve clinical outcome and minimize adverse reactions.

Aims Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose–response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. Methods and results Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1–3 clinical studies. Dose–response models were developed for bempedoic acid monotherapy and bempedoic acid–statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose–response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. Conclusion These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.

Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID‐19) treatment in a large‐scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients’ drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub‐payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug‐induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two‐to‐seven points, p

Introduction Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy. Areas covered The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism. Expert opinion Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.

Background: A theoretical interaction exists between human immunodeficiency virus (HIV) antiretroviral (ARV) agents and direct oral anticoagulants (DOACs), although the clinical significance is unclear. Objective: This study aimed to assess characteristics, prescribing patterns, and outcomes associated with concomitant therapy. Methods: A single-center, retrospective review was performed on patients older than 18 years prescribed a DOAC for any indication with concurrent interacting ARV(s) from June 2016 through June 2019. The primary endpoint was to assess prescribing and population characteristics. Secondary endpoints were to evaluate safety outcomes, DOAC level monitoring, readmissions, outpatient follow-up, and DOAC modification interventions. Results: Thirty-six patients (72 hospital admissions) were identified. The most common DOAC was apixaban (83.3%) and ARV was ritonavir (50%). Of the 72 encounters, 26 (36.1%) DOACs were dosed appropriately per guideline recommendations. Twenty pharmacy interventions for therapy modification were recognized. Eleven (30.6%) patients experienced bleeding and 2 (5.6%) thrombosis. Of the adverse events, all patients had renal impairment. Conclusions: As DOAC utilization grows, increasing use in HIV could be expected. More frequent adjustment or avoidance is recommended per guidelines. Our data suggest the majority of patients receive CYP3A4-inhibiting regimens. Caution should be employed with renal insufficiencies. Further studies are warranted to assess safety and efficacy within this population.

Bovis Calculus Artifactus (BCA) is the main substitute for natural Calculus bovis, a traditional drug in China used to treat high fever, convulsion, and sore throat. The effect of BCA on cytochrome P450 (CYP) activities is unknown. This study was to investigate the effect of BCA on eight rat hepatic microsomal CYPisozymes to evaluate the potential drug interactions using the cocktail approach.Metabolites of the eight isoform probe substrates of CYP isozymes were quantified by LC-MS/MS. The method was validated by incubating known CYP inhibitors α-naphthoflavone (CYP1A2), thiotepa (CYP2B1), quercetin (CYP2C7), sulfaphenazole (CYP2C6), ticlopidine (CYP2C11), quinidine (CYP2D1), ketoconazole (CYP3A1),4-methylpyrazole (CYP2E1) with individual probe substrate and rat liver microsomes. The formation rates of the corresponding metabolites of the eight probe substrates were determined to evaluate the activity of each isozyme.The results showed that BCA has different degrees of inhibitory effect on four CYP450 isoforms (CYP2C6, CYP2C11, CYP2D1, CYP3A1) (p p > 0.05). Attention should be paid to the BCA-drug interactions by careful monitoring and appropriate dosage adjustments in the concurrent use of the drugs which are metabolized by CYP1A2, CYP2C19, and CYP3A4. Abbreviations: BCA, bovis calculus artifactus; CYP, cytochrome P450; DDIs, drug-drug interactions; ESI, electrospray ionization; MRM, multiple reaction monitoring; NBC, Natural Bovis Calculus; QC, quality control; T CM, traditional Chinese medicine. Bovis Calculus Artifactus (BCA) is the main substitute for natural Calculus bovis, a traditional drug in China used to treat high fever, convulsion, and sore throat. The effect of BCA on cytochrome P450 (CYP) activities is unknown. This study was to investigate the effect of BCA on eight rat hepatic microsomal CYPisozymes to evaluate the potential drug interactions using the cocktail approach. Metabolites of the eight isoform probe substrates of CYP isozymes were quantified by LC-MS/MS. The method was validated by incubating known CYP inhibitors α-naphthoflavone (CYP1A2), thiotepa (CYP2B1), quercetin (CYP2C7), sulfaphenazole (CYP2C6), ticlopidine (CYP2C11), quinidine (CYP2D1), ketoconazole (CYP3A1),4-methylpyrazole (CYP2E1) with individual probe substrate and rat liver microsomes. The formation rates of the corresponding metabolites of the eight probe substrates were determined to evaluate the activity of each isozyme. The results showed that BCA has different degrees of inhibitory effect on four CYP450 isoforms (CYP2C6, CYP2C11, CYP2D1, CYP3A1) (p p > 0.05). Attention should be paid to the BCA-drug interactions by careful monitoring and appropriate dosage adjustments in the concurrent use of the drugs which are metabolized by CYP1A2, CYP2C19, and CYP3A4. Abbreviations: BCA, bovis calculus artifactus; CYP, cytochrome P450; DDIs, drug-drug interactions; ESI, electrospray ionization; MRM, multiple reaction monitoring; NBC, Natural Bovis Calculus; QC, quality control; T CM, traditional Chinese medicine.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are increasingly used for advanced non-small cell lung cancer (NSCLC) as first-line therapy. The bioavailability and efficacy of oral EGFR-TKIs could be affected by acid suppression (AS) therapy such as PPIs and H2RAs which are reported to be over-prescribed. Hence, there is a need to investigate the effect of AS on the overall survival (OS), progression-free survival (PFS) and adverse effect profile in patients treated with EGFR TKIs. METHODS: An electronic database search of Medline and Embase was performed following PRISMA guidelines on 17 January 2021. Studies analyzing interactions between EGFR TKIs and PPIs/H2RAs in NSCLC patients were included. Abstracts, non-English or non-Japanese studies or studies using non-EGFR TKIs were excluded. Hazard ratios (HRs) were pooled using generic inverse variance random effects model. Effect sizes for dichotomous variables were pooled using Mantel-Haenszel random effects model. Significance was considered at P≤0.05. Heterogeneity was assessed with Cochran Q-test and I2 test. Publication bias was assessed with funnel plots. The assessment of quality and risk of bias of randomized and non-randomized studies were undertaken with RoB 2 and the ROBINS-I tool respectively. RESULTS: Out of 1,173 potentially relevant articles, 14 articles were included in the final analysis. The pooled prevalence of AS in patients taking EGFR TKI was 30.71% in 4,010 individuals. Patients who were treated only with EGFR TKI had significantly better OS (HR =1.46, 95% CI: 1.27–1.72; P

Purpose Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. Methods We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). Results Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8–8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30–90 min and were 2–3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration. Conclusion Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose.

Introduction: Hypertensive disease can cause various complications, such as cardiovascular disease, stroke, diabetes mellitus, and kidney failure. To overcome these complications, patients are given polypharmacy therapy, which can potentially lead to drug interactions. Aim: The purpose of this study was to determine the potential incidence of drug interactions in hypertensive inpatients at the Persahabatan Hospital in 2015. Methods: The research is a descriptive study with retrospective data by purposive sampling technique using secondary data, medical records of hypertensive inpatients. The study of drug interactions was conducted theoretically, based on a literature study using Drug Interaction Facts 2014. Results: The results showed out of 174 hypertensive patients, 141 (81.0%) had potential drug interactions, with a total of 1444 cases. The highest drug interactions were at three levels of significance in 383 cases (26.5%), with 554 cases (38.4%) of pharmacodynamic mechanisms.

Almonertinib is a novel third-generation EGFR tyrosine kinase inhibitor. It is mainly metabolized by CYP3A in vitro, and N-desmethylated almonertinib (HAS-719) is the major active metabolite in human plasma. In this study, we investigated the effects of CYP3A inhibitor itraconazole and CYP3A inducer rifampicin on the pharmacokinetics of almonertinib and HAS-719 in 64 healthy volunteers. We found that when co-administered with itraconazole, the maximal plasma concentration (C(max)) and the plasma exposure (AUC(0–t)) of almonertinib were increased by 56.3% and 2.38-fold, respectively, whereas the C(max) and AUC(0–t) of HAS-719 were reduced by 86.8% and 71.8%, respectively. Co-administration with rifampicin reduced the C(max) and AUC(0–t) of almonertinib by 79.3% and 92.6%, but the AUC(0–t) of HAS-719 was unexpectedly decreased by 72.5%. In vitro assays showed that both almonertinib and HAS-719 were substrates of CYP3A and P-gp. Co-administration of rifampicin in Beagle dogs reduced the fecal recovery of almonertinib and HAS-719, and markedly increased the levels of metabolites derived from further metabolism of HAS-719, which was consistent with human plasma data, suggesting that although rifampicin was also a potent inducer of P-gp, the pharmacokinetic alternation of HAS-719 was mainly due to its further metabolism but not excretion changes. Moreover, we revealed that almonertinib was a moderately sensitive substrate of CYP3A in vivo. Special attention should be paid to the interaction between almonertinib and drugs or food affecting CYP3A activity in the clinical application of almonertinib.

Cytochrome P450 2C8 (CYP2C8) is a major drug-metabolizing enzyme in humans and is responsible for the metabolism of ∼5% drugs in clinical use. Thus, inhibition of CYP2C8, which causes potential adverse drug events, cannot be neglected. The in vitro drug interaction studies guidelines for industry issued by the FDA also point out that it needs to be determined whether investigated drugs are CYP2C8 inhibitors before clinical trials. However, current studies mainly focus on predicting the inhibitors of other major P450 enzymes, and the importance of CYP2C8 inhibition has been overlooked. Therefore, there is a need to develop models for identifying potential CYP2C8 inhibition. In this study, in silico classification models for predicting CYP2C8 inhibition were built by five machine-learning methods combined with nine molecular fingerprints. The performance of the models built was evaluated by test and external validation sets. The best model had AUC values of 0.85 and 0.90 for the test and external validation sets, respectively. The applicability domain was analyzed based on the molecular similarity and exhibited an impact on the improvement of prediction accuracy. Furthermore, several representative privileged substructures such as 1H-benzo[d]imidazole, 1-phenyl-1H-pyrazole, and quinoline were identified by information gain and substructure frequency analysis. Overall, our results would be helpful for the prediction of CYP2C8 inhibition.

Introduction Calcineurin inhibitors are commonly used in hematopoietic stem cell transplant (HSCT) patients to prevent graft versus host disease, but as CYP3A4 substrates they are frequently involved in drug-drug interactions. The purpose of this study is to characterize the effects of isavuconazole, fluconazole, and posaconazole on tacrolimus and cyclosporine serum concentrations and dose adjustments in allogeneic HSCT patients. Methods This retrospective study included patients admitted to Oregon Health and Science University between April 2008 and December 2018 who underwent hematopoietic stem cell transplantation and received concomitant tacrolimus or cyclosporine and fluconazole, isavuconazole or posaconazole therapy. Data on patient characteristics, drug dosing, and serum drug concentrations were collected through chart review, and descriptive statistics were used to summarize the results. Results A total of 139 patients were included in this study. We found fluconazole initiation leads to a 25% reduction in both tacrolimus and cyclosporine doses in order to maintain goal serum concentrations. Posaconazole and isavuconazole initiation requires tacrolimus dose reductions by 53% and 21%, respectively. Conclusions Based on our experience, FLC, POS, and ISA initiation may require CNI dose reductions and close monitoring of CNI levels to ensure levels remain within goal serum concentrations. Larger studies are needed to fully quantify the percentage in CNI dose reductions and characterize differences among these antifungals.

Hee Ji Shin,1,&ast; Min Jeong Jo,1,&ast; Ik Sup Jin,1 Chun-Woong Park,1 Jin-Seok Kim,2 Dae Hwan Shin1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women’s University, Seoul, 04310, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Dae Hwan ShinCollege of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, 28160, Republic of KoreaTel +82 43 261 2820Fax +82 43 268 2732Email dshin@chungbuk.ac.krPurpose: We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles.Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles.Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration–time curve from 0 to 2 h (AUC0– 2 h) and 0 to 8 h (AUC0– 8 h) and plasma concentration at time zero (Co) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEG-b-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution.Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEG-b-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.Keywords: combination therapy, drug interaction, cytotoxicity, biodistribution, bioavailability

The aim of this study was to determine pharmacokinetics of α-amanitin, a toxic bicyclic octapeptide isolated from the poisonous mushrooms, following intravenous (iv) or oral (po) administration in mice using a newly developed and validated liquid chromatography-high resolution mass spectrometry. The iv injected α-amanitin disappeared rapidly from the plasma with high a clearance rate (26.9-30.4 ml/min/kg) at 0.1, 0.2, or 0.4 mg/kg doses, which was consistent with a rapid and a major excretion of α-amanitin via the renal route (32.6%). After the po administration of α-amanitin at doses of 2, 5, or 10 mg/kg to mice, the absolute bioavailability of α-amanitin was 3.5-4.8%. Due to this low bioavailability, 72.5% of the po administered α-amanitin was recovered from the feces. When α-amanitin is administered po, the tissue to plasma area under the curve ratio was higher in stomach > large intestine > small intestine > lung ~ kidneys > liver but not detected in brain, heart, and spleen. The high distribution of α-amanitin to intestine, kidneys, and liver is in agreement with the previously reported major intoxicated organs following acute α-amanitin exposure. In addition, α-amanitin weakly or negligibly inhibited cytochrome P450 and 5'-diphospho-glucuronosyltransferase enzymes activity in human liver microsomes as well as major drug transport functions in mammalian cells overexpressing transporters. Data suggested remote drug interaction potential may be associated with α-amanitin exposure.

Combined oral contraception and treatment of new coronavirus infection (COVID-19): issues of drug interaction This article examines the interaction of combined oral contraceptives with drugs recommended in the treatment of new coronavirus infection (COVID-19) at the pharmacodynamic and pharmacokinetic levels, with an assessment of the effectiveness and safety of therapy for the female body.

Background and Objectives Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. Methods Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. Results Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC0–24h), maximum plasma concentration (Cmax), and plasma concentration at 24 h post-dose (C24h) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC0–24h and Cmax were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. Conclusion These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-021-01046-1.

Objective To evaluate the literature on a potential dexamethasone–direct oral anticoagulant (DOAC) drug interaction and provide management considerations with COVID hypercoagulability. Data Sources A search of EMBASE, PubMed, and Google Scholar (January 1990 to May 2021), limited to the English language, using applicable search terms resulted in 137 articles, with 21 relevant articles included. Regulatory agency and clinical guidance documents were also reviewed. Study Selection and Data Extraction Included articles describe in vitro or in vivo animal or human data for dexamethasone induction of cytochrome P450 (CYP) 3A4 or P-glycoprotein (P-gp). Data Synthesis Dexamethasone has the potential to interact with the DOACs via CYP3A4 and/or P-gp induction. Only apixaban and rivaroxaban have CYP3A4 metabolism. Dexamethasone can increase CYP3A4 activity by up to 70% and reduce the area under the concentration-time curve (AUC) of CYP3A4 substrates by >40%, which is consistent with criteria for a weak CYP inducer. In rodents, dexamethasone P-gp induction is associated with AUC reductions of 20% to 50%. Human data are lacking. Relevance to Patient Care and Clinical Practice Severe COVID-19 infection is associated with hypercoagulability. Although heparins are the preferred anticoagulants for hospitalized COVID-19 patients, DOACs are being utilized. Dexamethasone is recommended for hospitalized COVID-19 patients requiring supplemental oxygen. The concurrent use of dexamethasone and apixaban or rivaroxaban in such patients carries the potential for reduced anticoagulant effect during a state of heightened thrombotic risk. Conclusions Concurrent use of dexamethasone and apixaban or rivaroxaban in hospitalized COVID-19 patients with laboratory evidence of COVID coagulopathy should be avoided until higher-quality data are available.

Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO2). The current study used that model to assess the impact on respiration of non‐benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO2 above the oxycodone effect. Analyses indicated that most pCO2 interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO2 recorded with oxycodone‐paroxetine co‐administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug‐drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co‐administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.

Spastic reactions of smooth muscles of visceral organs play an important role in the pathogenesis of many diseases, the main drugs for relief of which are antispasmodic drugs. The article describes in detail the mechanisms of development of spastic abdominal pain and possible ways to correct it. The mechanisms of influence of the main myotropic antispasmodics on the gastrointestinal tract are given. Particular attention is paid to the peculiarities of pharmacodynamics, pharmacokinetics, listed indications, contraindications, features of drug interaction.

Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

Over the past 15 years, there has been an increase in the development and utilization of newer antifungal agents. The ideal antifungal, however, in regard to spectrum of activity, pharmacokinetic/pharmacodynamic properties, development of resistance, safety, and drug interaction profile remains elusive. This article reviews pharmacologic aspects of Food and Drug Administration-approved polyenes, flucytosine, azoles, and echinocandins as well as promising pipeline antifungal agents. Unique properties of these newer agents are highlighted. The clinical role of established and investigational antifungal agents as treatment and/or prevention of invasive fungal infections is discussed.

The CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) is a genetic mutation-targeted treatment in cystic fibrosis that results in profound improvements in clinical outcomes. Each of the compounds are substrates of CYP3A4/5, the cytochrome P450 enzyme family for which tacrolimus is also a substrate. The use of these compounds in an individual with a solid organ transplant has not been previously studied and there is potential for a drug interaction. In this report, we describe a pediatric liver transplant recipient with clinical decline related to cystic fibrosis who improved substantially with ETI, without significant impact on the systemic exposure of either ETI or tacrolimus.

Drug-drug interactions (DDIs) between warfarin (WF) and fluoropyrimidines are well known. Co-administration of WF and 5-fluorouracil (5-FU) leads to elevations in prothrombin time international normalised ratio (PT-INR). The inhibition of drug metabolism through suppression of CYP activity is a possible cause of prolonged PT-INR elevations. 5-FU and its metabolites are suspected to inhibit CYPs, but the precise mechanisms of action remain unknown. This study aimed to investigate the possible DDI effects of the co-administration of 5-FU with WF using PT-INR and PT-INR/dose ratio as pharmacodynamic parameters. Retrospective case series data were collected from patients who received parenteral 5-FU chemotherapy from April 2009 to December 2019 at the University of the Ryukyus Hospital. Seven patients who received 5-FU in combination with WF were analysed. There was a significant increase in PT-INR and PT-INR/dose during the co-administration of WF and 5-FU (p = 0.0018 and p = 0.0187, respectively; paired t-test). The findings demonstrated significant DDI between 5-FU and WF evident as elevated PT-INR and PT-INR/dose ratio.

Monoclonal antibodies (mAT) to calcitonin-gene-related peptide (CGRP) have become the fi rst class of preventive medications specifically designed to treat migraines. The article examines the mechanism of action of mAT from the standpoint of a modern view of the pathophysiology of migraine, discusses the issues of immunogenicity and drug interaction. The review describes in detail the monoclonal antibody erenumab, which became available in Russia from February 2020. The action of erenumab is associated with blocking the CGRP receptor, since it is the only one of the existing mAT that competes with the CGRP molecule for binding to the receptor. This review summarizes the pharmacological characteristics of erenumab, presents in detail the results of clinical trials with an emphasis on the publications of the last year. The article also presents the role of this method of treatment in real clinical practice: the eff ectiveness and safety of erenumab in various forms of migraine are described in detail, the possibility of transition (“reverse transformation”) from chronic migraine to episodic form on erenumab therapy is shown, impressive results of treatment of intractable cases in resistant and refractory migraines are presented. Erenumab is the only one of the mAT drugs for which the results of five-year clinical observations have been published, which have proved the sustained effectiveness and safety in long-term use, as well as the economic feasibility of using this therapeutic approach.

Ipatasertib is a pan-AKT inhibitor in development for the treatment of cancer. Ipatasertib was metabolized by CYP3A4 to its major metabolite, M1 (G-037720), and was a P-gp substrate and OATP1B1/1B3 inhibitor in vitro. A phase I drug-drug interaction (DDI) study (n = 15) was conducted in healthy subjects to evaluate the effect of itraconazole (200-mg solution QD, 4 days), a strong CYP3A4 and P-gp inhibitor, on pharmacokinetics of ipatasertib (100-mg single dose). Itraconazole increased the Cmax and AUC0-∞ of ipatasertib by 2.3- and 5.5-fold, respectively, increased the half-life by 53%, and delayed the tmax by 1 hour. The Cmax and AUC0-72h of its metabolite M1 (G-037720) reduced by 91% and 68%, respectively. This study confirmed that CYP3A4 plays a major role in ipatasertib clearance. Furthermore, the interaction of ipatasertib with coproporphyrin (CP) I and CPIII, the two endogenous substrates of OATP1B1/1B3, was evaluated in this study. CPI and CPIII plasma levels were unchanged in the presence of ipatasertib, both at exposures of 100 mg and at higher exposures in combination with itraconazole. This indicated no in vivo inhibition of OATP1B1/1B3 by ipatasertib. Additionally, it was shown that CPI and CPIII were not P-gp substrates in vitro, and itraconazole had no effect on CPI and CPIII concentrations in vivo. The latter is an important finding because it will simplify interpretation of future DDI studies using CPI/CPIII as OATP1B1/1B3 biomarkers. SIGNIFICANCE STATEMENT This drug-drug interaction study in healthy volunteers demonstrated that CYP3A4 plays a major role in ipatasertib clearance, and that ipatasertib is not an organic anion transporting polypeptide 1B1/1B3 inhibitor. Furthermore, it was demonstrated that itraconazole, an inhibitor of CYP3A4 and several transporters, did not affect CPI/CPIII levels in vivo. This increases the understanding and application of these endogenous substrates as well as itraconazole in complex drug interaction studies.

The article is devoted to the topical problem of neonatology and pediatric neurology — the diagnosis and treatment of seizures in newborns and young children. The work presents an algorithm for the diagnosis and treatment of epileptic seizures in children. It is indicated that the therapeutic effect of most antiepileptic drugs consists of modulation of voltage-gated and ligand-gated channels of membranes of neurons of the cerebral cortex, enhancement of inhibitory synaptic transmission or inhibition of activating synaptic transmission. The issues of the pharmacokinetics and pharmacodynamics of antiepileptic drugs are considered, taking into account the age characteristics of the child's body, in particular, newborns and early age children. The problems of drug interaction were discussed. The properties of individual antiepileptic drugs, which are used in newborns and young children, are considered. Emphasized are «polar» differences in the work of phenobarbital, which depend on the stage of epileptogenesis, namely: suppression of epileptiform activity at the early stage of epileptogenesis and its enhancement in the already formed epileptic focus (epileptic system). The literature data on the differentiated treatment of certain epileptic syndromes are presented. The issues on the prospects for the treatment of genetically determined diseases, which are accompanied by seizures associated with metabolic disorders, are considered. The modern high-tech methods of treatment of these diseases are noted. The role of diet therapy, co-factor therapy in the treatment of hereditary metabolic disorders, in particular, the ketogenic diet as a method of alternative treatment for drug-resistant epilepsy in children, is shown. No conflict of interest was declared by the authors. Key words: newborn, epilepsy, epileptic encephalopathy, treatment, antiepileptic drugs, review.