Risk Of Potential Drug Interactions Research Articles

An in vitro evaluation on metabolism of mitragynine to 9-O-demethylmitragynine

Kratom (Mitragyna Speciosa Korth.) is an indigenous tree native to Southeast Asia whose leaves have been traditionally ingested as a tea and has seen its popularity increase in the United States. Although kratom and its constituents presently have no approved uses by the Food and Drug Administration, its major alkaloids (e.g., mitragynine) have psychoactive properties that may hold promise for the treatment of opioid cessation, pain management, and other indications. 9-O-demethylmitragynine is a major metabolite formed from mitragynine metabolism (36 % total metabolism) and displays similar pharmacologic activity. Cytochrome P450 (CYP) 3A4 has been identified as a major enzyme involved in mitragynine metabolism; however, the in vitro metabolism parameters of 9-O-demethylmitragynine formation are not well defined and a risk of potential drug interactions exists. Using human liver S9 fractions, 9-O-demethylmitragynine formation was generally linear for enzyme concentrations of 0–0.25 mg/mL and incubation times of 5–20 min. 9-O-demethylmitragynine displayed a Km 1.37 μM and Vmax of 0.0931 nmol/min/mg protein. Known CYP inhibitors and compounds that might be concomitantly used with kratom were assessed for inhibition of 9-O-demethylmitragynine formation. Ketoconazole, a CYP3A index inhibitor, demonstrated a significant effect on 9-O-demethylmitragynine formation, further implicating CYP3A4 as a major metabolic pathway. Major cannabinoids (10 μg/mL) displayed minor inhibition of 9-O-demethylmitragynine formation, while all other compounds had minimal effects. Mixtures of physiological achievable cannabinoid concentrations also displayed minor effects on 9-O-demethylmitragynine formation, making a metabolic drug interaction unlikely; however, further in vitro, in vivo, and clinical studies are necessary to fully exclude any risk.

Structural Basis of Main Proteases of Coronavirus Bound to Bofutrelvir

Globally, the continuous spread and evolution of SARS-CoV-2, along with its variants, profoundly impact human well-being, health, security, and the growth of socio-economic. In the field of development of drugs against COVID-19, the main protease (Mpro) is a critical target as it plays a core role in the lifecycle of SARS-CoV-2. Bofutrelvir acts as a potent inhibitor of SARS-CoV-2 Mpro, demonstrating high efficacy and broad-spectrum antiviral activity. Compared to therapies that require pharmacokinetic boosters, such as ritonavir, the monotherapy approach of Bofutrelvir reduces the risk of potential drug interactions, making it suitable for a wider patient population. However, further studies on the potency and mechanism of inhibition of Bofutrelvir against the Mpro of COVID-19 and its variants, together with other coronaviruses, are needed to prepare for the possibility of a possible re-emerging threat from an analogous virus in the future. Here, we reveal the effective inhibition of Bofutrelvir against the Mpro of SARS-CoV-2, SARS-CoV, and HCoV-229E through FRET and crystallographic analysis. Furthermore, the inhibitory mechanisms of Bofutrelvir against two SARS-CoV-2 Mpro mutants (G15S and K90R) were also elucidated through FRET and crystallographic studies. Through detailed analysis and comparison of these crystal structures, we identified crucial structural determinants of inhibition and elucidated the binding mode of Bofutrelvir to Mpros from different coronaviruses. These findings are hopeful to accelerate the development of safer and more potent inhibitors against the Mpro of coronavirus, and to provide important references for the prevention and treatment of similar viruses that may emerge in the future.

Thermodynamic stability of cisplatin-loaded polymeric micelles and the phenotypic switching of the tumor-associated macrophages induced by combination of cisplatin-loaded micelles and Anti-PD-L1 antibody

Chemotherapy is an effective anti-tumor treatment. Some anticancer chemotherapeutic drugs can not only induce cell death, but can also elicit antitumor immune responses. Here, the stability of cisplatin-loaded polymeric micelles (CDDP-PMs), pharmacokinetic drug-drug interactions of CDDP and anti-PD-L1 antibody (aPD-L1) in vivo and the alteration of the tumor microenvironment by combination of CDDP-PMs and aPD-L1 were evaluated. CDDP-PMs were fabricated by coordinated complexation and self-assembly method for tumor targeting. CDDP-PMs with higher mass ratio of copolymer have higher thermodynamic stability. The pharmacokinetic study showed that the CDDP and aPD-L1 were metabolized and cleared by two different pathways, suggesting that there is almost no risk of potential drug interactions between CDDP and aPD-L1 and the combination of aPD-L1 and CDDP- PMs may not alter the tissue distribution of CDDP. In vivo antitumor test showed that the tumor growth inhibition rates of CDDP-PMs combined with medium-dose aPD-L1 and CDDP-PMs combined with high-dose PD-L1 were 89.41% and 93.16%, respectively and therapeutic efficacy can be further increased by increasing the dose of aPD-L1 in co-administration group. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between them and holds great potential to offer better safety and antitumor efficacy profiles.

Potential and real drug interactions in patients treated with abiraterone or enzalutamide in clinical practice

ABSTRACT Background Abiraterone and enzalutamide, androgen receptor pathway inhibitors (ARPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), are at high risk of potential drug interactions (PDIs). We aimed to describe PDIs and their management, and triggered adverse events (AEs) in clinical practice. Methods We conducted a cross-sectional study in mCRPC patients who started treatment with abiraterone or enzalutamide in a university hospital between August 1st, 2016 and July 31st, 2020. Lexicomp® was used to identify and analyze PDIs, and the clinical records to assess their management and the occurrence of AEs. Results We included 173 patients: 36.8% and 93.0% treated with abiraterone and enzalutamide, respectively, had at least 1 PDI. Globally, 6.3% of PDIs had X-risk (contraindication due to high probability of AE). Treatment was modified in 9.2% of patients and 9.8% suffered AEs due to PDIs. Factors associated with a higher risk of PDIs were polypharmacy (OR= 41.0, p 0.003) and treatment with enzalutamide (OR= 128.26, p < 0.001). Conclusions At least two-thirds of patients treated with ARPI suffered a PDI. Overall, abiraterone would have a more favorable PDI profile. Knowing these interaction profiles may be helpful to develop a more efficient therapeutic follow-up and to select the safest treatment.

Drug-Drug Interaction Potential, Cytotoxicity, and Reactive Oxygen Species Production of Salix Cortex Extracts Using Human Hepatocyte-Like HepaRG Cells.

Herbal preparations of willow bark (Salix cortex) are available in many countries as non-prescription medicines for pain and inflammation, and also as dietary supplements. Currently only little information on toxicity and drug interaction potential of the extracts is available. This study now evaluated the effects of two Salix cortex extracts on human hepatocyte-like HepaRG cells, in view of clinically relevant CYP450 enzyme activity modulation, cytotoxicity and production of reactive oxygen species (ROS). Drug metabolism via the CYP450 enzyme system is considered an important parameter for the occurrence of drug-drug interactions, which can lead to toxicity, decreased pharmacological activity, and adverse drug reactions. We evaluated two different bark extracts standardized to 10 mg/ml phenolic content. Herein, extract S6 (S. pentandra, containing 8.15 mg/ml total salicylates and 0.08 mg/ml salicin) and extract B (industrial reference, containing 5.35 mg/ml total salicylates and 2.26 mg/ml salicin) were tested. Both Salix cortex extracts showed no relevant reduction in cell viability or increase in ROS production in hepatocyte-like HepaRG cells. However, they reduced CYP1A2 and CYP3A4 enzyme activity after 48 h at ≥25 μg/ml, this was statistically significant only for S6. CYP2C19 activity inhibition (0.5 h) was also observed at ≥25 μg/ml, mRNA expression inhibition by 48 h treatment with S6 at 25 μg/ml. In conclusion, at higher concentrations, the tested Salix cortex extracts showed a drug interaction potential, but with different potency. Given the high prevalence of polypharmacy, particularly in the elderly with chronic pain, further systematic studies of Salix species of medical interest should be conducted in the future to more accurately determine the risk of potential drug interactions.

Potential drug interactions between targeted oral antineoplastic agents and concomitant medication in clinical practice

ABSTRACT Objectives Our objective was to analyze potential drug interactions (PDIs) between targeted OAAs and concomitant therapy in clinical practice. Methods A cross-sectional observational study was performed in cancer outpatients who started treatment with a targeted OAA between 1 December 2015 and 31 May 2019. PDIs were analyzed using the Lexicomp® and the database About Herbs®. PDIs were classified according to severity, risk, and reliability ratings and their underlying mechanism. Univariate and multivariate analysis were performed to identify risk factors associated with PDIs. Results A total of 881 patients were included, of whom 50.9% had at least 1 PDI between the OAA and the concomitant medication. The factors associated with a higher risk of PDIs were polypharmacy (≥5 concomitant medicines) (OR = 3.64 (2.54–5.20), p < 0.001), type of tumor (prostate cancer [OR = not available, p < 0.001], chronic myelogenous leukemia [OR = 5.10 (1.08–24.05), p = 0.040], sarcoma [OR = 4.97 (1.05–23.55), p = 0.043]), and treatment with hormone therapies (OR = not available, p < 0.001). Conclusion A search of PDIs should be prioritized, especially in patients receiving targeted OAAs with risk factors, such as polymedication, prostate cancer, chronic myelogenous leukemia, sarcoma, and treatment with hormone therapies.

Consider the risk of potential drug interactions when co-prescribing triptans with other medications

Triptans generally have a low potential for drug interactions, with pharmacodynamic interactions likely to be of greater clinical significance than pharmacokinetic interactions. The most notable pharmacodynamic interactions include additive vasoconstrictor effects (e.g. with concomitant ergots) and serotonin syndrome (e.g. with concomitant selective serotonin reuptake inhibitors).

Incidence of potential drug interactions in medication prescriptions for children and adolescents in the University Hospital Olomouc, Czech Republic

Drug interactions are important potential causes of adverse drug reactions. However, studies of their occurrence in children are almost entirely lacking. This study evaluates the incidence of potential drug interactions (PDIs) in medication prescriptions for children. The study was performed at the University Hospital in Olomouc. PDIs in each patient's prescriptions were identified. Multivariate analysis was performed in order to assess the risk factors confounding the potential interactions. Univariate analysis was used to assess which diagnostic groups and medication groups significantly increase or lower the odds of a potential drug-drug interaction. A total of 6,078 patients meeting the inclusion criteria entered the study. They received 19,522 prescriptions. PDIs were identified in 3.83 % of patients (moderate-to-severe cases in 0.47 %). Patient age (p = 0.008), the average number of prescriptions per visit (p < 0.0001), and the number of visits per year (p < 0.0001) were found to increase the risk of drug interaction. The presence of epilepsy, leukemia, or rheumatoid arthritis and related disease diagnoses were discovered to increase the risk of PDIs significantly. The risk of PDIs in children is low, but it increases significantly with age and the number of drugs prescribed, particularly antiepileptics and immunosuppressants. The finding of a potential interaction in 0.47 % of all children in whom any medication was prescribed should not be underestimated since it means a significant risk for one child out of every 200, and it is also substantially higher in the chronically ill. Pediatricians should be aware of relevant interactions and should prevent them by therapeutic drug monitoring or appropriate clinical and laboratory monitoring.

521 – Serotoninergic antidepressants and anticoagulants in psychogeriatric wards, mental hospital kromeriz, czech republic - what shall we do to prevent from serious drug interactions?

Introduction Both serotoninergic antidepressants and anticoagulants are widely udes in psychogeriatry. These drugs can develop drug interactions with subsequent risk of bleeding. Objectives, aims To determine risk of potential drug interactions between serotoninergic antidepressants and anticoagulants serotoninergic antidepressants and anticoagulants with subsequent risk of bleeding. Methods Retrospective analysis of medical records and laboratory checks (INR values) in senior patients treated with serotoninergic antidepressants and anticoagulants (Mental hospital Kromeriz, Czech republic, year 2011). Results In 15.5% of patients treated with combination serotoninergic antidepressant / anticoagulant the dosage of anticoagulant had to be decreased due to unwanted elevation of INR value. In 0.6% of patients the risk of bleeding was clinically evident. Conclusion Serotoninergic antidepressants and anticoagulants are common drugs used in treating seniors with mental disorder and potential drug interactions between them should be taken into account.

De-Risking Bio-therapeutics for Possible Drug Interactions Using Cryopreserved Human Hepatocytes

Inflammatory diseases such as rheumatoid arthritis and psoriasis are characterized by increases in circulating cytokines, which play an important role in modulation of the disease state. Several marketed bio-therapeutics target cytokines and act as effective treatment strategies. Previous in-vitro and in-vivo studies have suggested that cytokines may have both direct and indirect effects on drug metabolizing enzyme levels in the liver. Few studies have characterized models to evaluate the risk of potential drug interactions that might be mediated by changes in cytokine levels. In the present studies the potential of three cytokines (IL-2, IL-6 and TNF-α) to modulate gene expression and activity of the major human cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A4) in cryopreserved human hepatocytes (CHH) was investigated. Significant decreases in the activity of all 6 CYP isoforms occurred in hepatocytes incubated with TNF-α or IL-6 (17-85%; and 22-76% of untreated control values, respectively). TNF-α down-regulated the gene expression of CYP1A2, 2D6 and 3A4 only, whereas IL-6 down-regulated gene expression of all of the tested CYP isoforms except 2D6. IL-2 had only mild effects on CYP activity and mRNA levels of examined isoforms. In CHH exposed to TNF-α, changes in CYP activity were not always paralleled by gene expression alterations for three of the examined CYP isoforms. These studies highlight several potential pitfalls in using isolated human hepatocytes for determination of drug interactions by bio-therapeutics including lack of correlation of mRNA and activity measurements for some CYP isoforms when using single time point determinations, and appropriateness of the model for indirect acting cytokine and cytokine modulators.

Polypharmacy and pain treatment

Pain is a frequent symptom in clinical practice. Elderly and chronically ill patients are particularly affected. On account of the high prevalence of polypharmacy among these patients, pharmacological pain therapy becomes a challenge for physicians. Drug side effects and drug-drug interactions have to be taken into account so as to minimize the health risk for these patients. Especially the group of NSAID has a high risk of adverse drug reactions and drug interactions. The gastrointestinal, the cardiovascular, the renal and the coagulation system are particularly affected. Except for the toxic effect on the liver (in a high dose) Paracetamol (acetaminophen) has similar risks, to a minor degree, though. According to current data Metamizol is actually better than its reputation. The risk of potential drug interactions seems to be low. Beside the risk of sedation in combination with other drugs, Tramadol and other opioids such as Pethidin may induce the Serotonin syndrome. In order to avoid dangerous drug interactions and adverse side effects in the case of polypharmacy, it is recommended to prefer individual choices instead of sticking to the pain management as proposed by the WHO.

Bryostatin Enhances the Cytotoxic Effects of Anti-CD22 Immunotoxins in CLL by Two Distinct Mechanisms: Implications for a Sequential Therapy.

Abstract 3429Poster Board III-317Recently, treatment of CLL has been improved by the addition of Rituximab, a monoclonal antibody directed against CD20. Although Rituximab displays modest activity when used as monotherapy, the combination of Rituximab and chemotherapy has demonstrated impressive efficacy in CLL. However, even though remissions can be achieved in the majority of patients, CLL still remains an incurable disease for most patients. Therefore, alternative treatment options are needed. BL22 is a recombinant protein composed of the variable region of a monoclonal antibody, which binds to CD22 on the surface of normal and malignant B-cells and of PE38, a truncated Pseudomonas exotoxin. Previously, we demonstrated that BL22 induced cell death in CLL, involving the intrinsic apoptotic pathway. However, apoptosis induction correlates with expression of CD22 on the surface of CLL cells and was only moderate in CD22low expressing cells. The aim of this study was to increase BL22 cytotoxicity by modulating the surface expression of CD22 on CLL cells. Bryostatin is a macrocyclic lactone which structurally mimics the PKC-activating second messenger diacylglycerol. This PKC modulator has demonstrated anti-leukemic effects in CLL by itself in vivo. Here we show that Bryostatin up-regulates the expression of CD22 on CLL cells in a PKC dependent pathway, thereby increasing the cytotoxic effects of BL22. However, PKC-mediated up-regulation of Mcl-1 attenuated the anti-leukemic effects of BL22. We unravel that CD22 and Mcl-1 up-regulation by Bryostatin occurs in a dose dependent manner. Importantly, higher doses of Bryostatin prevented the undesirable up-regulation of Mcl-1 by inhibition of PKC in spite of CD22 up-regulation. Therefore, combined treatment of BL22 and Bryostatin seems to be a promising approach to enhance the cytotoxic effects of the immunotoxin by modulating PKC activity and CD22 up-regulation. In addition, our data provide evidence for a sequential therapy with both drugs, since CLL cells can be primed with Bryostatin. After a single dose of Bryostatin, PKC-modulation lasts for several days, allowing to administer BL22 at later time points, thereby decreasing the risk of potential drug interactions. Finally we demonstrate that stromal cell mediated drug resistance in CLL can be overcome by Bryostatin/ BL22 therapies. Conclusively, Bryostatin enhances the anti-leukemic effects of BL22 in CLL. Clinical trails are needed to prove if such an approach has clinical impact on the treatment and prognosis of B-CLL. DisclosuresNo relevant conflicts of interest to declare.

Prevalência de potenciais interações medicamentosas droga-droga em unidades de terapia intensiva

Drug interactions occur when effects and/or toxicity of a drug are affected by presence of another drug. They are usually unpredictable and undesirable. A study was conducted to verify the prevalence and clinical value of potential drug interactions in intensive care units All patients, of three intensive care units were included in a cross-sectional study, over a period of two months. Patients with less than a 2 days length of stay were excluded. Data were collected from twenty-four hour prescriptions and all possible paired combinations drug-drug were recorded. Prevalence and clinical value (significance) were checked at the end of follow-up. One hundred and forty patients were analyzed, 67.1% presented with some significant potential drug interactions and of the 1069 prescriptions, 39.2% disclosed the same potential. Of 188 different potential drug interactions, 29 were considered highly significant. Univariate analysis showed that in the group with significant potential drug interactions a higher number of different drugs, drugs/day had been used, there were more prescribing physicians and extended stay in intensive care units. Adjusted to the multivariate logistic regression model, only the number of drugs/day correlated with increased risk of significant potential drug interaction (p = 0.0011) and, furthermore that use of more than 6 drugs/day increased relative risk by 9.8 times. Critically ill patients are submitted to high risk of potential drug interactions and the number of drugs/day has a high positive predictive value for these interactions. Therefore, it is imperative that critical care physicians be constantly alert to recognize this problem and provide appropriate mechanisms for management, thereby reducing adverse outcomes.

Risk factors for potential drug interactions in general practice

Objective: To identify patient- and practice-related factors associated with potential drug interactions. Methods: A register analysis study in general practices in the county of Funen, Denmark. Prescription data were retrieved from a population-based prescription database (Odense University Pharmacoepidemiologic Database, OPED) covering prescriptions to all inhabitants in the county of Funen, Denmark. All individuals exposed to concurrent use of two or more drugs (polypharmacy) were identified. Combinations of drugs with potential interactions were registered and classified as major, moderate, or minor, depending on the severity of outcome and the quality of documentation. A two-level random coefficient logistic regression model was used to investigate factors related to potential drug interactions. Results: One-third of the population was exposed to polypharmacy, and 6% were exposed to potential drug interactions during 1 year. Patient factors associated with increased risk of potential drug interactions were high age, a high number of concurrently used drugs, and a high number of prescribers. Practice factors associated with potential drug interactions were a high percentage of elderly patients and a low percentage of female patients listed.Conclusion: Prescription data may be useful in quality-improvement programmes to identify groups of patients and practices at increased risk of drug interactions.

Severe Rhabdomyolysis and Acute Renal Failure Secondary to Concomitant Use of Simvastatin, Amiodarone, and Atazanavir

To report a case of a severe interaction between simvastatin, amiodarone, and atazanavir resulting in rhabdomyolysis and acute renal failure. A 72-year-old white man with underlying human immunodeficiency virus, atrial fibrillation, coronary artery disease, and hyperlipidemia presented with generalized pain, fatigue, and dark orange urine for 3 days. The patient was taking 80 mg simvastatin at bedtime (initiated 27 days earlier); amiodarone at a dose of 400 mg daily for 7 days, then 200 mg daily (initiated 19 days earlier); and 400 mg atazanavir daily (initiated at least 2 years previously). Laboratory evaluation revealed 66,680 U/L creatine kinase, 93 mg/dL blood urea nitrogen, 4.6 mg/dL creatinine, 1579 U/L aspartate aminotransferase, and 738 U/L alanine aminotransferase. Simvastatin, amiodarone, and the patient's human immunodeficiency virus medications were all temporarily discontinued and the patient was given forced alkaline diuresis and started on dialysis. Nine days later the patient's creatine kinase had dropped to 1695 U/L and creatinine was 3.3 mg/dL. The patient was discharged and continued outpatient dialysis for 1 month until his renal function recovered. The risk of rhabdomyolysis is increased in the presence of concomitant drugs that inhibit simvastatin metabolism. Simvastatin is metabolized by CYP3A4. Amiodarone and atazanavir are recognized CYP3A4 inhibitors. Pharmacokinetic differences in statins are an important consideration for assessing the risk of potential drug interactions. In patients requiring the concurrent use of statins and CYP3A4 inhibitors, pravastatin, fluvastatin, and rosuvastatin carry the lowest risk of drug interactions; atorvastatin carries moderate risk, whereas simvastatin and lovastatin have the highest risk and should be avoided in patients taking concomitant CYP3A4 inhibitors.

Antimalarial Artemisinin Drugs Induce Cytochrome P450 and MDR1 Expression by Activation of Xenosensors Pregnane X Receptor and Constitutive Androstane Receptor

Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved. Because the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been shown to mediate induction of drug-metabolizing enzymes and drug transporters, we investigated the hypothesis that artemisinin induces cytochrome P450 expression by activating PXR and/or CAR. By combining in vitro transfection methods and quantitative analyses of gene expression in cell lines and primary human hepatocytes, we here show that artemisinin drugs activate human PXR as well as human and mouse CAR and induce the expression of CYP2B6, CYP3A4, and MDR1 in primary human hepatocytes and in the human intestinal cell line LS174T. Furthermore, we demonstrate that artemisinin acts as a ligand of both nuclear receptors, because it modulates the interaction of the receptors with coregulators. In conclusion, activation of PXR and CAR and especially the resulting induction of CYP3A4 and MDR1 demonstrate that artemisinin has a higher risk of potential drug interactions than anticipated previously.