Case Report: Performing a Medication Safety Review Assisted by Pharmacogenomics to Explain a Prescribing Cascade Resulting in a Patient Fall.

Pharmacotherapy for major depressive disorder (MDD) typically consists of trial-and-error and clinician preference approaches, where patients often fail one or more antidepressants before finding an optimal regimen. Pharmacogenomics (PGx) can assist in prescribing appropriate antidepressants, thereby reducing the time to MDD remission and occurrence of adverse drug events. Since many antidepressants are metabolized by and/or inhibit cytochrome P450 enzymes (e.g., CYP2C19 or CYP2D6), drug-induced phenoconversion is common in patients on antidepressant combinations. This condition influences the interpretation of a patient's PGx results, overall risk of ineffective/adverse medication response due to multi-drug interactions, and the recommendations. This complex case describes a patient with MDD, generalized anxiety disorder, and chronic pain who experienced a fall due to excessive sedation following a prescribing cascade of fluoxetine, bupropion, and doxepin. These antidepressants delivered a significant additive sedative effect and interacted with the patient's hydrocodone, potentially contributing to uncontrolled pain, upward dose titration of hydrocodone, and a higher overall sedative burden. The PGx results and drug-induced phenoconversion described in this case report explain the patient's excessive sedation and possibly ineffective/toxic antidepressant and opioid treatment. This case report also illustrates how a more timely multi-drug interaction assessment (preferably in conjunction with preemptive PGx testing) may have informed a different prescribing pattern, reduced/avoided a prescribing cascade, and potentially prevented a drug-related fall.

Community Masks - from an Emergency Solution to an Innovation Booster for the Textile Industry.

The COVID-19 pandemic resulted in shortages of personal protective equipment and medical devices in the initial phase. Agile small and medium-sized enterprises from regional textile industries reacted quickly. They delivered alternative products such as textile-based community masks in collaboration with industrial partners and research institutes from various sectors. The current mask materials and designs were further improved by integrating textiles with antiviral and antimicrobial properties and enhanced protection and comfort by novel textile/membrane combinations, key factors to increase the acceptance and compliance of mask wearing. The innocuity and sustainability of masks, as well as taking into account particular needs of vulnerable persons in our society, are new fields for textile-based innovations. These innovations developed for the next generation of facemasks have a high adaptability to other product segments, which make textiles an attractive material for hygienic applications and beyond.

Chronic Inflammatory Status Observed in Patients with Type 2 Diabetes Induces Modulation of Cytochrome P450 Expression and Activity.

Diabetes mellitus is a metabolic disease that causes a hyperglycemic status which leads, over time, to serious damage to the heart, blood vessels, eyes, kidneys and nerves. The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes. As the aging population is exposed to polypharmacy along with inflammatory comorbidities, consideration of phenoconversion related to drug metabolizing enzymes is of importance when applying pharmacogenomic results and establishing personalized and more precise drug regimens.

Determination of CYP450 Expression Levels in the Human Small Intestine by Mass Spectrometry-Based Targeted Proteomics.

The human small intestine can be involved in the first-pass metabolism of drugs. Under this condition, members of the CYP450 superfamily are expected to contribute to drug presystemic biotransformation. The aim of this study was to quantify protein expression levels of 16 major CYP450 isoforms in tissue obtained from nine human organ donors in seven subsections of the small intestine, i.e., duodenum (one section, N = 7 tissue samples), jejunum (three subsections (proximal, mid and distal), N = 9 tissue samples) and ileum (three subsections, (proximal, mid and distal), N = 9 tissue samples), using liquid chromatography tandem mass spectrometry (LC-MS/MS) based targeted proteomics. CYP450 absolute protein expression levels were compared to mRNA levels and enzyme activities by using established probe drugs. Proteins corresponding to seven of sixteen potential CYP450 isoforms were detected and quantified in various sections of the small intestine: CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, CYP3A5 and CYP4F2. Wide inter-subject variability was observed, especially for CYP2D6. CYP2C9 (p = 0.004) and CYP2C19 (p = 0.005) expression levels decreased along the small intestine. From the duodenum to the ileum, CYP2J2 (p = 0.001) increased, and a trend was observed for CYP3A5 (p = 0.13). CYP3A4 expression was higher in the jejunum than in the ileum (p = 0.03), while CYP4F2 expression was lower in the duodenum compared to the jejunum and the ileum (p = 0.005). CYP450 protein levels were better correlated with specific isoform activities than with mRNA levels. This study provides new data on absolute CYP450 quantification in human small intestine that could improve physiologically based pharmacokinetic models. These data could better inform drug absorption profiles while considering the regional expression of CYP450 isoforms.

Disease-Induced Modulation of Drug Transporters at the Blood-Brain Barrier Level.

The blood-brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies. Pathophysiological stressors, age, and age-associated disorders may alter the expression level and functionality of transporter protein elements that modulate drug distribution and accumulation into the brain, namely, drug efficacy and toxicity. This review focuses and sheds light on the influence of inflammatory conditions and diseases such as Alzheimer's disease, epilepsy, and stroke on the expression and functionality of the BBB drug transporters, the consequential modulation of drug distribution to the brain, and their impact on drug efficacy and toxicity.

Pharmacist-Led Medication Evaluation Considering Pharmacogenomics and Drug-Induced Phenoconversion in the Treatment of Multiple Comorbidities: A Case Report.

Pharmacogenomic (PGx) information can guide drug and dose selection, optimize therapy outcomes, and/or decrease the risk of adverse drug events (ADEs). This report demonstrates the impact of a pharmacist-led medication evaluation, with PGx assisted by a clinical decision support system (CDSS), of a patient with multiple comorbidities. Following several sub-optimal pharmacotherapy attempts, PGx testing was recommended. The results were integrated into the CDSS, which supported the identification of clinically significant drug-drug, drug-gene, and drug-drug-gene interactions that led to the phenoconversion of cytochrome P450. The pharmacist evaluated PGx results, concomitant medications, and patient-specific factors to address medication-related problems. The results identified the patient as a CYP2D6 intermediate metabolizer (IM). Duloxetine-mediated competitive inhibition of CYP2D6 resulted in phenoconversion, whereby the patient's CYP2D6 phenotype was converted from IM to poor metabolizer for CYP2D6 co-medication. The medication risk score suggested a high risk of ADEs. Recommendations that accounted for PGx and drug-induced phenoconversion were accepted. After 1.5 months, therapy changes led to improved pain control, depression status, and quality of life, as well as increased heart rate, evidenced by patient-reported improved sleep patterns, movement, and cognition. This case highlights the pharmacist's role in using PGx testing and a CDSS to identify and mitigate medication-related problems to optimize medication regimen and medication safety.

Cannabis Dopaminergic Effects Induce Hallucinations in a Patient with Parkinson's Disease.

Cannabis products that contain the tetrahydrocannabinol (THC) cannabinoid are emerging as promising therapeutic agents for the treatment of medical conditions such as chronic pain. THC elicits psychoactive effects through modulation of dopaminergic neurons, thereby altering levels of dopamine in the brain. This case report highlights the complexity associated with medicinal cannabis and the health risks associated with its use. A 57-year-old male with Parkinson's disease was experiencing worsening tremors and vivid hallucinations despite therapy optimization attempts. It was discovered that the patient took cannabis for chronic back pain, and a pharmacogenomics (PGx) test indicated the presence of variants for the COMT and HTR2A genes. These variants could increase dopamine levels and predispose patients to visual hallucinations. Once the cannabis was discontinued, the patient's hallucinations began to slowly dissipate. Cannabis use continues to expand as it gains more acceptance legally and medicinally, but cannabis can affect the response to drugs. This patient case suggests that cannabis use in combination with dopamine-promoting drugs, especially in a patient with genetic variants, can increase the risk for vivid hallucinations. These conditions support the importance of considering herb-drug interactions and PGx data when performing a medication safety review.

Activity and mRNA expression levels of selected cytochromes P450 in various sections of the human small intestine.

AIMS: To characterize mRNA expression levels (17 cytochromes P450) and activity (9 isoforms) of major cytochromes P450 expressed throughout the human small intestine. METHODS: Tissue samples were obtained from 9 deceased subjects and intestinal sections (n = 10) were isolated for each subject. Relative mRNA expression levels were determined using quantitative real-time PCR. Intestinal microsomes were prepared from 5 subsections: duodenum, jejunum (proximal and mid-jejunum) and ileum (proximal and mid-ileum) regions. In vitro incubations were performed with various cytochrome P450 probe substrates: bupropion (CYP2B6), repaglinide (CYP2C8), tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), chlorzoxazone (CYP2E1), ebastine (CYP2J2), midazolam (CYP3A4/5) and lauric acid (CYP4A11). Metabolite formation was assessed using validated liquid chromatography-tandem mass spectrometry assays. RESULTS: Cytochrome P450 mRNA levels ranked as follows: CYP3A4 > CYP2C9 > CYP2C19 > CYP2J2 > CYP4F2. Cytochrome P450 mRNA transcripts showed different patterns in their relative expression from 1 region to the other but CYP3A4, CYP2C9, CYP2C19 and CYP2J2 displayed the highest levels of mRNA expression (>5%) in all intestinal sections. Cytochrome P450 activities were greater in proximal part of the small intestine with the jejunum showing the greatest drug-metabolism activity. Spearman's correlation analyses indicated that cytochrome P450 mRNA expressions and corresponding cytochrome P450 activities in the human intestine were moderately associated for CYP2C19, CYP2D6 and CYP4A11 (rs  = 0.44-0.56). CONCLUSIONS: Our study provides new and additional information on the expression and activities of selected cytochromes P450 in various sections of the human small intestine.

Development and validation of probe drug cocktails for the characterization of CYP450-mediated metabolism by human heart microsomes.

1. The objective of our study was to develop and validate a cocktail approach to allow the simultaneous characterization of various CYP450-mediated oxidations by human heart microsomes for nine probe drug substrates, namely, 7-ethoxyresorufin, bupropion, repaglinide, tolbutamide, bufuralol, chlorzoxazone, ebastine, midazolam and dodecanoic acid. 2. The first validation step was conducted using recombinant human CYP450 isoenzymes by comparing activity measured for each probe drug as a function of (1) buffer used, (2) selectivity towards specific isoenzymes and (3) drug interactions between probes. Activity was all measured by validated LC-MSMS methods. 3. Two cocktails were then constituted with seven of the nine drugs and subjected to kinetic validation. Finally, all probe drugs were incubated with human heart microsomes prepared from ventricular tissues obtained from 12 patients undergoing cardiac transplantation. 4. Validated cocktail #1 including bupropion, chlorzoxazone, ebastine and midazolam was used to characterize CYP2B6-, 2E1-, 2J2- and 3A5-mediated metabolism in human hearts. 5. Cocktail #2 which includes bufuralol, 7-ethoxyresorufin and repaglinide failed the validation step. Substrates in cocktail #2 as well as tolbutamide and dodecanoic acid had to be incubated separately because of their physico-chemical characteristics (solubility and ionization) or drug interactions. 6. Activity in HHM was the highest towards ebastine, chlorzoxazone and tolbutamide.

A Pilot Study towards the Impact of Type 2 Diabetes on the Expression and Activities of Drug Metabolizing Enzymes and Transporters in Human Duodenum.

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein-1 min-1) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D (p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.

Evaluation of Limited Sampling Methods for Oral Busulfan Pharmacokinetic Monitoring in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: Monitoring busulfan area under the plasma concentration-time curve (AUC) to establish the dose regimen for stem cell transplantation desirable to achieve efficacy while avoiding toxicity. OBJECTIVE: Our objective was to compare AUCs calculated by 18 limited sampling methods (LSMs) from 2 to 5 samples to reference AUCs determined from 10 samples in a retrospective study of 103 adult patients receiving oral busulfan. LSMs using 2 or 3 samples were ineffective. METHODS: Four LSMs using 4 or 5 blood samples that accurately characterized busulfan AUC were identified. The best 2 methods were obtained with sampling at 0.5, 1, 2, 4, and 6 hours and after 1, 1.5, 2, 4, and 6 hours postdose. For these LSMs, the incidence of 20% difference between AUCs from LSMs and reference AUCs was less than 1.3%. CONCLUSIONS: Effective and safe determination of AUC for oral busulfan can be made with strategies using only 4 or 5 concentration timepoints.

Effects of ß-blockers and tricyclic antidepressants on the activity of human organic anion transporting polypeptide 1A2 (OATP1A2).

The organic anion transporting polypeptide 1A2 (OATP1A2), a membrane drug transporter expressed on important organs (such as the brain, kidney, and intestine) may be a key element in the disposition of drugs. Previous studies demonstrated that it could transport a broad spectrum of substrates, including endogenous molecules and clinically relevant drugs, such as several ß-blockers and 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. The primary objective of this study was to investigate OATP1A2 transport activity using rosuvastatin as a probe substrate and evaluate competitive inhibition of its transport by ß-blockers. Rosuvastatin transport was saturable, with a Km of 60.2 µM. With the exception of carvedilol (IC50 of 3.2 µM), all of the other ß-blockers that were evaluated had a small or insignificant effect on OATP1A2-mediated uptake of rosuvastatin. Carvedilol differs from the other ß-blockers by the tricyclic moiety in its chemical structure. As a secondary objective, the transport of a series of tricyclic compounds by OATP1A2 and their potential for rosuvastatin transport inhibition were evaluated. Tricyclic compounds were not OATP1A2 substrates. On the other hand, tricyclic compounds with a short aliphatic amine chain inhibited OATP1A2-mediated rosuvastatin transport. Our data suggest that these drugs may modulate the transport of OATP1A2 substrates and may affect drug actions.

Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy.

OBJECTIVE: To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? METHODS: A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. RESULTS: Testing of VKORC1 (-1639G>A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. SIGNIFICANCE: This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.

The dual role of pharmacogenetics in HIV treatment: mutations and polymorphisms regulating antiretroviral drug resistance and disposition.

Significant intra- and interindividual variability has been observed in response to use of pharmacological agents in treatment of HIV infection. Treatment of HIV infection is limited by high rates of adverse drug reactions and development of resistance in a significant proportion of patients as a result of suboptimal drug concentrations. The efficacy of antiretroviral therapy is challenged by the emergence of resistant HIV-1 mutants with reduced susceptibility to antiretroviral drugs. Moreover, pharmacotherapy of patients infected with HIV is challenging because a great number of comorbidities increase polypharmacy and the risk for drug-drug interactions. Drug-metabolizing enzymes and drug transporters regulate drug access to the systemic circulation, target cells, and sanctuary sites. These factors, which determine drug exposure, along with the emergence of mutations conferring resistance to HIV medications, could explain variability in efficacy and adverse drug reactions associated with antiretroviral drugs. In this review, the major factors affecting the disposition of antiretroviral drugs, including key drug-metabolizing enzymes and membrane drug transporters, are outlined. Genetic polymorphisms affecting the activity and/or the expression of cytochromes P450 or UGT isozymes and membrane drug transport proteins are highlighted and include such examples as the association of neurotoxicity with efavirenz, nephrotoxicity with tenofovir, hepatotoxicity with nevirapine, and hyperbilirubinemia with indinavir and atazanavir. Mechanisms of drug resistance conferred by specific viral mutations are also reviewed, with particular attention to replicative viral fitness and transmitted HIV drug resistance with the objectives of providing a better understanding of mechanisms involved in HIV drug resistance and helping health care providers to better manage interpatient variability in drug efficacy and toxicity.

Exploring the impact of CYP2D6 and UGT2B7 gene-drug interactions, and CYP-mediated DDI on oxycodone and oxymorphone pharmacokinetics using physiologically-based pharmacokinetic modeling and simulation.

Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. Our simulations demonstrate that the combination of CYP2D6 UM and a UGT2B7Y (268) mutation may lead to a 2.3-fold increase in oxymorphone exposure compared to individuals who are phenotyped as CYP2D6 NM / UGT2B7 NM. The extent of oxymorphone exposure increases up to 3.2-fold in individuals concurrently taking CYP3A4 inhibitors, such as ketoconazole. Inhibition of the CYP3A4 pathway results in a relative increase in the partial metabolic clearance of oxycodone to oxymorphone. Oxymorphone is impacted to a higher extent by GDIs and DDIs than oxycodone. We predict oxymorphone exposure to be highest in CYP2D6 UMs/UGT2B7 PMs in the presence of ketoconazole (strong CYP3A4 index inhibitor) and lowest in CYP2D6 PMs/UGT2B7 NMs in the presence of rifampicin (strong CYP3A4 index inducer) covering a 55-fold exposure range.

Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors.

BACKGROUND: Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier. OBJECTIVES: To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU. PATIENTS AND MEASUREMENTS: In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1ß, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1ß, and monocyte chemotactic protein-1. RESULTS: Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05). CONCLUSIONS: Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status. These data suggest that iatrogenic coma and delirium are not mechanistically linked.

Multidrug Interactions: Why Do They Occur and How to Handle?

A nonoptimized medication therapy (NOMT) event is an iatrogenic hazard or incident associated with medications and is a leading cause of death, serious injury, and illness. NOMT events are often related to multidrug interactions in patients with polypharmacy. In these patients, NOMT events can be avoided by using advanced clinical decision support systems and clinical interventions such as separating the time of administration of certain drugs during the day. At the individual level, medication reconciliation is a first logical step for reducing adverse side effects. Then, intersubject variability in drug response should be considered to optimize patient drug regimens. Furthermore, patient pharmacogenomic status information can help ensure appropriateness of drug therapy. However, in patients with polypharmacy, such information is most valuable when combined with phenoconversion probability. At a population level, the virtual addition of drugs to various drug regimens and the use of a medication risk score can help predict the risk of NOMT events. This review outlines some of the mechanisms behind multidrug interactions and their association with drug safety and NOMTs, polypharmacy and its impact on patient outcomes, the value of pharmacogenomics, and an assessment of simulation studies and the virtual addition of drugs to a drug regimen using real-world data.

Colombian Sustainability Perspective on Fused Deposition Modeling Technology: Opportunity to Develop Recycled and Biobased 3D Printing Filaments.

In the context of the preservation of natural resources, researchers show a growing interest in developing eco-friendly materials based on recycled polymers and natural fiber biocomposites to minimize plastic and agroindustrial waste pollution. The development of new materials must be integrated within the circular economy concepts to guarantee sustainable production. In parallel, fused deposition modeling, an additive manufacturing technology, provides the opportunity to use these new materials in an efficient and sustainable manner. This review presents the context of plastics and agro-industrial fiber pollution, followed by the opportunity to give them added value by applying circular economy concepts and implementing these residues to develop new materials for the manufacture of fused deposition modeling 3D printing technique feedstock. Colombian perspective is highlighted since 3D printing technology is growing there, and Colombian biodiversity represents a high reservoir of materials. Also, recycling in Colombia promotes compliance with the 2030 Agenda and the Sustainable Development Goals.

The Association of Serotonin Toxicity with Combination Linezolid-Serotonergic Agent Therapy: A Systematic Review and Meta-Analysis.

Linezolid (LZD) has a longstanding reported association with the onset of serotonin toxicity (ST), secondary to drug-drug interactions with serotoninergic agents. There have been no conclusive data supporting the incidence or contributing risk factors to date. The study evaluated the incidence of ST in patients treated with LZD and serotonergic agents concomitantly versus LZD alone. The secondary objectives included a comparison of ST incidence in patients treated with one serotonergic agent + LZD versus two or more serotonergic agents + LZD. The studies used for this meta-analysis were retrieved from PubMed, Scopus, and Google Scholar. All studies including a comparison between LZD alone and LZD + a serotonergic agent published between 1 January 2000 and 1 October 2023 and meeting the quality standards were considered for inclusion. Fourteen studies were identified, with five meeting all inclusion and exclusion criteria with no significant heterogeneity. For the analysis of LZD monotherapy vs. SA combination therapy, four studies with 6025 patients total were analyzed and yielded an odds ratio of 1.78 (CI [1.04, 3.02]; I2 = 49%; GRADE certainty: low). Four studies and 2501 patients were included in the analysis of one versus more than one SA with an odds ratio of 5.18 (CI [1.05, 25.49]; I2 = 44.87; GRADE certainty: moderate). The Newcastle-Ottawa score, visual inspection of the funnel plot, and Egger's statistic were used to evaluate quality and heterogeneity. The Peto method was used to calculate the summary odds ratios. All analyses were performed using Comprehensive Meta-Analysis version 3.0 and R, while GRADE was used to evaluate the quality of the final recommendation. The number of concomitant serotonergic agents may play a role in the development of serotonin toxicity in patients prescribed linezolid. In patients requiring linezolid therapy and serotonergic agents, risk versus benefit analysis should pay attention to the number of interacting drugs.

Pharmacogenetic Testing in a 70-Year-Old Woman with Polypharmacy and Multiple Comorbidities: A Case Report.

BACKGROUND Comorbidities and polypharmacy are difficult to manage, as polypharmacy hinders identification and prevention of medication-related problems. Risk for adverse drug events (ADEs) can be minimized through pharmacogenomic (PGx) testing and related therapeutic adjustments. CASE REPORT A 70-year-old woman with comorbidities and medications enrolled in the Program of All-inclusive Care for the Elderly presented with left lower extremity (LLE) pain, generalized weakness, and major depressive disorder. The provider requested a medication safety review, where the clinical pharmacist-recommended PGx testing given the LLE pain and weakness while taking a statin and inconsistent INR readings taking warfarin. The pharmacist recommended switching atorvastatin to pravastatin to minimize the risk for statin-associated ADEs due to CYP3A4 inhibition and switching fluoxetine to citalopram due to uncontrolled depression/anxiety and to mitigate drug-drug interactions with carvedilol to reduce the risk of orthostatic hypotension. Recommendations were accepted and upon follow-up the patient reported minor LLE pain and improved wellbeing on citalopram. Following PGx testing, the patient had decreased function at SLCO1B1 and was an intermediate metabolizer for CYP2C9 and CYP2D6. This case demonstrates how preemptive PGx testing would have identified drug-gene interactions (DGIs) at the time of prescribing and reduced the risk of statin-associated muscular symptoms, highlighting the utility of panel-based PGx testing in older adults at high risk for ADEs and/or therapy failure. CONCLUSIONS Decreased function at SLCO1B1 increases exposure to statins, leading to statin-induced myalgias, as displayed in this case. PGx testing can help identify DGIs, choose optimal therapies in medically complex older adults, and minimize ADE risk.