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.

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.

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.

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.

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.

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.

Recycling of Bottle Grade PET: Influence of HDPE Contamination on the Microstructure and Mechanical Performance of 3D Printed Parts.

As part of a project that aims to provide people with disabilities with simple assistive devices in Colombia, the possibility of creating a PET filament that can be printed by Fused Deposition Modelling (FDM) from beverage bottle waste was investigated, with the aim to remain as simple as possible in terms of plastic collection, sorting, processing, and printing. Recycled PET filaments were thus produced by extrusion from collected PET bottles, with the potential addition of HDPE, which comes from caps and rings. The microstructure, mechanical performance, and printing quality of parts produced with these filaments were investigated in comparison to commercial PET virgin and recycled filaments. HDPE presence as an immiscible blend did not affect the ease of extrusion or the quality of the printing, which were all satisfactory. In some conditions, the addition of 5 wt% of HDPE to recycled PET had a toughening effect on otherwise brittle samples. This behavior was attributed to the presence of elongated HDPE inclusions resulting from shear forces induced by the layer-by-layer printing, provided that the interface temperature remained high between layer depositions. This confirms that the mechanical performance of recycled PET is very sensitive to the processing conditions, especially in the case of 3D printing. Nonetheless, this low-cost process that did not require sophisticated compatibilization schemes allowed for the printing of parts with mechanical properties comparable to those obtained with high purity, commercially recycled filaments, opening interesting perspectives for a low-cost PET recycling process.

Utilizing Pharmacogenomics Results to Determine Opioid Appropriateness and Improve Pain Management in a Patient with Osteoarthritis.

The opioid epidemic in the United States has exposed the need for providers to limit opioid dispensing and identify at-risk patients prior to prescribing opioids. With pharmacogenomic testing, clinicians can analyze hundreds of medications-including commonly prescribed opioids-against genetic results to understand and predict risk and response. Moreover, knowledge of genotypic variants and altered function can help decrease trial and error prescribing, identify patients at-risk for adverse drug events, and improve pain control. This patient case demonstrates how pharmacogenomic test results identified drug-gene interactions and provided insight about a patient's inadequate opioid therapy response. With pharmacogenomic information, the patient's healthcare team discontinued opioid therapy and selected a more appropriate regimen for osteoarthritis (ie, celecoxib), resulting in improved pain control and quality of life.

Pharmacist-driven interventions to de-escalate urinary antimuscarinics in the Programs of All-Inclusive Care for the Elderly.

BACKGROUND: Given associations with serious cognitive and physical adverse effects (e.g., dementia, falls), strong anticholinergics, like urinary antimuscarinics (UAMs), should be avoided in older adults. This feasibility study aimed to (1) evaluate the implementation rate of pharmacists' recommendations intended to de-escalate UAMs, (2) quantify the change in overall anticholinergic dosing exposure from these recommendations, and (3) investigate factors that predict recommendation implementation. METHODS: This was a retrospective, observational, before-and-after study. Pharmacists (n = 18) devised strategies to de-escalate UAMs in 187 participants (mean age 72.4 ± 9.4; 77.0% female; mean number of medications 12.9 ± 4.6) of 35 Programs of All-Inclusive Care for the Elderly (PACE). PACE prescribers (non-physicians and physicians) determined whether to implement recommendations. Implementation was defined as a change in the prescription records consistent with the pharmacist's recommendation at 2-, 4-, 6-, and 9-months post-recommendation. Anticholinergic dosing exposure was measured at each time point using standardized daily doses (SDD). Multivariable logistic regression was used to identify factors that predicted recommendation implementation. RESULTS: Across 9 months, recommendations were implemented in 118 out of 187 participants, yielding a 63.1% implementation rate. Of these, 77.1% (n = 91/118) implemented by month 2. Implementers' mean overall anticholinergic SDD decreased 65.4% from baseline (baseline: 2.6 [95% CI: 2.2, 3.0] to month 9: 0.9 [95% CI: 0.6,1.2], p < 0.001) whereas non-implementers demonstrated no significant change (p = 0.52). Taking <10 baseline medications (OR 2.75; 95% CI: 1.09, 7.61); baseline UAM SDD ≥2 (OR 2.20; 95% CI: 1.11, 4.44); uncomplicated recommendations (OR 3.38; 95% CI: 1.67-7.03); and baseline calcium channel blocker use (OR 2.19; 95% CI: 1.09, 4.52) predicted implementation. CONCLUSION: Our high implementation rate indicates that pharmacists' recommendations to de-escalate UAMs as a way to reduce overall anticholinergic exposure is feasible in medically complex, community-dwelling older adults. Future research should investigate whether these recommendations benefit cognitive (e.g., delirium, dementia) and/or physical functioning (e.g., falls).

Revisiting conclusions on the empiric segmentation of high-risk patients.

The authors provide feedback on generalizations made regarding interventions for high-risk populations in previous research.

Sustainable polyesters via direct functionalization of lignocellulosic sugars.

The development of sustainable plastics from abundant renewable feedstocks has been limited by the complexity and efficiency of their production, as well as their lack of competitive material properties. Here we demonstrate the direct transformation of the hemicellulosic fraction of non-edible biomass into a tricyclic diester plastic precursor at 83% yield (95% from commercial xylose) during integrated plant fractionation with glyoxylic acid. Melt polycondensation of the resulting diester with a range of aliphatic diols led to amorphous polyesters (Mn = 30-60 kDa) with high glass transition temperatures (72-100 °C), tough mechanical properties (ultimate tensile strengths of 63-77 MPa, tensile moduli of 2,000-2,500 MPa and elongations at break of 50-80%) and strong gas barriers (oxygen transmission rates (100 µm) of 11-24 cc m-2 day-1 bar-1 and water vapour transmission rates (100 µm) of 25-36 g m-2 day-1) that could be processed by injection moulding, thermoforming, twin-screw extrusion and three-dimensional printing. Although standardized biodegradation studies still need to be performed, the inherently degradable nature of these materials facilitated their chemical recycling via methanolysis at 64 °C, and eventual depolymerization in room-temperature water.

Pharmacogenomics and Drug-Induced Phenoconversion Informed Medication Safety Review in the Management of Pain Control and Quality of Life: A Case Report.

Utilizing pharmacogenomics (PGx) and integrating drug-induced phenoconversion to guide opioid therapies could improve the treatment response and decrease the occurrence of adverse drug events. Genetics contribute to the interindividual differences in opioid response. The purpose of this case report highlights the impact of a PGx-informed medication safety review, assisted by a clinical decision support system, in mitigating the drug-gene and drug-drug-gene interactions (DGI and DDGI, respectively) that increase the risk of an inadequate drug response and adverse drug events (ADEs). This case describes a 69-year-old female who was referred for PGx testing for uncontrolled chronic pain caused by osteoarthritis and neuropathy. The clinical pharmacist reviewed the PGx test results and medication regimen and identified several (DGIs and DDGIs, respectively) at Cytochrome P450 (CYP) 2C19 and CYP2D6. The recommendations were to: (1) switch tramadol to buprenorphine transdermal patch, an opioid with lower potential for ADEs, to mitigate a CYP2D6 DDGI; (2) gradually discontinue amitriptyline to alleviate the risk of anticholinergic side effects, ADEs, and multiple DDGIs; and (3) optimize the pregabalin. The provider and the patient agreed to implement these recommendations. Upon follow-up one month later, the patient reported an improved quality of life and pain control. Following the amitriptyline taper, the patient experienced tremors in the upper and lower extremities. When the perpetrator drug, omeprazole, was stopped, the metabolic capacity was no longer impeded; the patient experienced possible amitriptyline withdrawal symptoms due to the rapid withdrawal of amitriptyline, which was reinitiated and tapered off more slowly. This case report demonstrates a successful PGx-informed medication safety review that considered drug-induced phenoconversion and mitigated the risks of pharmacotherapy failure, ADEs, and opioid misuse.

A functional approach towards the design, development, and test of an affordable dynamic prosthetic foot.

Humanitarian actors involved in physical rehabilitation, such as the International Committee of the Red Cross (ICRC), usually provide their beneficiaries with lower-limb prostheses comprising Solid Ankle Cushion Heel (SACH) feet as these are considered appropriate (price, durability, low profile to fit a majority of patients, appearance) and reliable for all ambulation levels. However, individuals in low-resource settings having higher ambulation abilities would greatly benefit from dynamic prosthetic feet with improved biomechanics and energy storage and release. Some attempts tried to address this increasing need (e.g. Niagara Foot) but most products proposed by large manufacturers often remain unaffordable and unsuitable to the context of low-resource settings. The design requirements and a price target were defined in partnership with the ICRC according to their initial assessment and used as a starting point for the development process and related technological choices. Numerical simulation and modeling were used to work on the design and to determine the required materials properties (mechanical, chemical, wear), and a cost modeling tool was used to select suitable materials and relevant processing routes (price vs. performance). A prosthetic foot comprising an internal keel made of composite materials, a filling foam, and a cosmetic shell with a foot shape was developed. Manufacturing processes meeting the cost criteria were identified and prototype feet were produced accordingly. These were successfully tested using a compression testing system before gait analyses were performed in the laboratory with non-amputees wearing testing boots. After validation in laboratory conditions, the prototype foot was tested in the field (Vietnam) with 11 trans-tibial unilateral amputees, who showed an increased mobility compared with the SACH foot. The collaboration of different research fields led to the development of a prosthetic foot which met the technical requirements determined by the ICRC's specific needs in its field of operation. The materials and selected production processes led to a manufacturing cost of less than 100 USD per part.

On the durability of surgical masks after simulated handling and wear.

After the spread of COVID-19, surgical masks became highly recommended to the public. They tend to be handled and used multiple times, which may impact their performance. To evaluate this risk, surgical masks of Type IIR were submitted to four simulated treatments: folding, ageing with artificial saliva or sweat and washing cycles. The air permeability, mechanical integrity, electrostatic potential, and filtration efficiency (FE) of the masks were measured to quantify possible degradation. Overall, air permeability and mechanical integrity were not affected, except after washing, which slightly degraded the filtering layers. Electrostatic potential and FE showed a strong correlation, highlighting the role of electrostatic charges on small particle filtration. A slight decrease in FE for 100 nm particles was found, from 74.4% for the reference masks to 70.6% for the mask treated in saliva for 8 h. A strong effect was observed for washed masks, resulting in FE of 46.9% (± 9.5%), comparable to that of a control group with no electrostatic charges. A dry store and reuse strategy could thus be envisaged for the public if safety in terms of viral and bacterial charge is ensured, whereas washing strongly impacts FE and is not recommended.

Physiologically Based Pharmacokinetic Modeling to Assess the Impact of CYP2D6-Mediated Drug-Drug Interactions on Tramadol and O-Desmethyltramadol Exposures via Allosteric and Competitive Inhibition.

Tramadol is an opioid medication used to treat moderately severe pain. Cytochrome P450 (CYP) 2D6 inhibition could be important for tramadol, as it decreases the formation of its pharmacologically active metabolite, O-desmethyltramadol, potentially resulting in increased opioid use and misuse. The objective of this study was to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol pharmacokinetics using quinidine and metoprolol as prototypical perpetrator drugs. A physiologically based pharmacokinetic model for tramadol and O-desmethyltramadol was developed and verified in PK-Sim version 8 and linked to respective models of quinidine and metoprolol to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol exposure. Our results show that there is a differentiated impact of CYP2D6 inhibitors on tramadol and O-desmethyltramadol based on their mechanisms of inhibition. Following allosteric inhibition by a single dose of quinidine, the exposure of both tramadol (51% increase) and O-desmethyltramadol (52% decrease) was predicted to be significantly altered after concomitant administration of a single dose of tramadol. Following multiple-dose administration of tramadol and a single-dose or multiple-dose administration of quinidine, the inhibitory effect of quinidine was predicted to be long (≈42 hours) and to alter exposure of tramadol and O-desmethyltramadol by up to 60%, suggesting that coadministration of quinidine and tramadol should be avoided clinically. In comparison, there is no predicted significant impact of metoprolol on tramadol and O-desmethyltramadol exposure. In fact, tramadol is predicted to act as a CYP2D6 perpetrator and increase metoprolol exposure, which may necessitate the need for dose separation.

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.

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.

Quantifying Anticholinergic Burden and Sedative Load in Older Adults with Polypharmacy: A Systematic Review of Risk Scales and Models.

BACKGROUND: Patients taking medication with high anticholinergic and sedative properties are at increased risk of experiencing poor cognitive and physical outcomes. Therefore, precise quantification of the cumulative burden of their drug regimen is advisable. There is no agreement regarding which scale to use to simultaneously quantify the burden associated with medications. OBJECTIVES: The objective of this review was to assess the strengths and limitations of available tools to quantify medication-related anticholinergic burden and sedative load in older adults. We discuss specific limitations and agreements between currently available scales and models and propose a comprehensive table combining drugs categorized as high, moderate, low, or no anticholinergic or sedative activity as excerpted from the selected studies. METHODS: A targeted search was carried out using the National Library of Medicine through PubMed using medical subject heading terms and text words around the following search terms: (anticholinergic OR sedative) AND (load OR burden OR scale) for studies published between 1 January 1945 and 5 June 2021. In addition, the following databases were searched using the same terms: MEDLINE-EBSCO, APA PsycInfo, CINAHL Plus, Cochrane Library, Scopus, OAIster, OVID-MEDLINE, Web of Science, and Google Scholar. Screening by titles was followed by an abstract and full-text review. After blind evaluation, agreement between reviewers was reached to establish drug characteristics and categories. RESULTS: After 3163 articles were identified, 13 were included: 11 assigned risk scores to anticholinergic drugs and two to sedative drugs. Considerable variability between anticholinergic scales was observed; scales included between 27 and 548 drugs. We generated a comprehensive table combining the anticholinergic and sedative activities of drugs evaluated and proposed a categorization of these drugs based on available scientific and clinical evidence. Our table combines information about 642 drugs and categorizes 44, 25, 99, and 474 drugs as high, moderate, low, or no anticholinergic and sedative activity, respectively. CONCLUSIONS: Variability and inconsistency exists among scales used to categorize drugs with anticholinergic or sedative burden. In this review, we provide a comprehensive table that proposes a new categorization of these drugs. A longitudinal study will be required to validate the new proposed anticholinergic and sedative burden catalog in an evidence-based manner.

Use of Drug Claims Data and a Medication Risk Score to Assess the Impact of CYP2D6 Drug Interactions among Opioid Users on Healthcare Costs.

Cytochrome P450 2D6 (CYP2D6) activity is highly variable due to several factors, including genetic polymorphisms and drug-drug-gene interactions. Hydrocodone, oxycodone, codeine, and tramadol the most commonly prescribed CYP2D6-activated opioids for pain. However, the co-administration of CYP2D6 interacting drugs can modulate CYP2D6-medicated activation of these opioids, affecting drug analgesia, effectiveness, and safety, and can impact healthcare costs. A retrospective, observational cohort analysis was performed in a large (n = 50,843) adult population. This study used drug claims data to derive medication risk scores and matching propensity scores to estimate the effects of opioid use and drug-drug interactions (DDIs) on medical expenditures. 4088 individuals were identified as opioid users; 95% of those were prescribed CYP2D6-activated opioids. Among those, 15% were identified as being at risk for DDIs. Opioid users had a significant increase in yearly medical expenditure compared to non-opioid users ($2457 vs. $1210). In matched individuals, average healthcare expenditures were higher for opioid users with DDIs compared to those without DDIs ($7841 vs. $5625). The derived medication risk score was higher in CYP2D6 opioid users with interacting drug(s) compared to no DDI (15 vs. 12). Higher costs associated with CYP2D6 opioid use under DDI conditions suggest inadequate CYP2D6 opioid prescribing practices. Efforts to improve chronic opioid use in adults should reduce interacting drug combinations, especially among patients using CYP2D6 activated opioids.

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.