Pharmacodynamic Drug Interactions Research Articles

Analisis Interaksi Obat Secara Farmakokinetik dan Farmakodinamik Terhadap Pasien Nefropati Diabetik di Rumah Sakit X Kota Jambi Tahun 2022

Diabetic nephropathy (ND) is a complication of diabetes in the kidney. Nephropathy, or kidney disease, is the leading cause of death and disability in diabetes. The first clinical manifestation of diabetic nephropathy is microalbuminuria. If a patient is diagnosed with microalbuminuria, the development of end-stage renal and cardiovascular disease can be prevented by controlling blood pressure, glucose, and lipids. This study aimed to determine pharmacokinetic and pharmacodynamic drug interactions, determine drug interactions and severity in patients, determine the relationship between age and drug severity and gender relationship with drug severity in patients with diabetic nephropathy at X Hospital Jambi City in 2022. The method used in this research is descriptive method. The data collected in this study came from the medical records of diabetic nephropathy patients at X Hospital Jambi City in 2022. The total population in this study was 67 patients with a total sample of 46 patients. The results showed that the highest prevalence in the sample was female (56.52%), elderly patients aged 46-55 years (47.83%), drugs that interact with lantus ˃˂ novorapid (8.43%), patients experiencing drug interactions (71.74%), pharmacodynamic interactions (92.77%), pharmacokinetic interactions (4.82%), minor (10.84%), moderate (78.31%), and major severity (10.84%). The conclusions drawn from this study were based on the interaction mechanism, namely there were 6 cases (7.23%) of pharmacokinetic interactions and 77 cases of pharmacodynamic interactions (92.77%). Based on interactions with 9 cases of minor severity (10.84%), 65 cases of moderate severity (78.31%), and 9 cases of major severity (10.84%). And there is no relationship between the severity of the drug and age and gender.

Pharmacokinetic/pharmacodynamic analysis of ceftazidime/avibactam and fosfomycin combinations in an in vitro hollow fiber infection model against multidrug-resistant Escherichia coli.

Mechanistic understanding of pharmacodynamic interactions is key for the development of rational antibiotic combination therapies to increase efficacy and suppress the development of resistances. Potent tools to provide those insights into pharmacodynamic drug interactions are semi-mechanistic modeling and simulation techniques. This study uses those techniques to provide a detailed understanding with regard to the direction and strength of the synergy of ceftazidime-avibactam and ceftazidime-fosfomycin in a clinical Escherichia coli isolate expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Enhanced killing effects in combination were identified as a driver of the synergy and were translated from static time-kill experiments into the dynamic hollow fiber infection model. These findings in combination with a suppression of the emergence of resistance in combination emphasize a potential clinical benefit with regard to increased efficacy or to allow for dose reductions with maintained effect sizes to avoid toxicity.

Management of the interactions’ risks when using phytomedicines in children

phytomedicines play an essential role in the treatment of children's diseases. Means of
 plant origin have a better safety profile, and due to the content of biologically active substances, they af-fect various links of pathological processes. However, data on the safety and efficacy of phytomedicines
 in children are limited and mostly derived from studies in adults. In addition, there are risks of pharma-cokinetic and pharmacodynamic drug interactions. This study aims to study the risks of interaction when
 using phytomedicines and drugs in children. 100 parents participated in the study, most of whom had1 or 2 children. An analysis of the pharmacotherapy courses of 50 children was also done. It has beenestablished that parents when choosing medicines for children, consider their origin. Thus, more than70% of respondents consider phytomedicines to be safer for children and choose them for the treatmentof acute respiratory viral infections (73%), diseases of the throat (64%), oral cavity (59%), disorders ofthe gastrointestinal tract (28%) and others. The phytomedicines of choice were: Chlorophyllip, Sinupret,Wormil Phyto, Proteflazid, Darsil, Cholelesan, etc., which 80% of respondents used in combination withother medicinal products and without a doctor's prescription (75% of respondents). It was revealed that
 10% of respondents noted the appearance of undesirable reactions after using phytomedicines, in com-bination with other medicinal products in children, the manifestations of which were: allergic reactions,
 digestive disorders, headache/dizziness. Based on the results of the analysis of the pharmacotherapycourses, it was established that the children received an average of 5.8 ± 1.7 medicines. In particular,28% received 2 or more phytomedicines. In more than 40% of children, the risks of pharmacokineticinteraction of phytomedicines with other medicinal products were revealed. Thus, 10% received herbal
 remedies based on St. John's wort, which is a CYP3A4 inducer and reduces the effectiveness of albenda-zole, omeprazole, pantoprazole, and levocetirizine. While more than 30% of children received products
 based on turmeric, silymarin, or grapefruit extract, which are strong CYP3A4 inhibitors. Risks of phar-macokinetic interaction at the stage of absorption (6% of children) were associated with the use of flax
 and plantain seeds. In 10% of children, the risk of pharmacodynamic interaction due to the use of thickeucalyptus leaf extract and an antiseptic agent was revealed. Therefore, when using phytomedicines in
 children, it is necessary to consider the risks of drug interactions. Phytomedicines can affect the pharmacokinetics of other drugs and change the realization of the clinical effect. When choosing and usingphytomedicines the interaction of the doctor-pharmacist-parent is essential.

Pharmacokinetics and pharmacodynamics of Rh2 and aPPD ginsenosides in prostate cancer: a drug interaction perspective.

Ginsenoside Rh2 and its aglycon (aPPD) are one of the major metabolites from Panax ginseng. Preclinical studies suggest that Rh2 and aPPD have antitumor effects in prostate cancer (PCa). Our aims in this review are (1) to describe the pharmacokinetic (PK) properties of Rh2 and aPPD ginsenosides; 2) to provide an overview of the preclinical findings on the use of Rh2 and aPPD in the treatment of PCa; and (3) to highlight the mechanisms of its PK and pharmacodynamic (PD) drug interactions. Increasing evidence points to the potential efficacy of Rh2 or aPPD for PCa treatment. Based on the laboratory studies, Rh2 or aPPD combinations revealed an additive or synergistic interaction or enhanced sensitivity of anticancer drugs toward PCa. This review reveals that enhanced anticancer activities were demonstrated in preclinical studies through interactions of Rh2 and/or aPPD with the proteins related to PK (e.g., cytochrome P450 enzymes, transporters) or PD of the other anticancer drugs or PCa signaling pathways. In conclusion, combining Rh2 or aPPD with anti-prostate cancer drugs leads to PK or PD interactions which could facilitate either therapeutically beneficial or toxic effects.

Pharmacodynamic and Pharmacokinetic Drug Interactions between Fexuprazan, a Novel Potassium-Competitive Inhibitor, and Aspirin, in Healthy Subjects

Acid-reducing agents are commonly used for the prevention of aspirin-induced gastrointestinal complications such as peptic ulcers. As a novel potassium-competitive acid blocker, fexuprazan is expected to prevent aspirin-induced gastrointestinal complications. This randomized, open-label study aimed to evaluate the pharmacodynamic and pharmacokinetic interactions between aspirin and fexuprazan in healthy Koreans. Subjects randomized to the aspirin group received 500 mg aspirin in combination with 80 mg fexuprazan. For the fexuprazan group, fexuprazan 80 mg was administered alone and then in combination with aspirin 500 mg. Platelet aggregation inhibited by aspirin and the pharmacokinetic parameters of aspirin and fexuprazan were compared between monotherapy and combination therapy. A total of 22 subjects completed the study. The platelet aggregation-inhibitory activity and systemic exposure to aspirin were not significantly affected by fexuprazan coadministration. The systemic exposure of fexuprazan was decreased up to 20% by aspirin coadministration, which was not regarded as clinically meaningful considering the previously reported exposure-response relationship. In conclusion, there were no clinically relevant pharmacodynamic or pharmacokinetic interactions between aspirin and fexuprazan. This finding suggests the potential of fexuprazan for the prevention of aspirin-induced gastrointestinal complications, serving as a baseline for optimizing its therapeutic application with aspirin.

Identification of Drug Interactions on Prescribing Patients with Type 2 Diabetes Mellitus at Puskesmas X

Indonesia occupies the top ten countries with the highest population of people with Diabetes Mellitus in the world, which is ranked 5th with a range of 19.5 million people, and it is estimated that in 2045 it will increase to 28.6 million. Diabetes Mellitus is a chronic disease that is often accompanied by complications. This can lead to drug interactions. Drug interactions can affect the body's response to treatment. The purpose of this study was to determine the percentage of drug interactions on prescriptions received by patients with Type 2 Diabetes Mellitus at a health center in Surakarta. This research is a descriptive observational study. Data collection was carried out retrospectively through tracking records of drug use by patients with Diabetes Mellitus Type 2 at Puskesmas X. The sample in this study was all prescriptions for patients with Diabetes Mellitus Type 2 in April-December 2018. The results showed that the most prescribed antihyperglycemic drugs were 38, 89%, analgesics 16.20%, vitamins 14.2%, and antihypertensives 12.19%. The types of drugs that were most widely used in prescriptions were metformin at 18.98%, amlodipine at 11.57%, and paracetamol at 8.64%. The potential incidence of drug interactions is 62.5% of prescriptions. The conclusion of this study showed that the potential for pharmacokinetic drug interactions was 1.36%, the potential for pharmacodynamic drug interactions was 46.94%, and the incidence of unknown drug interactions was 51.70%.

Comorbid epilepsy and depression-pharmacokinetic and pharmacodynamic drug interactions.

Background: Major depressive disorder may be encountered in 17% of patients with epilepsy and in patients with drug-resistant epilepsy its prevalence may reach 30%. This indicates that patients with epilepsy may require antidepressant treatment. Purpose: Both pharmacodynamic and pharmacokinetic interactions between antiepileptic (antiseizure) and antidepressant drugs have been reviewed. Also, data on the adverse effects of co-administration of antiepileptic with antidepressant drugs have been added. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. Methods: The review of relevant literature was confined to English-language publications in PUBMED databases. Table data show effects of antidepressants on the seizure susceptibility in experimental animals, results of pharmacodynamic interactions between antiepileptic and antidepressant drugs mainly derived from electroconvulsions in mice, as well as results concerning pharmacokinetic interactions between these drugs in clinical conditions. Conclusion: Antidepressant drugs may exert differentiated effects upon the convulsive threshold which may differ in their acute and chronic administration. Animal data indicate that chronic administration of antidepressants could reduce (mianserin, trazodone) or potentiate the anticonvulsant activity of some antiepileptics (fluoxetine, reboxetine, venlafaxine). There are also examples of neutral interactions (milnacipran).

New In Vitro Interaction-Parasite Reduction Ratio Assay for Early Derisk in Clinical Development of Antimalarial Combinations.

The development and spread of drug-resistant phenotypes substantially threaten malaria control efforts. Combination therapies have the potential to minimize the risk of resistance development but require intensive preclinical studies to determine optimal combination and dosing regimens. To support the selection of new combinations, we developed a novel in vitro-in silico combination approach to help identify the pharmacodynamic interactions of the two antimalarial drugs in a combination which can be plugged into a pharmacokinetic/pharmacodynamic model built with human monotherapy parasitological data to predict the parasitological endpoints of the combination. This makes it possible to optimally select drug combinations and doses for the clinical development of antimalarials. With this assay, we successfully predicted the endpoints of two phase 2 clinical trials in patients with the artefenomel-piperaquine and artefenomel-ferroquine drug combinations. In addition, the predictive performance of our novel in vitro model was equivalent to that of the humanized mouse model outcome. Last, our more informative in vitro combination assay provided additional insights into the pharmacodynamic drug interactions compared to the in vivo systems, e.g., a concentration-dependent change in the maximum killing effect (Emax) and the concentration producing 50% of the killing maximum effect (EC50) of piperaquine or artefenomel or a directional reduction of the EC50 of ferroquine by artefenomel and a directional reduction of Emax of ferroquine by artefenomel. Overall, this novel in vitro-in silico-based technology will significantly improve and streamline the economic development of new drug combinations for malaria and potentially also in other therapeutic areas.

Optimized Rhombic Experimental Dynamic Checkerboard Designs to Elucidate Pharmacodynamic Drug Interactions of Antibiotics

PurposeQuantification of pharmacodynamic interactions is key in combination therapies, yet conventional checkerboard experiments with up to 10 by 10 combinations are labor-intensive. Therefore, this study provides optimized experimental rhombic checkerboard designs to enable an efficient interaction screening with significantly reduced experimental workload.MethodsBased on the general pharmacodynamic interaction (GPDI) model implemented in Bliss Independence, a novel rhombic ‘dynamic’ checkerboard design with quantification of bacteria instead of turbidity as endpoint was developed. In stochastic simulations and estimations (SSE), the precision and accuracy of interaction parameter estimations and classification rates of conventional reference designs and the newly proposed rhombic designs based on effective concentrations (EC) were compared.ResultsAlthough a conventional rich design with 20-times as many combination scenarios provided estimates of interaction parameters with higher accuracy, precision and classification rates, the optimized rhombic designs with one natural growth scenario, three monotherapy scenarios per combination partner and only four combination scenarios were still superior to conventional reduced designs with twice as many combination scenarios. Additionally, the rhombic designs were able to identify whether an interaction occurred as a shift on maximum effect or EC50 with > 98%. Overall, effective concentration-based designs were found to be superior to traditional standard concentrations, but were more challenged by strong interaction sizes exceeding their adaptive concentration ranges.ConclusionThe rhombic designs proposed in this study enable a reduction of resources and labor and can be a tool to streamline higher throughput in drug interaction screening.

Evaluation of Pharmacodynamic interaction between Tinospora Cordifolia Alcoholic extract and Gliclazide : An herb-drug interaction study

Many diabetic people today consume herbs or herbal formulations along with prescription and non-prescription medications which may result in the herb-drug interaction Tinospora Cordifolia, with berberine being one of the most abundant active phytoconstituent widely used as an antidiabetic While Gliclazide is indicated to treat type 2 diabetes mellitus whichacts asan insulin secretagogue .T. Cordifolia is a potent inhibitor of CYP2C9 and Gliclazide is known to be metabolized by this enzyme. Potential Pharmacodynamic herb drug interaction might be possible in case of co administration of both. The pharmacodynamic interaction between TCE and Gliclazide was evaluated on hypoglycemic activity in normal and streptozotocinnicotinamide-induced diabetic rats. The study was conducted in 2 parts viz. acute study and sub-acute study in both normal and diabetic animals. The serum triglyceride level and histopathology of pancreawas performed to assess effect on glucose metabolism and pancreas.FTIR Analysis was also carried out to evaluate the interaction between functional groups. The combination showed pharmacodynamic interaction as reduction the time of onset of action and increasing the duration of action of gliclazide when administered in combination with T. cardiofolia. In FTIR studies of combination showed no physical interaction betweenfunctional groups suggesting both drugs might be acting on the different receptors. The study concludes that the combination of Gliclazide with TCE showed an increase in the hypoglycemic effect as compared to the gliclazide alone in STZ-NIC induced diabetic rats. This might be utilized clinically as a beneficial drug interaction in patients after thorough investigations in clinical studies

Drug-Drug Interactions of Artemisinin-Based Combination Therapies in Malaria Treatment: A Narrative Review of the Literature.

Artemisinin is an antimalarial compound derived from the plant Artemisia annua L., also known as sweet wormwood. According to the World Health Organization, artemisinin-based combination therapy (ACT) is an essential treatment for malaria, specifically Plasmodium falciparum, which accounts for most malaria-related mortality. ACTs used to treat uncomplicated malaria include artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-sulphadoxine-pyrimethamine, and dihydroartemisinin-piperaquine. Although the mechanism of action and clinical capabilities of artemisinin in malaria treatment are widely known, more information on the potential for drug interactions needs to be further investigated. Some studies show pharmacokinetic and pharmacodynamic drug interactions with HIV antiviral treatment but few studies have been conducted on most other drug classes. Based on known genotypes of cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A are primarily involved in the metabolism of artemisinin and its derivatives. Reduced functions in these enzymes can lead to subtherapeutic concentrations of the active metabolite, dihydroartemisinin, that may cause treatment failure, which has been shown in some studies with cardiovascular, antibiotic, and antiparasitic drugs. Although the clinical importance remains unclear to date, clinicians should be aware of potential drug-drug interactions and monitor patients on ACT closely.

Acute Hyperkinetic Movement Disorders as a Multifactorial Pharmacodynamic Drug Interaction Between Methylphenidate and Risperidone in Children and Adolescents.

Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics. We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants-antipsychotics in the US Food and Drug Administration Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants-antipsychotics through January 13, 2020. We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants-antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n = 23 [64%]), followed by amphetamine products (n = 9 [25%]) and atomoxetine (n = 4 [11%]). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n = 20 [56%]). Most of the cases were reported in boys (n = 31 [86%]) aged 6 to 12 years (n = 27 [75%]). Approximately 53% of the cases reported a time to onset within 24 hours of the drug change. Acute dystonic reactions (n = 27 [75%]) were the most frequently reported movement disorder. As outlined in changes to the US prescribing information for all methylphenidate and risperidone products, health care professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder.

Drug Interactions Affecting Antiarrhythmic Drug Use.

Antiarrhythmic drugs (AAD) play an important role in the management of arrhythmias. Drug interactions involving AAD are common in clinical practice. As AADs have a narrow therapeutic window, both pharmacokinetic as well as pharmacodynamic interactions involving AAD can result in serious adverse drug reactions ranging from arrhythmia recurrence, failure of device-based therapy, and heart failure, to death. Pharmacokinetic drug interactions frequently involve the inhibition of key metabolic pathways, resulting in accumulation of a substrate drug. Additionally, over the past 2 decades, the P-gp (permeability glycoprotein) has been increasingly cited as a significant source of drug interactions. Pharmacodynamic drug interactions involving AADs commonly involve additive QT prolongation. Amiodarone, quinidine, and dofetilide are AADs with numerous and clinically significant drug interactions. Recent studies have also demonstrated increased morbidity and mortality with the use of digoxin and other AAD which interact with P-gp. QT prolongation is an important pharmacodynamic interaction involving mainly Vaughan-Williams class III AAD as many commonly used drug classes, such as macrolide antibiotics, fluoroquinolone antibiotics, antipsychotics, and antiemetics prolong the QT interval. Whenever possible, serious drug-drug interactions involving AAD should be avoided. If unavoidable, patients will require closer monitoring and the concomitant use of interacting agents should be minimized. Increasing awareness of drug interactions among clinicians will significantly improve patient safety for patients with arrhythmias.

TREN PENGGUNAAN ANTIBIOTIKA LINI 3 DI RS X BEKASI PERIODE TRIWULAN I TAHUN 2020 DIBANDINGKAN DENGAN TRIWULAN IV TAHUN 2019

Antibiotics are the most widely used drugs in the treatment of infections caused by bacteria. Resistance of microorganisms to antibiotics, pharmacokinetic and pharmacodynamic factors, drug interactions and side effects and cost factors are needed to be considered in their use. The use of antibiotics needs to be evaluated quantitatively and qualitatively. The study was conducted to determine and evaluate the use of line 3 antibiotics quantitatively in the X Bekasi Hospital in the first quarter of 2020 compared to the fourth quarter of 2019. It was descriptive study with retrospective data collection using total sampling technique. There are 13 types of antibiotics that are included in the line 3 antibiotics used at X Bekasi Hospital. The percentage of use of line 3 antibiotics in the first quarter of 2020 compared to the fourth quarter of 2019 increased by 26.9% for the use of amikacin 250 mg injection but decreased by 100% for the use of amikacin 500 mg injection, increased by 17.8% for the use of meropenem 0.5 g injection but decreased by 16.1% for the use of meropenem 1 g injection, decreased by 100% for the use of imipenem-cilastatin injection, linezolid 600 mg injection and vancomycin 500 mg injection, decreased by 212.5%, 53.6%, 41.2% and 69.2% each for the use of doripenem 500 mg injection, decreased, ceftazidime 1 g injection, cefepime 1 g injection and piperacillin tazobactam injection, and increased 75% for the use of tigecycline 50 mg injection. The use of line 3 antibiotics in X Bekasi Hospital was very large and varied in the fourth quarter of 2019 compared to the first quarter of 2020. A very significant amount was seen in the use of imipenem-cilastatin injection, linezolid 600 mg injection and vancomycin 500 mg injection.

Oxycodone-Related Deaths: The Significance of Pharmacokinetic and Pharmacodynamic Drug Interactions.

Background and ObjectivesOxycodone is frequently prescribed as well as detected in postmortem cases. Concurrent use of pharmacodynamically or pharmacokinetically interacting drugs can cause adverse effects or even fatal intoxication. The aims of this study were to investigate differences in prescriptions for and toxicological findings of pharmacodynamically and pharmacokinetically interacting drugs in fatal oxycodone-related intoxications and other causes of death. We also aimed to investigate the differences in prevalence of oxycodone prescriptions, and the detected postmortem oxycodone concentrations between fatal oxycodone-related intoxications and other causes of death.MethodsForensic autopsy cases (2012–2018) where oxycodone was identified in femoral blood (n = 1236) were included. Medical history and prescription data were retrieved from national databases and linked to the forensic toxicology findings.ResultsOxycodone-related deaths were found to have higher blood concentrations of oxycodone (median 0.30 µg/g vs. 0.05 µg/g) and were less likely to have a prescription for oxycodone (OR 0.62) compared to nonintoxication deaths. Pharmacodynamically interacting drugs were prescribed in 79% and found in blood in 81% of the cases. Pharmacokinetically interacting drugs were rarely prescribed (1%). Oxycodone-related deaths were more likely to have prescriptions for a pharmacodynamically interacting drug (OR 1.7) and more often have co-findings of one or multiple pharmacodynamically interacting drugs (OR 5.6).ConclusionThe results suggest that combined use of oxycodone and pharmacodynamically interacting drugs is associated with oxycodone-related death and that non-medical use of oxycodone is a potential risk factor for oxycodone-related intoxication.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13318-021-00750-9.

Individual Pharmacotherapy Management (IPM) - I: a group-matched retrospective controlled clinical study on prevention of complicating delirium in the elderly trauma patients and identification of associated factors

BackgroundDelirium is one of the most frequent complications in hospitalized elderly patients with additional costs such as prolongation of hospital stays and institutionalization, with risk of reduced functional recovery, long-term cognitive impairment, and increased morbidity and mortality. We analyzed the effect of individual pharmacotherapy management (IPM) in the University Hospital Halle in geriatric trauma patients on complicating delirium and aimed to identify associated factors.MethodsIn a retrospective controlled clinical study of 404 hospitalized trauma patients ≥70 years we compared the IPM intervention group (IG) with a control group (CG) before IPM implementation. Delirium was recorded from the hospital discharge letter. The medication review and data records included baseline data, all medications, diagnoses, electrocardiogram (ECG), laboratory and vital parameters during hospitalization. The IPM internist and the senior trauma physician guaranteed personnel and structural continuity in the implementation of the interdisciplinary patient rounds.ResultsThere was a highly matched congruence between CG and IG in terms of age, gender, residency, BMI, most diagnoses, and injury patterns to compare the two groups. The total number of medications per patient was 11.1 ± 4.9 (CG) versus 10.4 ± 3.6 (IG). Our targeted IPM focus on 6 frontline aspects with reduction of antipsychotics, anticholinergic burden, benzodiazepines, serotonergic opioids, elimination of pharmacokinetic and pharmacodynamic drug interactions and overdosage reduced complicating delirium from 5% to almost zero at 0.5%. The association of IPM with a significant 10-fold reduction, OR = 0.09 [95% CI 0.01–0.7], in univariable regression, maintained of clinical relevance in multivariable regression OR = 0.1 [95% CI 0.01–1.1]. Factors most strongly associated with complicating delirium in univariable regression were cognitive dysfunction, nursing home residency, muscle relaxants, antiparkinsonian agents, xanthines, transient disorientation documented in the fall risk scale, antibiotic-requiring infections, antifungals, antipsychotics, and intensive care stay, the two latter maintaining significance in multivariable regression.ConclusionsIPM is associated with a highly effective prevention of complicating delirium in the elderly trauma patients. For patient safety it should be integrated as an essential preventative contribution. The associated factors help identify patients at risk.

Revisiting CYP2C9-Mediated drug-drug Interactions: A Review

Drug-drug interactions (DDI) are the most common cases that occur in our healthcare in which are very alarming as it may lead to severe complications. Consumption of natural products concomitantly with conventional drugs or treatment using polypharmacy have become the norm that promoting the potential of pharmacokinetic or pharmacodynamic drug interactions as the combination may mimic, increase or reduce the effects of the drug or the herb which could result in clinically significant interactions. CYP2C9 is the second major isoform from CYP450 family of enzyme, which responsible in phase 1 metabolism of 15-20% clinical drugs. Up to date, many substrates of CYP2C9 have been discovered and these discoveries may open more doors for potential drug-drug interactions in patients. Many studies have been done to evaluate the effect of drugs on the activity of CYP2C9 and how it influenced the effectiveness of therapy in patients. Various data regarding CYP2C9 related DDI from in vitro, in vivo and clinical studies were critically discussed in this review to provide insights on how these drugs and natural products may exhibit drug interactions clinically. This review could be beneficial reference material for health practitioners and researchers.

Impact of Anticonvulsant - Methotrexate Interactions on High Dose Methotrexate Clearance and Outcomes in Patients with Primary CNS Lymphoma

Background: Patients with primary CNS Lymphoma (PCNSL) often present with neurologic complications such as focal defects, neuropsychiatric symptoms, increased intracranial pressure, aphasia, seizures, and ocular symptoms which require initiation of prophylactic or therapeutic anticonvulsants. Most anticonvulsants are notorious for their pharmacodynamic and pharmacokinetic drug interactions. The cornerstone of PCNSL therapy is the utilization of high-dose methotrexate (HD-MTX). The pharmacokinetics of HD-MTX are uniquely sensitive to both disease biology and drug interactions. Due to the importance of both HD-MTX and anticonvulsants in PCNSL patients, these medications are frequently given in concert with one another despite theoretical and proven drug interactions published in the literature. This is a retrospective analysis of patients treated with a modified R-MPV regimen (rituximab, methotrexate, procarbazine, vincristine alternating with intrathecal methotrexate) and the effects of various anticonvulsants on HD-MTX clearance.Methods: Patients ≥18 years of age with a biopsy proven diagnosis of PCNSL at Roswell Park Comprehensive Cancer Center who received R-MPV between January 2002 and December 2019 were included in this retrospective analysis. The electronic health record of each patient was reviewed for specific patient demographics, laboratory results, confounding drug interactions, toxicity, and treatment outcomes. Descriptive statistics were computed for all categorical variables. The time to MTX clearance in hours and the potential impact of concomitant use of various anticonvulsants were assessed using the Wilcoxon Rank Sum test in the case of ordinal responses and the Pearson chi-square test or Fisher's Exact test for categorical variables where appropriate.Results: A total of 67 patients met the inclusion criteria of which 53 patients (79.1%) received anticonvulsants (189 cycles of R-MPV) and 14 did not (69 cycles of R-MPV). Patients who had seizures or frontal brain PCNSL were more likely to receive anticonvulsants (p <0.001). When considering all possible medication interactions with HD-MTX, use of any interacting medication within 48 hours prior to HD-MTX was a predictor of delayed clearance (p = 0.0398). The most common confounding interaction seen in this population were with proton pump inhibitors. Levetiracetam was the most common anticonvulsant used at any point in time during treatment (83.1%). Compared to no anticonvulsant, levetiracetam did not significantly prolong HD-MTX clearance (52.6h v. 72.7h, p = 0.1586). Other anticonvulsants utilized included phenytoin (24.5%), gabapentin (3.8%), valproate (3.8%), carbamazepine (1.9%), lacosamide (1.9%), lamotrigine (1.9%), and phenobarbital (1.9%). Of the patients who received an anticonvulsant, 11 received more than one over the treatment period. Time to clearance of HD-MTX for patients not on an anticonvulsant was 53.8 hours compared to a clearance time of 68.2 hours for those who received an anticonvulsant (p = 0.0571). Patients who received anticonvulsants had a significantly higher complete response rate (79.2% vs 35.7%, p = 0.009), longer progression free survival (25.4 mo vs 3 mo, p = 0.014) and overall survival (56.6 mo vs 4.6 mo, p = 0.002) compared to those who did not (Table 1). There was no difference in grade 3/4 toxicities between anticonvulsants and no anticonvulsants except for thrombocytopenia (p = 0.047) and respiratory side effects (p = 0.035).Conclusion: Anticonvulsants are an essential component to PCNSL therapy in patients on HD-MTX. They are well tolerated, do not alter HD-MTX clearance in a clinically significant manner and may help improve patient outcomes. [Display omitted] DisclosuresTorka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Cluster Gauss-Newton and CellNOpt Parameter Estimation in a Small Protein Signaling Network of Vorinostat and Bortezomib Pharmacodynamics.

Ordinary differential equation (ODE)-based models of signal transduction pathways often contain parameters that are unidentifiable or unmeasurable by experimental data, and calibrating such models to data remains challenging. Here, two efficient parameter estimation methods, cluster Gauss-Newton (CGN) and CellNOpt (CNO), were applied to fit a signaling network model of U266 multiple myeloma cells to the activity dynamics of key proteins in response to vorinostat and/or bortezomib. A logic-based network model was constructed and transformed to 17 ODEs with 79 parameters estimated within broad ranges of biologically plausible values. The top 10% best-fit parameters by both methods had high uncertainties with CV > 50% for the majority of parameters. The root mean square and prediction errors were comparable without statistically significant differences between the two methods. Despite uncertain parameter estimation, protein dynamics after the sequential combination of bortezomib and vorinostat was predicted with reasonable accuracy and precision. Global sensitivity analyses of partial rank correlation coefficients and Sobol sensitivity demonstrated that apoptosis induction was most sensitive to parameters governing the activity of the proteasome-JNK-caspase-8 axis. Simulations revealed that the greatest magnitude of pharmacodynamic drug interactions between bortezomib and vorinostat occurred at caspase-9, AKT, and Bcl-2. Two sequential combinations were explored in silico, and the outcome matched qualitatively with an empirical evaluation of the pharmacodynamic interaction based on cell viability. Overall, the CGN and CNO algorithms performed similarly for this ODE-based network model calibration, and the calibrated model provided meaningful insights into cellular signaling mechanisms in response to pharmacological perturbations.

A Review on Pharmacokinetic and Pharmacodynamic Drug Interactions of Adrenergic β-blockers with Clinically Relevant Drugs-An Overview

Adrenergic β-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the β-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those β-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. β-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, β-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John's wort and Yohimbine. This article focuses on clinically relevant drug interactions of β-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with β-blockers to prevent possible adverse drug interactions.