Clinical treatment and management of invasive fungal disease in recipients of solid organ transplantation / 器官移植

With widespread application of solid organ transplantation (SOT), the incidence of postoperative invasive fungal disease (IFD) in SOT recipients has been increased year by year. In recent years, the awareness of preventive antifungal therapy for SOT recipients has been gradually strengthened. However, the problem of fungal resistance has also emerged, leading to unsatisfactory efficacy of original standardized antifungal regimens. Drug-drug interaction and hepatorenal toxicity induced by drugs are also challenges facing clinicians. In this article, the characteristics of drug-drug interaction and hepatorenal toxicity among triazole, echinocandin and polyene antifungal drugs and immunosuppressants were reviewed, and postoperative preventive strategies for IFD in different types of SOT recipients and treatment strategies for IFD caused by infection of different pathogens were summarized, aiming to provide reference for physicians in organ transplantation and related disciplines.

Pharmaceutical Interventions for Cancer Chemotherapy Utilizing Drug Information / 医薬品情報学

Objective: In patients with specific backgrounds, comprehensive identification of health problems and proactive pharmacist intervention are crucial to providing safe and effective medical care. However, there are insufficient reports on chemotherapy regimen selection and supportive care management in patients taking immunosuppressants. In this study, to circumvent adverse events, pharmacists intervened with a patient administering tacrolimus (TAC) using known information, focusing on multiple factors attributable to the patient in addition to drug interactions.Methods: The patient was a male in their 70s who received palliative chemotherapy for gastric cancer during their dermatomyositis treatment with TAC. Pharmaceutical support for cancer chemotherapy was provided using the following four procedures: (1) Patient information was collected from interviews and electronic medical records to identify patient-specific problems; (2) Basic pharmacological information was collected from tertiary sources, focusing on the interaction between TAC and aprepitant (APR). Furthermore, clinical reports were collected, and the pharmacokinetic drug interaction significance classification system was used for quantitative predictions; (3) The information obtained in steps 1) and 2) was evaluated, and comprehensive proposals linked to the patient information were presented; (4) Adverse events, TAC blood level, and patient outcomes were monitored after treatment initiation.Results: A chemotherapy regimen consisting of S-1/oxaliplatin therapy without APR was selected. The adverse effects were controllable, and the treatment was completed without many adverse events. Meanwhile, TAC adherence was unaffected by cancer chemotherapy, and the TAC blood concentration or dose ratios were controlled within the same range as previously reported.Conclusion: In cancer chemotherapy, for cases with limited evidence or information, comprehensive pharmaceutical support was provided using known patient information, considering multiple patient factors. This report is beneficial as an example of supportive care management by a pharmacist and contributes to providing optimal service in cases with specific backgrounds.

Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus (T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1, and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM. Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug-drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug-drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.

Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients

The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters. Non-alcoholic steatohepatitis (NASH) causes disease-specific alterations to the absorption, distribution, metabolism, and excretion (ADME) processes, including a decrease in protein expression of basolateral uptake transporters, an increase in efflux transporters, and modifications to enzyme activity. This can result in increased drug exposure and adverse drug reactions (ADRs). Our goal was to predict drugs that pose increased risks for ADRs in NASH patients. Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease, mainly non-alcoholic fatty liver disease (NAFLD), 54 of which are known substrates of transporters and/or metabolizing enzymes. Since NASH is the progressive form of NAFLD but is most frequently undiagnosed, we identified other drugs at risk based on NASH-specific alterations to ADME processes. Here, we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH, based on their transport and/or metabolism processes. It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients, especially when eliminated through multiple pathways altered by the disease. Therefore, these results may inform clinicians regarding the selection of drugs for use in NASH patients.

The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation

Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes [e.g., cytochrome P450 3A4 (CYP3A4)] and transporters. Although the regulation of PXR target genes is well-characterized, less is known about the regulation of PXR protein level. By screening an RNAi library, we identified the F-box-only protein 44 (FBXO44) as a novel E3 ligase for PXR. PXR abundance increases upon knockdown of FBXO44, and, inversely, decreases upon overexpression of FBXO44. Further analysis revealed that FBXO44 interacts with PXR, leading to its ubiquitination and proteasomal degradation, and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction. In summary, FBXO44 regulates PXR protein abundance, which has downstream consequences for CYP3A4 levels and drug-drug interactions. The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3 ubiquitin ligase activities will affect PXR-mediated drug metabolism.

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019

Abstract Hepatic injury has been documented in patients with coronavirus disease 2019 (COVID-19). However, pharmacotherapy can frequently impact liver alterations, given the known hepatotoxic potential of drugs not effective to treat COVID-19. The objective of the present study was to evaluate reports of suspected liver reactions to drugs used for treating COVID-19, compare their use for other indications among patients with COVID-19, and assess possible interactions between them. We obtained reports on drugs used to treat COVID-19 (tocilizumab, remdesivir, hydroxychloroquine, and/or lopinavir/ritonavir), registered on June 30, 2020, from the Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard. We then analyzed the risk of developing liver events with these drugs by calculating the reported odds ratios (ROR). We identified 662, 744, and 1381 reports related to tocilizumab, lopinavir/ ritonavir, and hydroxychloroquine use, respectively. The RORs (95% confidence intervals) were 6.32 (5.28-7.56), 6.12 (5.22-7.17), and 9.07 (8.00-10.29), respectively, demonstrating an increased risk of liver events among patients with COVID-19 when compared with uninfected patients. The elevated risk of reporting adverse liver events in patients with COVID-19 who receive these drugs, alone or in combination, highlights the need for careful drug selection and efforts to reduce drug combinations without notable benefits. Similar to any other condition, the use of drugs without established efficacy should be avoided.

Prevalence of Drug Interactions and Potentially Inappropriate Medications Among Geriatric Patients in India.

Aim: The study aimed to determine the prevalence of potential drug-drug interactions (PDDIs) and potentially inappropriate medications (PIMs) among geriatrics. Methods: A prospective observational study was conducted for six months in the Department of Geriatrics, M.S. Ramaiah Teaching Hospital, Bangalore. PDDIs and PIMS were analyzed using micromedex database and Beer's criteria respectively. Results: Among 395 prescriptions, 221(56%) prescriptions showed 559 pDDIs and 41(10.4%) PIMs. Almost 281(50.3%), 260(46.5%), 16(2.7%) and 2(0.3%) pDDIs were categorised as major, moderate, minor and contraindicated respectively. Almost 321(57.5%) were synergistic and 196(35.0%) were antagonistic drug interactions. Pearson correlation value (R) is 0.9957 which showed a strong positive correlation. Conclusion: This study created awareness on drug interactions among geriatrics and help the practitioners to prescribe drugs with a low risk of pDDIs. The authors suggest PIM monitoring in geriatrics to avoid adverse effects and improve patients' quality of life.

An observational study on potential drug-drug interaction among hypertensive patients in a tertiary care hospital

Background: Drug-drug interactions are quite prevalent, especially in the geriatric population with comorbidities. It affects the effectiveness, safety, and tolerability of the medications they use. Aims and Objectives: This study aims to analyze and identify potential drug-drug interactions (pDDIs) in hypertensive patients using Medscape databases. Materials and Methods: A prospective and observational study was conducted in the Hypertension clinic of KMC, Chennai, for 3 months during November 2019–January 2020. Hypertensive patients of both sexes attending hypertension clinics with an age of more than 18 years and taking more than two antihypertensive drugs were included in the study. The use of Medscape databases enabled the appropriate data to be gathered and evaluated for pDDIs. Results: Three hundred patients in all were enrolled for the trial. One hundred and forty out of the 300 patients had pDDIs. Out of 140 patients, the majority (55%) were between the ages of 40 and 60. Males (56.4%) had a higher prevalence of pDDIs than females (43.6%). Atenolol, enalapril, and furosemide were the most frequently used medications in the present study that caused pDDIs, accounting for 29.8%, 19.5%, and 18.6%, respectively. Conclusion: The prevalence of pDDIs was found to be 46.6% overall, and an increase in comorbidities and polypharmacy were revealed to be important risk factors for the emergence of several pDDIs. Most of the antihypertensives were shown to interact frequently with calcium carbonate.

Elaboration of guideline for monitoring in relative bioavailability / pharmaceutical bioequivalence study by the sponsor / Elaboração de diretriz para monitoramento em biodisponibilidade relativa / estudo de bioequivalência farmacêutica pelo patrocinador / Elaboración de la directriz para el seguimiento en la biodisponibilidad relativa / estudio de bioequivalencia farmacéutica por parte del promotor

For registration of generic and similar drugs, it is necessary to carry out pharmaceutical equivalence (PE) tests and pharmaceutical bioequivalence (PB). To carry out these tests, duly qualified research centers are contracted, which need to be monitored by the sponsor who is legally responsible for the activities. To this end, it is the recommendation of the Document of the Americas, periodic monitoring to verify compliance with quality requirements, Standard Operating Procedures, Good Clinical Practices (GCP), Good Laboratory Practices (GLP), of the applicable regulatory framework, as well as of compliance with the study protocol. Thus, monitoring is a methodical and documented process to evaluate the degree of adhesion of the center to the planned design for the evaluation of the formulations. To this end, the implementation of a standardized and easily completed guideline is a very important tool to guarantee a consistent evaluation and maintain the organizational memory of the evaluated items by monitors designated by the sponsor, contributing to the constant improvement of the contracted centers and supporting traceability of the studies. This work provided a systemic view of the evidence process related mainly to pharmaceutical bioequivalence, with the monitoring guideline summarizing the items of greatest relevance to be verified.

Para registro de medicamentos genéricos e similares, é necessária a realização de testes de equivalência farmacêutica (EF) e bioequivalência farmacêutica (BF). Para a realização desses testes, são contratados centros de pesquisa devidamente habilitados, que precisam ser monitorados pelo patrocinador legalmente responsável pelas atividades. Há também a recomendação do Documento das Américas de realizar monitoramentos periódicos para verificar o cumprimento dos requisitos de qualidade, Procedimentos Operacionais Padrão, Boas Práticas Clínicas (BPC), Boas Práticas de Laboratório (BPL), de marco regulatório aplicável, bem como de cumprimento do protocolo do estudo. Assim, o monitoramento é um processo metódico e documentado para avaliar o grau de adesão do centro ao desenho planejado para a avaliação das formulações. Para tanto, a implantação de uma diretriz padronizada e de fácil preenchimento é uma ferramenta muito importante para garantir uma avaliação consistente e manter a memória organizacional dos itens avaliados por monitores designados pelo patrocinador, contribuindo para a melhoria constante dos centros contratados e apoiando rastreabilidade dos estudos. Este artigo forneceu uma visão sistêmica do processo de evidência relacionado principalmente à bioequivalência farmacêutica, com a diretriz de monitoramento resumindo os itens de maior relevância a serem verificados.

Para el registro de medicamentos genéricos y similares, es necesario realizar pruebas de equivalencia farmacéutica (EP) y de bioequivalencia farmacéutica (PB). Para llevar a cabo estas pruebas se contratan centros de investigación debidamente cualificados, que deben ser supervisados por el promotor, que es el responsable legal de las actividades. Para ello, es la recomendación del Documento de las Américas, el monitoreo periódico para verificar el cumplimiento de los requisitos de calidad, los Procedimientos Operativos Estándar, las Buenas Prácticas Clínicas (BPC), las Buenas Prácticas de Laboratorio (BPL), del marco regulatorio aplicable, así como del cumplimiento del protocolo del estudio. Así, la monitorización es un proceso metódico y documentado para evaluar el grado de adhesión del centro al diseño previsto para la evaluación de las formulaciones. Para ello, la implantación de una pauta estandarizada y de fácil cumplimentación es una herramienta muy importante para garantizar una evaluación consistente y mantener la memoria organizativa de los elementos evaluados por parte de los monitores designados por el promotor, contribuyendo a la mejora constante de los centros contratados y apoyando la trazabilidad de los estudios. Este trabajo proporcionó una visión sistémica del proceso de evidencia relacionado principalmente con la bioequivalencia farmacéutica, con la pauta de monitoreo que resume los ítems de mayor relevancia a ser verificados.

Predictores de potenciales reacciones adversas e interacciones medicamentosas en pacientes post accidente cerebrovascular en Perú

Objetivo Identificar los predictores clínicos y farmacoterapéuticos asociados a los niveles de severidad de las reacciones adversas (RAM) e interacciones medicamentosas (IM) en pacientes hospitalizados post accidente cerebrovascular. Métodos Estudio analítico, predictivo y transversal mediante el modelo de regresión lineal múltiple. Los niveles de severidad de las potenciales reacciones adversas e interacciones medicamentosas se evaluaron mediante Drugs.com. Resultados De la evaluación de 992 prescripciones médicas de 55 (56,7%) pacientes mujeres y 42 (43,3%) varones post accidente cerebrovascular isquémico 62 (63,9%) y hemorrágico 35 (36,1%), se identificó un total de 11 790±46,8 potenciales reacciones adversas y 1 034±9,8 interacciones medicamentosas. La hipertensión arterial se asoció a las reacciones adversas graves y moderadas, en tanto que la neumonía intrahospitalaria y alcalosis metabólica a reacciones adversas leves y moderadas. La alcalosis metabólica se asoció a las interacciones medicamentosas moderadas y leves. Los predictores farmacoterapéuticos como la prescripción en polifarmacia y el uso de antibióticos se relacionaron con reacciones adversas graves, moderadas y leves; los antidiabéticos se relacionaron con interacciones medicamentosas graves, moderadas y los fármacos para terapia cardiaca con interacciones medicamentosas leves. Conclusiones Las variables clínicas como factores de riesgo cardiovascular, presencia de comorbilidades que exacerban las enfermedades crónicas no trasmisibles, los signos y síntomas de alarma, el mayor tiempo de estancia hospitalaria y la prescripción en polifarmacia fueron predictores de mayor frecuencia de reacciones adversas e interacciones medicamentosas graves y moderadas que requieren especial vigilancia y estudio individualizado.

Objective To identify clinical and pharmacotherapeutic predictors associated with severity levels of adverse reactions and drug-drug interactions in post-stroke hospita-lized patients. Methods Analytic, predictive, cross-sectional study using multiple linear regression modeling. Severity levels of potential adverse reactions and drug-drug interactions were assessed using Drugs.com. Results From the evaluation of 992 medical prescriptions of 55 (56.7%) female and 42 (43.3%) male patients post ischemic stroke 62(63.9%) and hemorrhagic stroke 35 (36.1%); a total of 11 790±46.8 potential adverse reactions and 1 034±9.8 drug-drug interactions were identified; arterial hypertension was associated with severe and moderate adverse reactions; while in-hospital pneumonia and metabolic alkalosis with mild and moderate adverse reactions. While metabolic alkalosis was associated with moderate and mild drug-drug interactions. Pharmacotherapeutic predictors such as polypharmacy prescription and antibiotic use were related to moderate and mild severe adverse reactions; antidiabetic drugs were related to moderate and severe drug-drug interactions and cardiac therapy drugs were related to mild drug-drug interactions. Conclusions Clinical variables such as cardiovascular risk factors, presence of comorbidities that exacerbate chronic noncommunicable diseases, alarm signs and symptoms, longer hospital stay, as well as polypharmacy prescriptions, were predictors of a higher frequency of severe and moderate adverse reactions and drug-drug interactions, which require special vigilance and individualized study.

Application of Physiologically Based Pharmacokinetic Modeling of Lamotrigine Using PK-Sim in Predicting the Impact of Drug Interactions and Dosage Adjustment

Objectives To build a lamotrigine (LTG) physiologically based pharmacokinetic (PBPK) model (LTG PBPK) and compare it to the clinical data from South Asian Indian patients and use this model to understand the drug interactions of LTG and explore the optimal doses. Methods and Material The PBPK model was developed using the PK-Sim software platform and qualified with LTG plasma concentration data from an Indian study. The European population database was chosen as the patient setting in the software. Physiochemical data of LTG and enzyme kinetic data were incorporated from the literature. Dosing protocols were as per the previous study. Interaction models for drug interactions with carbamazepine and valproate were also simulated. Results Most of the model predicted concentration-time profiles of LTG at steady-state were well within the observed concentrations. The developed models were suitably qualified. The drug interaction model was used to assess the impact of induction and inhibition of the pharmacokinetic profile of LTG. Conclusions The predicted plasma concentrations of the developed PBPK models using the European population database were very similar to the data from Indian patients. The developed LTG PBPK models are applicable in predicting the impact of drug interactions and can yield appropriate LTG doses to be administered.

A comparative study of knowledge, attitude, and practice of drug-drug interactions among interns and nurses in a tertiary care hospital

Background: Increasing use of drugs has led to drug-drug interactions (DDIs) which necessitate their awareness among the health-care providers to reduce the hospital admissions due to their adverse drug reactions. Aim and Objectives: This study aims to assess and compare the knowledge, attitude, and practice (KAP) of DDIs among interns and nurses and to evaluate the impact of an educational program with a pre-and post-test questionnaire. Materials and Methods: An educational program about DDIs was conducted for the interns and nurses to evaluate their KAP by a pre-test and post-test pre-verified 20-point questionnaire about DDI. Results: There was a statistical significant difference (P < 0.05) in gender (females: Males = 77:16) among the interns and nurses and their mean age was 23 ± 0.87 years and 21.3 ± 0.83 years, respectively. Both the groups fared well in post-test compared to pre-test in the knowledge (questions=7), attitude (questions=5), and practice (questions=8) domain which was statistically significant. On comparing the post-test scores, both the groups showed no difference statistically (P > 0.05) in the knowledge and attitude domain, while the nurses group showed more improved mean score than interns in terms of practice of DDI. Conclusion: The educational program about DDIs was effective among the interns and nurses with regard to their KAP assessment and they equally performed well. This implies that the awareness program about DDIs was successful among the interns and nurses who form the lower strata in delivering the health-care needs to the society.

Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy / 医学前沿

The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.

Drug selection for simultaneous treatment of tuberculosis combined with hepatitis C virus infection / 中华肝脏病杂志

Clinically, patients with tuberculosis (TB) combined with hepatitis C virus (HCV) infection often require simultaneous treatment. Consequently, when anti-HCV and TB drugs are used in combination drug-drug interactions (DDIs), anti-TB drug-induced hepatotoxicity, and liver disease states need to be considered. This paper focuses on discussing the metabolic mechanisms of commonly used anti-TB and HCV drugs and the selection options of combined drugs, so as to provide rational drug use for TB patients combined with HCV infection.

Influence of traditional Chinese medicines on the in vivo metabolism of lopinavir/ritonavir based on UHPLC-MS/MS analysis / 药物分析学报

A fast,reliable,and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019,namely,Lianhua Qingwen granules,Huoxiang Zhengqi capsules,Jinhua Qinggan granules,Shufeng Jiedu capsules,and Angong Niuhuang pills,on the pharmacokinetics of lopinavir/ritonavir in rats.Blood samples were prepared using the protein precipitation method and atazanavir was selected as the internal standard(IS).Separation was performed on an Agilent ZORBAX eclipse plus C18(2.1 mm x 50 mm,1.8 μm)column using acetonitrile and water containing 0.1％formic acid as the mobile phase for gradient elution.The flow rate was 0.4 mL/min and the injection volume was 2 μL Agilent Jet Stream electrospray ionization was used for mass spectrometry detection under positive ion multiple reaction monitoring mode at a transition of m/z 629.3→447.3 for lopinavir,m/z 721.3→296.1 for rito-navir,and m/z 705.4→168.1 for the IS.The method showed good linearity in the concentration range of 25-2500 ng/mL(r=0.9981)for lopinavir and 5-500 ng/mL(r=0.9984)for ritonavir.The intra-day and inter-day precision and accuracy were both within±15％.Items,such as dilution reliability and residual effect,were also within the acceptable limits.The method was used to determine the effects of five types of traditional Chinese medicines on the pharmacokinetics of lopinavir/ritonavir in rats.The pharmaco-kinetic results showed that the half-life of ritonavir in the groups administered Lianhua Qingwen granules and Huoxiang Zhengqi capsules combined with lopinavir/ritonavir was prolonged by approx-imately 1.5-to 2-fold relative to that in the control group.Similarly,the pharmacokinetic parameters of lopinavir were altered.Overall,the results of this study offer important theoretical parameters for the effective clinical use of five types of traditional Chinese medicines combined with lopinavir/ritonavir to reduce the occurrence of clinical adverse reactions.

Advances in uridine diphosphate glucuronosyltransferase-mediated drug interactions with tyrosine kinase inhibitors / 中国临床药理学与治疗学

Drug-drug interactions (DDI) of tyrosine kinase inhibitors (TKIs) mediated by metabolic enzymes and transporters have become an important issue in clinical practice recently. In addition to CYP450 enzymes, uridine diphosphate glucuronidases (UGTs) are another class of metabolic enzymes involved in the metabolism of TKIs, and most TKIs can inhibit the UGTs in vitro. Potential clinically meaningful DDIs may occur with the co-administration of TKIs and substrates or inhibitors of UGTs. This paper will mainly focus on the UGTs-mediated drug-drug and the effect of UGT1A genotype on the drug interactions of TKIs and explores strategies to address, aiming to provide clinicians and pharmacists with references for the safe and rational application of TKIs.

Quality control and drug-drug interactions between commercially available Metoprolol and Glimepiride tablets

Abstract Quality is paramount and needs to be maintained throughout the shelf life of pharmaceuticals. The current study aimed to evaluate the quality, potency, and drug-drug interaction in an in vivo animal model by using two drugs, namely, metoprolol and glimepiride. Tablets were selected for their physical characteristics, such as shape, size, and color. Quality control tests, such as weight variation, hardness, friability, and disintegration tests, and invitro drug release studies were performed as per USP. Drug-drug interaction and in vivo studies were carried out according to the standard protocol of the animal ethics committee. Quality control tests of both the tablets were within the specified range. The cumulative release percentages of the drugs were 81.12% and 85.36% for Metoprolol Tartrate and Glimepiride, respectively, in a physiological buffer solution within 1 h. The combination of metoprolol and Glimepiride also significantly decreased the blood glucose level in diabetic animals. However, the blood glucose level increased in the group receiving metoprolol only, but the difference was not significant. The result suggested that the formulations are safe. However, the chronic use of this combination requires frequent monitoring of blood glucose level to improve its efficacy and for the patient's safety.

Risk factors for potential drug-drug interactions of statins in patients with acute coronary syndrome

Abstract The aim of our study was to assess risk factors for potential drug-drug interactions (pDDIs) of statins across different phases of treatment of acute coronary syndrome (ACS) patients: from the point of first medical contact to the coronary angiography (first phase), after coronary angiography to the last day of hospitalization (second phase) and at discharge from hospital (third phase). This was a post hoc analysis of the data collected during the retrospective observational cohort study conducted at the Clinic for Cardiology of the Clinical Centre Kragujevac, Serbia. Patients prescribed statins were identified from the original study population: 156, 240 and 236 patients for the first, second and third phases, respectively. At least one statin pDDI was present in 113 (72.4%), 161 (67.1%) and 139 (58.9%) patients in the first, second and third phases, respectively. Heart failure, arrhythmias after ACS, CRP, triglycerides, length of hospitalization, number of prescribed drugs, antiarrhythmic drugs, and clopidogrel seem to increase the risk of statin pDDIs in at least one treatment phase. Physicians should be vigilant to the possibility of statin pDDIs in ACS patients who have factors that may increase their rate.

Potential drug-drug interactions among patients with spontaneous intracerebral hemorrhage treated at the Neurological Intensive Care Unit: a single-center experience

Abstract Our aim was to determine the prevalence of potential drug-drug interactions (pDDIs) and to identify relevant factors associated with the occurrence of the most dangerous or contraindicated pDDIs (pCDDIs) in hospitalized patients with spontaneous intracerebral hemorrhage (sICH). A retrospective cross-sectional study was performed enrolling all consecutive patients with sICH treated at the Neurological Intensive Care Unit, Clinical Center in Kragujevac, Serbia, during the three-year period (2012-2014). The inclusion criteria encompassed patients aged 18 years and over, those diagnosed with ICH, and those prescribed at least two drugs during hospitalization, while we did not include patients whose hospitalization lasted less than 7 days, those who were diagnosed with other neurological diseases and patients with incomplete medical files. For each day of hospitalization, the online checker Micromedex® software was used to identify pDDIs and classify them according to severity. A total of 110 participants were analysed. A high prevalence of pDDIs (98.2%) was observed. The median number of pDDIs regardless of severity, was 8.00 (IQR 4.75-13.00;1-30). The pairs of drugs involving cardiovascular medicines were the most commonly identified pDDIs. Twenty percent of the total number of participants was exposed to pCDDIs. The use of multiple drugs from different pharmacological-chemical subgroups and the prescribing of anticoagulant therapy significantly increase the chance of pCDDI (aOR with 95% CI 1.19 (1.05-1.35) and 7.40 (1.13-48.96), respectively). This study indicates a high prevalence of pDDIs and pCDDIs in patients with sICH. The use of anticoagulant therapy appears to be the only modifiable clinically relevant predictor of pCDDIs.