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Primary studies have demonstrated that despite being useful, most of the drug-drug interaction (DDI) alerts generated by clinical decision support systems are overridden by prescribers. To provide more information about this issue, we conducted a systematic review and meta-analysis on the prevalence of DDI alerts generated by CDSS and alert overrides by physicians. The search strategy was implemented by applying the terms and MeSH headings and conducted in the MEDLINE/PubMed, EMBASE, Web of Science, Scopus, LILACS, and Google Scholar databases. Blinded reviewers screened 1873 records and 86 full studies, and 16 articles were included for analysis. The overall prevalence of alert generated by CDSS was 13% (CI95% 5-24%, p-value <0.0001, I^2 = 100%), and the overall prevalence of alert override by physicians was 90% (CI95% 85-95%, p-value <0.0001, I^2 = 100%). This systematic review and meta-analysis presents a high rate of alert overrides, even after CDSS adjustments that significantly reduced the number of alerts. After analyzing the articles included in this review, it was clear that the CDSS alerts physicians about potential DDI should be developed with a focus on the user experience, thus increasing their confidence and satisfaction, which may increase patient clinical safety.
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Sistemas de Apoio a Decisões Clínicas , Interações Medicamentosas , Sistemas de Registro de Ordens Médicas , Sistemas de Apoio a Decisões Clínicas/estatística & dados numéricos , Humanos , Sistemas de Registro de Ordens Médicas/estatística & dados numéricos , Erros de Medicação/prevenção & controleRESUMO
Background: The standard neoadjuvant therapy for rectal cancer involves fluoropyrimidines and radiotherapy and, most recently, total neoadjuvant therapy (TNT). A drug-drug interaction between fluoropyrimidines and proton-pump inhibitors (PPI) was suggested, with a negative impact on oncological outcomes in breast, colon and gastric cancers. Little is known about such an effect on rectal tumours. We aimed to evaluate the impact of PPI utilisation on the pathological response after chemoradiation for rectal cancer. Materials and methods: Retrospective multicentre study of rectal cancer patients treated with neoadjuvant chemoradiotherapy with capecitabine (cohort 1) or 5-fluororuracil (5-FU) (cohort 2); TNT with oxaliplatin-based regimens was allowed. The pathological response was considered a complete (ypCR) or complete + partial (ypCR + ypPR) according to American Joint Committee on Cancer. PPI use was considered at any time during the neoadjuvant period if concomitant to fluoropyrimidines. Results: From January 2007 to November 2020, 251 patients received capecitabine and 196 5-FU. The rates of PPI use in cohorts 1 and 2 were 20.3% and 26.5%, respectively. TNT was offered to 18.3% in cohort 1. PPI use did not influence ypCR in cohort 1 (yes versus no: 29.4% versus 19.5%; p = 0.13) or 2 (yes versus no: 25.0% versus 26.4%; p = 1.0). Similar ypCR + ypPR were observed in both cohorts 1 (76.5% versus 72.0%; p = 0.60) and 2 (86.5% versus 76.4%; p = 0.16). PPI use was not associated with pathological response in multivariable analysis. PPI users experienced more grade 3 or higher diarrhoea and infections. Conclusion: PPI concomitant to capecitabine/5-FU chemoradiation did not influence the pathological response in rectal cancer but was associated with more treatment-related adverse events.
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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.
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Introduction: Patients undergoing cancer treatment usually have comorbidities, and psychiatric disorders are commonly seen in these patients. For the treatment of these psychiatric disorders, the use of psychotropic drugs is common, turning these patients susceptible to untoward drug interactions. Therefore, the aim of this study was to estimate the prevalence of clinically relevant drug-drug interactions (DDI) between chemotherapeutic and psychotropic agents in patients with cancer treated at an oncology service in southern Brazil. Methods: An observational epidemiological study with a cross-sectional census-type design was carried out between October and December 2020. The drug-drug interactions were identified through consultation and analysis of the Medscape Drug Interaction Check and Micromedex databases. The interactions were classified as major, when the interaction can be fatal and/or require medical intervention to avoid or minimize serious adverse effects and moderate, when the interaction can exacerbate the patient's condition and/or requires changes in therapy. Results: A total of 74 patients was included in the study among the 194 patients seen in the oncology service during the period studied. A total of 24 (32.4%) DDIs were found, 21 (87.5%) of which were classified as being of major risk and 3 (12.5%) as moderate risk. According to the mechanism of action, 19 (79.1%) were classified as pharmacodynamic interactions and 5 (20.9%) as pharmacokinetic interactions. Conclusion: It was shown that a considerable percentage of patients undergoing intravenous chemotherapy are at risk of pharmacological interaction with psychotropic drugs. Thus, it is essential that the oncologist considers all psychotropic drugs and other drugs used by patients in order to avoid drug-drug interactions.
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INTRODUCTION: Drug-drug interactions among people with suicidal behavior is a challenging topic, considering the harm it poses for patients already vulnerable and the lack of literature on the thematic. This aspect must not be neglected in research and clinical practice, and thus requires thorough investigation. OBJECTIVE: to investigate predictors of drug-drug interaction of prescribed drugs and the prescription of two or more drugs for people admitted due to suicidal behavior in a psychiatric emergency department (short-stay hospital ward). METHOD: A cross-sectional study with retrospective approach, carried out in a Brazilian psychiatric emergency unit in 2015. Data about first and last medical prescriptions were collected from 127 patients' files. Descriptive statistics and the Zero Adjusted Logarithmic Distribution (ZALG) model were adopted, with the significance level α = 0.05. RESULTS: Potential drug-drug interactions were found in most of the first and last prescriptions. The sample majority were female, with previous suicide attempts, being discharged from the hospital with three drugs (or more) prescribed, and without referral to any health service. Age and comorbidities were predictors of more drug prescriptions and the amount of prescribed drugs was the most important predictor of drug-drug interactions (quantity and severity). CONCLUSIONS: the variables associated with drug-drug interactions and prescription of two or more drugs among people with suicidal behavior needs to be investigated in different contexts and addressed in interventions with the aim to promote patient safety.
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INTRODUCTION: Cancer patients with Covid-19 are exposed to treatment combinations that can potentially result in interactions that adversely affect patient outcomes. This study aimed to identify potential drug-drug interactions between antineoplastic agents and medicines used to treat Covid-19. METHODS: We conducted a search for potential interactions between 201 antineoplastic agents and 26 medicines used to treat Covid-19 on the Lexicomp® and Micromedex® databases. The following data were extracted: interaction severity ("major" and "contraindicated") and interaction effects (pharmacokinetic and pharmacodynamic). We also sought to identify the therapeutic indication of the antineoplastic drugs involved in the potential drug-drug interactions. RESULTS: A total of 388 "major" or "contraindicated" drug-drug interactions were detected. Eight drugs or combinations (baricitinib, lopinavir/ritonavir, atazanavir, darunavir, azithromycin, chloroquine, hydroxychloroquine, and sirolimus) accounted for 91.5% of these interactions. The class of antineoplastic agents with the greatest potential for interaction was tyrosine kinase inhibitors (accounting for 46.4% of all interactions). The findings show that atazanavir, baricitinib, and lopinavir/ritonavir can affect the treatment of all common types of cancer. The most common pharmacokinetic effect of the potential drug-drug interactions was increased plasma concentration of the antineoplastic medicine (39.4%). CONCLUSIONS: Covid-19 is a recent disease and pharmacological interventions are undergoing constant modification. This study identified a considerable number of potential drug-drug interactions. In view of the vulnerability of patients with cancer, it is vital that health professionals carefully assess the risks and benefits of drug combinations.
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Antineoplásicos , Antivirais , Tratamento Farmacológico da COVID-19 , Humanos , Antineoplásicos/efeitos adversos , Antivirais/efeitos adversos , Sulfato de Atazanavir , Combinação de Medicamentos , Lopinavir/efeitos adversos , Ritonavir/efeitos adversos , Interações MedicamentosasRESUMO
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.
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Humanos , Masculino , Feminino , Adulto , Pacientes/classificação , Organização Mundial da Saúde , Hemorragia Cerebral/patologia , Interações Medicamentosas , Unidades de Terapia Intensiva/classificação , Preparações Farmacêuticas/análise , Estudos Transversais/métodos , Hospitalização , Anticoagulantes/efeitos adversosRESUMO
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.
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Humanos , Masculino , Feminino , Adulto , Pacientes/classificação , Fatores de Risco , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Interações Medicamentosas , Síndrome Coronariana Aguda/patologia , Preparações Farmacêuticas/administração & dosagem , Cardiologia/classificação , Angiografia Coronária/instrumentação , Sérvia , ClopidogrelRESUMO
Erythropoietin (EPO) is a cytokine originally used for its effects on the hematopoietic system, and is widely prescribed around the world. In the present study, the effects of EPO administration on p-aminohippurate (PAH, a prototype organic anion) pharmacokinetics and on the renal expression of PAH transporters were evaluated. Male Wistar rats were treated with EPO or saline (control group). After 42 h, PAH was administered, and plasma samples were obtained at different time points to determine PAH levels. PAH levels in renal tissue and urine were also assessed. The renal expression of PAH transporters was evaluated by Western blotting. EPO-treated rats showed an increase in PAH systemic clearance, in its elimination rate constant, and in urinary PAH levels, while PAH in renal tissue was decreased. Moreover, EPO administration increased the expression of the transporters of the organic anions evaluated. The EPO-induced increase in PAH clearance is accounted for by the increase in its renal secretion mediated by the organic anion transporters. The goal of this study is to add important information to the wide knowledge gap that exists regarding drug-drug interactions. Owing to the global use of EPO, these results are useful in terms of translation into clinical practice.
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Ânions/farmacocinética , Eritropoetina/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Animais , Masculino , Ratos , Ratos WistarRESUMO
We present a case of a 48-year-old white HIV-1 positive man who presented an acute myocardial infarction. The patient was on ART for the last ten years with emtricitabine/tenofovir and ritonavir-boosted fosamprenavir. Eplerenone 25 mg/day was also initiated due to a left ventricular dysfunction. A week after discharge a routine laboratory examination revealed severe hyperkalaemia. Due to suspicion of a potential drug-drug interaction, both eplerenone and ARVs were interrupted. Despite daily treatment for hyperkalaemia, serum potassium levels normalized after two weeks. Eplerenone is metabolized by the hepatic P450 cytochrome isoenzyme CYP3A4; therefore, concomitant administration with CYP3A4 inhibitors, like ritonavir, may increase plasma levels of eplerenone and, therefore, the risk of side effects, mainly hyperkalaemia. Based on this case, it is important to alert the medical community of this possible life-threatening drug-drug interaction between eplerenone and ritonavir-boosted protease inhibitor.
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Infecções por HIV , Inibidores da Protease de HIV , Hiperpotassemia , Infarto do Miocárdio , Preparações Farmacêuticas , Interações Medicamentosas , Eplerenona/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Humanos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Ritonavir/efeitos adversosRESUMO
Over the past few years, considerable attention has focused on cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the two major constituents of Cannabis sativa, mainly due to the promising potential medical uses they have shown. However, more information on the fate of these cannabinoids in human subjects is still needed and there is limited research on the pharmacokinetic drug-drug interactions that can occur in the clinical setting and their prevalence. As the use of cannabinoids is substantially increasing for many indications and they are not the first-line therapy in any treatment, health care professionals must be aware of drug-drug interactions during their use as serious adverse events can happen related with toxic or ineffective outcomes. The present chapter overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD and THC in humans and discusses relevant drug-drug interactions, giving a plausible explanation to facilitate further research in the area.
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Canabinoides , Preparações Farmacêuticas , Canabidiol , Canabinoides/efeitos adversos , Dronabinol , Interações Medicamentosas , HumanosRESUMO
OBJECTIVE: To determine the incidence of acute kidney injury (AKI) in infants exposed to nephrotoxic drug combinations admitted to 268 neonatal intensive care units managed by the Pediatrix Medical Group. STUDY DESIGN: We included infants born at 22-36 weeks gestational age, ≤120 days postnatal age, exposed to nephrotoxic drug combinations, with serum creatinine measurements available, and discharged between 2007 and 2016. To identify risk factors associated with a serum creatinine definition of AKI based on the Kidney Disease: Improving Global Outcomes criteria, we performed multivariable logistic and Cox regression adjusting for gestational age, sex, birth weight, postnatal age, race/ethnicity, sepsis, respiratory distress syndrome, baseline serum creatinine, and duration of combination drug exposure. The adjusted odds of AKI were determined relative to gentamicin + indomethacin for the following nephrotoxic drug combinations: chlorothiazide + ibuprofen; chlorothiazide + indomethacin; furosemide + gentamicin; furosemide + ibuprofen; furosemide + tobramycin; ibuprofen + spironolactone; and vancomycin + piperacillin-tazobactam. RESULTS: Among 8286 included infants, 1384 (17%) experienced AKI. On multivariable analysis, sepsis, lower baseline creatinine, and duration of combination therapy were associated with increased odds of AKI. Furosemide + tobramycin and vancomycin + piperacillin-tazobactam were associated with a decreased risk of AKI relative to gentamicin + indomethacin in both the multivariable and Cox regression models. CONCLUSIONS: In this cohort, infants receiving longer durations of nephrotoxic combination therapy had an increased odds of developing AKI.
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Injúria Renal Aguda/epidemiologia , Anti-Inflamatórios/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Incidência , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Tempo de Internação/tendências , Masculino , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Data on drug-drug interactions (DDI) of antineoplastic drugs with anticoagulants is scarce. We aim to evaluate factors associated with DDI of antineoplastic and supportive care drugs with anticoagulants resulting in modification of pharmacokinetics of these last mentioned. A literature review on DDI databases and summaries of products characteristics (SmPC) was done. Drug-drug interactions of 257 antineoplastic and supportive care drugs with direct oral anticoagulants (DOACs), warfarin, enoxaparin, or fondaparinux were categorized as no clinically significant expected DDI, potentially weak DDI, potentially clinically significant DDI, and recommendation against coadministration. Logistic regression models were performed to analyze the association between the dependent variable potentially clinically significant interaction/recommendation against coadministration and the mechanisms of DDI. Of the 1799 associations, 84.4% were absence of DDI, 3.6% potentially weak DDI, 10.2% potentially clinically relevant DDI, and 2.0% recommendation against coadministration. Warfarin has higher DDI potential than other anticoagulants. Enoxaparin and fondaparinux have fewer DDI than others. There was no difference between DOACs. Drug-drug interactions with apixaban and rivaroxaban was independently associated with the absence of CYP3A4 competition, P-glycoprotein inhibition, CYP3A4 induction, and drug class of tyrosine kinase inhibitors. Drug-drug interactions with dabigatran and edoxaban was associated with inhibition of P-glycoprotein and tyrosine kinase inhibitors. Warfarin, induction of CYP3A4, and inhibition of CYP2C9. Enoxaparin and fondaparinux, only tyrosine kinase inhibitors. Direct oral anticoagulants did not differ regarding DDI with antineoplastic agents. Warfarin presented more DDI than other anticoagulants. P-glycoprotein inhibition and CYP3A4 induction were independently associated with DDI of antineoplastic agents with DOACs.
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Anticoagulantes/uso terapêutico , Antineoplásicos/uso terapêutico , Interações Medicamentosas/genética , Anticoagulantes/farmacologia , Antineoplásicos/farmacologia , HumanosRESUMO
Since the beginning of the HIV epidemic, research has been carried out to control the virus. Understanding the mechanisms of replication has given access to the various classes of drugs that over time have transformed AIDS into a manageable chronic disease. The class of protease inhibitors (PIs) gained notice in anti-retroviral therapy, once it was found that peptidomimetic molecules act by blocking the active catalytic center of the aspartic protease, which is directly related to HIV maturation. However, mutations in enzymatic internal residues are the biggest issue for these drugs, because a small change in biochemical interaction can generate resistance. Low plasma concentrations of PIs favor viral natural selection; high concentrations can inhibit even partially resistant enzymes. Food-drug/drug-drug interactions can decrease the bioavailability of PIs and are related to many side effects. Therefore, this review summarizes the pharmacokinetic properties of current PIs, the changes when pharmacological boosters are used and also lists the major mutations to help understanding of how long the continuous treatment can ensure a low viral load in patients.
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Inibidores da Protease de HIV/farmacocinética , Protease de HIV/metabolismo , HIV-1/enzimologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Protease de HIV/genética , Humanos , MutaçãoRESUMO
Hospitalized patients with left ventricular failure (LVF) are at high risk for potential drug-drug interactions (pDDIs) and its related adverse effects owing to multiple risk factors such as old age, comorbidities and polypharmacy. This cross-sectional study conducted in two tertiary care hospitals aim to identify frequency, levels and predictors of pDDIs in LVF patients. Data about patients' demographic, hospital stay, medication therapy, sign/symptoms and laboratory test results were collected for 385 patients with LVF. Micromedex Drug-Reax® was used to screen patients' medication profiles for pDDIs. Overall prevalence and severity-wise prevalence of pDDIs were identified. Chi-square test was performed for comparative analysis of various variables. Logistic regression was applied to determine the odds-ratios (OR) for predictors of pDDIs. The prevalence of pDDIs was 96.4% (n=371). Overall 335 drug-interacting pairs were detected, which were presented in a total of 2870 pDDIs. Majority of pDDIs were of major- (48.9%) and moderate-severity (47.5%). Logistic regression analysis shows significant association of >6 all types of pDDIs with >12 drugs as compared with <8 drugs (OR=16.5; p=<0.001). Likewise, there was a significant association of >4 major-pDDIs with men as compared with female (OR=1.9; p=0.007) and >12 drugs as compared with <8 drugs (OR=10.9; p=<0.001). Hypotension (n=57), impaired renal function (23) and increased blood pressure (22) were the most frequent adverse outcomes associated with pDDIs. This study shows high prevalence of pDDIs in LVF patients. Majority of pDDIs were of major- and moderate-severity. Male patients and those prescribed greater number of medicines were more exposed to major-pDDIs
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Pacientes , Preparações Farmacêuticas/análise , Disfunção Ventricular Esquerda/patologia , Interações Medicamentosas , Atenção Terciária à Saúde/ética , Demografia/classificação , Estudos Transversais/métodos , Fatores de Risco , Segurança do Paciente , Cardiopatias/classificação , HospitaisRESUMO
The aim of the current work was to evaluate a potential pharmacokinetic interaction between the flukicide triclabendazole (TCBZ) and the broad-spectrum benzimidazole (BZD) anthelmintic oxfendazole (OFZ) in sheep. To this end, both an in vitro assay in microsomal fractions and an in vivo trial in lambs parasitized with Haemonchus contortus resistant to OFZ and its reduced derivative fenbendazole (FBZ) were carried out. Sheep microsomal fractions were incubated together with OFZ, FBZ, TCBZ, or a combination of either FBZ and TCBZ or OFZ and TCBZ. OFZ production was significantly diminished upon coincubation of FBZ and TCBZ, whereas neither FBZ nor OFZ affected the S-oxidation of TCBZ towards its sulfoxide and sulfone metabolites. For the in vivo trial, lambs were treated with OFZ (Vermox® oral drench at a single dose of 5â¯mg/kg PO), TCBZ (Fasinex® oral drench at a single dose of 12â¯mg/kg PO) or both compounds at a single dose of 5 (Vermox®) and 12â¯mg/kg (Fasinex®) PO. Blood samples were taken to quantify drug and metabolite concentrations, and pharmacokinetic parameters were calculated by means of non-compartmental analysis. Results showed that the pharmacokinetic parameters of active molecules and metabolites were not significantly altered upon coadministration. The sole exception was the increase in the mean residence time (MRT) of OFZ and FBZ sulfone upon coadministration, with no significant changes in the remaining pharmacokinetic parameters. This research is a further contribution to the study of metabolic drug-drug interactions that may affect anthelmintic efficacies in ruminants.
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Anti-Helmínticos/farmacocinética , Benzimidazóis/farmacocinética , Triclabendazol/farmacocinética , Animais , Anti-Helmínticos/metabolismo , Área Sob a Curva , Benzimidazóis/metabolismo , Biotransformação , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Fenbendazol/metabolismo , Fígado/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Oxigenases/metabolismo , Ovinos , Triclabendazol/metabolismoRESUMO
PURPOSE: The aim of this study was to assess the pharmacokinetic interactions between a newly developed dipeptidyl peptidase (DPP)-4 inhibitor, gemigliptin, and metformin in healthy Mexican male volunteers, and the differences in the pharmacokinetic profile of gemigliptin between Korean and Mexican healthy volunteers. METHODS: This was a multiple-dose, randomized, open-label, 3-way, 3-period crossover study. Subjects were randomized to 1 of 3 treatment sequences and received gemigliptin 50mg once a day, metformin1000mg BID, or both drugs during a 7-day treatment period, and underwent sampling for pharmacokinetic analysis and tolerability assessments. Point estimates and 90% CIs of Cmax,ss and AUCτ,ss least squares mean (LSM) ratios of the concurrent administration of gemigliptinâ¯+â¯metformin to the administration of monotherapy with either drug were obtained, and the pharmacokinetic profile of gemigliptin observed was compared with that in healthy Korean volunteers studied during the initial development of gemigliptin. FINDINGS: The coadministration of gemigliptinâ¯+â¯metformin did not affect the pharmacokinetic characteristics of gemigliptin (LSM ratio [90% CI] for Cmax,ss and AUCτ,ss: 0.98 [0.87-1.10] and 0.94 [0.91-0.98], respectively) or metformin (LSM ratio [90% CI] for Cmax,ss and AUCτ,ss: 0.97 [0.88-1.08] and 1.02 [0.93-1.12], respectively) when administered as monotherapy and was well tolerated. In contrast with Korean healthy volunteers, Mexican subjects showed a modestly higher gemigliptin exposure (LSM ratio [90% CI] for AUCτ,ss: 1.22 [1.14-1.31]). IMPLICATIONS: The results of this study support, in ethnically different populations, the absence of drug-drug interactions between gemigliptin and metformin previously shown in Korean healthy volunteers. Considering the flat effect-concentration curve and wide therapeutic range of gemigliptin, the pharmacokinetic profile of gemigliptin observed in healthy Mexican and Korean subjects suggests that gemigliptin use in Mexican patients may be associated with outcomes, in terms of efficacy and tolerability, similar to those observed in the Korean population. ClinicalTrials.gov identifier: NCT03310749.
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Inibidores da Dipeptidil Peptidase IV/farmacocinética , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Piperidonas/farmacocinética , Pirimidinas/farmacocinética , Adulto , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Humanos , Masculino , México , República da Coreia , Adulto JovemRESUMO
UDP-glucuronosyltransferases (UGTs) are important phase II metabolic enzymes responsible for approximately 40-70% of endo and xenobiotic reactions. It catalyzes the transfer of glucuronic acid to lipophilic substrates, converting them into hydrophilic compounds that are excreted. There are 22 active human UGTs that belong to 4 families. This review focuses on human UGTs, highlighting the most current issues in order to connect all information available and allowing a discussion on the challenges already solved and those in which we need to move forward. Although, several UGTs studies have been conducted, the most recent ones addressing drug-drug interactions and polymorphism issues, there are still bottlenecks to overcome. Tridimensional structure is difficult to obtain due to overexpression, purification, and crystallization problems as well as the action mechanism - since overlapping of substrate specificities renders impasses on the identification of which isoform is responsible for a particular drug metabolic pathway. For this reason, bioinformatic tools are gaining more space, since it is a faster and less expensive reliable methodology that complements in vitro and in vivo researches. Combinations of quantum and molecular methods have become increasingly common, leading to the incorporation of enzyme features comprising their structure, dynamics and chemical reactions. Breakthroughs related to the enzyme, not only enable the discovery of new drugs essential for the treatment of various diseases, but also provide an improved action of the existing drugs.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glucuronosiltransferase/química , Glucuronosiltransferase/metabolismo , Humanos , Modelos MolecularesRESUMO
Parasitic diseases have a significant impact on livestock production. Nematodicidal drugs, such as fenbendazole (FBZ) or its oxidized metabolite oxfendazole (OFZ), can be used along with the trematodicidal triclabendazole (TCBZ), to broaden the spectrum of anthelmintic activity. However, co-exposure to these compounds could lead to drug-drug (D-D) interactions and eventually alter the clinical profile of each active principle. The aim of this study was to assess the presence of such interactions by means of two in vitro models, namely bovine liver microsomal fractions and bovine precision-cut liver slices (PCLSs). To this end, an in vitro assessment involving incubation of FBZ and TCBZ or a combination of FBZ and TCBZ was carried out. Results with microsomal fractions showed a 78.4% reduction (p = .002) in the rate of OFZ production upon co-incubation, whereas the sulfoxide metabolite of TCBZ (TCBZSO) exhibited a decreasing tendency. With PCLS, OFZ accumulation in the incubation medium increased 1.8-fold upon co-incubation, whereas TCBZSO accumulation decreased by 28%. The accumulation of FBZ and OFZ in the liver tissue increased upon 2-hr co-incubation, from 2.1 ± 1.5 to 18.2 ± 6.1 (p = .0009) and from 0.4 ± 0.1 to 1.3 ± 0.3 nmol (p = .0005), respectively. These results confirm the presence of D-D interactions between FBZ and TCBZ. Further studies are needed to determine the extent of involvement of drug-metabolizing enzymes and membrane transporters in interactions between compounds largely used in livestock production systems.
Assuntos
Benzimidazóis/farmacocinética , Bovinos , Fenbendazol/farmacocinética , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Albendazol/farmacocinética , Animais , Anti-Helmínticos/farmacocinética , Interações Medicamentosas , Manejo de Espécimes , TriclabendazolRESUMO
INTRODUCTION AND AIM: Hepatitis patients usually present with comorbidities and polypharmacy which increases risk of potential drug-drug interactions (pDDIs). We explored frequency, levels, predictors, and clinical relevance of pDDIs in hospitalized hepatitis patients. MATERIAL AND METHODS: Retrospective cohort study was used. Clinical profiles of 413 hepatitis patients were reviewed for pDDIs using Micromedex-DrugReax. Frequency, levels and clinical relevance of pDDIs were reported. Logistic regression analysis was used to calculate odds-ratios for predictors. RESULTS: Of total 413 patients, pDDIs were reported in 55.2%. Major-pDDIs were found in 35% patients. Total 660 pDDIs were identified, of which, 304 (46%) were of major-severity and 299 (45%) of moderateseverity. Patient's profiles of top-10 major-pDDIs were presented with signs/symptoms such as fever, hepatomegaly, anorexia, jaundice, hypertension, tachycardia, bradycardia, & pedal edema; and abnormalities in labs such as electrolytes-level, alanine aminotransferase, blood urea nitrogen, bilirubin-level, & serum creatinine. Significant association was observed for the presence of pDDIs with > 9 prescribed medicines (p < 0.001), hospitalization of > 5 days (p = 0.03), and stroke as comorbidity (p = 0.05). Moreover, odds of exposure to major-pDDIs were significantly higher in patients taking > 9 prescribed medicines (p < 0.001), hospitalization of > 5 days (p = 0.002), and stroke as comorbidity (p = 0.002). CONCLUSION: We observed hepatitis patients presented with a considerable number of clinically relevant pDDIs. Attention should be given to widespread major-pDDIs and their potential adverse outcomes. Clinically relevant parameters, such as labs and signs/symptoms should be monitored particularly in high risk patients having polypharmacy, prolong hospitalization, and stroke as comorbidity.