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1.
Pharm Res ; 36(11): 154, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482205

RESUMO

PURPOSE: Conjugation of nanocarriers with antibodies that bind to specific membrane receptors that are overexpressed in cancer cells enables targeted delivery. In the present study, we developed and synthesised two PAMAM dendrimer-trastuzumab conjugates that carried docetaxel or paclitaxel, specifically targeted to cells which overexpressed HER-2. METHODS: The 1H NMR, 13C NMR, FTIR and RP-HPLC were used to analyse the characteristics of the products and assess their purity. The toxicity of PAMAM-trastuzumab, PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined using MTT assay and compared with free trastuzumab, docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. The cellular uptake and internal localisation were studied using flow cytometry and confocal microscopy, respectively. RESULTS: The PAMAM-drug-trastuzumab conjugates in particular showed extremely high toxicity toward the HER-2-positive SKBR-3 cells and very low toxicity towards to HER-2-negative MCF-7 cells. As expected, the HER-2-positive SKBR-3 cell line accumulated trastuzumab from both conjugates rapidly; but surprisingly, although a large amount of PAMAM-ptx-trastuzumab conjugate was observed in the HER-2-negative MCF-7 cells. Confocal microscopy confirmed the intracellular localisation of analysed compounds. The key result of fluorescent imaging was the identification of strong selective binding of the PAMAM-doc-trastuzumab conjugate with HER-2-positive SKBR-3 cells only. CONCLUSIONS: Our results confirm the high selectivity of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates for HER-2-positive cells, and demonstrate the utility of trastuzumab as a targeting agent. Therefore, the analysed conjugates present an promising approach for the improvement of efficacy of targeted delivery of anticancer drugs such as docetaxel or paclitaxel.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Dendrímeros/química , Docetaxel/química , Paclitaxel/química , Receptor ErbB-2/metabolismo , Trastuzumab/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Interações de Medicamentos , Liberação Controlada de Fármacos , Corantes Fluorescentes/química , Humanos , Paclitaxel/farmacologia , Propriedades de Superfície , Trastuzumab/farmacologia , Resultado do Tratamento
2.
Chem Pharm Bull (Tokyo) ; 67(8): 778-785, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366827

RESUMO

Herbal formulae have a long history in clinical medicine in Asia. While the complexity of the formulae leads to the complex compound-target interactions and the resultant multi-target therapeutic effects, it is difficult to elucidate the molecular/therapeutic mechanism of action for the many formulae. For example, the Hua-Yu-Qiang-Shen-Tong-Bi-Fang (TBF), an herbal formula of Chinese medicine, has been used for treating rheumatoid arthritis. However, the target information of a great number of compounds from the TBF formula is missing. In this study, we predicted the targets of the compounds from the TBF formula via network analysis and in silico computing. Initially, the information of the phytochemicals contained in the plants of the herbal formula was collected, and subsequently computed to their corresponding fingerprints for the sake of structural similarity calculation. Then a compound structural similarity network infused with available target information was constructed. Five local similarity indices were used and compared for their performance on predicting the potential new targets of the compounds. Finally, the Preferential Attachment Index was selected for it having an area under curve (AUC) of 0.886, which outperforms the other four algorithms in predicting the compound-target interactions. This method could provide a promising direction for identifying the compound-target interactions of herbal formulae in silico.


Assuntos
Medicamentos de Ervas Chinesas/química , Algoritmos , Artrite Reumatoide/tratamento farmacológico , Composição de Medicamentos , Interações de Medicamentos , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Medicina Tradicional Chinesa
3.
Stud Health Technol Inform ; 264: 45-49, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437882

RESUMO

The aim of the study was to build a proof-of-concept demonstratrating that big data technology could improve drug safety monitoring in a hospital and could help pharmacovigilance professionals to make data-driven targeted hypotheses on adverse drug events (ADEs) due to drug-drug interactions (DDI). We developed a DDI automatic detection system based on treatment data and laboratory tests from the electronic health records stored in the clinical data warehouse of Rennes academic hospital. We also used OrientDb, a graph database to store informations from five drug knowledge databases and Spark to perform analysis of potential interactions betweens drugs taken by hospitalized patients. Then, we developed a machine learning model to identify the patients in whom an ADE might have occurred because of a DDI. The DDI detection system worked efficiently and computation time was manageable. The system could be routinely employed for monitoring.


Assuntos
Interações de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Registros Eletrônicos de Saúde , Automação , Big Data , Humanos , Farmacovigilância
4.
Stud Health Technol Inform ; 264: 1500-1501, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438201

RESUMO

Janusmed is a clinical decision support system, developed by the Stockholm County Council that supports physicians in identifying drug-drug interactions. To determine how Janusmed is used in and affects the clinical practice, an evaluation study is currently being carried out that analyzes multiple data sources through descriptive statistics. The study focuses on how Janusmed affects the behavior of the physicians, in particular, to what extent physicians reconsider their prescription decisions based on warnings from Janusmed.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Interações de Medicamentos , Humanos , Médicos
5.
Stud Health Technol Inform ; 264: 829-833, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438040

RESUMO

This document describes the development of a Business Intelligence (BI) dashboard for tracking the drug-drug interaction (DDI) alerts implemented as Clinical Decision Support Systems (CDSS) in Electronic Health Records (EHR). CDSS are known for their potential to reduce medical error. The use of requirements in the development of BI dashboards is crucial to obtain successful software. In this work, the requirements were analysed using a score methodology, considering the relevance of the indicators and visualization methods. CDSS effectiveness and acceptance have been questioned, so it is fundamental to monitor their behaviour and performance. The dashboard was designed in order to satisfy the needed indicators. Using BI as a tool for monitoring the CDSS performance made it possible to operationalize the EHR content repository, maximizing the understanding in relation to the override and, by inference, to optimize the CDSS system by opening new lines of work.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Interações de Medicamentos , Registros Eletrônicos de Saúde , Inteligência , Software
7.
Einstein (Sao Paulo) ; 17(4): eAO4725, 2019 Aug 22.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31460618

RESUMO

OBJECTIVE: To estimate the prevalence of drug interactions and associated factors among older adults followed up in a Comprehensive Medication Management Service at Primary Care. METHODS: Firstly, the Beers criteria 2015 was used to define drug interactions; later, drug interactions proposed by Dumbreck for patients with diabetes, depression, and heart failure were evaluated. The associated factors were assessed by univariate (Pearson's χ2) and multivariate analyses (logistic regression). The significance level of 5% was set for all analyses. RESULTS: The mean age of the studied population was 70.2±7.8 years; 52.2% were between 60 and 69 years, and 61.3% were female. Among the older adults, 94.5% used two or more drugs (condition for the occurrence of drug-drug interaction). The prevalence of drug interaction according to the Beers criteria was 4.9%. After multivariate analysis, diseases of the central nervous system, arrhythmia, number of medications, and female sex were positively associated with drug interaction. The prevalence of drug interaction according to Dumbreck was 27.2%. After multivariate analysis, the number of medications, the presence of heart failure, and Charlson comorbidity index greater than 1 were conditions positively associated with drug interactions. CONCLUSION: The holistic and individualized approach used in comprehensive medication management services for older patients is important, considering the prevalence of drug interactions and the need to minimize adverse events.


Assuntos
Interações de Medicamentos , Lista de Medicamentos Potencialmente Inapropriados , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Prescrição Inadequada/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prevalência , Atenção Primária à Saúde
8.
Stud Health Technol Inform ; 264: 724-728, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438019

RESUMO

Potential drug-drug interactions (PDDI) rules are currently represented without any common standard making them difficult to update, maintain, and exchange. The PDDI minimum information model developed by the Semantic Web in the Healthcare and Life Sciences Community Group describes PDDI knowledge in an actionable format. In this paper, we report implementation and evaluation of CDS Services which represent PDDI knowledge with Clinical Quality Language (CQL). The suggested solution is based on emerging standards including CDS Hooks, FHIR, and CQL. Two use cases are selected, implemented with CQL rules and tested at the Connectathon held at the 32nd Annual Plenary & Working Group Meeting of HL7.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Interações de Medicamentos , Linguagem , Semântica
9.
Pestic Biochem Physiol ; 158: 101-111, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378344

RESUMO

Standard chemical insecticides present mainly neurotoxic effects and are becoming less and less effective due to insects developing resistance to them. One of the innovative strategies to control insects pests is to find a way to increase the sensitivity of the target sites in the insect nervous system to the applied insecticides. In the presented research, we proposed menthol, a component of essential oils, as a factor increasing the effectiveness of bendiocarb, a carbamate insecticide. The aim of our study was to evaluate the potentiation of the bendiocarb effect by menthol. In toxicity tests performed on Periplaneta americana, menthol (0.1 µM) accelerated the lethal effect of bendiocarb, primarily in its low concentrations (lower than 0.05 mM). In the presence of menthol (1 and 0.1 µM), the ability of insects to turn back from its dorsal to the normal ventral side was significantly lower than with bendiocarb (1 µM) alone. We also evaluated the effectiveness of chemicals on the activity of the ventral nerve cord of the cockroach. In this preparation, bendiocarb (1 µM and higher concentrations) caused an irregular, spontaneous bursts of action potentials. The total nerve activity (including the response to stimulation and spontaneous firing) was much higher when bendiocarb was applied in the presence of menthol (1 µM). The effect of menthol was similar to the octopamine effect and was abolished by phentolamine, the octopamine receptor antagonist. Our results clearly indicated a strengthening effect of menthol on bendiocarb effectiveness; potentiation occurred through octopamine receptors activation.


Assuntos
Carbamatos/farmacologia , Baratas/efeitos dos fármacos , Inseticidas/farmacologia , Mentol/farmacologia , Óleos Voláteis/química , Fenilcarbamatos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Interações de Medicamentos , Resistência a Inseticidas
10.
BMC Bioinformatics ; 20(Suppl 13): 383, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31337333

RESUMO

BACKGROUND: Drug repurposing has been motivated to ameliorate low probability of success in drug discovery. For the recent decade, many in silico attempts have received primary attention as a first step to alleviate the high cost and longevity. Such study has taken benefits of abundance, variety, and easy accessibility of pharmaceutical and biomedical data. Utilizing the research friendly environment, in this study, we propose a network-based machine learning algorithm for drug repurposing. Particularly, we show a framework on how to construct a drug network, and how to strengthen the network by employing multiple/heterogeneous types of data. RESULTS: The proposed method consists of three steps. First, we construct a drug network from drug-target protein information. Then, the drug network is reinforced by utilizing drug-drug interaction knowledge on bioactivity and/or medication from literature databases. Through the enhancement, the number of connected nodes and the number of edges between them become more abundant and informative, which can lead to a higher probability of success of in silico drug repurposing. The enhanced network recommends candidate drugs for repurposing through drug scoring. The scoring process utilizes graph-based semi-supervised learning to determine the priority of recommendations. CONCLUSIONS: The drug network is reinforced in terms of the coverage and connections of drugs: the drug coverage increases from 4738 to 5442, and the drug-drug associations as well from 808,752 to 982,361. Along with the network enhancement, drug recommendation becomes more reliable: AUC of 0.89 was achieved lifted from 0.79. For typical cases, 11 recommended drugs were shown for vascular dementia: amantadine, conotoxin GV, tenocyclidine, cycloeucine, etc.


Assuntos
Reposicionamento de Medicamentos/métodos , Preparações Farmacêuticas/química , Área Sob a Curva , Interações de Medicamentos , Humanos , Preparações Farmacêuticas/metabolismo , Proteínas/química , Proteínas/metabolismo , Curva ROC , Aprendizado de Máquina Supervisionado
11.
Gan To Kagaku Ryoho ; 46(7): 1159-1163, 2019 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-31296822

RESUMO

Erlotinibis known as a key drug for the treatment of non-small-cell lung cancer. It is known to interact with gastric acid suppressing medications(AS). Concurrent administration of erlotinibwith AS is reported to decrease AUC and Cmax of erlotinib. From the result of a survey on concurrent administration of erlotinib with AS in our hospital, we considered that intake of erlotinib between meals in the morning and intake of AS after dinner or at bedtime certainly reduce the chance of drug interactions to a minimum. We suggested a direction of use of erlotinibto the doctors who used to prescribe this medication in their daily medical practice. We surveyed the doctors' perceptions of drug interactions. The results of the survey showed that 29% of the doctors were not concerned about drug interactions, although 81% of the doctors approved our proposal. By providing a suggestion for drug administration by analyzing drug information, the expectations of the doctors can be met and it also demonstrates the efficiency of pharmacists.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Cloridrato de Erlotinib/efeitos adversos , Neoplasias Pulmonares , Interações de Medicamentos , Ácido Gástrico , Humanos , Inquéritos e Questionários
12.
Stud Health Technol Inform ; 262: 388-391, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31349249

RESUMO

C3-Cloud is a project aiming to provide an ICT infrastructure, which will allow patient centric and integrated care, based on best practice guideline, for patients with multi-morbidity. Clinical Decision Support, by checking the patient's record for known adverse interactions when the medication changes. The drug interaction advisory service provides recommendations in the three languages used in the project's pilot sites, for over 1000 substances, based on the UK's NICE BNF body of knowledge.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Interações de Medicamentos , Consultores , Humanos , Planejamento de Assistência ao Paciente
13.
Expert Opin Drug Metab Toxicol ; 15(8): 619-631, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31271537

RESUMO

Introduction: The comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorders (BDs) is a frequent and severe condition characterized by a chronic course, high suicidal risk and tendency towards chronicity and treatment non-response. It represents a real challenge to psychiatrists, while requiring a careful and appropriate therapeutic management consisting in the combination of serotonergic antidepressants (ADs), such as serotonin reuptake inhibitors (SRIs), with mood stabilizers. This combination, like any other, raises the problems related to drug interactions that may lead to pharmacokinetic and pharmacodynamic changes, resulting in the modification of the pharmacologic effect and safety profile of a given compound. Areas covered: The aim of the present paper was to review the literature on the pharmacokinetic and pharmacodynamic changes resulting from the interactions of the different drugs prescribed in the OCD-BD comorbidity. Expert opinion: The literature data on pharmacokinetic and pharmacodynamic changes due to interactions of drugs commonly prescribed in the treatment of the OCD-BD comorbidity are extremely limited, and the information is inferred by findings gathered in psychiatric patients suffering from other disorders. This represents a gap in psychopharmacology that should be filled by specific studies on this important topic.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Antimaníacos/administração & dosagem , Antimaníacos/farmacocinética , Antimaníacos/farmacologia , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Transtorno Bipolar/complicações , Interações de Medicamentos , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacocinética , Inibidores de Captação de Serotonina/farmacologia
14.
Chem Biol Interact ; 310: 108744, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299239

RESUMO

The epidemic of loperamide abuse and misuse in the patients for the alternative to opioids has become an increasing worldwide concern and has led to considerations about the potential for drug-drug interactions between loperamide and other combined drugs, especially inhibitors of cytochrome P450 (CYP450) enzymes, such as axitinib. This study assessed the effects of axitinib on the metabolism of loperamide and its main metabolite N-demethylated loperamide in rats and in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4*1. The concentrations of both compounds were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The exposures (AUC(0-t), AUC(0-∞) and Cmax) of loperamide and N-demethylated loperamide showed a conspicuous increase when loperamide was co-administered with axitinib. The Tmax of loperamide increased while CLz/F decreased under the influence of axitinib. In vitro, axitinib inhibited loperamide metabolism with the IC50 of 18.34 µM for RLM, 1.705 µM for HLM and 1.604 µM for CYP3A4*1, and it was confirmed as a non-competitive inhibitor in all enzymes. Taken together, the results indicated that axitinib had an obvious inhibitory impact on loperamide metabolism both in vivo and in vitro. Thus, more attention should be paid to the concurrent use of loperamide and axitinib to reduce the risk of unexpected clinical outcomes.


Assuntos
Axitinibe/farmacologia , Loperamida/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/metabolismo , Desmetilação , Interações de Medicamentos , Humanos , Loperamida/antagonistas & inibidores , Loperamida/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Espectrometria de Massas em Tandem
15.
Toxicol Lett ; 313: 196-204, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278966

RESUMO

Fipronil is a chiral insecticide employed worldwide in crops, control of public hygiene and control of veterinary pests. Humans can be exposed to fipronil through occupational, food, and environmental contamination. Therefore, the risk assessment of fipronil in humans is important to protect human health. Fipronil sulfone is the major metabolite formed during fipronil metabolism by humans. Since the CYP450 enzymes are the main ones involved in drug metabolism, the evaluation of their inhibition by fipronil and its main metabolite is important to predict drug-pesticide interactions. The aim of this work was to investigate the inhibition effects of rac-fipronil, S-fipronil, R-fipronil and fipronil sulfone on the main human CYP450 isoforms. The results showed that CYP2D6 is the only CYP450 isoform inhibited by these xenobiotics. In addition, no enantioselective differences were observed in the inhibition of CYP450 isoforms by fipronil and its individuals' enantiomers. Rac-fipronil, S-fipronil and R-fipronil are moderate CYP2D6 inhibitors showing a competitive inhibition profile. On the other hand, the metabolite fipronil sulfone showed to be a strong inhibitor of CYP2D6 also by competitive inhibition. These results highlight the importance of metabolite evaluation on pesticide safety since the metabolism of fipronil into fipronil sulfone increases the risk of pesticide-drug interactions for drugs metabolized by CYP2D6.


Assuntos
Inibidores do Citocromo P-450 CYP2D6/toxicidade , Citocromo P-450 CYP2D6/metabolismo , Praguicidas/toxicidade , Pirazóis/toxicidade , Citocromo P-450 CYP2D6/química , Inibidores do Citocromo P-450 CYP2D6/química , Relação Dose-Resposta a Droga , Interações de Medicamentos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Biológicos , Praguicidas/química , Conformação Proteica , Pirazóis/química , Medição de Risco , Relação Estrutura-Atividade
16.
Rev. pesqui. cuid. fundam. (Online) ; 11(4): 900-907, jul.-set. 2019. tab
Artigo em Inglês, Português | LILACS, BDENF - Enfermagem | ID: biblio-1005715

RESUMO

Objetivo: Descrever o perfil sociodemográfico e clínico de idosos usuários crônicos de omeprazol. Método: Trata-se de um estudo transversal com usuários com idade superior a 60 anos, que retiraram o omeprazol na Farmácia Pública de Panambi/RS. Resultados: Participaram da pesquisa sessenta idosos, com idade média de 67,90 ±5,6 anos. Duas interações graves foram identificadas envolvendo citalopram e clopidogrel. Observou-se a presença nas prescrições de medicamentos que tem a sua absorção alterada pelo uso concomitante com o omeprazol como captopril (25%) e enalapril (16,7%). Conclusão: Dessa forma, evidenciou-se uma população suscetível a riscos que necessita de acompanhamento farmacêutico


Objective: To describe the sociodemographic and clinical profile of elderly chronic omeprazole users. Method: This is a cross-sectional study. Patients aged 60, from the Public Pharmacy of the city of Panambi / RS. Results: A total of 60 elderly chronic omeprazole users participated in the study with an average of 67.90 ± 5.6 years of age. Two serious interactions were identified involving citalopram and clopidogrel. There was the presence in the prescription of drugs that have their absorption altered by concomitant use of omeprazole as captopril (25%) and enalapril (16.7%). Conclusion: Thus, we highlight that there is a population susceptible to risks that needs pharmaceutical monitoring


Objetivo: Describir el perfil sociodemográfico y clínico de los ancianos usuarios crónicos de omeprazol. Método: Es un estudio transversal descriptivo cuantitativo. Participaron en el estudio pacientes con edad igual o mayor de 60 años, usuarios crónicos de omeprazol, y que acudieron al medicamento en la Farmacia Publica de la cuidad de Panambi/RS. Resultados: Participaron de la investigación 60 ancianos 51,7% del sexo femenino, con edad media de 67,90 ±5,6 años, 81,7% relataran alguna comorbilidad, siendo la más prevalente la hipertensión arterial sistémica (61,7%). Los medicamentos que actúan en el tracto alimentar y metabólico fueron los más frecuentes. Se identificaron dos graves interacciones relacionado al citalopram (8,4%) y clopidogrel (1,7%). Se observó en las prescripciones la presencia de medicamentos cuya absorción es alterada por el uso concomitante con el omeprazol, como el captopril (25%) y enalapril (16,7%). Conclusión: De esta forma, se ha evidenciado una populación susceptible a los riesgos y que necesita de acompañamiento farmacéutico


Assuntos
Humanos , Masculino , Feminino , Idoso , Idoso de 80 Anos ou mais , Omeprazol/efeitos adversos , Omeprazol/uso terapêutico , Saúde do Idoso , Interações de Medicamentos , Relações Profissional-Paciente , Antiulcerosos
17.
Chem Commun (Camb) ; 55(63): 9241-9250, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31328738

RESUMO

The field of chemical biology has introduced several approaches, typically using chemical probes, to measure the direct binding interaction of a small molecule with its biological target in cells. The use of these direct target engagement assays in pharmaceutical development can support mechanism of action hypothesis testing, rank ordering of compounds, and iterative improvements of chemical matter. This Feature Article highlights a newer application of these approaches: the quantification of target engagement in animal models to support late stage preclinical development and the nomination of a drug candidate to clinical trials. Broadly speaking, these efforts can be divided between compounds that covalently and reversibly interact with protein targets; recent examples for both categories are discussed for a range of targets, along with their limitations. New, promising technologies are also highlighted, in addition to the application of target engagement determination to new therapeutic modalities.


Assuntos
Modelos Animais , Preparações Farmacêuticas/metabolismo , Animais , Interações de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Preparações Farmacêuticas/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética
18.
Anticancer Res ; 39(7): 3303-3309, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262850

RESUMO

Combination therapies are used in the clinic to achieve cure, better efficacy and to circumvent resistant disease in patients. Initial assessment of the effect of such combinations, usually of two agents, is frequently performed using in vitro assays. In this review, we give a short summary of the types of analyses that were presented during the Preclinical and Early-phase Clinical Pharmacology Course of the Pharmacology and Molecular Mechanisms Group, European Organization for Research and Treatment on Cancer, that can be used to determine the efficacy of drug combinations. The effect of a combination treatment can be calculated using mathematical equations based on either the Loewe additivity or Bliss independence model, or a combination of both, such as Chou and Talalay's median-drug effect model. Interactions can be additive, synergistic (more than additive), or antagonistic (less than additive). Software packages CalcuSyn (also available as CompuSyn) and Combenefit are designed to calculate the extent of the combined effects. Interestingly, the application of machine-learning methods in the prediction of combination treatments, which can include pharmacogenomic, genetic, metabolomic and proteomic profiles, might contribute to further refinement of combination regimens. However, more research is needed to apply appropriate rules of machine learning methods to ensure correct predictive models.


Assuntos
Combinação de Medicamentos , Quimioterapia Combinada , Animais , Interações de Medicamentos , Humanos , Farmacologia Clínica , Pesquisa Médica Translacional
20.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1122-1123: 49-57, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31153131

RESUMO

Ertugliflozin (ERTU) is a novel, potent, and highly selective sodium glucose cotransporter 2 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. We describe a novel bioanalytical method using high-performance liquid chromatography (HPLC) coupled with fluorescence detection for quantitative determination of ERTU in rat plasma. Acetonitrile-based protein precipitation method was used for sample preparation, and chromatographic separation was performed on a Kinetex® C18 column with an isocratic mobile phase comprising acetonitrile and 10 mM potassium phosphate buffer (pH 6.0). The eluent was monitored by a fluorescence detector at an optimized excitation/emission wavelength pair of 277/320 nm. The method was validated to demonstrate the selectivity, linearity (ranging from 4 to 2000 ng/mL), precision, accuracy, recovery, matrix effect, and stability in line with the current FDA guidelines. The newly developed method was successfully applied to investigate the pharmacokinetic interactions of ERTU with mefenamic acid (MEF) and ketoconazole (KET). The findings of the present study revealed that the pharmacokinetics of ERTU may be altered by concurrent administration of MEF and KET in rats. To our knowledge, the present study is the first to develop a validated bioanalytical method for quantification of ERTU using HPLC coupled with fluorescence detection and to assess the drug interaction potential of ERTU with non-steroidal anti-inflammatory (MEF) and azole antifungal (KET) drugs.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Cetoconazol/farmacocinética , Ácido Mefenâmico/farmacocinética , Espectrometria de Fluorescência/métodos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Interações de Medicamentos , Cetoconazol/sangue , Cetoconazol/química , Limite de Detecção , Modelos Lineares , Masculino , Ácido Mefenâmico/sangue , Ácido Mefenâmico/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
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