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1.
Cancer Treat Rev ; 85: 101979, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078962

RESUMO

PURPOSE: The combination of an anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibody with platinum-based chemotherapy can improve outcomes for patients with advanced non-small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC) compared with chemotherapy alone. For patients receiving these new treatment regimens, it is important that toxicities be managed effectively. A particular challenge can be determining the etiology of an event, especially when there are overlapping symptoms that can be attributed to either immunotherapy or to platinum-based chemotherapy. Here, we evaluate adverse events (AEs) reported in clinical trials of combination therapy with an anti-PD-1 or anti-PD-L1 (anti-PD-[L]1) immunotherapy and chemotherapy to provide information on toxicity management. METHODS: We performed a systematic review of the literature focused on randomized controlled trials of anti-PD-(L)1 therapy combined with platinum-based chemotherapy for advanced/metastatic NSCLC and SCLC. RESULTS: Eleven reports from 9 randomized studies evaluating pembrolizumab, nivolumab, and atezolizumab combined with platinum-based chemotherapy in patients with advanced lung cancer were identified. Immune-mediated AEs and infusion reactions occurred more commonly in patients who received anti-PD-(L)1 immunotherapy with platinum-based chemotherapy compared with chemotherapy alone; however, there was no evidence of unexpected or unanticipated toxicity with these combinations. CONCLUSION: Combinations of anti-PD-(L)1 immunotherapy with platinum-based chemotherapy regimens improve outcomes for patients with NSCLC and SCLC, and toxicity is generally manageable. Strategies for appropriate workup of AEs to allow clinicians to make informed decisions regarding causality and treatment modifications when appropriate are an important element of management of patients receiving an anti-PD-(L)1 agent combined with platinum-based chemotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Nivolumabe/uso terapêutico , Prognóstico , Receptor de Morte Celular Programada 1/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
2.
Cancer Invest ; 38(2): 130-138, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31985314

RESUMO

Background: Pembrolizumab as an immune checkpoint inhibitor (ICI) has emerged as an effective treatment for many cancers. It has unique immune-related adverse events (irAE) and little is known about its risk of fatal adverse events (FAEs). We conducted a meta-analysis of clinical trials to determine the incidence and risk of FAEs with pembrolizumab.Methods: A systematic search for phase I-III clinical trials of pembrolizumab was conducted using databases including PUBMED and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until October 2018. Eligible studies included prospective clinical trials of pembrolizumab with available data on FAE. Data on FAE was extracted from each study and pooled for calculations. Incidence, relative risk (RR) and 95% confidence intervals (CI) were calculated by employing fixed or random-effects models.Results: A total of 11 clinical trials with 3713 patients were included for analysis. The overall incidence of FAE with pembrolizumab was 1.2% (95% CI: 0.5-2.8%). The incidence of FAE significantly varied among different tumor types (p = .02), ranging from 0.2% in melanoma to 3.1% in breast cancer, and with its combination with chemotherapy (0.7%, 95% CI: 0.4-1.2% versus 7.0%, 95% CI: 4.9-10%; p<.01). Chemotherapy plus pembrolizumab 7.0% (95%CI: 4.9-10) as compared to pembrolizumab alone 0.7%, (95% CI: 0.4-1.2; p < .001). There was no significant difference in the risk of FAEs when pembrolizumab was compared with chemotherapy with RR = 1.24 (95% CI: 0.8-1.89; p = .31). The most common FAEs were due to infectious complication (26.5%), cardiac toxicity (14.7%) and pneumonitis (13.2%).Conclusions: The risk of FAEs with pembrolizumab may be similar to chemotherapy in cancer patients and may vary with tumor types and its combination with chemotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Neoplasias/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , Incidência , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco
4.
Toxicol Lett ; 322: 104-110, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31981687

RESUMO

Isoniazid and rifampicin are well-known anti-mycobacterial agents and are widely used to treat pulmonary tuberculosis (TB) as part of the combined therapy approach, recommended by the World Health Organization. The ingestion of these first-line TB drugs are, however, not free of side effects, and are toxic to the liver, kidney, and central nervous system. These side effects are associated with poor treatment compliance, resulting in TB treatment failure, relapse and drug resistant TB. This occurrence has subsequently led to the recent application of novel research technologies, towards a better understanding of the underlying toxicity mechanisms of TB drugs in humans, mostly focussing on the 2 most important TB drugs: isoniazid and rifampicin. In this review, we discuss the contribution that one such an approach, termed metabolomics has made toward this field, and also highlight the impact that this might have towards the development of improved TB treatment regimens.


Assuntos
Antituberculosos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Isoniazida/toxicidade , Metabolômica/métodos , Rifampina/toxicidade , Testes de Toxicidade/métodos , Animais , Antituberculosos/metabolismo , Biomarcadores/metabolismo , Biotransformação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Humanos , Isoniazida/metabolismo , Rifampina/metabolismo , Medição de Risco
5.
BMC Neurol ; 19(1): 335, 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31864345

RESUMO

BACKGROUND: Myasthenia gravis is a chronic, autoimmune, neuromuscular junction disorder characterized by skeletal muscle weakness. Current therapies for myasthenia gravis are associated with significant side effects. The objective of this study was to characterize the side effects, and associated health-related quality of life and treatment impacts, of traditional myasthenia gravis treatments. METHODS: This study had two phases; a Phase 1 interview and a 2-part web-based survey in Phase 2 that included brainstorming (Step 1) and rating (Step 2) exercises using group concept mapping. In Phase 1, all 14 participants reported experiencing side effects from myasthenia gravis treatments which had significant impacts on daily life. In Phase 2, 246 participants contributed to Step 1; 158 returned for Step 2. RESULTS: The brainstorming exercise produced 874 statements about side effects and their impact, which were reduced to 35 side effects and 23 impact-on-daily life statements. When rating these statements on severity, frequency, and tolerability, blood clots, infections/decreased immunity, weight gain, and diarrhea were the least tolerable and most severely rated. The most frequent and severe impacts were sleep interference and reduced physical and social activities. CONCLUSIONS: Based on these findings, there appears to be a need for better and more tolerable treatments for myasthenia gravis patients.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Imunoterapia/efeitos adversos , Miastenia Gravis/tratamento farmacológico , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/psicologia , Feminino , Humanos , Imunoterapia/métodos , Masculino , Adesão à Medicação , Qualidade de Vida , Inquéritos e Questionários
6.
PLoS One ; 14(12): e0227101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31877199

RESUMO

BACKGROUND: The Ministry of Health in Brazil included ethambutol in the intensive phase of sensible tuberculosis (TB) treatment in March 2010, due to the increasing drug resistance, and implemented the fixed dose combination in the TB treatment guidelines. METHODS: A retrospective cohort study was performed to determine the impact of change from three to four drugs schemes on the TB cure and frequency of adverse drug reactions (ADRs) in TB patients. To answer this question, we used data from 730 randomly selected patients who received anti-TB treatment between January 2007 and December 2014 in a reference center from Salvador, Brazil. FINDINGS: TB patients who received the RHEZ regimen (n = 365) developed ADRs more frequently than those treated with the RHZ (n = 365) (86 [23.6%] vs. 55 [15.1%]; p = 0.01). This difference in ADR incidence was even higher in patients above 30 years-old (64 [74.4%] vs. 36 [65.5%]; p = 0.01). The overall number of ADR episodes was greater in patients from the RHEZ group than in the group that received RHZ (170 [61.4%] vs. 107 [38.6%]; p = 0.03). Multivariable logistic regression analysis adjusted for age, alcohol use and diabetes demonstrated that patients receiving the RHEZ regimen had increased odds of developing ADRs than those undertaking the RHZ scheme (odds ratio [OR]: 1.61, 95% confidence interval [CI]: 1.10-2.35; p = 0.015). The overall cure rate was similar between the distinct treatment groups. CONCLUSION: The patients treated with the four-drug regimen exhibited increased risk of ADRs compared to those who received the three-drug regimen, and especially in patients older than 30 years of age.


Assuntos
Antituberculosos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Tuberculose/tratamento farmacológico , Adulto , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Brasil/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
7.
Medicine (Baltimore) ; 98(44): e17745, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689827

RESUMO

The aim of this study was to analyze the clinical manifestations of adverse reactions after the use of SonoVue contrast agent from a large retrospective database, and to evaluate the nursing care strategies and the efficacy of standardized procedure for adverse reactions of SonoVue (SPARS).From January 1, 2012 to December 30, 2018, 34,478 cases of contrast-enhanced ultrasonography were performed in our center. The clinical manifestations of adverse reactions after the use of SonoVue contrast agent were identified and analyzed. The nursing care strategies were evaluated and the outcomes of patients with moderate and severe adverse reactions before and after the application of SPARS were compared.Of the 34,478 cases, 40 cases (0.12%) of adverse reactions after the use of SonoVue were identified. Adverse reactions included anaphylatic shock, skin allergies, nausea or vomiting, dizziness or headache, numbness, chest distress, back pain, and local reactions of the injection site. Most of the adverse reactions were mild and self-limited. Only 3 cases of anaphylatic shock and 2 cases of severe rash underwent further treatments. The 3 patients who were managed by SPARS recovered quicker and spent less comparing with the other 2 patients who were not.SonoVue was a safe contrast agent, with few and mostly mild adverse reactions. SPARS may be an efficient way in tackling moderate to severe adverse reactions, although of which the incidence was rare.


Assuntos
Meios de Contraste/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/enfermagem , Cuidados de Enfermagem/estatística & dados numéricos , Fosfolipídeos/efeitos adversos , Hexafluoreto de Enxofre/efeitos adversos , Ultrassonografia/efeitos adversos , Idoso , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ultrassonografia/métodos
8.
Semin Oncol ; 46(4-5): 362-371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31727344

RESUMO

The correlation between clinical outcomes and treatment-related adverse events (AEs) has always been a debated topic in clinical oncology. Despite toxicities pharmacodynamics effects, the misunderstanding has always been around the corner: AEs themselves could lead to morbidity and mortality; on the other hand, the choice of the clinical outcomes to measure is not univocal. After the advent of immune checkpoint inhibitors (ICIs), such as anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed death-1/programmed death ligand-1, new class-specific AEs have emerged, called immune-related AEs (irAEs). With irAEs, the correlation between toxicity and clinical outcomes has suddenly been suggested, but it is still to be proven. We conducted a systematic literature review regarding this emerging association, pointing out all the available data and speculating on the possible underlying mechanisms. Thirty-six studies were included in the analysis, involving different malignancies (mostly melanoma and lung cancer), with different measured clinical outcomes. The most of them were retrospective. Despite the high heterogeneity, and the enormous biases of the revised studies, we can assume that irAEs occurrence is linked to the therapeutic activity of immune checkpoint inhibitors, with a (certain) direct proportionality, maybe subtending the likelihood of an immunogenic phenotype. This phenomenon seems to occur with both anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed death-1/programmed death ligand-1, and across different solid malignancies.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Neoplasias/complicações , Neoplasias/epidemiologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Humanos , Terapia de Alvo Molecular/efeitos adversos , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Avaliação de Resultados da Assistência ao Paciente , Vigilância em Saúde Pública
9.
Zhongguo Fei Ai Za Zhi ; 22(10): 605-614, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31650941

RESUMO

The application of immunological checkpoint inhibitors (ICIs) has modified many treatment strategies of malignant tumors, which has become a milestone in cancer therapy. The principle of action can be explained as "brake theory". After releasing the brakes by ICIs, unprecedented systemic toxicities, even some refractory and fatal immune-related adverse effects (irAEs) may develop. In this article, we summarized the recommended treatments of grade 3-4 severe irAEs in the latest European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN)/American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC) and Chinese Society of Clinical Oncology (CSCO) guidelines and consensus. We also performed a systemic review of case reports and reviews of irAEs up to May 20, 2019 in PubMed and Chinese journals. Successful applications of specific immunosuppressive drugs and stimulating factors beyond the above guidelines and consensus were supplemented and highlighted, including agents blocking interleukin 6 (IL-6), rituximab, anti-tumor necrosis factor-α (TNFα) monoclonal antibody (mAb), anti-integrin 4 mAb, Janus kinase inhibitors, thrombopoietin receptor agonists and antithymocyte globulin (ATG) etc. We put some concerns of using high-dose steroids for long-term, and emphasize the secondary infections, tumor progression, and unavailability of ICI re-challenge during steroid treatment. We propose the "De-escalation Therapy" principle for severe and refractory irAEs, and suggest that immunosuppressive drugs specifically targeting cytokines should be used as early as possible. Many irAEs in the era of immunotherapy are unprecedented compared with traditional chemotherapy and small-molecule targeted therapy, which is a big challenge to oncologists. Therefore, the establishment of multidisciplinary system is very important for the management of cancer patients.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Imunoterapia/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia
10.
Zhongguo Fei Ai Za Zhi ; 22(10): 615-620, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31650942

RESUMO

Immunocheckpoint inhibitors (ICIs) activated the patients' tumor immunity to kill the tumor cell, and brought new hope to patients with tumor. However, a series of immunocheckpoint inhibitors related adverse effects (irAEs) may also occur based on immune injury. Glucocorticoids are the basis for the treatment of such irAEs. However, the usage, dosage and course of treatment of glucocorticoid in irAEs are different from those in classic autoimmune diseases. Meanwhile, long-term use of large doses of glucocorticoids may cause serious adverse effects too. In this paper, the mechanism, dosage forms, adverse effects and management of glucocorticoids are described in detail, providing references and suggestions for oncologists to apply glucocorticoids in clinical practice.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Glucocorticoides/farmacologia , Imunoterapia/efeitos adversos , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Glucocorticoides/uso terapêutico , Humanos
11.
Complement Ther Med ; 46: 123-130, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31519268

RESUMO

The prior medical literature offers little guidance as to how pain relief and side effect manifestation may vary across commonly used and commercially available cannabis product types. We used the largest dataset in the United States of real-time responses to and side effect reporting from patient-directed cannabis consumption sessions for the treatment of pain under naturalistic conditions in order to identify how cannabis affects momentary pain intensity levels and which product characteristics are the best predictors of therapeutic pain relief. Between 06/06/2016 and 10/24/2018, 2987 people used the ReleafApp to record 20,513 cannabis administration measuring cannabis' effects on momentary pain intensity levels across five pain categories: musculoskeletal, gastrointestinal, nerve, headache-related, or non-specified pain. The average pain reduction was -3.10 points on a 0-10 visual analogue scale (SD = 2.16, d = 1.55, p < .001). Whole Cannabis flower was associated with greater pain relief than were other types of products, and higher tetrahydrocannabinol (THC) levels were the strongest predictors of analgesia and side effects prevalence across the five pain categories. In contrast, cannabidiol (CBD) levels generally were not associated with pain relief except for a negative association between CBD and relief from gastrointestinal and non-specified pain. These findings suggest benefits from patient-directed, cannabis therapy as a mid-level analgesic treatment; however, effectiveness and side effect manifestation vary with the characteristics of the product used.


Assuntos
Cannabis/química , Maconha Medicinal/uso terapêutico , Dor/tratamento farmacológico , Analgésicos/efeitos adversos , Analgésicos/uso terapêutico , Canabidiol/efeitos adversos , Canabidiol/uso terapêutico , Cannabis/efeitos adversos , Dronabinol/efeitos adversos , Dronabinol/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Flores/química , Humanos , Maconha Medicinal/efeitos adversos
12.
BMC Bioinformatics ; 20(1): 479, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533622

RESUMO

BACKGROUND: The adverse reactions that are caused by drugs are potentially life-threatening problems. Comprehensive knowledge of adverse drug reactions (ADRs) can reduce their detrimental impacts on patients. Detecting ADRs through clinical trials takes a large number of experiments and a long period of time. With the growing amount of unstructured textual data, such as biomedical literature and electronic records, detecting ADRs in the available unstructured data has important implications for ADR research. Most of the neural network-based methods typically focus on the simple semantic information of sentence sequences; however, the relationship of the two entities depends on more complex semantic information. METHODS: In this paper, we propose multihop self-attention mechanism (MSAM) model that aims to learn the multi-aspect semantic information for the ADR detection task. first, the contextual information of the sentence is captured by using the bidirectional long short-term memory (Bi-LSTM) model. Then, via applying the multiple steps of an attention mechanism, multiple semantic representations of a sentence are generated. Each attention step obtains a different attention distribution focusing on the different segments of the sentence. Meanwhile, our model locates and enhances various keywords from the multiple representations of a sentence. RESULTS: Our model was evaluated by using two ADR corpora. It is shown that the method has a stable generalization ability. Via extensive experiments, our model achieved F-measure of 0.853, 0.799 and 0.851 for ADR detection for TwiMed-PubMed, TwiMed-Twitter, and ADE, respectively. The experimental results showed that our model significantly outperforms other compared models for ADR detection. CONCLUSIONS: In this paper, we propose a modification of multihop self-attention mechanism (MSAM) model for an ADR detection task. The proposed method significantly improved the learning of the complex semantic information of sentences.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Semântica , Atenção , Humanos
13.
Drugs Aging ; 36(11): 999-1005, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31478168

RESUMO

Constipation is a common condition, affecting up to half of all older adults during their lifetime. Untreated constipation has significant impacts, decreasing quality of life and potentially leading to urinary and/or faecal incontinence, faecal impaction and, in severe cases, hospitalisation. The increased constipation prevalence among older populations is multifactorial, with a number of age-related factors contributing to the rise in prevalence with aging. Laxatives are the mainstay of constipation management and are commonly used among older populations for both treatment and prevention of constipation. A range of laxative types including bulk forming agents, softeners and emollients, osmotic agents, stimulants, and the newer prokinetic and secretory agents are available. Despite laxatives being freely available without prescription in many countries and commonly used by older individuals, evidence regarding the effectiveness or safety of most laxatives in older populations is lacking. Additionally, age-related changes increase the risk of adverse effects associated with laxatives, such as electrolyte disturbances, among older persons. Caution must be taken when extrapolating recommendations for general adult populations to older populations. Laxative choice for older individuals should be tailored after careful assessment and consideration of comorbid conditions, concomitant medications and the potential for adverse effects.


Assuntos
Constipação Intestinal/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Laxantes/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Constipação Intestinal/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Feminino , Humanos , Laxantes/administração & dosagem , Laxantes/efeitos adversos , Masculino , Qualidade de Vida
14.
Int J Mol Sci ; 20(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487867

RESUMO

Molecular docking is an established in silico structure-based method widely used in drug discovery. Docking enables the identification of novel compounds of therapeutic interest, predicting ligand-target interactions at a molecular level, or delineating structure-activity relationships (SAR), without knowing a priori the chemical structure of other target modulators. Although it was originally developed to help understanding the mechanisms of molecular recognition between small and large molecules, uses and applications of docking in drug discovery have heavily changed over the last years. In this review, we describe how molecular docking was firstly applied to assist in drug discovery tasks. Then, we illustrate newer and emergent uses and applications of docking, including prediction of adverse effects, polypharmacology, drug repurposing, and target fishing and profiling, discussing also future applications and further potential of this technique when combined with emergent techniques, such as artificial intelligence.


Assuntos
Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular/métodos , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Polifarmacologia , Relação Quantitativa Estrutura-Atividade
15.
Drugs Aging ; 36(11): 1035-1045, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31552597

RESUMO

BACKGROUND: Synthetic oral cannabinoids (nabilone and dronabinol) may have adverse respiratory effects. Our purpose was to describe the scope, pattern, and patient characteristics associated with incident off-label synthetic oral cannabinoid use among older adults with chronic obstructive pulmonary disease (COPD) compared to older adults without COPD. METHODS: This was a retrospective, population-based, cohort study using Ontario, Canada, heath administrative data. Individuals aged 66 years or older were included, and physician-diagnosed COPD was identified using a previously validated, highly specific algorithm. Incident off-label oral cannabinoid use was examined between April 1, 2005 and March 31, 2015. Descriptive statistics were used to describe drug use patterns. Multiple logistic regression was used to identify patient characteristics associated with incident drug use. RESULTS: There were 172,282 older adults with COPD and 1,068,256 older adults without COPD identified between April 1, 2005 and March 31, 2015. Incident synthetic oral cannabinoid use during this period occurred with significantly greater (p < 0.001) frequency among older adults with COPD (0.6%) versus older adults without COPD (0.3%). Compared to those without COPD, older adults with COPD used synthetic cannabinoids for significantly longer durations and more frequently at higher doses. CONCLUSIONS: Although incident off-label oral cannabinoid use was relatively low among all older Ontarian adults, this drug class was used with greater frequency and more often in potentially concerning ways among older adults with COPD. These findings raise possible safety concerns, but further research on the respiratory safety of oral cannabinoids among individuals with COPD is needed.


Assuntos
Dronabinol/análogos & derivados , Uso de Medicamentos/estatística & dados numéricos , Prescrição Inadequada/estatística & dados numéricos , Uso Off-Label/estatística & dados numéricos , Medicamentos sob Prescrição/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Idoso , Algoritmos , Estudos de Coortes , Dronabinol/administração & dosagem , Dronabinol/efeitos adversos , Dronabinol/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Ontário , Medicamentos sob Prescrição/efeitos adversos , Medicamentos sob Prescrição/uso terapêutico , Estudos Retrospectivos
16.
Indian J Cancer ; 56(3): 207-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389382

RESUMO

PURPOSE: There is no study till date determining the spectrum of adverse events of pazopanib in Indian patients with advanced sarcoma. MATERIALS AND METHODS: We conducted a retrospective study by analyzing the case records of metastatic sarcoma patients treated with pazopanib from January 2016 to July 2017 in sarcoma medical oncology clinic. Toxicity was assessed according to CTCAE v.4.03 criteria. SPSS version 23 was used for statistical evaluation. RESULTS: A total of 33 patients received pazopanib. The median age was 41 years (range, 19-75 years), with a male predominance (54.5%). Twenty-six patients (78.8%) had ECOG performance status 1 at the time of pazopanib initiation. The most common type of sarcoma was synovial sarcoma, and the mean duration of pazopanib intake in patients was 4.12 months. The median follow-up was 13 months. Median progression-free survival was 5 months, and median overall survival was 18 months. Overall response rate was 6.0%. Out of the 33 patients, 42.4% (n = 14) received it after first line of therapy. Six patients (18.2%) required dose reductions due to toxicity. Thirteen (39.4%) patients experienced CTCAE grade 3 or 4 toxicities. Most common grade 3 and 4 toxicities experienced among patients were hand-foot skin reaction (18.2%) and proteinuria (9.1%). No significant difference was seen when analyzed for variables such as age, sex, ECOG performance status, comorbidities, and number of previous lines received in patients experiencing grade 3 and 4 toxicities. CONCLUSIONS: The spectrum of adverse events in Indian patients at doses lower than the recommended dose is distinctly different from the western population. However, this unique toxicity profile needs to be validated in prospective studies.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Pirimidinas/efeitos adversos , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Sulfonamidas/efeitos adversos , Adulto , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Sarcoma/secundário , Neoplasias de Tecidos Moles/patologia , Taxa de Sobrevida , Adulto Jovem
17.
J Evid Based Med ; 12(3): 227-231, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441236

RESUMO

Anticholinergic drugs are prescribed for a range of conditions including gastrointestinal disorders, overactive bladder, allergies, and depression. While in some circumstances anticholinergic effects are therapeutic, they also pose many undesired or adverse effects. The overall impact from concomitant use of multiple medications with anticholinergic properties is termed anticholinergic burden (ACB). Greater ACB is associated with increased risks of impaired physical and cognitive function, falls, cardiovascular events, and mortality. This has led to the development of interventions aimed at reducing ACB through the deprescribing of anticholinergic drugs. However, little is known about the implementation issues that may influence successful embedding and integration of such interventions into routine clinical practice. In this paper, we present the protocol for our systematic review that aims to identify the qualitative evidence for the barriers and facilitators to reduce ACB from the perspectives of patients, carers, and healthcare professionals. A comprehensive search strategy will be conducted across OVID Medline, EMBASE, PsycInfo, and CINAHL. The review will be conducted in accordance with ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) and has been registered with PROSPERO (Registration CRD42018109084). Normalization process theory (NPT) will be used to explore, understand, and explain qualitative data in relation to factors that act as barriers or facilitators to ACB reduction.


Assuntos
Antagonistas Colinérgicos/efeitos adversos , Antagonistas Colinérgicos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Segurança do Paciente , Cuidadores/estatística & dados numéricos , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Medicina Baseada em Evidências , Pessoal de Saúde/estatística & dados numéricos , Humanos , Determinação de Necessidades de Cuidados de Saúde , Pesquisa Qualitativa , Medição de Risco
18.
BMJ Case Rep ; 12(8)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451475

RESUMO

A 62-year-old previously healthy male was admitted with new onset generalised tonic-clonic seizures. Treatment was initiated with the antiepileptic levetiracetam and he had no further episodes of seizures. Creatine kinase (CPK) level was 1812 IU/L 12-hour postadmission. Despite good hydration, his CPK levels continued to rise dramatically and reached a level of 19 000 IU/L on day 5. This rise was unexplained as he did not have any further seizures and had a normal renal function. In the absence of other risk factors, the rare possibility of levetiracetam being responsible for the disproportionately high CPK was considered. Within 12 hours of withdrawal of levetiracetam, there was a downward trend in the CPK levels, with a 10-fold decrease in CPK levels over the next 4 days. This is only the ninth case reported in literature regarding this rare and potentially serious adverse effect of levetiracetam.


Assuntos
Creatina Quinase/sangue , Substituição de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Levetiracetam , Rabdomiólise , Convulsões/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Levetiracetam/administração & dosagem , Levetiracetam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Fenitoína/administração & dosagem , Rabdomiólise/sangue , Rabdomiólise/induzido quimicamente , Rabdomiólise/diagnóstico , Rabdomiólise/terapia , Convulsões/diagnóstico , Resultado do Tratamento
19.
J Neurooncol ; 145(1): 1-9, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31452071

RESUMO

INTRODUCTION: Immune checkpoint inhibitors (ICPI), a breakthrough immunotherapy for cancer, can cause serious neurological adverse events (AEs). We aimed to investigate the characteristics of the neurological and related AEs associated with ICPI treatment, using a large pharmacovigilance database from Japan. METHODS: We conducted disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database containing 566,698 patient cases recorded between April 2004 and March 2019, to detect neurological and related AE signals associated with ICPI treatment by calculating reporting odds ratio (ROR). RESULTS: Among 7604 cases with ICPI usage, we identified 583 cases (7.67%) with a significantly high reporting of neurological and related AEs (lower 95% of the ROR > 1), including myasthenia gravis (MG), inflammatory myositis, non-infectious encephalitis/myelitis, non-infectious meningitis, hypophysitis/hypopituitarism, and peripheral neuropathy including Guillain-Barre syndrome (GBS). Among the ICPI subtypes, when compared to nivolumab as a reference, number of hypophysitis, hypopituitarism, and meningitis reports from the use of ipilimumab and number of encephalitis/myelitis and meningitis reports from the use of anti-programmed cell death-ligand-1 (PD-L1) agents were significantly higher. Additionally, time to AE onset of symptoms post administration was short in meningitis (median 21 days), MG (median 28 days), myositis (median 28 days), and encephalitis/myelitis (median 32.5 days), while it was longer in peripheral neuropathy (median 42 days), hypophysitis (median 94 days), and hypopituitarism (median 112 days). CONCLUSIONS: Our results showed characteristic features of neurological and related AEs associated with each ICPI subtype, reported in a large number of Japanese patients. This would help in prompt identification and treatment of neurological AEs associated with ICPI treatment.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Antineoplásicos Imunológicos/efeitos adversos , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Farmacovigilância , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Feminino , Humanos , Imunoterapia/efeitos adversos , Masculino , Neoplasias/patologia , Prognóstico
20.
BMC Health Serv Res ; 19(1): 583, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426786

RESUMO

BACKGROUND: Medication safety in cancer patients receiving complex medication regimens is an important problem in various settings. Medication related events, interceptions and interventions are not well described in this area. We intended to study incidence, types, settings and stages involved, root cause analysis, medication classes involved and the level of harm cause by medication errors in two hospitals providing oncology services comparatively. The severity of incidents and interventions are studied. METHODS: It was a prospective cross sectional study among cancer in-patients of two tertiary care hospitals of KPK. Scale by NCC-MERP was used for evaluation of all medication related incidents. The data obtained was analyzed by IBM SPSS statistics 22 with 95% confidence interval and used the same for other descriptive statistics. RESULTS: All medication orders were reviewed at both sites (Computerized Prescription Order Entry and HWP systems). Potential ADEs incidence was found high at site 2 (97.5%) while medication errors without harm was high at site 1 (97.5%). Most events occur at prescribing level 87.6 and 81.7% at both sites 1 and 2. Types highly reported involved improper dose 31.4 and 15.5%, monitoring error 14.6 and 15.2% at site 1 and 2. Medications involved in these incidents were antibiotics 44 and 12.7%, antiemetic 7.5 and 15.8% and antineoplastic 2.9 and 9.4% at site 1 and 2. Severity of 3.6 and 36.5% incidents had potential to cause harm at site 1 and 2. Root causes were human factors 62.6 and 72.3%, drug selection 33.6 and 38.8%, and dose selection 39.6 and 15.3% at sites 1 and 2. Contributing factors including staff training 33.6 and 24.3%, system for covering patient care 14.9 and 36.6%, communication system 2.4 and 20.3%, interruptions 9.7 and 7.3% and others 78.8 and 68.6% were highly reported. Preventability of medication errors was 99% at both sites. Intervention was taken in 90.5% events at site 1 (CPOE system) while the incidence lowest at site 2 (HWP system). CONCLUSION: Medication related events are high among cancer in-patients at the site lacking updated electronic system for medication prescribing. Proper training about medication safety, reporting and interventions are required.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Erros de Medicação/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Antibacterianos/efeitos adversos , Antieméticos/efeitos adversos , Antineoplásicos/efeitos adversos , Estudos Transversais , Prescrições de Medicamentos , Humanos , Incidência , Paquistão , Estudos Prospectivos , Análise de Causa Fundamental , Centros de Atenção Terciária/estatística & dados numéricos
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