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1.
Pharmacol Res Perspect ; 9(1): e00705, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33421347

RESUMO

Drug-drug interaction (DDI) is a common clinical problem that has occurred as a result of the concomitant use of multiple drugs. DDI may occur in patients under treatment with medications used for coronavirus disease 2019 (COVID-19; i.e., chloroquine, lopinavir/ritonavir, ribavirin, tocilizumab, and remdesivir) and increase the risk of serious adverse reactions such as QT-prolongation, retinopathy, increased risk of infection, and hepatotoxicity. This review focuses on summarizing DDIs for candidate medications used for COVID-19 in order to minimize the adverse reactions.


Assuntos
Antivirais/uso terapêutico , /tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Cloroquina/uso terapêutico , Interações Medicamentosas , Humanos , Lopinavir/uso terapêutico , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico
2.
Medicina (Kaunas) ; 57(1)2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33435185

RESUMO

Effective platelet inhibition is the main goal of the antiplatelet therapy recommended as a standard treatment in the secondary prevention of non-embolic ischemic stroke. Acetylsalicylic acid (aspirin) and clopidogrel are commonly used for this purpose worldwide. A low biological response to antiplatelet agents is a phenomenon that significantly reduces the therapeutic and protective properties of the therapy. The mechanisms leading to high on-treatment platelet reactivity are still unclear and remain multifactorial. The aim of the current review is to establish the background of resistance to antiplatelet agents commonly used in the secondary prevention of ischemic stroke and to explain the possible mechanisms. The most important factors influencing the incidence of a low biological response were demonstrated. The similarities and the differences in resistance to both drugs are emphasized, which may facilitate the selection of the appropriate antiplatelet agent in relation to specific clinical conditions and comorbidities. Despite the lack of indications for the routine assessment of platelet reactivity in stroke subjects, this should be performed in selected patients from the high-risk group. Increasing the detectability of low antiaggregant responders, in light of its negative impact on the prognosis and clinical outcomes, can contribute to a more individualized approach and modification of the antiplatelet therapy to maximize the therapeutic effect in the secondary prevention of stroke.


Assuntos
Aspirina/uso terapêutico , Clopidogrel/uso terapêutico , Resistência a Medicamentos/fisiologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Disponibilidade Biológica , Interações Medicamentosas , Resistência a Medicamentos/genética , Humanos , Falência Renal Crônica/fisiopatologia , Síndrome Metabólica/fisiopatologia , Variantes Farmacogenômicos/genética , Ativação Plaquetária , Testes de Função Plaquetária , Medição de Risco , Prevenção Secundária , Fumar/fisiopatologia , Acidente Vascular Cerebral/prevenção & controle
3.
Postgrad Med ; 133(1): 1-9, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33423590

RESUMO

Pregabalin is one of the first-line treatments approved for the management of neuropathic pain (NeP). While many patients benefit from treatment with pregabalin, they are often treated with suboptimal doses, possibly due to unfamiliarity around prescribing the drug and/or side effects that can occur with up-titration. This narrative review discusses key aspects of initiating, titrating, and managing patients prescribed pregabalin therapy, and addresses concerns around driving and the potential for abuse, as well as when to seek specialist opinion. To ensure that patients derive maximum therapeutic benefit from the drug, we suggest a 'low and slow' dosing approach to limit common side effects and optimize tolerability alongside patients' expectations. When requiring titration to higher doses, we recommend initiating 'asymmetric dosing,' with the larger dose in the evening. Fully engaging patients in order for them to understand the expected timeline for efficacy and side effects (including their resolution), can also help determine the optimal titration tempo for each individual patient. The 'low and slow' approach also recognizes that patients with NeP are heterogeneous in terms of their optimal therapeutic dose of pregabalin. Hence, it is recommended that general practitioners closely monitor patients and up-titrate according to pain relief and side effects to limit suboptimal dosing or premature discontinuation.


Assuntos
Analgésicos/administração & dosagem , Neuralgia/tratamento farmacológico , Pregabalina/administração & dosagem , Pregabalina/efeitos adversos , Fatores Etários , Analgésicos/uso terapêutico , Condução de Veículo , Comorbidade , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Humanos , Adesão à Medicação , Medição da Dor , Educação de Pacientes como Assunto , Pregabalina/uso terapêutico , Fatores Sexuais , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle
7.
Toxicol Lett ; 337: 18-27, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232777

RESUMO

BACKGROUND AND OBJECTIVE: Optimal experimental design theory proposes choosing specific settings in experimental trials in order to maximize the precision of the resulting parameter estimates. In dose response experiments, this corresponds to choosing the optimal dose levels for every available observation, and can be applied both to singular dose-response relationships and to interaction experiments where two substances are given simultaneously at several different mixture ratios ("ray designs"). While the theory of experimental design for this situation is well developed, the mathematical complexity prevents widespread use in practical applications. A simple to use application making the theory accessible to practitioners is thus very desirable. METHODS: Results from established optimal experimental design theory are applied to dose response applications, focusing on log-logistic and Weibull class dose response functions. Suitable optimal design algorithms to solve these problems are implemented into an R-shiny based online application. RESULTS: The application provides an interface to easily calculate D-optimal designs not only for singular dose experiments, but also for interaction trials with several combination rays of substances. Furthermore, the app also allows evaluating the efficiency of existing candidate designs, and finally allows construction of designs which perform robustly under different assumptions in regard to the true parameters.


Assuntos
Algoritmos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Interações Medicamentosas , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Projetos de Pesquisa
8.
Clin Exp Pharmacol Physiol ; 48(2): 203-210, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33090501

RESUMO

The coronavirus disease 2019 (COVID-19) is an epidemic disease caused by the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) and spreading throughout the world rapidly. Here we evaluated the efficacy of the Lopinavir/Ritonavir (LPV/r) and its combination with other drugs in the treatment of COVID-19. We included 170 confirmed COVID-19 patients who had been cured and discharged. Their antiviral therapies were LPV/r alone or combinations with interferon (IFN), Novaferon and Arbidol. We evaluated the medication efficacy by comparing the time of the negative nucleic acid conversion and the length of hospitalization mainly. The LPV/r + Novaferon [6.00 (4.00-8.00) and 7.50 (5.00-10.00) days] had shorter time of the negative nucleic acid conversion (P = .0036) and shorter time of hospitalization (P < .001) compared with LPV/r alone [9.00 (5.00-12.00) and 12.00 (11.00-15.00) days] and LPV/r + IFN [9.00 (7.25-11.00) and 12.00 (10.00-13.50) days]. On the contrary, LPV/r + IFN [9.00 (7.25-11.00) and 12.00 (10.00-13.50) days] had shorter time of the negative nucleic acid conversion (P = .031) and shorter time of hospitalization (P < .001) compared with LPV/r + IFN +Novaferon [10.00 (8.00-11.25) and 13.50 (11.50-17.00) days] and LPV/r + IFN +Arbidol [14.00 (9.75-19.00) and 19.50 (13.25-24.00) days]. In conclusion, the combination of LPV/r and Novaferon may have better efficacy against COVID-19. However, adding IFN based on LPV/r + Novaferon or adding Arbidol based on LPV/r + IFN may not improve the efficacy.


Assuntos
/tratamento farmacológico , Lopinavir/farmacologia , Ritonavir/farmacologia , Adulto , Interações Medicamentosas , Feminino , Humanos , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ritonavir/uso terapêutico , Resultado do Tratamento
11.
Hautarzt ; 72(1): 44-49, 2021 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-33242135

RESUMO

Severe pharmacological side effects have an occurrence of 5-7% and represent a frequent reason for hospital admission. The prevalence of undesired pharmacological side effects during hospitalization is even higher with approximately 11.5%. The causes are often interactions between drugs due to the polypharmacy of multimorbid older patients. On average, a 65-year-old male patient will simultaneously be taking 5 medications. Due to the increasing use of systemic drugs in dermatology and the simultaneously increasing polypharmacy, knowledge of interactions between medications is essential for dermatologists in order to avoid severe side effects of drugs. This article provides assistance in order to identify patients and medications with a high risk for severe interactions and, therefore, to avoid the occurrence of undesired effects or the reduction of the therapeutic effects of active substances. We would like to point out that this article deals with individual aspects and does not mean that the testing of individual drug interactions with interaction programs can be omitted. It should also not be neglected that in addition to prescription-only drugs, foodstuffs, dietary supplements and herbs can also lead to interactions with medications.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Polimedicação , Idoso , Interações Medicamentosas , Hospitalização , Humanos , Masculino , Prevalência
12.
Eur J Pharmacol ; 891: 173694, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33130275

RESUMO

In the context of the current SARS-CoV-2 pandemic, associations of drugs which interfere with specific steps of the viral infectious cycle are currently being exploited as therapeutic strategies since a specific treatment by vaccination is still unavailable. A widespread association of repurposed agents is the combination of the antimalarial drug Hydroxychloroquine and the macrolide antibiotic Azithromycin in the setting of clinical trials. But a closer analysis of their mechanism of action suggests that their concomitant administration may be impractical, and this is supported by experimental data with other agents of the same classes. However a sequential administration of the lysosomotropic antimalarial with the addition of the macrolide proton pump inhibitor after the first has reached a certain threshold could better exploit their antiviral potential.


Assuntos
Azitromicina/farmacologia , Reposicionamento de Medicamentos , Hidroxicloroquina/farmacologia , Antibacterianos/farmacologia , Antimaláricos/farmacologia , /virologia , Interações Medicamentosas/fisiologia , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Humanos , /fisiologia
13.
Transplantation ; 105(1): 138-150, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32941394

RESUMO

BACKGROUND: The epidemiological and clinical characteristics of solid organ transplant (SOT) patients during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic remains unclear. We conducted a matched retrospective cohort study to compare clinical outcomes among SOT recipients with the general population and to assess immunosuppression management. METHODS: Adult SOT recipients with laboratory polymerase chain reaction-confirmed SARS-CoV-2 infection admitted to a tertiary-care hospital in Barcelona, Spain, from March 11 to April 25, 2020, were matched to controls (1:4) on the basis of sex, age, and age-adjusted Charlson's Index. Patients were followed for up to 28 days from admission or until censored. Primary endpoint was mortality at 28 days. Secondary endpoints included admission to the intensive care unit and secondary complications. Drug-drug interactions (DDI) between immunosuppressants and coronavirus disease 2019 (COVID-19) management medication were collected. RESULTS: Forty-six transplant recipients and 166 control patients were included. Mean (SD) age of transplant recipients and controls was 62.7 (12.6) and 66.0 (12.7) years, 33 (71.7%) and 122 (73.5%) were male, and median (interquartile range) Charlson's Index was 5 (3-7) and 4 (2-7), respectively. Mortality was 37.0% in SOT recipients and 22.9% in controls (P = 0.51). Thirty-three (71.7%) patients underwent transitory discontinuation of immunosuppressants due to potential or confirmed DDI. CONCLUSIONS: In conclusion, hospitalized SOT recipients with COVID-19 had a trend toward higher mortality compared with controls, although it was not statistically significant, and a notable propensity for DDI.


Assuntos
/complicações , Imunossupressores/uso terapêutico , Transplante de Órgãos/mortalidade , Idoso , Idoso de 80 Anos ou mais , Interações Medicamentosas , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplantados
14.
Res Social Adm Pharm ; 17(2): 483-486, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32327397

RESUMO

Background: Combinations of hydroxychloroquine (HCQ) and azithromycin have been promoted as treatments for COVID-19 based on small, uncontrolled clinical trials that have not assessed potential risks. Risks of treatment include QT segment prolongation, Torsades de Pointes (TdP), and death. This comparative pharmacovigilance analysis evaluated the risk of these events. Methods: Data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) (>13 million total reports) were used. Queries extracted reports based on exposures of HCQ/chloroquine (CQ) alone, azithromycin alone, HCQ/CQ + azithromycin, amoxicillin alone, HCQ/CQ + amoxicillin alone. Amoxicillin served as a control. Events of interest included death and TdP/QT prolongation as well as accidents/injuries and depression as control events. Proportional Reporting Ratios (PRR) and 95% confidence intervals (CI) were calculated where a lower limit of the of 95% CI (Lower95CI) value of ≥2.0 is interpreted as a potential safety signal. Results: Lower95CIs for HCQ/CQ alone showed no potential safety signals for TdP/QT prolongation, death, or any of the control events included. The PRRs and 95% CIs for TdP/QT prolongation was 1.43 (1.29-2.59) with HCQ/CQ use alone and 4.10 (3.80-4.42) for azithromycin alone. For the combined HCQ/CQ + azithromycin group, the PRR and 95% CI was 3.77 (1.80-7.87). For the control of amoxicillin, there were no safety signals when used alone or in combination with HCQ/CQ. Conclusions: HCQ/CQ use was not associated with a safety signal in this analysis of FAERS data. However, azithromycin used alone was associated with TdP/QT prolongation events and should be used with caution.


Assuntos
Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Cloroquina/uso terapêutico , Hidroxicloroquina/uso terapêutico , Síndrome do QT Longo/induzido quimicamente , Torsades de Pointes/induzido quimicamente , Antivirais/efeitos adversos , Azitromicina/efeitos adversos , /tratamento farmacológico , Cloroquina/efeitos adversos , Interações Medicamentosas , Quimioterapia Combinada , Humanos , Hidroxicloroquina/efeitos adversos , Síndrome do QT Longo/mortalidade , Farmacovigilância , Torsades de Pointes/mortalidade , Estados Unidos/epidemiologia
15.
Aquat Toxicol ; 230: 105673, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33221665

RESUMO

The negative effects induced in marine organisms by Climate Change related abiotic factors consequences, namely ocean warming, are well-known. However, few works studied the combined impacts of ocean warming and contaminants, as pharmaceutical drugs. Carbamazepine (CBZ) and cetirizine (CTZ) occur in the marine environment, showing negative effects in marine organisms. This study aimed to evaluate the impacts of ocean warming on the effects of CBZ and CTZ, when acting individually and combined (drug vs drug), in the edible clam Ruditapes philippinarum. For that, drugs concentration, bioconcentration factors and biochemical parameters, related with clam's metabolic capacity and oxidative stress, were evaluated after 28 days exposure to environmentally relevant scenarios of these stressors. The results showed limited impacts of the drugs (single and combined) at control and warming condition. Indeed, it appeared that warming improved the oxidative status of contaminated clams (higher reduced to oxidized glutathione ratio, lower lipid peroxidation and protein carbonylation levels), especially when both drugs were combined. This may result from clam's defence mechanisms activation and reduced metabolic capacity that, respectively, increased elimination and limited production of reactive oxygen species. At low stress levels, defence mechanisms were not activated which resulted into oxidative stress. The present findings highlighted that under higher stress levels clams may be able to activate defence strategies that were sufficient to avoid cellular damages and loss of redox homeostasis. Nevertheless, low concentrations were tested in the present study and the observed responses may greatly change under increased pollution levels or temperatures. Further research on this topic is needed since marine heat waves are increasing in frequency and intensity and pollution levels of some pharmaceuticals are also increasing in coastal systems.


Assuntos
Anticonvulsivantes/toxicidade , Bivalves/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Água do Mar/química , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Bivalves/metabolismo , Mudança Climática , Interações Medicamentosas , Modelos Teóricos , Oceanos e Mares , Temperatura
16.
Toxicol Lett ; 338: 10-20, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33253783

RESUMO

Meloxicam is a thiazole-containing NSAID that was approved for marketing with favorable clinical outcomes despite being structurally similar to the hepatotoxic sudoxicam. Introduction of a single methyl group on the thiazole results in an overall lower toxic risk, yet the group's impact on P450 isozyme bioactivation is unclear. Through analytical methods, we used inhibitor phenotyping and recombinant P450s to identify contributing P450s, and then measured steady-state kinetics for bioactivation of sudoxicam and meloxicam by the recombinant P450s to determine relative efficiencies. Experiments showed that CYP2C8, 2C19, and 3A4 catalyze sudoxicam bioactivation, and CYP1A2 catalyzes meloxicam bioactivation, indicating that the methyl group not only impacts enzyme affinity for the drugs, but also alters which isozymes catalyze the metabolic pathways. Scaling of relative P450 efficiencies based on average liver concentration revealed that CYP2C8 dominates the sudoxicam bioactivation pathway and CYP2C9 dominates meloxicam detoxification. Dominant P450s were applied for an informatics assessment of electronic health records to identify potential correlations between meloxicam drug-drug interactions and drug-induced liver injury. Overall, our findings provide a cautionary tale on assumed impacts of even simple structural modifications on drug bioactivation while also revealing specific targets for clinical investigations of predictive factors that determine meloxicam-induced idiosyncratic liver injury.


Assuntos
Anti-Inflamatórios não Esteroides/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Meloxicam/metabolismo , Microssomos Hepáticos/enzimologia , Tiazinas/metabolismo , Ativação Metabólica , Anti-Inflamatórios não Esteroides/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Mineração de Dados , Aprendizado Profundo , Interações Medicamentosas , Registros Eletrônicos de Saúde , Feminino , Humanos , Inativação Metabólica , Cinética , Masculino , Meloxicam/toxicidade , Pessoa de Meia-Idade , Especificidade por Substrato , Tiazinas/toxicidade
17.
Toxicol Lett ; 338: 51-57, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33290829

RESUMO

Belinostat is a pan-histone deacetylase (HDAC) inhibitor which recently approved for the treatment of relapsed/refractory Peripheral T-cell lymphomas (PTCL). To assess drug-drug interactions (DDIs) potential of belinostat via inhibition of UDP-glucuronosyltransferases (UGTs), the effects of belinostat on UGTs activities were investigated using the non-selective probe substrate 4-methylumbelliferone (4-MU) and trifluoperazine (TFP) by UPLC-MS/MS. Belinostat exhibited a wide range of inhibition against UGTs activities, particularly a potent non-competitive inhibition against UGT1A3, and weak inhibition against UGT1A1, 1A7, 1A8, 2B4 and 2B7. Further, in vitro-in vivo extrapolation (IVIVE) approaches were used to predict the risk of DDI arising from inhibition of UGTs. Our data indicate that the intravenous infusion of belinostat at clinical available dose can contribute a significant increase to the AUC of co-administrated drugs primarily cleared by UGT1A3 or UGT1A1, which will result in potential DDIs. In contrast, oral administrated belinostat is unlikely to cause significant DDIs through inhibition of glucuronidation.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Sulfonamidas/farmacologia , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Interações Medicamentosas , Glucuronosiltransferase/metabolismo , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/toxicidade , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/toxicidade , Infusões Intravenosas , Cinética , Sulfonamidas/administração & dosagem , Sulfonamidas/toxicidade
19.
J Affect Disord ; 279: 117-121, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33045553

RESUMO

In recent months, there has been a rapid spread of coronavirus disease (COVID-19), being now regarded as a global pandemic. In this context, the governments of different countries have established strict containment measures, and subsequent deconfinement measures, with consequential alterations in the rhythms and living habits of the population, including patients with bipolar disorder (BD), who are in an extremely vulnerable situation. The present paper aims to propose a number of recommendations, based on scientific evidence, for mental health professionals who may be in charge of BD patients during this health crisis in the coming months. Among these recommendations, careful monitoring of pharmacological treatment, reinforcing medication adherence, and surveillance of drug-drug interaction risk in cases where the patient is being treated for COVID-19 are of utmost importance.


Assuntos
Transtorno Bipolar/tratamento farmacológico , /epidemiologia , Interações Medicamentosas , Pessoal de Saúde , Humanos , Adesão à Medicação , Pandemias , /isolamento & purificação
20.
Xenobiotica ; 51(1): 1-4, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32571130

RESUMO

Challenges and opportunities within peptide ADME (absorption, distribution, metabolism and elimination) were presented and discussed at the 2nd workshop of the Peptide ADME Discussion Group in Cambridge, UK (17th of September 2019). This article summarises the presentations and discussions from this workshop. The following topics were covered: Peptide drug-drug interactions (DDIs) Regulatory perspectives on peptide ADME studies Bioavailability of therapeutic peptides impacted by metabolism and oligomerization in the subcutaneous compartment Regulated bioanalysis of parent peptide and active metabolites by immunoaffinity LC-MS/MS Peptide radiopharmaceutical development.


Assuntos
Peptídeos/metabolismo , Disponibilidade Biológica , Cromatografia Líquida , Interações Medicamentosas , Humanos , Espectrometria de Massas em Tandem
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