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2.
PLoS One ; 15(4): e0231252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294131

RESUMO

Drug induced liver injury (DILI) is one of the key safety concerns in drug development. To assess the likelihood of drug candidates with potential adverse reactions of liver, we propose a compound attributes-based approach to predicting hepatobiliary disorders that are routinely reported to US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Specifically, we developed a support vector machine (SVM) model with recursive feature extraction, based on physicochemical and structural properties of compounds as model input. Cross validation demonstrates that the predictive model has a robust performance with averaged 70% of both sensitivity and specificity over 500 trials. An independent validation was performed on public benchmark drugs and the results suggest potential utility of our model for identifying safety alerts. This in silico approach, upon further validation, would ultimately be implemented, together with other in vitro safety assays, for screening compounds early in drug development.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Simulação por Computador , Testes de Toxicidade/métodos , Bases de Dados Factuais , Previsões , Humanos , Fígado/efeitos dos fármacos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/classificação , Sensibilidade e Especificidade , Máquina de Vetores de Suporte , Estados Unidos , United States Food and Drug Administration
3.
PLoS One ; 15(4): e0231883, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302358

RESUMO

OBJECTIVE: A current assessment of case reports of possible drug-induced pancreatitis is needed. We systematically reviewed the case report literature to identify drugs with potential associations with acute pancreatitis and the burden of evidence supporting these associations. METHODS: A protocol was developed a priori (PROSPERO CRD42017060473). We searched MEDLINE, Embase, the Cochrane Library, and additional sources to identify cases of drug-induced pancreatitis that met accepted diagnostic criteria of acute pancreatitis. Cases caused by multiple drugs or combination therapy were excluded. Established systematic review methods were used for screening and data extraction. A classification system for associated drugs was developed a priori based upon the number of cases, re-challenge, exclusion of non-drug causes of acute pancreatitis, and consistency of latency. RESULTS: Seven-hundred and thirteen cases of potential drug-induced pancreatitis were identified, implicating 213 unique drugs. The evidence base was poor: exclusion of non-drug causes of acute pancreatitis was incomplete or poorly reported in all cases, 47% had at least one underlying condition predisposing to acute pancreatitis, and causality assessment was not conducted in 81%. Forty-five drugs (21%) were classified as having the highest level of evidence regarding their association with acute pancreatitis; causality was deemed to be probable or definite for 19 of these drugs (42%). Fifty-seven drugs (27%) had the lowest level of evidence regarding an association with acute pancreatitis, being implicated in single case reports, without exclusion of other causes of acute pancreatitis. DISCUSSION: Much of the case report evidence upon which drug-induced pancreatitis associations are based is tenuous. A greater emphasis on exclusion of all non-drug causes of acute pancreatitis and on quality reporting would improve the evidence base. It should be recognized that reviews of case reports, are valuable scoping tools but have limited strength to establish drug-induced pancreatitis associations. REGISTRATION: CRD42017060473.


Assuntos
Pancreatite/patologia , Preparações Farmacêuticas/classificação , Doença Aguda , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Pancreatite/induzido quimicamente
5.
Orv Hetil ; 161(10): 363-373, 2020 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-32115992

RESUMO

Retrometabolic drug design combines the structure-activity and structure-metabolism relationships, allowing the effective separation of drug action and side effects. This combination results in significant improvement of the therapeutic index. The main aim is not only to study the metabolism but to build into the drug molecule the desired metabolic route, in addition to the therapeutic activity. There are two basically different approaches to achieve this aim. Both use designed-in metabolism. The 1. chemical drug-targeting systems (CDS) and 2. soft drug, both control the drug targeting and action by strategically designed metabolism. In the case of the soft drugs, we want to rely on hydrolytic enzymes, avoiding the oxidative processes. In the present work, we focus on the clinical successes of the soft drugs designed in our laboratories. In order to show the difference, we briefly present a brain-targeted delivery system, where the originally inactive molecular construct undergoes sequential metabolism to allow specific concentration of the active drug in the brain. Among the soft drugs first we present the highly successful soft corticosteroids. Loteprednol etabonate has been used worldwide for over twenty years, and its use is constantly growing. In addition to the dramatically improved therapeutic index, the specific, serious ophthalmic side effects (elevation of intraocular pressure; glaucoma and cataract formation) were completely eliminated. Similarly designed second generation of soft corticosteroids are also presented, where the soft pharmacophore is structurally unexpected. The most recent soft drug design involves anticholinergics. Sofpironium bromide, a highly effective molecule but without the typical anticholinergic side effects, was first developed to treat hyperhidrosis, an unmet need. Phase III clinical studies were successfully completed and its marketing approval is pending. Since the soft drug design principles, methods and rules are general and specific in nature, a computerized expert system was also developed. Orv Hetil. 2020; 161(10): 363-373.


Assuntos
Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Soluções Oftálmicas/farmacologia , Preparações Farmacêuticas/classificação , Corticosteroides , Olho , Glaucoma , Humanos , Soluções Oftálmicas/química
6.
JAMA Netw Open ; 3(3): e200607, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32202643

RESUMO

Importance: Prior lethality analyses of suicide means have historically treated drug poisoning other than alcohol poisoning as a lumped category. Assessing risk by drug class permits better assessment of prevention opportunities. Objective: To investigate the epidemiology of drug poisoning suicides. Design, Setting, and Participants: This cross-sectional study analyzed censuses of live emergency department and inpatient discharges for 11 US states from January 1, 2011, to December 31, 2012, as well as Healthcare Cost and Utilization Project national live discharge samples for January 1 to December 31, 2012, and January 1 to December 31, 2016, and corresponding Multiple Cause of Death census data. Censuses or national samples of all medically identified drug poisonings that were deliberately self-inflicted or of undetermined intent were identified using diagnosis and external cause codes. Data were analyzed from June 2019 to January 2020. Main Outcomes and Measures: Distribution of drug classes involved in suicidal overdoses. Logistic regressions on the state data were used to calculate the odds and relative risk (RR) of death for a suicide act that involved a drug class vs similar acts excluding that class. Results: Among 421 466 drug poisoning suicidal acts resulting in 21 594 deaths, 19.6% to 22.5% of the suicidal drug overdoses involved benzodiazepines, and 15.4% to 17.3% involved opioids (46.2% men, 53.8% women, and <0.01% missing; mean age, 36.4 years). Opioids were most commonly identified in fatal suicide poisonings (33.3%-47.8%). The greatest RR for poisoning suicide completion was opioids (5.20 times the mean for suicide acts that did not involve opioids; 95% CI, 4.86-5.57; sensitivity analysis range, 3.99-6.86), followed by barbiturates (RR, 4.29; 95% CI, 3.35-5.45), antidepressants (RR, 3.22; 95% CI, 2.95-3.52), antidiabetics (RR, 2.57; 95% CI, 1.94-3.41), and alcohol (conservatively, because 30% of death certifiers do not test for alcohol; RR, 2.04; 95% CI, 1.84-2.26). The updated toxin diagnosis coding in International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, used to code the 2016 data revealed that calcium channel blockers also had a high RR of 2.24 (95% CI, 1.89-2.61). Translated to attributable fractions, approximately 81% of suicides involving opioids would not have been fatal absent opioids. Similarly, 34% of alcohol-involved suicide deaths were alcohol attributable. Conclusions and Relevance: These findings suggest that preventing access to lethal means for patients at risk for suicide should extend to drugs with high case fatality rates. Blister packing and securely storing lethal drugs seems advisable.


Assuntos
Overdose de Drogas/epidemiologia , Preparações Farmacêuticas/classificação , Suicídio/estatística & dados numéricos , Adolescente , Adulto , Criança , Estudos Transversais , Serviço Hospitalar de Emergência , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto Jovem
7.
J. pediatr. (Rio J.) ; 95(6): 682-688, Nov.-Dec. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1056659

RESUMO

ABSTRACT Objective: To assess spontaneous reports of suspected adverse drug reactions in children aged 0-12 years from the Brazilian Health Regulatory Agency between 2008 and 2013. Methods: A cross-sectional study on suspected adverse drug reactions reports related to medicines and health products in children was carried out for a six-year period (2008-2013). Year of report, origin of report by Brazilian state, gender, age, suspected drug, adverse reaction description and seriousness were included in the analysis. The data obtained was compared to the number of pediatric beds in health services and to global data from the VigiBase (World Health Organization). Results: A total of 3330 adverse drug reactions were reported in children in Brazil in the investigated period (54% were in boys). About 28% of suspected adverse drug reactions reports involved 0 to 1-year-old children. Almost 40% of reports came from the Southeast region. Approximately 60% were classified as serious events. There was death in 75 cases. Nearly 30% of deaths involved off-label use; 3875 medicines (465 active substances) were considered suspected drugs. Anti-infective (vancomycin, ceftriaxone, oxacillin, and amphotericin), nervous system (metamizole) and alimentary tract and metabolism medicines were more frequent in reports. Conclusions: The distribution of suspected adverse drug reactions reports by sex and age group corresponded to the profile of children hospitalized in Brazil. Data about seriousness and medicines reported may be useful to encourage regulatory actions and improve the safe use of medicines in children.


RESUMO Objetivo: Analisar relatos espontâneos de suspeitas de Reação Adversa a Medicamento (RAM) em crianças de 0 a 12 anos notificadas pela Agência Nacional de Vigilância Sanitária entre 2008 e 2013. Métodos: Um estudo transversal a partir de notificações de suspeitas de RAM relacionadas a medicamentos e produtos para a saúde em crianças foi realizado por um período de seis anos (2008-2013). O ano da notificação, a origem do relato por estado brasileiro, sexo, idade, o medicamento suspeito, a descrição da reação adversa e a gravidade foram incluídos na análise, bem como o número de leitos nos serviços de saúde e dados global da VigiBase. Resultados: Um total de 3330 reações adversas foram relatadas em crianças no Brasil no período investigado (54% em meninos). Cerca de 28% dos relatos de suspeitas de RAM envolveram crianças de 0 a 1 ano de idade. Quase 40% dos relatos vieram da região Sudeste. Aproximadamente 60% foram classificados como eventos graves. Houve ocorrência de morte em 75 casos. Quase 30% das mortes envolveram o uso off-label dos medicamentos. Um total de 3875 medicamentos (465 substâncias ativas) foram considerados fármacos suspeitos. Medicamentos anti-infecciosos (vancomicina, ceftriaxona, oxacilina e anfotericina), com ação no sistema nervoso (dipirona) e no trato digestivo foram os mais frequentemente notificados. Conclusões: As notificações de suspeitas de RAM por sexo e faixa etária corresponderam ao perfil de crianças hospitalizadas no Brasil. Os dados sobre gravidade e medicamentos relatados podem ser úteis para encorajar ações reguladoras e melhorar o uso seguro de medicamentos em crianças.


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Bases de Dados Factuais/estatística & dados numéricos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Brasil/epidemiologia , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/classificação , Fatores Sexuais , Estudos Transversais , Fatores Etários , Distribuição por Idade
8.
Presse Med ; 48(12): 1489-1495, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31757735

RESUMO

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Antioxidantes/uso terapêutico , Chalconas/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Citoproteção/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Humanos , Imidazóis/uso terapêutico , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Seleção de Pacientes , Preparações Farmacêuticas/classificação , Propionatos/uso terapêutico , Tiazolidinedionas/uso terapêutico
10.
J Leg Med ; 39(3): 247-261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31626574

RESUMO

This article reviews the U.S. Food and Drug Administration (FDA) regulation of generic medications-specifically, the use of bioequivalence to compare generic and brand prescriptions. New or "brand" drugs are subjected to extensive review by the FDA before they can be marketed to the public. Generics, which are posited to be identical to brands, are subject to a less extensive review process and must prove only that the generic is the "bioequivalent" (BE) of the brand drug. Generic medications are important because they comprise almost 80% of prescriptions filled in the United States and cost 80% to 85% less than brand drugs, playing a crucial role in patients' access to cost-effective treatments. However, there is dissension about whether they can be interchanged with brand drugs without any consequences for the patient, especially for Narrow Therapeutic Index (NTI) drugs, which have precise dosage requirements. The regulatory designation of bioequivalence also has implications for doctor-patient relationships, patient outcomes, and patient legal rights. This article aims to establish that there is insufficient evidence to conclude whether using bioequivalence is adequate to determine whether two drugs can be considered equivalent given the medical and legal implications that flow from deeming two drugs equivalent.


Assuntos
Medicamentos Genéricos/normas , Equivalência Terapêutica , United States Food and Drug Administration/legislação & jurisprudência , Medicamentos Genéricos/farmacocinética , Direitos do Paciente , Preparações Farmacêuticas/classificação , Guias de Prática Clínica como Assunto , Índice Terapêutico do Medicamento , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration/normas
11.
Int Marit Health ; 70(3): 143-150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31617937

RESUMO

BACKGROUND: The contents of the ship pharmacy, namely "medicine chest" and its compliance with therespective regulations concerning the type of drugs to be provided for merchant vessels involved in long distance voyages and without a doctor on board were analysed. The current existing disparity between regulations can make medical assistance more complicated, and more often of low quality, due to frequent off-label use of supplied drugs. This study may represent a starting point leading to a model high-quality medicine chest on board ships. MATERIALS AND METHODS: A comparative analysis between the medicine chest requirements of 12 European countries and the CEE Directive 31 March 1992 n.92/29 was made. Prescriptions of the aforementioned Directive were compared with the WHO Model List of Essential Medicines (third Edition). RESULTS: The investigation showed a lack of homogeneity of contents. It emerged that some medicinechests lack of several pharmaceutical categories required by the reference standards. The subsequentcomparison of the European Directive with the WHO Model List of Essential Medicines has highlightedthe absence of some therapeutic categories that in the ship environment can be of important to ensureadequate therapy in many situations. CONCLUSIONS: There are disparities regarding regulations concerning the ship medicine chests. It is crucial toharmonize these and create a single medicine chest for all the ships without a doctor on board, undergoingperiodic updates and revisions, based on epidemiological analysis that will ensure high-quality healthcareto seafarers around the world.


Assuntos
Medicina Naval/legislação & jurisprudência , Preparações Farmacêuticas/classificação , Navios , Europa (Continente) , União Europeia , Preparações Farmacêuticas/provisão & distribução
12.
Cad Saude Publica ; 35(5): e00033417, 2019 05 23.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31141025

RESUMO

During the post-marketing period, when medicines are used by large population contingents and for longer periods, unexpected adverse events (AE) can occur, potentially altering the drug's risk-benefit ratio enough to demand regulatory action. AE are health problems that can occur during treatment with a pharmaceutical product, which in the drug's post-marketing period can require a significant increase in health care and result in unnecessary and often fatal harm to patients. Therefore, a key objective for the health system is to identify AE as soon as possible in the post-marketing period. Some countries have pharmacovigilance systems responsible for collecting voluntary reports of post-marketing AE, but studies have shown that social networks can be used to obtain more and faster reports. The current project's main objective is to build a totally automated system using Twitter as a source to detect both new and previously known AE and conduct the statistical analysis of the resulting data. A system was thus built to collect, process, analyze, and assess tweets in search of AE, comparing them to U.S. Food and Drug Administration (FDA) data and the reference standard. The results allowed detecting new and existing AE related to the drug doxycycline, showing that Twitter can be useful in pharmacovigilance when employed jointly with other data sources.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Mineração de Dados/métodos , Doxiciclina/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Mídias Sociais , Bases de Dados Factuais , Humanos , Disseminação de Informação , Malária/tratamento farmacológico , Preparações Farmacêuticas/classificação , Farmacovigilância , Estados Unidos , United States Food and Drug Administration
13.
Cad Saude Publica ; 35(5): e00070018, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31141027

RESUMO

This study aimed to assess the level of therapeutic innovation of new drugs approved in Brazil over 13 years and whether they met public health needs. Comparative descriptive analysis of therapeutic value assessments performed by the Brazilian Chamber of Drug Market Regulation (CMED) and the French drug bulletin Prescrire for new drugs licensed in Brazil, from January 1st 2004 to December 31st 2016. The extent to which new drugs met public health needs was examined by: checking inclusions into government-funded drug lists and/or clinical guidelines; comparing Anatomical Therapeutic Chemical Classification (ATC) codes and drug indications with the list of conditions contributing the most to the national disease burden; and assessing new medicines aimed to treat neglected diseases. 253 new drugs were approved. Antineoplastics, immunossupressants, antidiabetics and antivirals were the most frequent. Thirty-three (14%) out of 236 drugs assessed by the Brazilian chamber and sixteen (8.2%) out of 195 assessed by the French bulletin Prescrire were considered innovative. Thirty-six drugs (14.2%) were selected for coverage by the Brazilian Unified National Health System (SUS), seven of which were therapeutically innovative, and none were aimed to treat neglected disease. About 1/3 of the drugs approved aimed to treat conditions among the top contributors to Brazil's disease burden. Few therapeutically innovative drugs entered the Brazilian market, from which only a small proportion was approved to be covered by the SUS. Our findings suggest a divergence between public health needs, research & development (R&D) and drug licensing procedures.


Assuntos
Difusão de Inovações , Medicamentos Essenciais/provisão & distribução , Preparações Farmacêuticas/provisão & distribução , Brasil , Avaliação de Medicamentos , Medicamentos Essenciais/classificação , Medicamentos Essenciais/normas , Humanos , Preparações Farmacêuticas/classificação , Preparações Farmacêuticas/normas , Saúde Pública/estatística & dados numéricos
14.
Sci Total Environ ; 677: 545-555, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31063896

RESUMO

The release of pharmacologically active compounds (PhACs) into aquatic ecosystems poses an environmental risk resulting in a chronic exposure of non-target organisms. A great variety of PhACs, of generally low concentrations, and the complicated sample preparation, makes circumstantial the accurate detection and quantification. Additionally, there is little information published about the spatiotemporal variation of the PhAC load in a larger catchment area utilised for touristic purposes. In addition to the natural biotic and abiotic changes, the seasonal variation of tourism also has a dramatic impact on water quality and the natural ecosystem in larger catchment areas. Therefore, our aim was to develop a reliable solid-phase extraction (SPE)-supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) method for simultaneous multi-residue analysis of drugs to reveal the spatiotemporal changes in the PhAC contaminations in the waters of an important touristic region, the catchment area of the largest shallow lake in Central Europe, Lake Balaton (Hungary). The environmental application of the developed method revealed 69 out of the traced 134 chemical compounds, including 15 PhACs, which were detected from natural waters for the first time. Wastewater treatment plant (WWTP) loads have a major role in the PhAC contamination of the studied area; at the same time, the mass tourism-induced PhAC contamination was also detectable. Furthermore, the impact of tourism was indicated by elevated concentrations of recreational substances (e.g., caffeine and illicit drugs) in the touristic season affecting the water quality of this important summer holiday destination.


Assuntos
Monitoramento Ambiental/métodos , Lagos/análise , Preparações Farmacêuticas/análise , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Poluentes Químicos da Água/análise , Férias e Feriados , Hungria , Preparações Farmacêuticas/classificação , Estações do Ano , Análise Espaço-Temporal , Viagem
15.
Arch. Soc. Esp. Oftalmol ; 94(2): 75-80, feb. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-180368

RESUMO

Antecedentes: El marcado descenso en los niveles de C-LDL producidos por los inhibidores de la proproteína convertasa plasmática subtilisina kexina tipo 9 (iPCSK9) podría asociarse con un mayor riesgo de cataratas. Métodos: Realizamos un metaanálisis que incluyó ensayos clínicos aleatorizados y controlados con iPCSK9, solos o combinados con otros fármacos hipolipidemiantes, que reportaron nuevos casos de cataratas, buscando en PubMed/Medline, bases de datos de EMBASE y Cochrane Clinical Trials. Se utilizó un modelo de efectos fijos y se realizó una metarregresión evaluando la relación entre el C-LDL intratratamiento y el riesgo de desarrollar cataratas. Resultados: Se tomaron en cuenta 5 estudios elegibles con iPCSK9 que incluyeron 83.492 pacientes para el análisis, refiriendo 531 nuevos casos de cataratas en el grupo con iPCSK9 frente a 532 en el grupo placebo. La terapia con iPCSK9 no se asoció con un mayor riesgo de presentar cataratas (OR: 0,96; IC 95%: 0,85-1,08; p = 0,86, I2: 0%]. Asimismo, no se encontró una asociación significativa entre la diferencia de C-LDL intratratamiento entre las ramas de los estudios y el riesgo de cataratas. Conclusión. En nuestro análisis, la utilización de iPCSK9 no se asoció con un mayor riesgo de cataratas


Background: The marked decrease in LDL-C levels produced by the inhibitors of the plasma proprotein convertase subtilisin/kexin type 9 (iPCSK9) could be associated with an increased risk of cataracts. Methods: A meta-analysis was performed that included randomised clinical trials controlled with iPCSK9, alone, or in combination with other lipid-lowering drugs, which reported new cases of cataracts, by searching PubMed/Medline, databases of EMBASE and Cochrane Clinical Trials. A fixed-effect model was used, and a meta-regression was carried out evaluating the relationship between intra-treatment LDL-C and the risk of developing cataracts. Results: Five eligible studies of iPCSK9 including 83,492 patients were taken into account for the analysis, and 531 new cases of cataracts in iPCSK9 group vs. 532 in placebo group were diagnosed. The iPCSK9 therapy was not associated with an increased risk of cataracts [OR: 0.96, 95% CI: 0.85-1.08; P = .86, I2: 0%]. Likewise, no significant association was found between on-treatment LDL-C levels, differences between study arms, and new cases of cataracts. Conclusion: In this analysis, the use of iPCSK9 was not associated with an increased risk of cataracts


Assuntos
Humanos , Oftalmopatias/classificação , Inibidores de Proteases/classificação , Lipoproteínas LDL/classificação , Preparações Farmacêuticas/classificação , Cardiopatias/classificação , Placebos/classificação , Colesterol/classificação , Grupos Controle
16.
Res Vet Sci ; 123: 239-246, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30685649

RESUMO

BACKGROUND: The voltage-gated K+-channel Kv11.1 has a central role in cardiac repolarization. Blockage of Kv11.1 has been linked to severe cardiovascular side effects, such as acquired long QT syndrome (aLQTS), torsade de pointes arrhythmia and sudden cardiac death (SCD). Kv11.1 is susceptible to unspecific drug interactions due to the presence of two aromatic amino acids residing in the inner vestibule of the pore. These aromatic residues are also present in the equine orthologue of Kv11.1. This suggests that equine Kv11.1 may also be prone to high-affinity block by a range of different chemical entities, which potentially could cause severe cardiac side effects and SCD in horses. AIM: To screen a series of commonly used drugs in equine medicine for interaction with Kv11.1. METHODS: High-throughput screening of selected compounds on human Kv11.1 expressed in a mammalian cell line was performed using an automated patch clamp system, the SyncroPatch 384PE (Nanion Technologies, Munich, Germany). Results were validated on equine Kv11.1 expressed in CHO-K1 cells by manual patch clamp. RESULTS: Acepromazine maleat (IC50 = 0.5 µM) trimethoprim (IC50 = 100 µM), diphenhydramine hydrochloride (IC50 = 2 µM) and cyproheptadine hydrochloride (IC50 = 1.84 µM) inhibited equine Kv11.1 current at clinically relevant drug concentrations. CONCLUSION: The results suggest that drug interaction with Kv11.1 can occur in horses and that some drugs potentially may induce repolarization disorders in horses.


Assuntos
Canal de Potássio ERG1/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Cavalos , Preparações Farmacêuticas/classificação , Animais , Células CHO , Cricetinae , Cricetulus , Humanos
17.
J Pharm Biomed Anal ; 166: 222-235, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30660807

RESUMO

In recent years, there has been a very active debate about the stability of drug products especially after exceeding the expiry dates. The regulatory authorities require comprehensive stability data for market approval. The shelf-life obtained determines the expiry date, which is typically between 1 and 5 years and commonly set in a conservative manner. Conducting stability studies is a resource- and time-consuming matter for the pharmaceutical manufacturer. Short shelf-lives of drug products are also a challenge for managers of hospitals, nursing homes, and strategic national stockpile agencies which have to dispose of large quantities of outdated medicines every year. This conflict raises the question whether shelf-lives are often longer than the labeled one. In the past years, the FDA has launched several programs for shelf-life extension in order to defer replacement costs and to prevent drug shortages due to supply disruption. The aim of this review was to bring together the available literature of expired drug products as well as historical pharmaceutical relicts with an age of more than 80 years and to discuss the actual shelf-life with regard to the respective dosage form and the affiliation of the drug class. It seems to be reasonable for a large portion of drugs to extend the expiry dates far beyond five years.


Assuntos
Rotulagem de Medicamentos/normas , Estabilidade de Medicamentos , Preparações Farmacêuticas/normas , Formas de Dosagem , Preparações Farmacêuticas/classificação , Controle de Qualidade , Fatores de Tempo
18.
Biopharm Drug Dispos ; 40(2): 51-61, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30635908

RESUMO

Solubility and permeability are recognized as key parameters governing drug intestinal absorption and represent the basis for biopharmaceutics drug classification. The Biopharmaceutics Classification System (BCS) is widely accepted and adopted by regulatory agencies. However, currently established low/high permeability and solubility boundaries are the subject of the ongoing scientific discussion. The aim of the present study was to apply data mining analysis on the selected drugs data set in order to develop a human permeability predictive model based on selected molecular descriptors, and to perform data clustering and classification to identify drug subclasses with respect to dose/solubility ratio (D/S) and effective permeability (Peff ). The Peff values predicted for 30 model drugs for which experimental human permeability data are not available were in good agreement with the reported fraction of drug absorbed. The results of clustering and classification analysis indicate the predominant influence of Peff over D/S. Two Peff cut-off values (1 × 10-4 and 2.7 × 10-4  cm/s) have been identified indicating the existence of an intermediate group of drugs with moderate permeability. Advanced computational analysis employed in the present study enabled the recognition of complex relationships and patterns within physicochemical and biopharmaceutical properties associated with drug bioperformance.


Assuntos
Biofarmácia/métodos , Mineração de Dados , Mucosa Intestinal/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/classificação , Humanos , Absorção Intestinal , Permeabilidade , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Solubilidade
19.
Expert Rev Clin Pharmacol ; 12(1): 1-7, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30484336

RESUMO

INTRODUCTION: Nutraceuticals, up today, do not have a specific definition distinct from those of other food-derived categories, e.g. food supplements, herbal products, pre and probiotics, functional foods, etc. They have, however, a pharmacological beneficial effect on health. Many studies have been recently addressed to assess their safety, efficacy, and regulation since they are getting growing attention by market and research, with the aim to clear the difference between them and other market available food-derived products that claim beneficial effect on health. Areas covered: The understanding of the potential mechanisms of action of pharmaceutically active substances contained in nutraceuticals that may improve health and reduce the risk of pathological conditions while enhancing overall well-being is the challenge for nutraceuticals to be considered as a preventive and therapeutic efficient tool in facing some diseases. Expert commentary: It is of utmost importance to have a proper and unequivocal definition of nutraceuticals and a shared regulation. Nevertheless, there is a lack of clear information and, often, the claimed health benefits may not be properly substantiated by safety and by efficacy in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed.


Assuntos
Suplementos Nutricionais/classificação , Legislação sobre Alimentos , Preparações Farmacêuticas/classificação , Suplementos Nutricionais/efeitos adversos , Humanos , Legislação de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Terminologia como Assunto
20.
Nucleic Acids Res ; 47(D1): D963-D970, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30371892

RESUMO

DrugCentral is a drug information resource (http://drugcentral.org) open to the public since 2016 and previously described in the 2017 Nucleic Acids Research Database issue. Since the 2016 release, 103 new approved drugs were updated. The following new data sources have been included: Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), FDA Orange Book information, L1000 gene perturbation profile distance/similarity matrices and estimated protonation constants. New and existing entries have been updated with the latest information from scientific literature, drug labels and external databases. The web interface has been updated to display and query new data. The full database dump and data files are available for download from the DrugCentral website.


Assuntos
Bases de Dados de Produtos Farmacêuticos , Aprovação de Drogas/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Expressão Gênica/efeitos dos fármacos , Preparações Farmacêuticas/classificação , Proteínas/classificação
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