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Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35-23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41-28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.
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Comirnaty™ and Spikevax™ were the first vaccines approved for human use based on modified non-replicating mRNA lipophilic nanoparticle (mRNA-LNP) technology, with great success in the treatment of COVID-19. They have been used massively worldwide. One of the major inconveniences of these vaccines is related to pharmaceutical stability issues. Proper transportation, storage, and in-use handling before administration to patients are critical steps since failures can potentially reduce potency. In this research, the in-use stability of Comirnaty™ and Spikevax™ clinical samples was analysed and the results were compared. As changes in the size of the mRNA-LNPs are related to potency, these modifications were analysed by qualitative Dynamic Light Scattering (DLS) as a stability-indicating method for control and stressed vaccine samples. Strong stress factors (accelerated light irradiation, manual shaking, and vortex vibration) and conditions that mimic in-use handling (exposure to natural light and room temperature, repeated cycles of injections, and 24 h storage in syringes) were checked. The morphology of the mRNA-LNPs was analysed by Transmission Electron Microscopy (TEM) to better interpret and support the DLS results. Although the two vaccines are based on the same mRNA-LNP technology, the results demonstrate that they are characterised by very different particle size profiles and behaviours against different handling/stress conditions.
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Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.
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Azatioprina , Doença de Crohn , Humanos , Azatioprina/efeitos adversos , Farmacogenética , Imunossupressores/uso terapêutico , Genótipo , Doença de Crohn/tratamento farmacológico , Metiltransferases/genética , Pirofosfatases/genéticaRESUMO
The SARS-CoV-2 infection has increased the number of patients entering Intensive Care Unit (ICU) facilities and antibiotic treatments. Concurrently, the multi-drug resistant bacteria (MDRB) colonization index has risen. Considering that most of these bacteria are derived from gut microbiota, the study of its composition is essential. Additionally, SARS-CoV-2 infection may promote gut dysbiosis, suggesting an effect on microbiota composition. This pilot study aims to determine bacteria biomarkers to predict MDRB colonization risk in SARS-CoV-2 patients in ICUs. Seventeen adult patients with an ICU stay >48 h and who tested positive for SARS-CoV-2 infection were enrolled in this study. Patients were assigned to two groups according to routine MDRB colonization surveillance: non-colonized and colonized. Stool samples were collected when entering ICUs, and microbiota composition was determined through Next Generation Sequencing techniques. Gut microbiota from colonized patients presented significantly lower bacterial diversity compared with non-colonized patients (p < 0.05). Microbiota in colonized subjects showed higher abundance of Anaerococcus, Dialister and Peptoniphilus, while higher levels of Enterococcus, Ochrobactrum and Staphylococcus were found in non-colonized ones. Moreover, LEfSe analysis suggests an initial detection of Dialister propionicifaciens as a biomarker of MDRB colonization risk. This pilot study shows that gut microbiota profile can become a predictor biomarker for MDRB colonization in SARS-CoV-2 patients.
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Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation.
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Azetidinas , Farmacogenética , Compostos de Benzil/efeitos adversos , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , GenótipoRESUMO
BACKGROUND: Despite restrictions on their production and use, most of the population is still exposed to Persistent Organic Pollutants (POPs), including organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs). These chemicals are thought to contribute to the aetiology of highly prevalent chronic conditions, such as cardiovascular diseases (CVDs), although current evidences are still controversial. OBJECTIVES: To explore the potential contribution of historical POP exposure to 15-year pharmaceutical consumption in relation to CVD. METHODS: This study is framed within GraMo adult cohort. Participants (n = 387) were recruited in two hospitals in Granada province, Southern Spain (2003-2004). Historical exposure to 5 OCPs and 3 non-dioxine-like PCBs was estimated by analysing adipose tissue concentrations at recruitment. Pharmaceutical consumption from recruitment until year 2017 was quantified by reviewing dispensation databases. Average consumption increase (ACI) in CVD medication was calculated by subtracting average consumption in 2002 to the average yearly consumption during follow-up. ACI was expressed as Defined Daily Dose (DDD)/year units. Data analyses were carried out using a multivariable multinomial logistic regression and weighted quantile sum regression (WQS), with ACI categorized in quartiles (Q) as the dependent variable. RESULTS: Concentrations of most pollutants showed a positive trend with the quartiles of ACI. Particularly, PCB-153 showed increasing and statistically significant odds ratios (ORs) for Q2 (OR: 1.27, 95% confidence interval (CI): 1.07-1.52), Q3 (OR: 1.49, 95 %CI: 1.17-1.88) and Q4 (OR: 1.42, 95 %CI: 1.13-1.78) vs Q1. Similarly, beta-hexachlorocyclohexane (ß-HCH) also showed increasing ORs, that reached statistical significance in Q4 (OR: 1.36, 95 %CI: 1.06-1.74) vs Q1. These findings were corroborated by WQS analyses, that revealed a significant mixture effect, predominantly accounted for by PCB-153 and ß-HCH. DISCUSSION: Our results suggest that long-term POP exposure might represent a modifiable risk factor for CVD. These findings are relevant for public health campaigns and management, since pharmaceutical consumption is considered an indicator of both morbidity and health expenditure.
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Doenças Cardiovasculares , Poluentes Ambientais , Hidrocarbonetos Clorados , Praguicidas , Preparações Farmacêuticas , Bifenilos Policlorados , Adulto , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Poluentes Ambientais/análise , Humanos , Hidrocarbonetos Clorados/análise , Poluentes Orgânicos Persistentes , Atenção Primária à SaúdeRESUMO
OBJECTIVE: To assess compliance in a Spanish intensive care unit (ICU) with 8 of the 13 quality indicators of the Spanish Society of Intensive Medicine and Coronary Units (Sociedad Española de Medicina Intensiva y Unidades Coronarias, SEMICyUC) related to nutrition and metabolism in critically ill patients. PATIENTS AND METHODS: The study included all patients over 18 years of age with an ICU stay of >48 hours between January and May 2019. The pharmacist was integrated into the daily activity of the multidisciplinary team of a 20-bed ICU to monitor and carry out the control of the quality indicators of the SEMICyUC. Studied indicators refer to: nutritional risk assessment and nutritional status (three indicators), glycaemic control, calculation of calorie-protein requirements, and use of early enteral nutrition or adequate parenteral nutrition. Compliance with each indicator was measured as the percentage of patients. RESULTS: 110 patients were included and 73 (66.4%) were male. Compliance results were: blood glucose range (90.7%), severe hypoglycaemia (0%), identification of patients at nutritional risk (58.2%) or with possible refeeding syndrome (8.9%), assessment of nutritional status at admission (58.2%), calculation of calorie-protein requirements (77.8%), early enteral nutrition (96.4%), and adequate use of parenteral nutrition (37.8%) CONCLUSION: Compliance with indicators related to glycaemic control and artificial nutrition (enteral and parenteral nutrition) was higher than reference standards, but there is a need to improve compliance with indicators related to nutritional risk and status at ICU admission. The hospital pharmacist integrated into the ICU multidisciplinary team can add value to the nutrition monitoring and quality indicators of the nutritional process of the critical patient, providing safe and effective nutritional therapy to patients.
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Estado Terminal , Estado Nutricional , Adolescente , Adulto , Estado Terminal/terapia , Humanos , Masculino , Nutrição Parenteral/métodos , Farmacêuticos , Indicadores de Qualidade em Assistência à SaúdeRESUMO
Very limited labelled indications have been approved for the newer antimicrobials. Data on the clinical uses, efficacy and safety of dalbavancin are scarce, thus here we sought to describe our clinical experience. 16-month observational prospective study was performed. 19 (86%) were used under off-label indications. 10 (46%) for osteoarticular infections, 5 (23%) bloodstream infections and 3 (14%) endocarditis. To highlight, one patient received dalbavancin as long-term suppressive therapy. Most frequent use reasons were promptly hospital discharge, 11 (65%), and the presence of resistant organisms involving limited treatment options, 5 (23%). Successful outcome was observed in >95% of the patients and only 1 (4.5%) adverse event was reported. Further evidence beyond labelled indications is urgently needed. Despite the limitations, dalbavancin appears to be a safe and efficient option for adult patients who have tried and/or failed other therapies due to multidrug-resistant Gram-positive organisms.
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Antibacterianos/uso terapêutico , Rotulagem de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Teicoplanina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Rotulagem de Medicamentos/normas , Farmacorresistência Bacteriana Múltipla/fisiologia , Feminino , Seguimentos , Infecções por Bactérias Gram-Positivas/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Teicoplanina/farmacologia , Teicoplanina/uso terapêuticoRESUMO
Ziv-aflibercept (ziv-AFL) is a complex fusion protein which is widely used in hospitals for the treatment of colorectal metastatic cancer. Charge variants are critical attributes for assessing post-transitional modifications (PMTs) that have to be controlled during the development and manufacture of these proteins and until their administration to patients. Cation exchange (CEX) chromatography is a charge-sensitive analytical method that is well suited for analysing charge variants in proteins. The aim of this paper is to analyse the charge variants of ziv-AFL in the medicine (Zaltrap®) when fresh and when degraded. Two CEX chromatographic methods were compared for this purpose. The former was an adaptation of the method used in the first published study in which charge variants were analysed via pH gradient elution using volatile, low ionic strength buffers with direct coupling to high-resolution Orbitrap mass spectrometry. The second method was developed and optimized during our research using the salt-mediated pH gradient mode and classical non-volatile, high ionic strength buffers which were incompatible with direct coupling with mass detection. Fresh and controlled degraded samples of ziv-AFL were used to evaluate the capacity of both CEX chromatographic strategies for detecting charge variants in ziv-AFL. In the controlled degradation study the samples of the medicine were subjected to three stress factors: temperature of 60⯰C for three hours, freeze/thaw process -two cycles-, and exposure to light for twelve hours. The CEX chromatographic method with non-volatile salts in the mobile phase enabled better detection of charge variants degraded ziv-AFL samples than the method using volatile salts with lower ionic strength. In addition, the complexity of the mass spectra data generated made it impossible to identify the multicharge variant species of ziv-AFL. Although charge variants were not separated in ziv-AFL fresh sample, our results indicate that the method with non-volatile salts in the mobile phase could be used to characterize and track changes in the charge variant UV chromatographic profile of ziv-AFL in fresh and degraded samples, even though it cannot be coupled to a mass detector and there is therefore no information about mass. The increase of basic protein degraded compounds were the most important degradation pattern detected in ziv-AFL (Zaltrap®).
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Química Farmacêutica/métodos , Receptores de Fatores de Crescimento do Endotélio Vascular/análise , Proteínas Recombinantes de Fusão/análise , Cátions , Cromatografia por Troca Iônica/métodos , Estudos de Viabilidade , Humanos , Concentração de Íons de Hidrogênio , Espectrometria de Massas/métodos , Concentração Osmolar , Estudo de Prova de Conceito , Proteólise , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Proteínas Recombinantes de Fusão/químicaRESUMO
EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the treatment of choice for advanced-stage (IIIB-IV) NSCLC patients with mutations in EGFR. However, EGFR-TKIs clinical outcomes vary from person to person and these inter-individual differences may be due to genetic factors such as single nucleotide polymorphisms (SNPs). SNPs in genes involved in EGFR-TKIs pharmacodynamics, metabolism and mechanism of action have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with EGFR-TKIs. Here we review the influence of gene polymorphisms in the EGFR pathway on clinical outcome and toxicity to EGFR-TKIs in advanced NSCLC patients. The EGFR-216 polymorphism has reported a strong association between response and/or survival to EGFR-TKIs in Caucasian population. Similarly, the effect of EGFR-CA repeats polymorphisms on survival of advanced NSCLC patients treated with EGFR-TKIs have been confirmed both in Caucasian and Asian population. The influence on toxicity of the -216, -191, CA repeats, Arg497Lys and Asp994Asp polymorphisms in EGFR have also been confirmed. Polymorphisms in AKT (rs1130214 and rs1130233) and SMAD3 (rs6494633, rs11071938 and rs11632964) have been associated with survival in advanced NSCLC patients treated with EGFR-TKIs. However, data come from a limited number of studies and need to be confirmed. Finally, polymorphisms in genes coding proteins of the membrane transporters and cytochrome P450 enzymes have been less extensively investigated. There are few studies with small samples, which complicated the generalization of their role in EGFR-TKIs treatment.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , HumanosRESUMO
Leishmaniasis is a chronic protozoan disease that is found in diverse geographical areas of the world. Leishmania spp. are endemic in the Mediterranean coasts of southern Europe. Tumour necrosis factor alpha (TNF-α) plays an important role in the defence of the host against infection by Leishmania spp. In this case report we describe Leishmania infection caused by a monoclonal antibody against TNF-α: infliximab. A 51-year-old patient with psoriatic arthritis treated with infliximab, 5 mg/kg every 6 weeks as immunomodulatory treatment and methotrexate 10 mg weekly as a conventional disease-modifying antirheumatic drug, visited his otorhinolaryngologist owing to a lesion in his left nostril. The lesion was diagnosed as cutaneous leishmaniasis so treatment with infliximab was suspended. The patient was then treated with liposomal amphotericin B and showed a total recovery of the lesion; liposomal amphotericin B was maintained at 5 mg/kg monthly.
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BACKGROUND: The objective of this review was to investigate trends in clinical trial design, specifically, the primary outcomes used, interpretation of results, and the magnitude of the benefits described in phase III controlled clinical trials in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). METHODS: Seventy-six trials published between 2000 and 2012 were selected from a total of 122 identified in a structured search. RESULTS: Overall survival (OS) was evaluated as the primary study endpoint in 50 (65.8%) trials, followed by progression-free survival (PFS) in 15 (19.7%), and other variables, such as toxicity, quality of life (QoL), and response rate in 11 (14.5%). Ten (66.7%) out of 15 clinical trials using PFS as the primary endpoint were published between 2010 and 2012. Median overall survival (mOS) was 9.90 months (interquartile range: 3.5) with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in mOS was obtained in only 13 (18.8%) trials. A total of 41 (53.9%) studies concluded that the result was positive. Of these, only 16 (39.1%) showed a statistically significant benefit in OS. QoL was assessed in 46 trials (60.5%) and of these, 10 (21.7%) reported significant improvements. CONCLUSIONS: These findings raise important questions about how clinical benefits are measured in clinical trials in advanced NSCLC. Appropriate clinically relevant outcome variables should be established and validated, and post-marketing studies should be requested by regulatory authorities to ensure meaningful clinical benefits in OS and QoL.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Determinação de Ponto Final/tendências , Neoplasias Pulmonares/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Tamanho da Amostra , Análise de Sobrevida , Resultado do TratamentoRESUMO
The extravasation of chemotherapeutic agents is a challenge for oncologic care teams. The management of nonliposomal (conventional) anthracyclines is well established in clinical practice guidelines, including general measures and specific antidotes, such as dexrazoxane. However, there is little scientific evidence on the management of liposomal and pegylated liposomal anthracyclines. The aim of this paper was to review the scientific literature on the extravasation of liposomal and pegylated liposomal anthracyclines and determine the clinical impact of this type of extravasation, focusing on dexrazoxane. The literature was searched using two databases: PubMed and Embase. Three searches were conducted, using liposomal anthracycline extravasation, pegylated liposomal anthracycline extravasation, and liposomal doxorubicin extravasation as keywords, respectively. Seven articles fulfilled the study eligibility criteria and included seventeen cases in humans. Extravasation occurred with three drugs: liposomal doxorubicin in nine (53%) patients, liposomal daunorubicin in four (23.5%) patients, and pegylated liposomal doxorubicin in four (23.5%) patients. General measures for extravasations were applied in all patients, but only three patients received dexrazoxane. All cases were completely resolved at 2-3 months, except for one patient, in whom dexrazoxane was not used. In animals, dexrazoxane decreased both the frequency of wounds produced by pegylated liposomal doxorubicin and their extent. The pharmacokinetic profiles of liposomal and pegylated liposomal anthracyclines differ from those of conventional anthracyclines, modifying their effectiveness and safety. General measures may be inadequate to heal areas affected by extravasation, which may require the administration of dexrazoxane. However, each case should be evaluated individually for the administration of dexrazoxane in off-label use until scientific evidence is available on its effectiveness and safety as an antidote for these formulations of anthracyclines.
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Antraciclinas/administração & dosagem , Dexrazoxano/administração & dosagem , Extravasamento de Materiais Terapêuticos e Diagnósticos/tratamento farmacológico , Animais , Antraciclinas/efeitos adversos , Antraciclinas/farmacocinética , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Daunorrubicina/farmacocinética , Dexrazoxano/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Humanos , Lipossomos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinéticaRESUMO
Multiple myeloma is a very heterogeneous disease with variable survival. Despite recent progress and the widespread use of new agents, patients with relapsed and refractory disease have a poor outcome. Immunomodulatory drugs play a key role in both the front-line and the relapsed/refractory setting. The combination of pomalidomide (POM) and dexamethasone is safe and effective in relapsed and refractory patients, even in those with high-risk cytogenetic features. Furthermore, it can be used in most patients without the need to adjust according to the degree of renal failure. In order to further improve the results, POM-based triplet therapies are currently used. This article highlights the most relevant issues of POM and POM-based combinations in the relapsed/refractory multiple myeloma setting, from a pharmacological and clinical point of view.
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Fatores Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Desenho de Fármacos , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Mieloma Múltiplo/patologia , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/uso terapêuticoRESUMO
PURPOSE: There is a widening range of antidiabetic medications available; however changes in consumption patterns remain poorly documented. The aim of this study is to analyze the evolution of consumption of antidiabetic medications during the period 2001-2014 in an Andalusian region. METHODS: All antidiabetic medicines on the market were selected for analysis. Consumption data were obtained for the 15-year period and were expressed in defined daily doses (DDD) per 1000 inhabitants per day (DHD). RESULTS: During the study period consumption of insulins grew only a 2.2%, from 17.9 DHD to 18.3 DHD, while oral agents increased a 27.6%, from 41.3 DHD to 52.7 DHD. Consumption of sulfonylureas was gradually reduced from 30.1 DHD to 16.4 DHD but metformin (alone) usage increased from 4.3 DHD to 23.7 DHD, and was the most consumed agent in 2014. A rise in consumption of dipeptidyl peptidase-4 inhibitors and "other hypoglycemic agents" was also noticed. Overall expenditure in antidiabetic medications increased notably from 4.5 in 2001 to 14.4 million euros in 2014. CONCLUSION: We highlight the market uptake of antidiabetic drugs commercialized during the last decade; despite further exploration is needed to clarify the cost-benefit ratio of these new antidiabetic medicines.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Padrões de Prática Médica/tendências , Comércio/economia , Comércio/tendências , Análise Custo-Benefício , Bases de Dados Factuais , Diabetes Mellitus Tipo 1/economia , Diabetes Mellitus Tipo 2/economia , Custos de Medicamentos/tendências , Prescrições de Medicamentos , Revisão de Uso de Medicamentos , Gastos em Saúde/tendências , Humanos , Hipoglicemiantes/economia , Padrões de Prática Médica/economia , Estudos Retrospectivos , Espanha , Fatores de TempoRESUMO
PURPOSE: The objective of this study was to measure the impact of an intervention on the prescription habits of general practitioners (GPs) in order to improve the quality of zolpidem prescriptions in patients aged 75 or older. METHODS: A prospective multicentric non-randomized trial was performed in the Metropolitan Granada Primary Healthcare Area (Andalusian Public Healthcare Service, Spain), which serves a total population of approximately 675,000 inhabitants. All health centers volunteering to participate in the trial were included. The intervention consisted of training sessions, individualized feedback, clinical information, and financial incentives. A daily dose over 5 mg was considered non-safe. Reduction in non-safe prescriptions of zolpidem in the elderly population became a quality prescribing indicator in a pay-for-performance scheme. RESULTS: Statistically significant differences versus baseline were found between the intervention and control groups in mean zolpidem prescription prevalence (28.5 vs. 37.5, respectively; p = 0.008) and mean non-safe zolpidem prescription prevalence (16.5 vs. 34.2, respectively; p < 0.001). At the end of the study period, the total number of non-safe prescriptions was 1309, 35% lower versus baseline, with a significant difference of p < 0.001; the number in the intervention (510 vs. 1118; p < 0.001) and control (799 vs. 893; p = 0.0064) groups was also significantly lower, with a significantly greater percentage reduction in the intervention group (54.4 vs. 10.5%, p < 0.001). CONCLUSION: The quality prescribing indicator in our area was improved by the intervention developed. Further studies that include an intervention group of GPs who receive no financial incentive are required to evaluate the relative importance of an economic reward in achieving this improvement.
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Hipnóticos e Sedativos/uso terapêutico , Atenção Primária à Saúde , Piridinas/uso terapêutico , Idoso , Humanos , Estudos Prospectivos , ZolpidemRESUMO
BACKGROUND: Clopidogrel has provided beneficial effects in acute coronary syndrome and percutaneous coronary intervention. Different polymorphisms have been associated with differences in clopidogrel response. The aim of this study was to check if CYP2C19/ABCB1-genotype-guided strategy reduces the rates of cardiovascular events and bleeding. METHODS: This experimental study included patients undergoing percutaneous coronary intervention with stent. The prospective genotype-guided strategy (intervention group) was compared against a retrospective non-tailored strategy (control group). Primary efficacy endpoint was the composite of cardiovascular death, acute coronary syndrome or stroke during 12months after intervention. Secondary endpoint was to compare the efficacy of the different antiplatelet therapies used in genotyping conditions. RESULTS: The study included 719 patients undergone stent, more than 86% with acute coronary syndrome. The primary endpoint occurred in 32 patients (10.1%) in the genotyping group and in 59 patients (14.1%) in the control group (HR 0.63, 95% CI (0.41-0.97), p =0.037). There was no difference in The Thrombolysis in Myocardial Infarction major and minor bleeding criteria between the two groups (4.1% vs. 4.7%, HR=0.80, 95% CI (0.39-1.63), p=0.55). In intervention group, there was no difference in the rate of events in patients treated with clopidogrel versus patients treated with other antiplatelet treatments (9.1% vs 11.5% p=0.44), or bleeding (3.7% vs 4.6%, p=0.69). CONCLUSIONS: The genotype-guided strategy could reduce the rates of composite of cardiovascular events and bleeding during 12months after percutaneous coronary intervention compared to a non-genotype-guide strategy.
Assuntos
Citocromo P-450 CYP2C19/genética , Genótipo , Intervenção Coronária Percutânea/tendências , Inibidores da Agregação Plaquetária/uso terapêutico , Stents , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/terapia , Idoso , Morte , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/métodos , Intervenção Coronária Percutânea/mortalidade , Estudos Prospectivos , Estudos RetrospectivosRESUMO
The objective of this review was to analyze trends in outcomes and in the quality of phase III randomized controlled trials on advanced NSCLC published between 2000 and 2012, selecting 76 trials from a total of 122 retrieved in a structured search. Over the study period, the number of randomized patients per trial increased by 14 per year (P = 0.178). The sample size significantly increased between 2000 and 2012 in trials of targeted agents (460.1 vs. 740.8 patients, P = 0.009), trials of >1 drug (360.4 vs. 584.8, P = 0.014), and those including patients with good performance status (675.3 vs. 425.6; P = 0.003). Quality of life was assessed in 46 trials (60.5%), and significant improvements were reported in 10 of these (21.7%). Platinum-based regimens were the most frequently investigated (86.8% of trials). Molecular-targeted agents were studied in 25.0% of chemotherapy arms, and the percentage of trials including these agents increased each year. The median (interquartile range) overall survival (MOS) was 9.90 (3.5) months with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in MOS was obtained in only 13 (18.8%) trials. The median progression-free survival was 4.9 (1.9) months, with a nonsignificant increase of 0.026 months per year (P > 0.05). There has been a continuous but modest improvement in the survival of patients with advanced NSCLC over the past 12 years. Nevertheless, the quality of clinical trials and the benefit in outcomes should be carefully considered before the incorporation of novel approaches into clinical practice.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Mortalidade , Metástase Neoplásica , Estadiamento de Neoplasias , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
AIM: To study the association of ABCB1 and CYP2C19 polymorphisms and the clopidogrel response in Spanish peripheral artery disease patients following percutaneous transluminal angioplasty (PTA) and to perform a meta-analysis. MATERIALS & METHODS: 72 patients were recruited and 122 patients included in the meta-analysis. We evaluated the effect of ABCB1 3435 C>T, CYP2C19*2 and CYP2C19*3 and primary end point (restenosis/occlusion of the treated lesions) during 12 months after PTA. RESULTS: CYP2C19*2 and/or ABCB1 TT patients were associated with primary end point (OR: 5.00; 95% CI: 1.75-14.27). The meta-analysis confirmed the association of CYP2C19*2 and new atherothrombotic ischemic events (OR: 5.40; 95% CI: 2.30-12.70). CONCLUSION: The CYP2C19 and ABCB1 polymorphisms could be genetic markers of cardiovascular events in peripheral artery disease patients following PTA treated with clopidogrel.
Assuntos
Angioplastia , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/genética , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo Genético/genética , Ticlopidina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Aterosclerose/genética , Aterosclerose/cirurgia , Clopidogrel , Citocromo P-450 CYP2C19/genética , Feminino , Genótipo , Oclusão de Enxerto Vascular/epidemiologia , Oclusão de Enxerto Vascular/genética , Humanos , Extremidade Inferior/irrigação sanguínea , Masculino , Espanha , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11-21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases.