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1.
Br J Cancer ; 130(5): 808-818, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38225422

RESUMO

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. METHODS: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). RESULTS: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. CONCLUSIONS: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.


Assuntos
Antineoplásicos , Deficiência da Di-Hidropirimidina Desidrogenase , Humanos , Fluoruracila/efeitos adversos , Di-Hidrouracila Desidrogenase (NADP)/genética , Heterozigoto , Genótipo , Capecitabina/efeitos adversos
2.
Pharmacol Res ; 181: 106290, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35680010

RESUMO

Glioblastoma multiforme (GBM) is an aggressive brain tumor, often occurring with seizures managed with antiepileptic drugs, such as levetiracetam (LEV). This study is aimed at associating progression-free survival (PFS) and overall survival (OS) of GBM patients with LEV plasma concentration, MGMT promoter methylation, and sex. In this retrospective, non-interventional, and explorative clinical study, GBM patients underwent surgery and/or radiotherapy and received LEV during adjuvant temozolomide (TMZ) treatment. A high-performance liquid chromatography with UV-detection was used for therapeutic drug monitoring of LEV plasma concentrations. Follow-up average drug concentration was related to patients' clinical characteristics and outcomes. Forty patients (42.5 % female; mean age=54.73 ± 11.70 years) were included, and GBM MGMT methylation status was assessed. All were treated with adjuvant TMZ, and LEV for seizure control. Patients harboring methylated MGMT promoter showed a longer median PFS (460 vs. 275 days, log-rank p < 0.001). The beneficial effect of MGMT promoter methylation was more evident for females (p < 0.001) and in patients with LEV concentration ≤ 20.6 µg/mL (562 days vs. 274.5 days, p = 0.032). Female patients also showed longer OS (1220 vs. 574 days, p = 0.03). Also, higher LEV concentration (>20.6 µg/mL) synergized with MGMT promoter methylation by extending the OS (1014 vs. 406 days of patients with no methylation and low LEV average concentration, p = 0.021). Beneficial effect of higher LEV plasma levels was more evident in males (p = 0.024). Plasma concentrations of LEV may support better outcomes for chemoradiotherapy when other positive prognostic factors are lacking and may promote overall survival by synergizing with MGMT promoter methylation and male sex.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Quimiorradioterapia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/uso terapêutico , Dacarbazina/uso terapêutico , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Levetiracetam/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/genética
3.
Clin Exp Rheumatol ; 40(1): 49-55, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33427624

RESUMO

OBJECTIVES: To investigate the prognostic significance of concomitant autoimmune diseases (ADs) in myeloproliferative neoplasms (MPNs). METHODS: 435 subjects with a diagnosis of MPNs were included in this observational single institution longitudinal study. Of them, 34 patients presented an overt AD at diagnosis of MPN. Clinical presenting features, progression-free and overall survival were compared between MPN subgroups in relation to co-existence of AD at diagnosis of MPN. RESULTS: Compared to cases without ADs, the subjects with ADs were significantly younger, had lower haemoglobin and haematocrit levels and more frequently presented with splenomegaly. The clinical and biological features associated to progression-free and overall survival were: age, presence of splenomegaly, histotype (MF vs. PV vs. ET), anaemia, high platelet count and presence of any AD at diagnosis of MPN. The age-adjusted hazard ratio (HR) of progression for the presence of AD at diagnosis of MPN was 2.76. Overall survival was not significantly associated to AD at diagnosis, but the HR of progression for the presence of AD at diagnosis of MPN was 2.18. CONCLUSIONS: A possible common genetic predisposition, the inflammatory bone marrow microenvironment and the activation of theJAK/STAT pathway could be considered as responsible for the observed association between MPNs and ADs.


Assuntos
Doenças Autoimunes , Transtornos Mieloproliferativos , Neoplasias , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Humanos , Estudos Longitudinais , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , Modelos de Riscos Proporcionais , Microambiente Tumoral
4.
J Antimicrob Chemother ; 76(4): 1025-1031, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33378458

RESUMO

BACKGROUND: Avibactam is a ß-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-ß-lactamases (MBL). Optimal dosing of aztreonam with avibactam is not well-defined in critically ill patients and contingent on ceftazidime/avibactam product labelling. OBJECTIVES: To identify a pragmatic dosing strategy for aztreonam with avibactam to maximize the probability of target attainment (PTA). METHODS: We conducted a prospective observational pharmacokinetic study. Five blood samples were collected around the fourth dose of aztreonam or ceftazidime/avibactam and assayed for all three drugs. Population pharmacokinetic (PK) analysis coupled with Monte Carlo simulations were used to create a dosing nomogram for aztreonam and ceftazidime/avibactam based on drug-specific pharmacodynamic (PD) targets. RESULTS: A total of 41 participants (59% male) median age of 75 years (IQR 63-79 years) were enrolled. They were critically ill (46%) with multiple comorbidities and complications including burns (20%). Population PK analysis identified higher volume of distribution and lower clearance (CL) compared with typical value expectations for aztreonam and ceftazidime/avibactam. Estimated glomerular filtration (eGFR) rate using the CKD-EPI equation predicted CL for all three drugs. The need for high doses of aztreonam and ceftazidime/avibactam above those in the existing product labels are not predicted by this analysis with the exception of ceftazidime/avibactam for patients with eGFR of 6-15 mL/min, in whom suboptimal PTA of ≤71% is predicted. CONCLUSIONS: Pragmatic and lower daily-dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min. These options should be tested prospectively.


Assuntos
Aztreonam , Ceftazidima , Idoso , Antibacterianos/uso terapêutico , Compostos Azabicíclicos , Combinação de Medicamentos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , beta-Lactamases
5.
Pharmacol Res ; 157: 104866, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32387301

RESUMO

COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Hematologia/métodos , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , COVID-19 , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Síndrome de Ativação Macrofágica/tratamento farmacológico , Pandemias , SARS-CoV-2
6.
Stem Cells ; 36(5): 633-640, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29352734

RESUMO

Among the potential mechanisms involved in resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer, the manifestation of stem-like properties in cancer cells seems to have a crucial role. Alterations involved in the development of TKI resistance may be acquired in a very early phase of tumorigenesis, supporting the hypothesis that these aberrations may be present in cancer stem cells (CSCs). In this regard, the characterization of tumor subclones in the initial phase and the identification of the CSCs may be helpful in planning a specific treatment to target selected biomarkers, suppress tumor growth, and prevent drug resistance. The aim of this review is to elucidate the role of CSCs in the development of resistance to TKIs and its implication for the management of patients. Stem Cells 2018;36:633-640.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/citologia , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos
7.
Neurocrit Care ; 31(1): 116-124, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30607829

RESUMO

BACKGROUND: There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg. RESULTS: In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7-1366.3 h mg/L), paralleled by high-peak plasma concentration (Cmax) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17-6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-Cmax (range: 6.04-9.54 h). The terminal half-life between plasma and CSF was similar. tmax values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%. CONCLUSIONS: Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC, tmax and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.


Assuntos
Antibacterianos/farmacocinética , Infecção Hospitalar/sangue , Infecção Hospitalar/líquido cefalorraquidiano , Daptomicina/farmacocinética , Meningite/sangue , Meningite/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Antibacterianos/administração & dosagem , Infecção Hospitalar/tratamento farmacológico , Daptomicina/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Masculino , Meningite/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
8.
Ther Drug Monit ; 40(5): 602-609, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29979333

RESUMO

BACKGROUND: Several factors contribute to the high variability of linezolid plasma exposure in patients. Very recently, it has been suggested that linezolid could be an ABCB1 substrate. Therefore, the present clinical study was aimed at investigating whether ABCB1 polymorphisms could predict linezolid pharmacokinetics in 27 critically ill patients. METHODS: Genotypes were assessed through a real-time polymerase chain reaction allelic discrimination system, and linezolid plasma concentrations, considering trough concentration (Ctrough) and area under the time-concentration curve (AUC), were analyzed through a nonlinear mixed-effects modeling approach. RESULTS: A significant effect of abcb1 c.3435C>T polymorphism on linezolid clearance was found, whose values accounted for 13.19 L/h in wild-type homozygotes and 7.82 L/h in the remaining individuals. That difference was statistically significant despite the large interindividual variability (60.8%). Terminal half-life and volume of distribution values significantly differed between c.3435CC and c.3435CT/TT patients (2.78 versus 5.45 hours and 37.43 versus 46.71 L, respectively). On the contrary, a modest trend was observed for the difference in AUC and Ctrough based on c.3435C>T genotypes. Simulation according to the final model revealed that the cumulative response fraction for the AUC/MIC parameter was better for .3435CC individuals compared with individuals carrying at least one c.3435T allele with respect to methicillin-sensitive S. aureus, methicillin-resistant S. aureus, and Streptococcus pneumoniae species. CONCLUSIONS: The obtained results suggest the possible influence of ABCB1 in linezolid pharmacokinetics, bringing new interest for pharmacogenetic analyses in antimicrobial chemotherapy. These analyses could be incorporated in therapeutic protocols for precision medicine, including a combined use of genetic evaluation (for starting dose) and follow-up therapeutic drug monitoring.


Assuntos
Linezolida/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Alelos , Área Sob a Curva , Feminino , Genótipo , Humanos , Linezolida/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
9.
BMC Health Serv Res ; 17(1): 289, 2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28424057

RESUMO

BACKGROUND: Personalized medicine has the potential to allow patients to receive drugs specific to their individual disease, and to increase the efficiency of the healthcare system. There is currently no comprehensive overview of personalized medicine, and this research aims to provide an overview of the concept and definition of personalized medicine in nine European countries. METHODS: A targeted literature review of selected health databases and grey literature was conducted to collate information regarding the definition, process, use, funding, impact and challenges associated with personalized medicine. In-depth qualitative interviews were carried out with experts with health technology assessment, clinical provisioning, payer, academic, economic and industry experience, and with patient organizations. RESULTS: We identified a wide range of definitions of personalized medicine, with most studies referring to the use of diagnostics and individual biological information such as genetics and biomarkers. Few studies mentioned patients' needs, beliefs, behaviour, values, wishes, utilities, environment and circumstances, and there was little evidence in the literature for formal incorporation of patient preferences into the evaluation of new medicines. Most interviewees described approaches to stratification and segmentation of patients based on genetic markers or diagnostics, and few mentioned health-related quality of life. CONCLUSIONS: The published literature on personalized medicine is predominantly focused on patient stratification according to individual biological information. Although these approaches are important, incorporation of environmental factors and patients' preferences in decision making is also needed. In future, personalized medicine should move from treating diseases to managing patients, taking into account all individual factors.


Assuntos
Satisfação do Paciente , Medicina de Precisão/normas , Avaliação da Tecnologia Biomédica , Tomada de Decisões , Europa (Continente) , Previsões , Humanos , Entrevistas como Assunto , Preferência do Paciente , Qualidade de Vida
10.
Int J Mol Sci ; 18(1)2017 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-28067828

RESUMO

BACKGROUND: In the era of precision medicine, more attention is paid to the search for predictive markers of treatment efficacy and tolerability. Statins are one of the classes of drugs that could benefit from this approach because of their wide use and their incidence of adverse events. METHODS: Literature from PubMed databases and bibliography from retrieved publications have been analyzed according to terms such as statins, pharmacogenetics, epigenetics, toxicity and drug-drug interaction, among others. The search was performed until 1 October 2016 for articles published in English language. RESULTS: Several technical and methodological approaches have been adopted, including candidate gene and next generation sequencing (NGS) analyses, the latter being more robust and reliable. Among genes identified as possible predictive factors associated with statins toxicity, cytochrome P450 isoforms, transmembrane transporters and mitochondrial enzymes are the best characterized. Finally, the solute carrier organic anion transporter family member 1B1 (SLCO1B1) transporter seems to be the best target for future studies. Moreover, drug-drug interactions need to be considered for the best approach to personalized treatment. CONCLUSIONS: Pharmacogenetics of statins includes several possible genes and their polymorphisms, but muscular toxicities seem better related to SLCO1B1 variant alleles. Their analysis in the general population of patients taking statins could improve treatment adherence and efficacy; however, the cost-efficacy ratio should be carefully evaluated.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Proteínas de Membrana Transportadoras/genética , Proteínas Mitocondriais/genética , Farmacogenética , Polimorfismo Genético , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Epigenômica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Mitocondriais/metabolismo , Medicina de Precisão
11.
Eur J Clin Pharmacol ; 72(7): 839-48, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27048201

RESUMO

PURPOSE: Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens. METHODS: Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1-2 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4× MIC (fCmin > 4× MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR). RESULTS: Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean ± standard deviation (SD) value, 9.38 ± 4.47 L/h). Mean C min value was 7.90 ± 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective C min > 4× MIC values after 3- and 5-h i.v. infusions of meropenem 2 g × 3/day, respectively. On the contrary, the same total daily doses reached the target C min > 4× MIC values in 100 % of patients when administered as continuous i.v. infusions. CONCLUSIONS: Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets.


Assuntos
Antibacterianos/farmacocinética , Infecção Hospitalar/metabolismo , Infecções por Klebsiella/metabolismo , Sepse/metabolismo , Tienamicinas/farmacocinética , Adulto , Idoso , Antibacterianos/sangue , Antibacterianos/uso terapêutico , Estado Terminal , Infecção Hospitalar/tratamento farmacológico , Feminino , Humanos , Infusões Intravenosas , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae , Masculino , Meropeném , Pessoa de Meia-Idade , Modelos Biológicos , Sepse/tratamento farmacológico , Tienamicinas/sangue , Tienamicinas/uso terapêutico
12.
Mycopathologia ; 181(3-4): 297-303, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26588923

RESUMO

BACKGROUND: Trichoderma species are saprophytic filamentous fungi producing localized and invasive infections that are cause of morbidity and mortality, especially in immunocompromised patients, causing up to 53% mortality. Non-immunocompromised patients, undergoing continuous ambulatory peritoneal dialysis, are other targets of this fungus. Current molecular diagnostic tools, based on the barcode marker ITS, fail to discriminate these fungi at the species level, further increasing the difficulty associated with these infections and their generally poor prognosis. CASE REPORT: We report on the first case of endocarditis infection caused by Trichoderma longibrachiatum in a 30-year-old man. This patient underwent the implantation of an implantable cardioverter defibrillator in 2006, replaced in 2012. Two years later, the patient developed fever, treated successfully with amoxicillin followed by ciprofloxacin, but an echocardiogram showed large vegetation onto the ventricular lead. After CIED extraction, the patient had high-grade fever. The culturing of the catheter tip was positive only in samples deriving from sonication according to the 2014 ESCMID guidelines, whereas the simple washing failed to remove the biofilm cells from the plastic surface. Subsequent molecular (ITS sequencing) and microbiological (macromorphology) analyses showed that the vegetation was due to T. longibrachiatum. CONCLUSIONS: This report showed that T. longibrachiatum is an effective threat and that sonication is necessary for the culturing of vegetations from plastic surfaces. Limitations of the current barcode marker ITS, and the long procedures required by a multistep approach, call for the development of rapid monophasic tests.


Assuntos
Antifúngicos/uso terapêutico , Biofilmes/efeitos dos fármacos , Desfibriladores Implantáveis/efeitos adversos , Endocardite/tratamento farmacológico , Coração/microbiologia , Micoses/tratamento farmacológico , Trichoderma/efeitos dos fármacos , Adulto , Anfotericina B/uso terapêutico , Sequência de Bases , DNA Intergênico/genética , Endocardite/microbiologia , Humanos , Masculino , Micoses/microbiologia , Análise de Sequência de DNA , Trichoderma/classificação , Trichoderma/genética , Voriconazol/uso terapêutico
13.
Int J Mol Sci ; 16(9): 22811-29, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26402671

RESUMO

Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics and pharmacodynamics of BCR-ABL1 tyrosine kinase activity inhibitors (TKIs). Transmembrane transporters seem to influence in a significant manner the disposition of TKIs, especially that of imatinib at both cellular and systemic levels. In particular, members of the ATP-binding cassette (ABC) family (namely ABCB1 and ABCG2) together with solute carrier (SLC) transporters (i.e., SLC22A1) are responsible for the differences in drug pharmacokinetics. In the case of the newer TKIs, such as nilotinib and dasatinib, the substrate affinity of these drugs for transporters is variable but lower than that measured for imatinib. In this scenario, the investigation of genetic variants as possible predictive markers has led to some discordant results. With the partial exception of imatinib, these discrepancies seem to limit the application of discovered biomarkers in the clinical settings. In order to overcome these issues, larger prospective confirmative trials are needed.


Assuntos
Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Farmacogenética , Inibidores de Proteínas Quinases/farmacocinética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Inibidores de Proteínas Quinases/farmacologia
14.
Antimicrob Agents Chemother ; 58(4): 1972-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24419337

RESUMO

Gut colonization represents the main source for KPC-producing Klebsiella pneumoniae (KPC-Kp) epidemic dissemination. Oral gentamicin, 80 mg four times daily, was administered to 50 consecutive patients with gut colonization by gentamicin-susceptible KPC-Kp in cases of planned surgery, major medical intervention, or need for patient transfer. The overall decontamination rate was 68% (34/50). The median duration of gentamicin treatment was 9 days (interquartile range, 7 to 15 days) in decontaminated patients compared to 24 days (interquartile range, 20 to 30 days) in those with persistent colonization (P<0.001). In the six-month period of follow-up, KPC-Kp infections were documented in 5/34 (15%) successfully decontaminated patients compared to 12/16 (73%) persistent carriers (P<0.001). The decontamination rate was 96% (22/23) in patients receiving oral gentamicin only, compared to 44% (12/27) of those treated with oral gentamicin and concomitant systemic antibiotic therapy (CSAT) (P<0.001). The multivariate analysis confirmed CSAT and KPC-Kp infection as the variables associated with gut decontamination. In the follow-up period, KPC-Kp infections were documented in 2/23 (9%) of patients treated with oral gentamicin only and in 15/27 (56%) of those also receiving CSAT (P=0.003). No difference in overall death rate between different groups was documented. Gentamicin-resistant KPC-Kp strains were isolated from stools of 4/16 persistent carriers. Peak gentamicin blood levels were below 1 mg/liter in 12/14 tested patients. Oral gentamicin was shown to be potentially useful for gut decontamination and prevention of infection due to KPC-Kp, especially in patients not receiving CSAT. The risk of emergence of gentamicin-resistant KPC-Kp should be considered.


Assuntos
Antibacterianos/uso terapêutico , Gentamicinas/uso terapêutico , Infecções por Klebsiella/prevenção & controle , Klebsiella pneumoniae/efeitos dos fármacos , Administração Oral , Idoso , Antibacterianos/farmacologia , Feminino , Gentamicinas/farmacologia , Humanos , Infecções por Klebsiella/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
17.
Int Immunopharmacol ; 138: 112636, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38991629

RESUMO

Acute graft-versus-host disease (GVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), ranking as the second leading cause of death among recipients, surpassed only by disease relapse. Tacrolimus is commonly used for GVHD prophylaxis, but achieving therapeutic blood levels is challenging, particularly in pediatrics, due to the narrow therapeutic window and the high interindividual variability. The retrospective study conducted at IRCCS "Burlo Garofolo" in Italy aimed to assess the impact of early post-HSCT tacrolimus levels on transplant-related outcomes in pediatric recipients. The population pharmacokinetic model (POP/PK) was set up to describe tacrolimus pharmacokinetics. Elevated tacrolimus (>12-15 ng/ml) levels within the initial weeks post-HSCT are associated with reduced post-transplant infections (p < 0.0001) and decreased incidence of early transplant-related events (p < 0.01), including a lower incidence of acute GVHD (p < 0.05 on day 0). High tacrolimus exposure can lead to an increased risk of chronic GVHD (p < 0.0001) and reduced overall survival (p < 0.01). Personalized dosing and therapeutic monitoring of tacrolimus are crucial to ensure optimal outcomes. POP/PK could help achieve this goal, giving us a model by which we can balance immunosuppression while looking at the patient's general well-being and providing the necessary treatment.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunossupressores , Tacrolimo , Humanos , Tacrolimo/uso terapêutico , Tacrolimo/farmacocinética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Criança , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Feminino , Masculino , Imunossupressores/uso terapêutico , Imunossupressores/farmacocinética , Estudos Retrospectivos , Pré-Escolar , Adolescente , Lactente , Resultado do Tratamento , Transplante Homólogo , Itália
18.
Pharmaceutics ; 16(3)2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38543276

RESUMO

Ponatinib may be effective in chronic myeloid leukemia (CML) patients after failure of first/second line therapies. Although its efficacy for minimum plasma concentrations (Cmin) is >21.3 ng/mL (equal to 40 nM), ponatinib may cause adverse events (AE) that require dose optimization. The present study was aimed at investigating any possible correlations among ponatinib dose, plasma concentration, molecular response (MR), and tolerability in a real-world setting. Clinical and laboratory records (including MR and drug plasma concentrations) of 32 CML patients treated with ponatinib were harvested and analyzed. Twenty-seven patients (71%) had ponatinib Cmin values > 21.3 ng/mL, but Cmin values > 10.7 ng/mL (considered efficacious in BCR-Abl unmutated patients) were achieved by 80% of the patients receiving ≥30 mg/day and 45% of the subjects treated with 15 mg/day. No significant correlations were identified among clinical efficacy, tolerability, daily dose, and plasma concentration. Notably, patients who underwent dose tapering for tolerability or safety reasons did not experience treatment failure. In a real-world setting, adjustment of ponatinib daily doses lower than those registered may maintain therapeutic efficacy while reducing the risk of vascular events and improving tolerability. Further studies are warranted to confirm the present results in a larger cohort of patients.

19.
Angiogenesis ; 16(3): 481-92, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23389639

RESUMO

In the mid 1990s, researchers began to investigate the antiangiogenic activity of paclitaxel as a possible additional mechanism contributing to its antineoplastic activity in vivo. In the last decade, a number of studies showed that paclitaxel has antiangiogenic activity that could be ascribed to the inhibition of either tubule formation or cell migration, and to an antiproliferative effect towards activated endothelial cells. Furthermore, paclitaxel was shown to downregulate VEGF and Ang-1 expression in tumor cells, and to increase the secretion of TSP-1 in the tumor microenvironment. Moreover, the new pharmaceutical formulations of paclitaxel (such as liposome-encapsulated paclitaxel, ABI-007, and paclitaxel entrapped in emulsifying wax nanoparticles) enhanced the in vivo antiangiogenic activity of the drug. Thus, the preclinical data of paclitaxel may be exploited to implement a novel and rational therapeutic strategy to control tumor progression in patients.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Angiotensina I/metabolismo , Humanos , Lipossomos , Modelos Moleculares , Nanopartículas , Trombospondina 1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Antimicrob Agents Chemother ; 57(1): 601-2, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23089753

RESUMO

In a patient with mitral-aortic native-valve Streptococcus oralis endocarditis, daptomycin concentrations in aortic and mitral valves were 8.6 and 30.8 µg/g, respectively, and 26 µg/g in the mitral vegetation. In the case of porcine-aortic-valve Staphylococcus epidermidis endocarditis, the daptomycin concentrations were 53.1 µg/g in the valve and 18.1 µg/g in perivalvular tissues. Daptomycin achieved apparently adequate tissue concentrations. S. epidermidis was eradicated, whereas Streptococcus oralis persisted, and its daptomycin MIC displayed a 4-fold increase.


Assuntos
Antibacterianos/farmacocinética , Bioprótese/microbiologia , Daptomicina/farmacocinética , Endocardite Bacteriana/tratamento farmacológico , Próteses Valvulares Cardíacas/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Idoso , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Valva Aórtica/patologia , Valva Aórtica/cirurgia , Daptomicina/farmacologia , Daptomicina/uso terapêutico , Endocardite Bacteriana/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/patologia , Valva Mitral/cirurgia , Infecções Estafilocócicas/microbiologia , Staphylococcus/efeitos dos fármacos , Staphylococcus/crescimento & desenvolvimento , Staphylococcus epidermidis/efeitos dos fármacos , Staphylococcus epidermidis/crescimento & desenvolvimento , Suínos
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