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1.
Curr Drug Metab ; 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36503397

RESUMO

BACKGROUND: Iron-chelation therapy is life-saving in patients on a chronic transfusion regimen as it reduces organ damage related to iron deposition in the tissues. Deferasirox, an iron-chelator, is characterized by pharmacokinetics variability, and some patients may discontinue the treatment due to toxicities. OBJECTIVE: Understanding whether deferasirox plasma levels are related to patients' specific characteristics could help optimize DFX dosage. METHODS: We analyzed deferasirox plasma concentration in 57 transfusion-dependent anemic patients using the HPLC method in this prospective-retrospective cohort study. All outpatients (3 to 98 years) were treated with deferasirox (film-coated tablet) for at least one year (median dose, 16.5 mg/Kg once a day). Deferasirox plasma concentration was normalized for dose/Kg (C/dose) and corrected with a linear regression model that relates C/dose and the time of blood sampling (Cref/dose). RESULTS: No significant differences in Cref/dose were found between males and females, either between different types of hemoglobinopathies or depending on the presence of the UGT1A1*28 polymorphism. Cref/dose has a positive and significant correlation with age, creatinine, and direct bilirubin. Cref/dose, instead, has a negative and significant correlation with Liver Iron Concentration (LIC), ferritin, and eGFR. Cref/dose was significantly different between three age categories <18yrs, 18-50yrs, and >50yrs, with Cref/dose median values of 1.0, 1.2, and 1.5, respectively. CONCLUSION: The study evidenced that to ensure the efficacy of deferasirox in terms of control over LIC and, at the same time, a lesser influence on renal function, the dose of the drug to be administered to an elderly patient could be reduced.

2.
Pathogens ; 11(9)2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36145488

RESUMO

The annual movements of migratory birds can contribute to the spread of African ticks and tick-borne pathogens of potential public health concern across Europe. The aim of the study was to investigate their role in the possible introduction of African ticks and tick-borne pathogens into European countries during spring migration. A total of 2344 ticks were collected during three spring seasons from 1079 birds captured on three Italian stop-over islands during their northbound migration. Once identified, each tick was tested by RT-PCR for the presence of Crimean-Congo hemorrhagic fever (CCHFV), West Nile (WNV), and Usutu (USUV) viruses. Moreover, carcasses of birds found dead were collected and tested for the possible presence of WNV and USUV. Results confirmed a higher contribution of trans-Saharan migrants compared to intra-Palearctic ones and the prevalence of African tick species in the sample. CCHFV was detected for the second time in Italy in a Hyalomma rufipes, and WNV was found in two ticks of the same genus, all carried by trans-Saharan birds. WNV lineage 1 was also found in the organs of a Garden warbler. These results confirm the role of migratory birds in carrying African ticks, as well as viruses of zoonotic importance, from Africa into Europe.

4.
Vet Microbiol ; 263: 109262, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34715462

RESUMO

West Nile virus (WNV) and Usutu virus (USUV) are the two most widespread mosquito-borne flaviviruses in Europe causing severe neuroinvasive disease in humans. Here, following standardization of the murine model with wild type (wt) viruses, we engineered WNV and USUV genome by reverse genetics. A recombinant virus carrying the 5' UTR of WNV within the USUV genome backbone (r-USUV5'-UTR WNV) was rescued; when administered to mice this virus did not cause signs or disease as wt USUV suggesting that 5' UTR of a marked neurotropic parental WNV was not per se a virulence factor. Interestingly, a chimeric virus carrying the envelope (E) protein of USUV in the WNV genome backbone (r-WNVE-USUV) showed an attenuated profile in mice compared to wt WNV but significantly more virulent than wt USUV. Moreover, except when tested against serum samples originating from a live WNV infection, r-WNVE-USUV showed an identical antigenic profile to wt USUV confirming that E is also the major immunodominant protein of USUV.


Assuntos
Flavivirus , Febre do Nilo Ocidental , Vírus do Nilo Ocidental , Regiões 5' não Traduzidas , Animais , Flavivirus/genética , Flavivirus/imunologia , Genoma Viral , Camundongos , Virulência , Febre do Nilo Ocidental/prevenção & controle , Febre do Nilo Ocidental/veterinária , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/genética , Vírus do Nilo Ocidental/patogenicidade
5.
Pharmaceutics ; 13(8)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34452199

RESUMO

BACKGROUND: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2-17 years, who underwent an allogeneic hematopoietic stem cell transplantation. METHODS: IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling. RESULTS: The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (Ctrough) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (p-value < 0.0001, T-test and Fisher's exact tests) when Ctrough threshold values of 7.0 and 11.5 mg/L were chosen, respectively. CONCLUSIONS: The population pharmacokinetic model described the interindividual variability and identified Ctrough threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX.

6.
Insights Imaging ; 12(1): 24, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33595746

RESUMO

BACKGROUND: Lung perfusion defects (PDs) have been described in COVID-19 using dual-energy computed tomography pulmonary angiography (DE-CTPA). We assessed the prevalence and characteristics of PDs in COVID-19 patients with suspected pulmonary embolism (PE) and negative CTPA. METHODS: This retrospective study included COVID-19 and non-COVID-19 pneumonia groups of patients with DE-CTPA negative for PE. Two radiologists rated the presence of PD within the lung opacities and analyzed the type of lung opacities and PD pattern (i.e. homogeneous or heterogeneous). The clinical, biological, radiological characteristics including time from first symptoms and admission to DE-CTPA, oxygen requirements, CRP, D-dimer levels, duration of hospital admission and death were compared within the COVID-19 group between patients with (PD +) or without PD (PD-). RESULTS: 67 COVID-19 and 79 non-COVID-19 patients were included. PDs were more frequent in the COVID-19 than in the non-COVID-19 group (59.7% and 26.6% respectively, p < 0.001). Patterns of PDs were different, with COVID-19 patients exhibiting heterogenous PDs (38/40, 95%) whereas non-COVID-19 patients showed mostly homogeneous perfusion defects (7/21 heterogeneous PDs, 33%), p < 0.001. In COVID-19 patients, most consolidations (9/10, 90%) exhibited PDs while less than a third of consolidations (19/67, 28%) had PDs in non-COVID-19 patients. D-dimer, oxygen levels and outcome were similar between COVID-19 PD + and PD- patients; however, time between admission and DE-CTPA was longer in PD + patients (median [IQR], 1 [0-7] and 0 [0-2]; p = 0.045). CONCLUSION: Unlike in bacterial pneumonia, heterogeneous PDs within lung opacities are a frequent feature of COVID-19 pneumonia in PE-suspected patients.

7.
Complement Ther Med ; 51: 102402, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32507423

RESUMO

OBJECTIVES: To evaluate safety and pharmacokinetic parameters (PK) of medical cannabis in add-on for children and young adults with drug-resistant epilepsy. DESIGN, SETTING: Ten patients (4 females, 6 males, age 2.5-23.2 years) were enrolled in a prospective open trial with a galenic preparation (decoction) of Italian cannabis (FM2, ratio THC:CBD = 3:5, range THC 5.2-7.2 %; CBD 8.2-11.1 %). Patients received the first dose in Hospital, progressively augmented by CBD dose titration (from 1 to 4 mg/kg/day). OUTCOME MEASURES: In order to assess safety, blood parameters, heart rates and electrocardiograms (ECGs) were evaluated before the enrollment and during the follow up. The PK study was performed measuring THC and CBD concentrations by UHPLC-MS/MS in plasma samples collected during the first administration and at each follow-up visit. RESULTS: Two out of ten patients stopped the treatment for adverse events (detected in 6/10: gastroenteric, sleep or behavioral disorders) and difficulties in drug supply. We observed minor ECG alterations in two patients and asymptomatic transient reductions of fibrinogen after 6 months of therapy. The PK study during follow-up revealed statistically significant correlations between THC-CBD blood concentrations and: volumes of decoction, FM2 and THC-CBD daily dosages. CONCLUSIONS: The present study, although with some limitations, shows a good safety profile of medical cannabis in children and young patients with drug-resistant epilepsy and encourages the possibility of further studies with oral cannabis-based drugs. The correlations between THC-CBD plasma concentrations and their administered dosages underline the need of a therapeutic drug monitoring for cannabinoids therapy.


Assuntos
Epilepsia Resistente a Medicamentos/tratamento farmacológico , Maconha Medicinal/administração & dosagem , Maconha Medicinal/farmacocinética , Adolescente , Adulto , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Maconha Medicinal/efeitos adversos , Estudos Prospectivos , Adulto Jovem
8.
BMC Cardiovasc Disord ; 19(1): 212, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519196

RESUMO

BACKGROUND: Smoking is a strong risk factor for cancer and atherosclerosis. Cancer mortality, especially from lung cancer, overtakes cardiovascular (CV) death rate in patients with peripheral arterial disease (PAD). Only a few patients with lung cancer after PAD management may benefit from surgical excision. Circulating tumor cells (CTC) associated with low-dose chest CT (LDCT) may improve early cancer detection. This study focuses on a screening strategy that can address not only lung cancer but all tobacco-related cancers in this high-risk population. METHODS: DETECTOR Project is a prospective cohort study in two French University hospitals. Participants are smokers or former smokers (≥30 pack-years, quitted ≤15 years), aged ≥55 to 80 years, with atherosclerotic PAD or abdominal aortic aneurysm. After the first screening round combining LDCT and CTC search on a blood sample, two other screening rounds will be performed at one-year interval. Incidental lung nodule volume, volume doubling time and presence of CTC will be taken into consideration for adapted diagnostic management. In case of negative LDCT and presence of CTC, a contrast enhanced whole-body PET/CT will be performed for extra-pulmonary malignancy screening. Psychological impact of this screening strategy will be evaluated in population study using a qualitative methodology. Assuming 10% prevalence of smoking-associated cancer in the studied population, a total of at least 300 participants will be enrolled. DISCUSSION: Epidemiological data underline an increase incidence in cancer and related death in the follow-up of patients with PAD, compared with the general population, particularly for tobacco-related cancers. The clinical benefit of a special workup for neoplasms in patients with PAD and a history of cigarette smoking has never been investigated. By considering CTCs detection in this very high-risk selected PAD population for tobacco-induced cancer, we expect to detect earlier pulmonary and extra-pulmonary malignancies, at a potentially curable stage. TRIAL REGISTRATION: The study was registered in the French National Agency for Medicines and Health Products Safety (No N° EUDRACT_ID RCB: 2016-A00657-44) and was approved by the ethics Committee for Persons Protection (IRB number 1072 and n° initial agreement 2016-08-02; ClinicalTrials.gov identifier NCT02849041).


Assuntos
Detecção Precoce de Câncer , Neoplasias/sangue , Células Neoplásicas Circulantes/patologia , Doença Arterial Periférica/sangue , Fumar/sangue , Idoso , Idoso de 80 Anos ou mais , Ex-Fumantes , Feminino , França/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Neoplasias/diagnóstico por imagem , Neoplasias/epidemiologia , Neoplasias/patologia , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Projetos de Pesquisa , Fatores de Risco , Fumantes , Fumar/efeitos adversos , Fumar/epidemiologia , Fumar/patologia , Abandono do Hábito de Fumar
9.
Vet Ital ; 55(2): 131-141, 2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-31274174

RESUMO

In order to study the capability of a Bluetongue virus serotype 2 (BTV­2) field isolate to cross the placental barrier, 2 groups of 5 pregnant ewes were infected with a field BTV­2 Italian strain (Group A) or with the same strain passaged once in Culicoides cells (Kc) (Group B). Following infection, EDTA­blood and serum samples were collected weekly and tested for the presence of BTV RNA/infectious virus and anti­BTV­2 antibodies, respectively. At lambing, precolostral EDTA­blood and serum samples were collected from lambs and tested as before. The lambs were then sampled as scheduled for the dams. All sheep seroconverted on day 12 post­infection (pi) and remained seropositive throughout the sampling period (day 68 pi). BTV was isolated from day 7 pi to day 14 pi in animals of Group A and from day 5 pi to day 12 pi in animals of Group B. None of the 14 lambs born had pre­colostral antibodies. Three lambs born from two ewes of Group B were viraemic at birth and in one lamb infectious virus was isolated from blood up to 11 days of age. This study proved for the first time that a single passage of BTV­2 field strain in Kc cells is able to give to BTV the ability to cross the placenta barrier and infect foetal tissues.


Assuntos
Vírus Bluetongue/fisiologia , Bluetongue/transmissão , Transmissão Vertical de Doenças Infecciosas/veterinária , Placenta/virologia , Animais , Bluetongue/virologia , Linhagem Celular/virologia , Ceratopogonidae , Feminino , Itália , Gravidez , Distribuição Aleatória , Sorogrupo , Carneiro Doméstico
10.
Drug Metab Pers Ther ; 34(1)2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30840585

RESUMO

Background The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Genótipo , Metiltransferases/genética , Fenótipo , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Cromatografia Líquida de Alta Pressão , Doença Crônica , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Itália , Masculino , Metiltransferases/metabolismo
11.
Infect Genet Evol ; 68: 91-97, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30517880

RESUMO

Here we report studies of the antigenic relationship of West Nile virus (WNV) and Usutu virus (USUV), two zoonotic flaviviruses from Italy, together with a Japanese encephalitis virus (JEV) strain and compared them with their genetic relationship using the immunodominant viral E protein. Thirty-nine isolates and reference strains were inactivated and used to immunize rabbits to produce hyper immune sera. Serum samples were tested by neutralization against all isolates and results visualized by generating antigenic map. Strains of WNV, USUV, and JEV grouped in separate clusters on the antigenic map. JEV was closer antigenically to USUV (mean of 3.5 Antigenic Unit, AU, equivalent to a 2-fold change in antibody titer) than to WNV strains (mean of 6 AU). A linear regression model predicted, on average, one unit of antigenic change, equivalent to a 2-fold change in antibody titer, for every 22 amino acid substitutions in the E protein ectodomain. Overall, antigenic map was demonstrated to be robust and consistent with phylogeny of the E protein. Indeed, the map provided a reliable means of visualizing and quantifying the relationship between these flaviviruses. Further antigenic analyses employing representative strains of extant serocomplexes are currently underway. This will provide a more in deep knowledge of antigenic relationships between flaviviruses.


Assuntos
Antígenos Virais/imunologia , Infecções por Flavivirus/epidemiologia , Infecções por Flavivirus/imunologia , Flavivirus/imunologia , Zoonoses/epidemiologia , Zoonoses/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/química , Antígenos Virais/genética , Flavivirus/classificação , Flavivirus/genética , Infecções por Flavivirus/virologia , Soros Imunes/imunologia , Itália/epidemiologia , Filogenia , Testes Sorológicos , Zoonoses/virologia
12.
Ther Clin Risk Manag ; 14: 1649-1655, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30237719

RESUMO

To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommended.

13.
Sci Rep ; 8(1): 3929, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29500390

RESUMO

Metformin is an antidiabetic drug which possesses antiproliferative activity in cancer cells when administered at high doses, due to its unfavorable pharmacokinetics. The aim of this work was to develop a pharmacological tool for the release of metformin in proximity of the tumor, allowing high local concentrations, and to demonstrate the in vivo antitumor efficacy after a prolonged metformin exposition. A 1.2% w/w metformin thermoresponsive parenteral formulation based on poloxamers P407 and P124, injectable at room temperature and undergoing a sol-gel transition at body temperature, has been developed and optimized for rheological, thermal and release control properties; the formulation is easily scalable, and proved to be stable during a 1-month storage at 5 °C. Using NOD/SCID mice pseudo-orthotopically grafted with MDA-MB-231/luc+ human breast cancer cells, we report that multiple administrations of 100 mg of the optimized metformin formulation close to the tumor site cause tissue accumulation of the drug at levels significantly higher than those observed in plasma, and enough to exert antiproliferative and pro-apoptotic activities. Our results demonstrate that this formulation is endowed with good stability, tolerability, thermal and rheological properties, representing a novel tool to be pursued in further investigations for adjuvant cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Géis/química , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Animais , Apoptose , Neoplasias da Mama/patologia , Proliferação de Células , Preparações de Ação Retardada , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Infusões Parenterais , Metformina/administração & dosagem , Metformina/farmacocinética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
New Microbiol ; 41(1): 47-51, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29313863

RESUMO

This case series explored the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of meropenem (MEM) in adult cystic fibrosis (CF) patients hospitalized for a pulmonary exacerbation. From January 2015 to June 2016, all adult patients with cystic fibrosis (CF) and chronic pulmonary infection due to meropenem (MEM)-susceptible/intermediate Pseudomonas aeruginosa who received at least 48 h of MEM as an extended 3-hour infusion for treating a pulmonary exacerbation were enrolled. MEM plasma concentrations were determined by high-performance liquid chromatography. Six adult CF patients with a median age of 47 years were included in the study. MEM showed a high Vd (mean 45.98 L, standard deviation [SD] ±34.45). A minimal PK/PD target of 40% T > minimum inhibitory concentration (MIC) with respect to the MEM MIC of P. aeruginosa strains isolated from sputum during exacerbation was achieved in 5/6 patients (83%). MEM failed to achieve this target only in one patient, whose strain showed the highest MEM MIC in our cohort (8 mg/L). In all patients, MEM was well tolerated, and no adverse events were reported. In conclusion, high-dose, extended-infusion MEM during pulmonary exacerbation showed a high Vd in six adult CF patients with high median age, and was well tolerated.


Assuntos
Fibrose Cística/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Tienamicinas/farmacocinética , Tienamicinas/uso terapêutico , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Farmacorresistência Bacteriana , Feminino , Humanos , Masculino , Meropeném , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Infecções por Pseudomonas/sangue , Pseudomonas aeruginosa/efeitos dos fármacos , Tienamicinas/administração & dosagem , Tienamicinas/sangue
15.
Oncotarget ; 8(38): 63177-63186, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28968980

RESUMO

42 pediatric patients with iron overload, who underwent liver biopsy and DFX treatment after hematopoietic stem cell transplantation were included in the study group. The patients were divided into two groups diversified according to deferasirox trough plasma concentrations (DFX Ctrough) with cut-off equal to10 mcg/mL. The average dose of DFX was 25.9 mg/kg in the DFX Ctrough < 10 mcg/mL group versus 19.2 mg/kg in the DFX Ctrough > 10 mcg/mL group (p=0,0003). The mean duration of DFX treatment was 135.7 days in the DFX Ctrough < 10 mcg/mL group versus 41.8 days in the DFX Ctrough > 10 mcg/mL group (p<0.0001). The mean tissue iron concentration in the DFX Ctrough < 10 mcg/mL group was 261.9 µmol/g versus 133.4 µmol/g in the DFX Ctrough > 10 mcg/mL group (p < 0.0001). 21 patients (100%) in the DFX Ctrough > 10 mcg/mL group had ductopenia which was complete in 47.6% of them and severe in 52.4%. All patients with particularly high Ctrough (> 25 mcg/mL) were found to have total ductopenia. 90.5% of all deferasirox-related adverse events and 100% of major adverse events occurred in the DFX Ctrough > 10 mcg/mL group. In the DFX Ctrough < 10 mcg/mL group only one patient interrupted chelation therapy versus 16 (84.2%) patients in the DFX Ctrough > 10 mcg/mL group. We would recommend a close monitoring in pediatric hematopoietic transplant recipients subjected to deferasirox-based therapy because we have observed a high incidence of adverse events and discontinuation of chelation treatment.

16.
Virulence ; 8(1): 66-73, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27430122

RESUMO

The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae , Tienamicinas/farmacocinética , Tienamicinas/uso terapêutico , Idoso , Antibacterianos/sangue , Proteínas de Bactérias/biossíntese , Colistina/sangue , Colistina/uso terapêutico , Estado Terminal , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Gentamicinas/sangue , Gentamicinas/uso terapêutico , Humanos , Infecções por Klebsiella/sangue , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/patogenicidade , Masculino , Meropeném , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Minociclina/análogos & derivados , Minociclina/sangue , Minociclina/uso terapêutico , Tienamicinas/administração & dosagem , Tienamicinas/sangue , Tigeciclina , beta-Lactamases/biossíntese
17.
Int Ophthalmol ; 37(2): 417-421, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27324371

RESUMO

The purpose of this study was to evaluate the aqueous humor concentrations of bromfenac ophthalmic solution 0.09 % in patients undergoing phacoemulsification. Patients requiring cataract extraction received one drop (50 µL) of bromfenac 0.09 % solution in the eye to be operated, before bedtime the day before surgery or the morning of the surgery. The last administration was recorded. At the time of paracentesis, an aqueous humor sample was collected with a 30-gauge needle attached to a TB syringe and was later analyzed by high-performance liquid chromatography for drug concentration. 188 treated volunteers and 48 control, untreated, subjects were included in the study. The mean aqueous concentration of bromfenac in the treated group was 37.60 ± 68.86 and 0 nM (nmol/L) in the control group (p < 0.0001). Correlation coefficient in bromfenac group between time elapsed from instillation and drug concentration was -0.16 (p not significant). Bromfenac showed properties of good penetration and stable concentration in aqueous humor up to about 12 h after instillation.


Assuntos
Humor Aquoso/química , Benzofenonas/análise , Bromobenzenos/análise , Cromatografia Líquida de Alta Pressão/métodos , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/farmacocinética , Benzofenonas/administração & dosagem , Benzofenonas/farmacocinética , Bromobenzenos/administração & dosagem , Bromobenzenos/farmacocinética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/farmacocinética , Facoemulsificação , Cuidados Pré-Operatórios , Estudos Prospectivos , Fatores de Tempo
19.
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
20.
Infect Genet Evol ; 40: 109-112, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26932578

RESUMO

In March 2013, EDTA-blood and serum samples were collected from 119 cattle and 159 dromedaries at the slaughterhouse of Nouakchott, the capital city of the Islamic Republic of Mauritania. Serum samples were screened for the presence of Bluetongue (BT) antibodies by competitive ELISA (cELISA). Positive samples were then tested by serum-neutralization (SN) to determine BTV serotype. RNA from blood samples was first tested by a genus-specific quantitative RT-PCR assay which is able to detect all 27 existing BTV serotypes (RT-qPCR1-27). Positive samples were further screened by a RT-qPCR assay which, instead, is able to detect the classical 24 BTV serotypes only (RT-qPCR1-24). Of the 278 serum samples tested, 177 (mean=63.7%; 95% CI: 57.9%-69.1%) resulted positive by cELISA. Of these, 69 were from cattle (mean=58.0%; 95% CI: 49.0%-66.5%) and 108 from dromedaries (mean=67.9%; 95% CI: 60.3%-74.7%). BTV-26 neutralizing antibodies were by far the most frequently found as they were detected in 146 animals with titres ranging from 1:10 to 1:80. Out of 278 blood samples, 25 (mean=9.0%; 95% CI: 6.2%-12.9%) were found positive for BTV by RT-qPCR1-27, 20 (mean=16.8%; 95% CI: 11.2%-24.6%) were from cattle and 5 (mean=3.1%; 95% CI: 1.4%-7.1%) from dromedaries. When tested by RT-qPCR1-24 the 25 BTV positive samples were negative. Unfortunately, no genetic information by molecular typing or by next generation sequencing has been obtained as for the very low levels of RNA in the blood samples.


Assuntos
Vírus Bluetongue/classificação , Bluetongue/epidemiologia , Camelus/virologia , Doenças dos Bovinos/virologia , Animais , Bluetongue/virologia , Vírus Bluetongue/genética , Bovinos , Programas de Rastreamento/métodos , Mauritânia/epidemiologia , Vigilância da População , Sorogrupo , Sorotipagem , Ovinos/virologia
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