RESUMO
Estrogens and progestins are widely used in combination in human medicine and both are present in aquatic environment. Despite the joint exposure of aquatic wildlife to estrogens and progestins, very little information is available on their combined effects. In the present study we investigated the effect of ethinylestradiol (EE2) and Levonorgestrel (LNG), alone and in mixtures, on the expression of the brain specific ER-regulated cyp19a1b gene. For that purpose, recently established zebrafish-derived tools were used: (i) an in vitro transient reporter gene assay in a human glial cell line (U251-MG) co-transfected with zebrafish estrogen receptors (zfERs) and the luciferase gene under the control of the zebrafish cyp19a1b gene promoter and (ii) an in vivo bioassay using a transgenic zebrafish expressing GFP under the control of the zebrafish cyp19a1b gene promoter (cyp19a1b-GFP). Concentration-response relationships for single chemicals were modeled and used to design the mixture experiments following a ray design. The results from mixture experiments were analyzed to predict joint effects according to concentration addition and statistical approaches were used to characterize the potential interactions between the components of the mixtures (synergism/antagonism). We confirmed that some progestins could elicit estrogenic effects in fish brain. In mixtures, EE2 and LNG exerted additive estrogenic effects both in vitro and in vivo, suggesting that some environmental progestin could exert effects that will add to those of environmental (xeno-)estrogens. Moreover, our zebrafish specific assays are valuable tools that could be used in risk assessment for both single chemicals and their mixtures.
Assuntos
Aromatase/genética , Encéfalo/efeitos dos fármacos , Estrogênios/farmacologia , Etinilestradiol/farmacologia , Levanogestrel/farmacologia , Progestinas/farmacologia , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Bioensaio , Encéfalo/metabolismo , Linhagem Celular , Interações Medicamentosas , Embrião não Mamífero , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Luciferases/genética , Luciferases/metabolismo , Peixe-ZebraRESUMO
PURPOSE: The lack of drugs specifically assessed for paediatric use results in a widespread off-label drug use. The aim of this work is to identify experiences and attitudes towards paediatrics off-label prescribing in a university teaching paediatric hospital. METHODS: A questionnaire of 24 items was sent by email to 409 paediatricians in February 2013. DATA COLLECTED: frequency of off-label prescribing, sources of information, concern about safety and adverse events with off-label drug use, proportion of parents informed and order with "off-label" mention. RESULTS: Eighty questionnaires were returned. Over 81% of responders were familiar with the concept of off-label drugs prescribing. The most common reason given for off-label prescribing was for a younger age (74%) and for another indication (28%). They (79%) used a colleague's opinion and the most important sources of information used were the literature (72%), international guidelines (62%), the French National Formulary Vidal (56%) and national guidelines (46%). Although 54% of responders expressed concerns about safety about off-label prescription, only 29% had observed adverse event with off-label drug use. Two third of respondents informed the parents but off-label prescribing cannot be always explained to family. Many respondents (81%) did not write "off-label" mention on prescription. However, 52% stated that they would be willing to undertake off-label prescription monitoring with a local observatory. CONCLUSION: Our study describes the perceptions and attitudes of paediatrician's regarding off-label prescribing for children. Patient information and documentation in the patient file remain incomplete. The prospective collection of off-label prescription will locally be performed.
Assuntos
Atitude do Pessoal de Saúde , Uso Off-Label , Pediatras , Adulto , Criança , Prescrições de Medicamentos , França , Hospitais Pediátricos , Hospitais de Ensino , Humanos , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: We developed a training program for pharmacy students aiming at supporting patients receiving vitamin K antagonists (VKAs). The objective was to estimate how the program impacts VKA-treated patient knowledge acquisition and/or improvement on their anticoagulant treatment. METHOD: Using dedicated tools, pharmacy students received education on VKA treatment. Once appointed to clinical wards of Assistance publique-Hôpitaux de Paris, they were in charge of evaluating patient's knowledge on VKA treatment before and after training. Evaluation was conducted using a face-to-face standardized interview (14-item questionnaire). A global score was calculated for each patient. An univariate and multivariate analysis was performed to identify potential variables influencing score result. RESULTS: One hundred and seventy VKA-treated patients were recruited in seven hospitals for evaluation of their knowledge on VKA treatment and on clinical at risk situations. Before intervention, patients obtained an average score of 12.3±3.2 (maximum: 18). Factors significantly associated with the score were possession of a VKA information booklet, VKA treatment duration, treatment initiation and age. Fifty-two patients with a low score were further trained by the pharmacy student. After intervention, their initial score was improved significantly, from 9.9±3.3 to 13.5±2.3 (P<0.0001). DISCUSSION AND CONCLUSION: Increasing patient knowledge is a way to decrease the rate of adverse effects. This study demonstrates that patients with primary poor knowledge improved it significantly thanks to pharmacy students' intervention. This may contribute to lower the VKA-associated risk of adverse events and consequently to the improvement of patients quality of life and healthcare expenditures.
Assuntos
Anticoagulantes/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , Educação de Pacientes como Assunto/métodos , Estudantes de Farmácia , Vitamina K/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Feminino , Humanos , Internato não Médico , Masculino , Pessoa de Meia-Idade , Pacientes , Risco , Adulto JovemRESUMO
The effects of parasite infection by the cestode Ligula intestinalis on the reproductive function and endocrine system of wild roach Rutilus rutilus were evaluated. Gonad maturation, plasma vitellogenin, plasma steroid concentrations (i.e. progesterone, 11-keto-testosterone and 17-beta-estradiol) and brain aromatase activity were investigated in relation with parasitization. A low prevalence (8%) of ligulosed roach and a moderate impact of parasitization (mean parasitization index of 8.8%) were found in the studied population. Inhibition of gonad maturation generally resulted from infestation but 5% of the ligulosed roach nevertheless reached maturity. Main sex steroid plasma content was depleted in both genders. Male 11-keto-testosterone, female 17-beta-estradiol and progesterone plasma concentrations of both genders were, respectively, 27, 5 and 3 times lower in ligulosed fish when compared to their non-infected counterparts. Progesterone levels were negatively correlated with the parasitization index in females. Brain aromatase activity of infected roach was reduced to 50% of that of the non-infected fish. These results demonstrate significant negative effects on the reproductive function of wild roach infected by the tapeworm L. intestinalis collected from a site with low contamination.
Assuntos
Cestoides/fisiologia , Cyprinidae/parasitologia , Sistema Endócrino/parasitologia , Interações Hospedeiro-Parasita , Reprodução , Animais , Aromatase/metabolismo , Encéfalo/enzimologia , Cyprinidae/sangue , Cyprinidae/fisiologia , Feminino , Masculino , Densidade Demográfica , Esteroides/sangue , Vitelogeninas/sangueRESUMO
BACKGROUND: Injectable lorazepam (IL) is marketed in many countries but in France is only available within the framework of a compassionate use program for refractory status epilepticus. This study aims to evaluate the differences of pediatric use and status of IL in the hospitals of the Mother-Child French-speaking Network (Réseau mère-enfant de la francophonie, i.e., RMEF). METHODS: Inclusion criteria are: firstly, RMEF member; secondly, one site per town; thirdly, all the Assistance publique-Hôpitaux de Paris hospitals. After a phone-recruitment in each selected hospital, a survey was sent by e-mail. The data collected concerned the number of beds in the hospital, the official status of IL, its place in the therapeutic strategy, in hospital consumption in 2008 (in milligram) and the therapeutic alternatives. RESULTS: Among the 18 hospitals selected, 17 were contacted and 12 (70%) replied. IL is not marketed in Tunisia and Lebanon. In Switzerland, Canada and Belgium, IL is marketed and used in all the polled hospitals (6.2 to 48.0mg per bed). In France, only the Robert Debré Hospital uses it (3.2mg per bed). In the countries where it is marketed, IL was firstly prescribed for the studied indication. In the other countries, injectable diazepam was the first line treatment (six out of eight hospitals). DISCUSSION/CONCLUSION: France is the only country where IL is available though not marketed. The pharmacokinetic data favor use of IL instead of its principal therapeutic alternative (injectable diazepam) but no currently available evidence concludes that IL is superior to diazepam in the management of pediatric status epilepticus. The official indication of IL in France (last intention) is in contradiction with its use in the countries where it is marketed and with the data of the literature in favor of the first intention. This works presents the first evaluation on the use of IL in pediatric status epilepticus in the RMEF hospitals. It highlights the discrepancies in the management of status epilepticus in comparable pediatric hospitals.
Assuntos
Anticonvulsivantes/uso terapêutico , Lorazepam/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Bélgica , Canadá , Diazepam/uso terapêutico , Uso de Medicamentos , França , Guias como Assunto , Pesquisas sobre Atenção à Saúde , Hospitais , Humanos , Injeções Intravenosas , Lorazepam/administração & dosagem , Lorazepam/farmacocinética , Inquéritos e Questionários , SuíçaRESUMO
UNLABELLED: STATE OF THE PROBLEM AND OBJECTIVES: French pharmacists are quasi absent from hospital wards. Our objective was to describe the implantation of pharmaceutical care in a patient unit of a French paediatric hospital. MATERIAL AND METHODS: Following an internship in pharmaceutical care at the Sainte-Justine hospital (SJ) in Montreal, a French pharmacist returned to France to implement the pharmaceutical model in a paediatric unit at Robert Debré hospital (RD) in Paris. We first collected pharmaceutical interventions carried out during a 5-month period. In a second phase, we compared pharmaceutical interventions provided by the team composed of the same French pharmacist and a pharmacist from Québec in both settings during 14 days respectively. RESULTS: In the first phase, 556 interventions were done (8.2+/-2,0 per day) with a significant increase observed during the first 2 months. In the second phase, 216 interventions were done at RD and 174 at SJ. The interventions were mainly related to drug information, modification of treatment and seamless care with the pharmacy of the hospital or a community pharmacy. The interventions targeted junior (30.5 to 55.4%), senior physicians (16.2 to 38.5%) and pharmacy (11.5 to 16.2%) in the different phases and sites. A high level of physician acceptance was observed, with respectively 86.0 and 93.1% at RD and SJ. DISCUSSION: French pharmacists can apply the pharmaceutical care model following a specific training. Further studies are required to evaluate the feasibility and the impact of pharmaceutical care in France.
Assuntos
Implementação de Plano de Saúde/organização & administração , Hospitais Pediátricos/organização & administração , Serviço de Farmácia Hospitalar/organização & administração , Atitude do Pessoal de Saúde , Criança , Comportamento Cooperativo , Comparação Transcultural , França , Hospitais Universitários/organização & administração , Humanos , Relações Interprofissionais , Equipe de Assistência ao Paciente/organização & administração , Equipe de Assistência ao Paciente/estatística & dados numéricos , Serviço de Farmácia Hospitalar/estatística & dados numéricos , Quebeque , Revisão da Utilização de Recursos de Saúde/estatística & dados numéricosRESUMO
The prescription of unlicensed oral medicines in paediatrics leads the hospital pharmacists to compound hard capsules, such as busulfan, an alkylating agent prescribed in preparative regimens for bone marrow transplantation. In this study, we have investigated how the general principle of process analytical technology (PAT) can be implemented at the small size of our hospital pharmacy manufacturing unit. Near infrared spectroscopy (NIRS) was calibrated for raw material identification, blend uniformity analysis and final content uniformity of busulfan hard capsules of 11 different strengths. Measurements were performed on capsules from 2 to 40 mg (n=440). After optimisation, accuracy and linearity of the NIRS quantitative method was demonstrated after comparison with a previously validated quantitative high performance thin layer chromatography (HPTLC) method. Such a comparison led to attractive NIRS precision: +/-0.7 to +/-1.0 mg for capsules from 2 to 40 mg, respectively. As NIRS is a rapid and non-destructive technique, the individual control of a whole batch of busulfan paediatric capsules intended to be administrated is possible. Actually, mastering the process of busulfan paediatric capsules with the NIRS integrated into the notion of PAT is a powerful analytical tool to assess the process quality and to perform content uniformity of at least 5mg busulfan-containing capsules.
Assuntos
Alquilantes/análise , Bussulfano/análise , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Cápsulas , Criança , Cromatografia Líquida de Alta Pressão , Hospitais Universitários , Humanos , Serviço de Farmácia Hospitalar , Controle de QualidadeRESUMO
OBJECTIVE: To study reconstitution and preparation dosing errors of liquid oral medications given by caregivers to children. METHODS: A prospective observational study was carried out in the departments of general paediatrics and emergency paediatrics at the Robert-Debré Children's University Hospital. An interview with caregivers involved (1) practical reconstitution and preparation of an oral liquid medication from a prescription drawn at random (amoxicillin (Clamoxyl, dosing spoon) or josamycin (Josacine, dose-weight pipette)) and (2) a questionnaire about their use. RESULTS: One hundred caregivers were included. Clamoxyl and Josacine were incorrectly reconstituted in 46% (23/50) and 56% (28/50) of cases, respectively, with a risk of underdosing of Clamoxyl (16/23) and overdosing of Josacine (23/28). Dose preparation with the dosing spoon was incorrect in 56% of cases, and in 10% of cases with the dose-weight pipette. Female sex, native French speaker, and age were significantly associated with correct reconstitution. Male sex and medication were significantly associated with correct preparation. CONCLUSIONS: This study highlights the high incidence of errors made by caregivers in reconstituting and preparing doses of these liquid oral medicines, which are associated with considerable risks of over- and underdosing. Factors associated with these errors have been identified which could help health professionals to optimise their strategy for educating families about the use of liquid oral medications and the need to check that they understand these instructions.
Assuntos
Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Josamicina/administração & dosagem , Erros de Medicação/estatística & dados numéricos , Administração Oral , Adolescente , Adulto , Cuidadores , Criança , Pré-Escolar , Feminino , Hospitais Pediátricos , Humanos , Incidência , Masculino , Pediatria , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
A prospective study was performed in a paediatric hospital to evaluate the incidence of bacterial contamination in enteral nutrition bags and to determine the critical points of process. During two separate one-month periods, all children receiving pump-assisted enteral nutrition were enrolled in the study. Samples for microbiological analysis were collected from enteral nutrition bags after administration in the first and second study period (sample T(2)). In the second study period, two additional samples were made at the end of the feed preparation process. One was refrigerated immediately (sample T(0)) and the other was sealed in a tube that followed the enteral nutrition solution until the end of its administration (sample T(1)). Bacterial contamination was detectable above 10(2)cfu/mL. Twenty-six out of 40 patients were included in the first study period and 14 out of 44 in the second study period. Contamination (>10(2)cfu/mL) occurred in nine of 26 samples (35%) and seven of 14 samples (50%) in the first and second study periods, respectively. Of these, five (20%) and three (21%) contained significant contamination (>/=10(4)cfu/mL). Bacteria of low pathogenicity were found in T(0) samples. Bacteria present in T(2) samples were pathogenic and multiple in 50% of cases. These results suggest that manipulation of the enteral nutrition bags at the bedside is critical for bacterial safety.
Assuntos
Nutrição Enteral/instrumentação , Equipamentos e Provisões Hospitalares/microbiologia , Microbiologia de Alimentos , Alimentos Formulados/microbiologia , Hospitais Pediátricos , Adolescente , Bactérias/isolamento & purificação , Criança , Pré-Escolar , Contagem de Colônia Microbiana , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/etiologia , Infecção Hospitalar/prevenção & controle , Contaminação de Equipamentos/prevenção & controle , Feminino , França/epidemiologia , Humanos , Lactente , Recém-Nascido , Controle de Infecções , Masculino , Estudos ProspectivosRESUMO
The Robert Debré Hospital pharmacy unit ensures an annual manufacturing rate of 20,000 parenteral nutrition bags. Until 1999, these bags consisted in binary admixtures, fat emulsions being administered to the patient via a "Y" connexion on the catheter. Since then, all-in-one standard formulae have been established and are manufactured using a Baxa MM23 automated compounder. The aim of this study was to assess the physico-chemical stability of all-in-one admixtures, in order to ensure patient administration safety (mainly avoiding precipitation risks between the nutrients). Three bags of each standard formula were manufactured in monocompartmental bags. Stability assays consisted in the assessment of the admixture's (1) macroscopic aspect, (2) drop size measurement, (3) zeta potential measurement, (4) pH measurement, and (5) osmolality measurement. Tests were conducted between D0 (manufacturing day) and D10 (10 days after manufacture). All-in-one admixtures manufactured according to the established standard formulae were found to be stable for at least 10 days, provided they are kept away from light and at a temperature of +4 degrees C.
Assuntos
Nutrição Parenteral/normas , Aminoácidos/análise , Precipitação Química , Criança , Estabilidade de Medicamentos , Eletrólitos/análise , Emulsões Gordurosas Intravenosas/análise , Humanos , Concentração de Íons de Hidrogênio , Concentração Osmolar , Oligoelementos/análise , Vitaminas/análiseRESUMO
Cholestyramine ointment is an hospital preparation used as a second-intention treatment for severe perianal skin lesions. These preparations have to be declared to AFSSAPS. The aim of this study was to assess the equivalence of Orabase, a marketed paste, with intention of substitution. A clinical trial was performed to evaluate the effectiveness of cholestyramine ointment versus Orabase paste. This study was conducted in the neonatalogy unit. The principal evaluation criterion was the time to clinical recovery. Nurses also gave their subjective evaluation of each product. Although 34 children were included in the study, the time to clinical recovery delay was evaluated in 28. Time to clinical recovery was 90.5 hours for the cholestyramine ointment and 81 hours for Orabase paste. Concerning the subjective assessment, Orabase paste achieved a higher score than cholestyramine ointment (p<0.01). Orabase paste was considered to be equivalent to cholestyramine ointment.
Assuntos
Carboximetilcelulose Sódica/análogos & derivados , Dermatopatias/tratamento farmacológico , Nádegas , Carboximetilcelulose Sódica/uso terapêutico , Resina de Colestiramina/uso terapêutico , Feminino , Hospitalização , Humanos , Recém-Nascido , Masculino , Pomadas , Índice de Gravidade de DoençaRESUMO
Assessment of exposure and effect of fish to pharmaceuticals that contaminate aquatic environment is a current major issue in ecotoxicology and there is a need to develop specific biological marker to achieve this goal. Benzyloxy-4-trifluoromethylcoumarin-O-debenzyloxylase (BFCOD) enzymatic activity has been commonly used to monitor CYP3A activity in fish. In this study, we assessed the capacity of a panel of toxicologically relevant chemicals to modulate BFCOD activity in fish, by using in vitro and in vivo bioassays based on fish liver cell lines (PLHC-1, ZFL, RTL-W1) and zebrafish embryos, respectively. Basal BFCOD activity was detectable in all biological models and was differently modulated by chemicals. Ligands of human androgens, glucocorticoids, or pregnanes X receptors (i.e., dexamethasone, RU486, rifampicin, SR12813, T0901317, clotrimazole, ketoconazole, testosterone, and dihydrotestosterone) moderately increased or inhibited BFCOD activity, with some variations between the models. No common feature could be drawn by regards to their capacity to bind to these receptors, which contrasts with their known effect on mammalian CYP3A. In contrast, dioxins and polycyclic aromatic hydrocarbons (PAHs) strongly induced BFCOD activity (up to 30-fold) in a time- and concentration-dependent manner, both in vitro in all cell lines and in vivo in zebrafish embryos. These effects were AhR dependent as indicated by suppression of induced BFCOD by the AhR pathway inhibitors 8-methoxypsoralen and α-naphthoflavone. Altogether our result further question the relevance of using liver BFCOD activity as a biomarker of fish exposure to CYP3A-active compounds such as pharmaceuticals.
Assuntos
Citocromo P-450 CYP1A1/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/enzimologia , Poluentes Ambientais/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Peixe-Zebra/embriologia , Animais , Linhagem Celular , Poluentes Ambientais/metabolismo , Feminino , Humanos , Ligantes , Fígado/enzimologia , MasculinoRESUMO
Slices from rat cerebral cortex incubated in the presence of 2-deoxy[3H]glucose accumulate the sugar mainly in the form of its phosphorylated derivative. 2-Deoxy[3H]glucose uptake, measured under conditions of initial velocity, is stimulated by 50-100% in the presence of depolarising agents (KCl, veratridine) or the excitatory amino acids L- and D-glutamate, L-aspartate and L-cysteate in millimolar concentrations. In contrast a variety of putative neurotransmitters are ineffective on this test. The stimulations elicited by KCl or excitatory amino acids consist in significant increases in both the apparent Km and Vmax values of the 2-deoxyglucose transport system. The effect of excitatory amino acids is not significantly modified in the presence of tetrodotoxin or when the extracellular Ca2+ concentration is diminished, whereas it is significantly reduced in the presence of ouabain. Hence stimulation of 2-deoxy[3H]glucose uptake and phosphorylation may indirectly reflect the activation of Na+, K+-adenosine 5'-triphosphatases triggered by excitatory amino acids in target cells. The stimulation of 2-deoxy[3H]glucose uptake elicited by the three excitatory amino acids is antagonised in an apparently competitive manner by glutamate diethyl ester (apparent Ki value of congruent to 15 mM) whereas the KCl-induced stimulation is not modified. In contrast a variety of other amino acid agonists (including quisqualate, kainate, N-methyl D-aspartate) or antagonists (including gamma-D-glutamyl glycine acid and 2-amino-5-phosphonovalerate) are inactive, indicating that the metabolic response is not mediated by any of the receptor subclasses identified electrophysiologically.
Assuntos
Aminoácidos/farmacologia , Córtex Cerebral/metabolismo , Desoxiaçúcares/metabolismo , Desoxiglucose/metabolismo , Animais , Ácido Aspártico/farmacologia , Ácido Cisteico/farmacologia , Glutamatos/farmacologia , Ácido Glutâmico , Técnicas In Vitro , Cinética , Masculino , Potássio/farmacologia , Ratos , Veratridina/farmacologiaRESUMO
A study of the pharmacokinetic parameters of cefotaxime (CTX) and desacetylcefotaxime (dCTX) in newborns was conducted; the former is commonly used for neonatal infections. The elimination half life of CTX correlated with gestational age (GA) and postnatal age (PNA). Elimination of dCTX was longer permitting a synergistic or additive effect with CTX against Gram-negative bacteria. CTX is indicated in the treatment of neonatal sepsis because of the increasing resistance of Escherichia coli to ampicillin and its good efficacy against group B streptococcus.
Assuntos
Cefotaxima/análogos & derivados , Cefotaxima/farmacocinética , Recém-Nascido Prematuro/metabolismo , Cefotaxima/administração & dosagem , Cefotaxima/farmacologia , Esquema de Medicação , Escherichia coli/efeitos dos fármacos , Idade Gestacional , Humanos , Recém-Nascido , Streptococcus agalactiae/efeitos dos fármacosRESUMO
OBJECTIVE: During the last few years, in an attempt to reduce the side effects of glucocorticoid (GC) therapy, we have been treating polymyositis-dermatomyositis (PM-DM) patients with a lower starting dose of GC than is classically recommended. In order to validate this approach, we performed a functional re-evaluation of these PM-DM patients. METHODS: A comprehensive protocol evaluating muscle strength, muscle function, CK levels, persistence of spontaneous activity on electromyography, disability in daily life activities and degree of dependence was applied in 25 non-cancer-associated biopsy-proven PM-DM patients, 15 of whom had been treated with a high-dose regimen (i.e. > 0.5 mg prednisolone/kg/day) and 10 with a low-dose regimen (i.e. < or = 0.5 mg prednisolone/kg/day). RESULTS: Our results indicate that the functional outcome of PM-DM patients given a low-dose starting regimen of GC does not differ from that observed in patients given higher doses. Interestingly, vertebral fractures were less common in patients treated with lower GC doses. CONCLUSIONS: Although our analysis has certain shortcomings, including the small number of patients investigated and their uncontrolled assignment to a low-dose or a high-dose GC regimen, the results of this retrospective study suggest that a low-dose starting regimen of GC can achieve a good functional outcome in PM-DM patients, with a reduction of treatment-related disability. This approach would be welcome as a step forward should it be validated by a longitudinal study.
Assuntos
Glucocorticoides/administração & dosagem , Polimiosite/tratamento farmacológico , Polimiosite/reabilitação , Prednisolona/administração & dosagem , Atividades Cotidianas , Adulto , Creatina Quinase/sangue , Dermatomiosite/sangue , Dermatomiosite/tratamento farmacológico , Dermatomiosite/reabilitação , Avaliação da Deficiência , Relação Dose-Resposta a Droga , Eletromiografia , Glucocorticoides/efeitos adversos , Humanos , Pessoa de Meia-Idade , Polimiosite/sangue , Valor Preditivo dos Testes , Prednisolona/efeitos adversos , Estudos RetrospectivosRESUMO
This paper evaluates the influence of pharmacokinetics monitoring of HDMTX in the treatment of localized operable previously untreated high grade osteosarcoma. 44 patients (group 1) received a T10 protocol with dose adapted only to age. 27 other patients (group 2) had a pharmacokinetics monitored dose adaptation of MTX. The pharmacokinetics monitoring leads to higher dosage, higher area under the concentration/time curve and permits higher toxicity to be avoided. The higher dose intensity of MTX gave higher histologic response rate (66% compared to 45%) and higher 5 year disease free survival (92% compare to 76%). HDMTX treatment of osteosarcoma should be dose adapted to indivi-dual pharmacokinetics.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Metotrexato/administração & dosagem , Osteossarcoma/tratamento farmacológico , Adolescente , Adulto , Neoplasias Ósseas/sangue , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/cirurgia , Quimioterapia Adjuvante , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucovorina/uso terapêutico , Masculino , Metotrexato/efeitos adversos , Metotrexato/sangue , Metotrexato/farmacocinética , Metástase Neoplásica , Osteossarcoma/sangue , Osteossarcoma/mortalidade , Osteossarcoma/cirurgia , Projetos Piloto , Prognóstico , Indução de Remissão , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: We aimed to create a model for Ifosfamide (IFX) pharmacokinetics for drug monitoring in order to improve protocol dose intensity. MATERIAL AND METHODS: We studied ifosfamide pharmacokinetics in 12 patients aged 8-19 years. Sixteen courses were modelled (6 g/m2, on 5 days). The auto-induction of ifosfamide was taken into account in the model. Ifosfamide measurement was performed on serum samples by gas chromatography with thermo-ionic detection. Two pharmacokinetic models were compared. The following parameters were estimated: volume of distribution (Vd), clearance at the beginning of the induction (CLi), clearance extrapolated to infinity (CLf), clearance at the end of infusion (CL120), a rate constant (Kc) indicating the clearance variation with time and the lag time (Lag) indicating the time elapsed between the start of infusion and the start of induction. The Wilcoxon test was used to investigate possible differences between models. We tested the hypothesis that Boddy's model is an acceptable simplification of Levy's model. RESULTS: Four of six parameters were significantly different between the two models (p = 0.05). The best curve fitting was obtained using the Levy's model which provided the following estimates, Cli = 2.46 +/- 0.94 L.h-1.m-2, CLf = 5.22 +/- 1.02 L.h-1.m-2, Kc = 0.024 +/- 0.014 h-1, Vd = 18.84 +/- 5.04 L and Lag = 4.86 +/- 6.61 h. The most important difference is found for the distribution volume. CONCLUSION: Levy's model is more accurate and takes into account the integration of clearance.
Assuntos
Antineoplásicos Alquilantes/farmacocinética , Ifosfamida/farmacocinética , Modelos Biológicos , Adolescente , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Área Sob a Curva , Neoplasias Ósseas/tratamento farmacológico , Criança , Feminino , Humanos , Masculino , Matemática , Taxa de Depuração Metabólica , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológicoRESUMO
This article resumes the work we have accomplished in the past few years. Cholecystokinin sulfation is an important post-translational modification necessary for the biological activity of this peptide hormone. The tyrosyl protein sulfotransferase (TPST) activity from rat cerebral cortex was characterized. TPST activity is most probably responsible for the endogenous sulfation of CCK. TPST reaction kinetic properties were studied using radiolabeled 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and the non-sulfated peptide acceptor terbutyloxycarbonyl-cholecystokinin octapeptide (BocCCK-8(ns)) as substrates, and brain microsomes as the enzyme source. The BocCCK-8 sulfating reaction data is consistent with the idea that TPST forward reaction follows an ordered Bi Bi mechanism. PAPS biosynthesis and availability was studied in slices from rat cerebral cortex incubated in the presence of [35S]sulfate. There is a rapid and dynamic turnover of the steady-state level of PAPS in brain cells which is decreased by depolarizing agents such as potassium, veratridine and glutamate. Furthermore, the presence of a membrane-bound PAPS biosynthesis inhibitor was observed. These results are discussed in view of the biological importance that the cell sulfating pathways might play in nerve cell activity.
Assuntos
Córtex Cerebral/enzimologia , Fosfoadenosina Fosfossulfato/biossíntese , Sincalida/metabolismo , Sulfotransferases/metabolismo , Animais , Técnicas In Vitro , Fosfoadenosina Fosfossulfato/metabolismo , Processamento de Proteína Pós-Traducional , Ratos , Sulfatos/metabolismoRESUMO
Although guidelines for the parenteral use of vitamin preparations in pediatric patients have been published, there are very limited data on the efficiency of these preparations and on the exact needs of infants and children on total parenteral nutrition (TPN). We report here an open, prospective, study of the blood levels of water-soluble vitamins in infants and children on TPN before and during supplementation with a new water-soluble multivitamin formula containing per vial unit: B1, 3 mg; B2, 3.6 mg; B6, 4 mg; niacin, 40 mg; pantothenate, 15 mg; ascorbate, 100 mg; biotin, 60 micrograms; folic acid, 400 micrograms; B12, 5 micrograms. Thirteen children, 9 months to 15 yr old, on home TPN for 1.5 months to 7 yr, and 17 hospitalized infants and children, 1 week to 15 yr old, receiving TPN were studied for 2 weeks to 4 months. Daily doses were given according to age: 1/2 vial if less than 18 months; 1 vial if greater than 18 months and less than 10 years; 1.5 vials if greater than 10 years. Assays for B1, B2, biotin, niacin, plasma and red blood cell (RBC) folates were performed by microbiologic methods, B12 was measured by radioimmunoassay. During the study, B1 levels were consistently above the upper limit of the normal range, B2 and B12 remained in the normal range although there was a slight decrease in B12 values. Almost half of the patients had initially low levels of biotin, niacin, and folates. Biotin, after a significant sharp rise during the first month of supplementation returned to normal range. Niacin levels were initially low in infants and rose toward normal values during treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Nutrição Parenteral Total , Complexo Vitamínico B/sangue , Adolescente , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/sangue , Ácido Ascórbico/farmacologia , Biotina/administração & dosagem , Biotina/sangue , Peso Corporal , Criança , Pré-Escolar , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/sangue , Humanos , Lactente , Masculino , Niacina/administração & dosagem , Niacina/sangue , Estudos Prospectivos , Complexo Vitamínico B/administração & dosagemRESUMO
The analytical and microbiological stability of meglumine gadoterate (Dotarem) repackaged in polypropylene syringe for 3 months at either +4 degrees C or room temperature was studied. For analytical study: six polypropylene syringes (20 ml) were filled with 15 ml of meglumine gadoterate. Three syringes were stored at 4+/-2 degrees C and three at 25+/-2 degrees C, all syringes were kept upright and protected from daylight. Samples were taken on days 0, 6, 14, 30, 45, 60, 75 and 90. Meglumine gadoterate and its degradation product (free Gd3+) concentrations were obtained using a specific HPLC assay. Osmolality and pH determination were made on days 0, 14, 45 and 90. For microbiological study: 28 plastic syringes (5 ml) were filled with 2.5 ml of meglumine gadoterate. Syringes were stored at 25+/-2 degrees C and protected from daylight. At each day of analysis (0, 15, 35, 45, 60, 75 and 90), four syringes were tested as described in European Pharmacopoeia. After 90 days the concentration of gadoterate remained unchanged and no free Gd3+ were detected. The injectable solution of this gadolinium contrast agent was sterile according to European Pharmacopoeia guidelines. The meglumine gadoterate repackaged in polypropylene syringe was stable for 3 months at all the temperatures studied.