Optimum Methotrexate Exposure in Patients With Suspected or Confirmed CNS Invasive Hematological Malignancies: A Systematic Critical Review.

BACKGROUND AND METHODS: The present review aims to evaluate the current state-of-the-art dosing regimens of high-dose (HD) and intrathecal methotrexate (MTX) using therapeutic drug monitoring (TDM) to optimize its therapeutic response and minimize associated toxicity, particularly in the central nervous system (CNS). RESULTS: MTX is administered systemically in a HD regimen (>1 g/m 2 ) for the treatment of various hematological neoplasms. HD-MTX treatment becomes complicated by marked interindividual drug elimination variability. TDM is specified to manage this high variability. Approximately 3%-7% of adults with acute lymphoblastic leukemia are diagnosed with CNS involvement, and the incidence of CNS relapse in patients, despite receiving prophylaxis, ranges from 5% to 10%. HD-MTX penetrates the blood-brain barrier and can be administered intrathecally, making this drug an important component of chemotherapy regimens for patients with hematologic malignancies involving the CNS or those at high risk of CNS relapse. CONCLUSIONS: The major evidence found was that an MTX area under the curve target between 1000 and 1100 µmol hour -1 L is associated with better clinical outcomes. However, there seems to be a clinical gap in the prospective validation of HD and IT MTX management to optimize clinical outcomes and minimize toxicity, using the relationship between exposure level (area under the curve MTX) and optimal response to MTX, at systemic and CNS exposure.

Non-fatal Bihemispheric Penetrating Brain Injury from a Crossbow Arrow with Good Clinical Outcome: Case Report

Crossbow injuries to the head have seldom been reported in the literature, and they represent a unique type of penetrating brain injury (PBI) in which a low-velocity arrow results in an intracranial fragment larger than most high-velocity projectiles, usually with a lethal outcome.We present the case of a 34-year-oldman who attempted suicide with a self-inflicted cranial injury from a crossbow arrow, with a right parietal point of entry and a palpable subcutaneous tip in the left parietal region. The emergency team reported a Glasgow coma scale (GCS) score of 15, and the patient was brought sedated and intubated. Computed tomography (CT) imaging scans showed that the arrow crossed both parietal lobes, with mild subarachnoid hemorrhage and small cerebral contusions adjacent to its intracranial path. Careful retrograde removal of the penetrating arrow was performed in the CT suite, followed by an immediate CT scan, which excluded procedure-related complications. The patient woke up easily and was discharged 3 days later withmild left hand apraxia and no other neurologic deficits. To the best of our knowledge, there are no similar case reports describing both good clinical outcome and rapid discharge after a bihemispheric PBI. Individualizing the management of each patient is therefore crucial to achieve the best possible outcome as PBI cases still represent a major challenge to practicing neurosurgeons worldwide.

Capacitação da pessoa para o autocuidado marcha / Person training for gait self-care

O presente relatório descreve o processo de aquisição de competências nas atividades desenvolvidas no estágio final na área da neurologia, evidencia também os resultados obtidos no projeto de intervenção de enfermagem de reabilitação. Neste trabalho procura-se contribuir para a demonstração da eficácia dos cuidados de enfermagem de reabilitação na reabilitação da função motora. Atendendo a esta prioridade surge a importância de uma abordagem sistemática, e detalhada no doente/pessoa com a marcha comprometida. Partindo da identificação de tal compromisso, aplicou-se um programa de reabilitação cujo objetivo foi a capacitação de sete doentes/pessoas vítimas de Acidente Vascular Cerebral (AVC), visando a autonomia para o autocuidado marcha, avaliando os compromissos que a inviabilizam como a força muscular, e o equilíbrio, avaliação da sua evolução com recurso ao uso de escalas, escala de Lawer para avaliação da força muscular, Escala de Berg para o equilíbrio corporal, escala de Holden para avaliação da marcha, e índice de Bartel para os autocuidados, e a descrição dos resultados evidenciados. As pessoas/doentes que integraram o programa revelaram progressos significativos na força muscular, no equilíbrio e no autocuidado marcha, aumentando a sua autonomia para os autocuidados. Os resultados obtidos também demostram a concretização das competências de especialista em reabilitação e de mestre, competências do domínio da melhoria contínua da qualidade, gestão dos cuidados, responsabilidade profissional, ética e legal, e competências do domínio das aprendizagens profissionais.

This report describes the process of acquisition of competencies in the activities developed in the final stage in the area of neurology, also shows the results obtained in the project of intervention of rehabilitation nursing. This paper aims to contribute to the demonstration of the efficacy of rehabilitation nursing care in the rehabilitation of motor function. Given this priority comes the importance of a systematic, detailed approach in the patient/ person with the gait involved. Based on the identification of such commitment, a rehabilitation program was implemented, whose objective was the training of seven patients / persons victims of Stroke, aiming at the autonomy for self-care walking, evaluating the commitments that make it unfeasible as the force muscle balance and balance, evaluation of its evolution using scales, Lawer scale for muscle strength assessment, Berg scale for body balance, Holden scale for gait evaluation, and Bartel index for self-care, and the description of the results evidenced. The people / patients who joined the program showed significant progress in muscle strength, balance and self-care gait, increasing their autonomy for self-care. The results also demonstrate the skills of specialist in rehabilitation and master, skills in the field of continuous quality improvement, care management, professional responsibility, ethics and legal, and skills in the field of professional learning.

Vancomycin therapeutic drug monitoring and population pharmacokinetic models in special patient subpopulations.

Vancomycin is a fundamental antibiotic in the management of severe Gram-positive infections. Inappropriate vancomycin dosing is associated with therapeutic failure, bacterial resistance and toxicity. Therapeutic drug monitoring (TDM) is acknowledged as an important part of the vancomycin therapy management, at least in specific patient subpopulations, but implementation in clinical practice has been difficult because there are no consensus and agglutinator documents. The aims of the present work are to present an overview of the current knowledge on vancomycin TDM and population pharmacokinetic (PPK) models relevant to specific patient subpopulations. Based on three published international guidelines (American, Japanese and Chinese) on vancomycin TDM and a bibliographic review on available PPK models for vancomycin in distinct subpopulations, an analysis of evidence was carried out and the current knowledge on this topic was summarized. The results of this work can be useful to redirect research efforts to address the detected knowledge gaps. Currently, TDM of vancomycin presents a moderate level of evidence and practical recommendations with great robustness in neonates, pediatric and patients with renal impairment. However, it is important to investigate in other subpopulations known to present altered vancomycin pharmacokinetics (eg neurosurgical, oncological and cystic fibrosis patients), where evidence is still unsufficient.

Expression of CYP1A1 and CYP1A2 in the liver and kidney of rabbits after prolonged infusion of propofol.

BACKGROUND: Propofol biotransformation occurs in the liver via hydroxylation by CYP450 enzymatic complex and by glucuronidation, however extra-hepatic metabolism has also been described. OBJECTIVES: To better understand the metabolic pathways involved in propofol biotransformation, the expression of CYP1A1, CYP1A2, the enzymatic and non-enzymatic antioxidant activity and the amount of propofol and its non-conjugated metabolites were investigated. METHODS: Twenty-one NewZealand rabbits were allocated into three groups continuously treated for 20h. Each group received: NaCl 0.9%, vehicle (SMOFlipid) and propofol 2% (Lipuro). At the end, liver and kidney samples were collected for histopathology and immunohistochemistry and plasma for quantification of propofol and its metabolites. RESULTS: CYP1A1 and CYP1A2 were observed in zone 1 and zone 3 regions of the liver acinus. The propofol and saline groups showed a higher expression of CYP1A1 when compared to vehicle group. Propofol significantly increased CYP1A2 expression, compared to saline. CYP1A1 and CYP1A2 immunoexpression were observed in the kidney but no differences were registered between groups. CONCLUSIONS: This suggests that propofol may act as selective inhibitor of CYP1A1 and an inducer of CYP1A2 expression in different regions of the liver. Propofol seems to have an antioxidative protective effect on liver parenchyma, comparatively to the emulsion alone. In the rabbit, extra-hepatic propofol biotransformation may also occur in the kidney.

Evidence of Different Propofol Pharmacokinetics under Short and Prolonged Infusion Times in Rabbits.

Propofol is an anaesthetic widely used in both human beings and animals. However, the characterization of propofol pharmacokinetics (PK) is not well understood when long-term infusions are used. The main objective of this study was to explore the PK behaviour of propofol in a rabbit model during short and prolonged propofol infusions and to develop an internally validated PK model, for propofol dose individualization in the rabbit for future use. Population 1 (P1) was constituted by seven New Zealand rabbits and was used to characterize the PK profile of propofol at short infusions. Animals were anaesthetized with a bolus of 20 mg/kg, followed by an infusion rate of 50 mg/kg/hr of propofol at 1%, which was then maintained for 30 min. A second rabbit population (P2, n = 7) was sedated according to reflexes responses and Index of Consciousness values, for 20 consecutive hours using propofol 2% aiming at characterizing propofol behaviour at long-term infusions. Clinical data and blood samples were collected at specific time-points in both populations. Propofol plasma concentrations were determined by gas chromatography/ion trap mass spectrometry. The NONMEM VII software was used to evaluate the relationships between dose and plasma concentrations. A linear two-compartment model with different central compartment volume and plasma clearance (separately modelled in the two populations) was the one that best described propofol concentrations. The time course of propofol plasma concentrations was well characterized by the PK model developed, which simultaneously accounts for propofol short- and long-term infusions and can be used to optimize future PK studies in rabbits.

Drug-related problems in institutionalized, polymedicated elderly patients: opportunities for pharmacist intervention.

BACKGROUND: An aging population and the increasing prevalence of chronic diseases have led to the increased use of medicines. Portugal is one of the European countries where more medicines are consumed and the associated expense is higher. Medicines are associated with enormous health benefits but also with the potential to cause illness and death. A drug related problem (DRP) is an "an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes". In the U.S., they represent the 4th-6th leading cause of death and have an estimated cost of 130 billion dollars. Moreover, many of these DRP can be avoided. Elderly are at increased risk of DRP due to multiple factors: pluripathology and consequent polypharmacy, complex dosing regimens, pharmacokinetic/pharmacodynamic and functional/cognitive changes. Therefore, this population would be the one who would benefit most from the prevention, detection and control of DRP. The role of the pharmacist as an integral element of health care has been recognized by various international and European organizations. Providing pharmaceutical care as a patient-centered activity, focusing on their needs related to pharmacotherapy, contributes to guarantee that drug expenditure is a good investment, with benefits that outweigh potential risks. OBJECTIVE: To evaluate the need for pharmaceutical care implementation in institutionalized, polymedicated elderly. METHODS: Descriptive observational cross-sectional study carried out in six Portuguese nursing homes, selected by convenience, in November-December 2013. Each institution selected up to six patients, according to the following inclusion criteria: age ≥65 years, number of medications ≥5 and ability to respond to an interview. All participants signed an informed consent form. Pharmacists carried out a structured interview with each patient and consulted patient medical records to gather demographic data and information on health problems and medications used. To identify DRP, official drug information sources were consulted, and the STOPP and START tool was used. The ATC, the ICD-10 and the PCNE Classification V 6.2 classification systems were used for medicines, health problems and DRP classifications, respectively. For each medicine used, the cheapest equivalent available was also identified. RESULTS: The sample included 31 elderly (64.52 % female, mean age 81.65 ± 6.86). On average, subjects presented a mean of 7.94 ± 2.76 health problems with diseases of the circulatory system being the most common. The sample used a median of ten medicines per patient. Those medicines working in the cardiovascular, nervous and digestive systems were the most frequently used (29.75, 29.43 and 19.30 %, respectively). A total of 484 DRP (median: 15 DRP/patient) was found. The most common DRP were Adverse Drug Event, non-allergic (49.51 %), Drug treatment more costly than necessary (19.11 %), Effect of drug treatment not optimal (14.82 %) and Unnecessary drug treatment (6.16 %). The most cost-effective proposal, would lead to a saving of 3,950/year in the studied sample. CONCLUSION: These results reinforce the need for the implementation of pharmaceutical care services to institutionalized elderly, necessary to improve medicines efficacy and safety, better clinical outcomes and cost reduction.

Future perspectives of Smartphone applications for rheumatic diseases self-management.

Rheumatic diseases (RD) self-management interventions are designed to improve health-related quality of life, health care utilization, and perceived self-efficacy. Despite these demonstrated good results, there are several issues that hinder or render less appealing these interventions. One economically and socially viable solution is exploiting the potential of Smartphone technology. This potential comes from Smartphones pervasive presence in actual society, combined with the advantages of being personal, intuitive, and computationally powerful, with capability to support applications and assist its user throughout different activities of daily living and environments persistently. With their global acceptance increasing quickly, there is a great opportunity for mobile health in using Smartphone applications for RD self-management. Besides the potential of such applications, research on the development and evaluation of such applications is in the early stages. Therefore, it is important to foresee its future applicability in order to meet the needs of the twenty-first century.

Genetic polymorphisms in low-dose methotrexate transporters: current relevance as methotrexate therapeutic outcome biomarkers.

Methotrexate (MTX) is used in low doses to treat a variety of diseases. Although the mechanism responsible for its therapeutic action is unknown, MTX membrane transport proteins (influx and/or efflux) can be major determinants of pharmacokinetics, adverse drug reactions and clinical response profiles. With progess in pharmacogenomics, the improvement of the prediction of patients' therapeutic outcome treated with low doses of MTX will offer a powerful tool for the translation of transporter SNPs into clinical practice and will be essential to sustain a breakthrough in the field of personalized medicine. Therefore, this paper provides an update on the current data on SNPs in genes encoding low-dose MTX membrane transport proteins and their relevance as possible biomarkers of MTX therapeutic outcome.

The dilemma of the gender assignment in a Portuguese adolescent with disorder of sex development due to 17ß-hydroxysteroid-dehydrogenase type 3 enzyme deficiency.

UNLABELLED: The development of male internal and external genitalia in an XY fetus requires a complex interplay of many critical genes, enzymes, and cofactors. The enzyme 17ß-hydroxysteroid-dehydrogenase type 3 (17ßHSD3) is present almost exclusively in the testicles and converts Delta 4-androstenodione (Δ4) to testosterone. A deficiency in this enzyme is rare and is a frequently misdiagnosed autosomal recessive cause of 46,XY, disorder of sex development. The case report is of a 15-year-old adolescent, who was raised according to female gender. At puberty, the adolescent had a severe virilization and primary amenorrhea. The physical examination showed a male phenotype with micropenis and blind vagina. The Tanner stage was A3B1P4, nonpalpable gonads. The karyotype revealed 46,XY. The endocrinology study revealed: testosterone=2.38 ng/ml, Δ4>10.00 ng/ml, and low testosterone/Δ4 ratio=0.23. Magnetic resonance imaging of the abdominal-pelvic showed the presence of testicles in inguinal canal, seminal vesicle, prostate, micropenis, and absence of uterus and vagina. The genetic study confirmed the mutation p.Glu215Asp on HSD17B3 gene in homozygosity. The dilemma of sex reassignment was seriously considered when the diagnosis was made. During all procedures the patient was accompanied by a child psychiatrist/psychologist. The teenager desired to continue being a female, so gonadectomy was performed. Estrogen therapy and surgical procedure to change external genitalia was carried out. In this case, there was a severe virilization at puberty. It is speculated to be due to a partial activity of 17ßHSD3 in the testicles and/or extratesticular ability to convert Δ4 to testosterone by 17ßHSD5. Prenatal exposure of the brain to androgens has increasingly been put forward as a critical factor in gender identity development, but in this case the social factor was more important for the gender assignment. LEARNING POINTS: In this case, we highlight the late diagnosis, probably because the patient belongs to a poor family without proper primary medical care.We emphasize the psychological and social aspects in the sex assignment decision.

Aggressive pituitary lesion with a remarkably high Ki-67.

The uncommon aggressive pituitary tumors are named carcinomas when metastases are detected, either in the central nervous system and/or systemically. Some cases are associated with hormonal overproduction, but most are diagnosed because of local symptoms. These neoplasias are generally refractory to current treatments. A 51 year-old woman presented sudden onset of headache, left arm paresis and left facial hypoesthesia. Computed tomography scan and magnetic resonance imaging revealed a pituitary tumor invading the left sphenoidal and cavernous sinuses. Laboratory data excluded hormonal hypersecretion. The patient underwent transsphenoidal surgery and histological findings showed a neoplasia with Ki-67 estimated at 75%. Medical imaging excluded both a primary occult tumor and central nervous system or systemic dissemination. Three weeks postoperatively, neurological condition worsened, with new onset of ataxia, bilateral ptosis, ophthalmoplegia and an increase in the size of the lesion, leading to surgical intervention by craniotomy, followed by only a few sessions of radiotherapy, because of severe disease progression. Patient died nearly 2 months after the initial manifestations. This case illustrates the aggressiveness of some pituitary lesions, the limited efficacy of current treatment modalities such as surgery or radiotherapy and the pitfalls of the current pituitary tumors classification. To our knowledge, this case corresponds to one of the most aggressive pituitary neoplasms reported so far, with a very high Ki-67 index (75%) and short survival (2 months). Ki-67 index could be of prognostic value in pituitary tumors. Pituitary tumors World Health Organization (WHO) classification could be revisited.

SLC19A1, SLC46A1 and SLCO1B1 polymorphisms as predictors of methotrexate-related toxicity in Portuguese rheumatoid arthritis patients.

Methotrexate (MTX) is used for rheumatoid arthritis (RA) treatment showing a wide toxicity profile. This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding for MTX transporters with the occurrence of MTX-related toxicity (overall and gastrointestinal). A total of 233 Portuguese RA patients were genotyped for 23 SNPs. Haplotype analyses were performed and a toxicogenetic risk index (TRI) was created for SNPs that revealed to be statistically significant. Regarding MTX overall toxicity, an increased risk was associated to SLC19A1 rs7499 G carriers (p = 0.017), SLC46A1 rs2239907 GG (p = 0.030) and, SLCO1B1 rs4149056 T carriers (p = 0.040) and TT (p = 0.019). TRI revealed that patients with Index 3 were 18-fold more likely to present an adverse drug reaction when compared to those with Index 1 (p = 0.001). For MTX gastrointestinal toxicity, results demonstrated an increased risk associated with SLC19A1 rs7499 G carriers (p = 0.012) and GG (p = 0.045), SLC19A1 rs1051266 G carriers (p = 0.034), SLC19A1 rs2838956 A carriers (p = 0.049) and, SLCO1B1 rs4149056 T carriers (p = 0.042) and TT (p = 0.025). Haplotype analyses showed association between GGAG haplotype for SLC19A1 rs7499, rs1051266, rs2838956 and rs3788200 with MTX gastrointestinal toxicity (p = 0.029). TRI revealed that patients with Index 4 were 9-fold more likely to present a gastrointestinal disorder when compared to those with Index 1 (p = 0.020). This study demonstrated that SLC19A1, SLC46A1 and SLCO1B1 genotypes may help to identify patients with increased risk of MTX-related overall toxicity and that SLC19A1 and SLCO1B1 genotypes, and SLC19A1 haplotypes may help to identify patients with increased risk of MTX-related gastrointestinal toxicity.

Aggressive pituitary lesion with a remarkably high Ki-67 / Lesão pituitária agressiva com Ki-67 notavelmente elevado

The uncommon aggressive pituitary tumors are named carcinomas when metastases are detected, either in the central nervous system and/or systemically. Some cases are associated with hormonal overproduction, but most are diagnosed because of local symptoms. These neoplasias are generally refractory to current treatments. A 51 year-old woman presented sudden onset of headache, left arm paresis and left facial hypoesthesia. Computed tomography scan and magnetic resonance imaging revealed a pituitary tumor invading the left sphenoidal and cavernous sinuses. Laboratory data excluded hormonal hypersecretion. The patient underwent transsphenoidal surgery and histological findings showed a neoplasia with Ki-67 estimated at 75%. Medical imaging excluded both a primary occult tumor and central nervous system or systemic dissemination. Three weeks postoperatively, neurological condition worsened, with new onset of ataxia, bilateral ptosis, ophthalmoplegia and an increase in the size of the lesion, leading to surgical intervention by craniotomy, followed by only a few sessions of radiotherapy, because of severe disease progression. Patient died nearly 2 months after the initial manifestations. This case illustrates the aggressiveness of some pituitary lesions, the limited efficacy of current treatment modalities such as surgery or radiotherapy and the pitfalls of the current pituitary tumors classification. To our knowledge, this case corresponds to one of the most aggressive pituitary neoplasms reported so far, with a very high Ki-67 index (75%) and short survival (2 months). Ki-67 index could be of prognostic value in pituitary tumors. Pituitary tumors World Health Organization (WHO) classification could be revisited.

Os raros tumores pituitários agressivos são chamados carcinomas quando são detectadas metástases, sejam sistêmicas e/ou em sistema nervoso central. Alguns casos estão associados com superprodução de hormônio, mas a maioria é diagnosticada em função dos sintomas locais. Essas neoplasias são geralmente refratárias aos tratamentos atuais. Uma mulher com 51 anos de idade apresentou dor de cabeça de início súbito, paralisia de braço esquerdo e hipoestesia facial esquerda. A tomografia e a ressonância magnética revelaram um tumor pituitário invadindo os seios esfenoidal e cavernoso esquerdos. Os dados laboratoriais excluíram hipersecreção hormonal. A paciente foi submetida à cirurgia transesfenoidal, e os achados histológicos mostraram uma neoplasia com Ki-67 estimado em 75%. As imagens excluíram tanto um tumor oculto primário quanto disseminação sistêmica ou do sistema nervoso central. Três semanas após a cirurgia, a condição neurológica apresentou piora com início de ataxia, ptose bilateral, oftalmoplegia e aumento do tamanho da lesão, levando à intervenção cirúrgica por craniotomia, seguida por apenas algumas sessões de radioterapia devido à progressão grave da doença. A paciente veio a óbito depois de quase dois meses das manifestações iniciais. O caso ilustra a agressividade de algumas lesões pituitárias, a eficácia limitada das modalidades atuais de tratamento, como a cirurgia ou a radioterapia, e as limitações da classificação atual de tumores pituitários. Até onde sabemos, esse caso corresponde a uma das neoplasias pituitárias mais agressivas descritas até hoje, com um nível muito alto de Ki-67 (75%) e sobrevida curta (2 meses). O nível de Ki-67 pode ser de valor prognóstico em tumores pituitários. A classificação da Organização Mundial da Saúde (OMS) para tumores pituitários deveria ser revisitada.

Prediction of methotrexate clinical response in Portuguese rheumatoid arthritis patients: implication of MTHFR rs1801133 and ATIC rs4673993 polymorphisms.

OBJECTIVE: Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. METHODS: Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. RESULTS: Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. CONCLUSION: Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment.

Online drug databases: a new method to assess and compare inclusion of clinically relevant information.

BACKGROUND: Evidence-Based Practice requires health care decisions to be based on the best available evidence. The model "Information Mastery" proposes that clinicians should use sources of information that have previously evaluated relevance and validity, provided at the point of care. Drug databases (DB) allow easy and fast access to information and have the benefit of more frequent content updates. Relevant information, in the context of drug therapy, is that which supports safe and effective use of medicines. Accordingly, the European Guideline on the Summary of Product Characteristics (EG-SmPC) was used as a standard to evaluate the inclusion of relevant information contents in DB. OBJECTIVE: To develop and test a method to evaluate relevancy of DB contents, by assessing the inclusion of information items deemed relevant for effective and safe drug use. METHOD: Hierarchical organisation and selection of the principles defined in the EGSmPC; definition of criteria to assess inclusion of selected information items; creation of a categorisation and quantification system that allows score calculation; calculation of relative differences (RD) of scores for comparison with an "ideal" database, defined as the one that achieves the best quantification possible for each of the information items; pilot test on a sample of 9 drug databases, using 10 drugs frequently associated in literature with morbidity-mortality and also being widely consumed in Portugal. Main outcome measure Calculate individual and global scores for clinically relevant information items of drug monographs in databases, using the categorisation and quantification system created. RESULTS: A--Method development: selection of sections, subsections, relevant information items and corresponding requisites; system to categorise and quantify their inclusion; score and RD calculation procedure. B--Pilot test: calculated scores for the 9 databases; globally, all databases evaluated significantly differed from the "ideal" database; some DB performed better but performance was inconsistent at subsections level, within the same DB. CONCLUSION: The method developed allows quantification of the inclusion of relevant information items in DB and comparison with an "ideal database". It is necessary to consult diverse DB in order to find all the relevant information needed to support clinical drug use.

Serial transverse enteroplasty (STEP): intermediate outcomes in children with short bowel syndrome.

Short bowel syndrome is the most common cause of intestinal failure in children. The treatment is based on a multidisciplinary approach involving pediatricians, pediatric surgeons, and nutritionists. Surgical procedures for intestinal lengthening may be decisive, having been revalued after the recent description of serial transverse enteroplasty (STEP). We reviewed the patients who underwent the STEP operation for short bowel syndrome in our hospital in order to evaluate medium-term outcome. Between April 2006 and December 2008, three children were submitted to STEP without postoperative complications directly related to the procedure. In two cases the autonomy for oral/enteric feeding was obtained within 3 and 7 months after surgery with sustained growth, persisting at 5 years of follow-up after STEP. One child remained dependent of parenteral nutrition and was submitted to intestinal transplantation 30 months after STEP. However, since STEP until transplantation, it was possible to increase enteric volume and decrease intestinal dilation and the frequency of occlusive episodes. STEP is an effective and safe technique for intestinal lengthening that may allow increased tolerance to oral/enteric feeding or at least alleviate some complications of short bowel syndrome.

Effect of age on systemic exposure and haematological toxicity of carboplatin in advanced non-small cell lung cancer patients.

The aim of this study was to evaluate systemic exposure to carboplatin and its haematological toxicity in patients with advanced non-small cell lung cancer both older and younger than 70 years when the target area under the curve (AUC) in elderly patients was reduced by 20%. For this purpose, a population pharmacokinetic model was developed and the haematological toxicity of the drug was assessed. A total of 33 patients received carboplatin on day 1 and gemcitabine (1250 mg/m(2) ) on days 1 and 8. This schedule was repeated every 21 days. The Calvert-Crokcoft-Gault formula was employed to calculate a dose of carboplatin with a target AUC of 5 mg/min./mL in patients under 70 years and 4 mg/min./mL in patients aged 70 or older. The data of 24 patients were treated for population modelling performed with the nonmem (University of California, San Francisco, CA, USA) approach. Haematological toxicity was evaluated for all 33 patients enrolled in the study. The carboplatin systemic exposure measured by the AUC (mg/min./mL) was 5.98 (5.45; 6.51) and 5.36 (5.02; 5.69) for the younger patients and older groups, respectively. No significant differences were observed between the two groups with respect to rates of grade 3+ anaemia, neutropenia or thrombocytopenia. In clinical practice, a target AUC of 4 mg/min./mL carboplatin is applied to patients aged 70 and over, but the actual systemic exposure to the drug is higher. This supports a target AUC of 4 mg/min./mL carboplatin for patients older than 70 years when the dose is calculated by means of the Calvert-Crokcoft-Gault formula.

Performance of anesthetic depth indexes in rabbits under propofol anesthesia: prediction probabilities and concentration-effect relations.

BACKGROUND: The permutation entropy, the approximate entropy, and the index of consciousness are some of the most recently studied electroencephalogram-derived indexes. In this work, a thorough comparison of these indexes was performed using propofol anesthesia in a rabbit model. METHODS: Six rabbits were anesthetized with three propofol infusion rates: 70, 100, and 130 mg · kg⁻¹ · h⁻¹, each maintained for 30 min, in a random order for each animal. Data recording was performed in the awake animals 20, 25, and 30 min after each infusion rate was begun in the recovered animals and consisted of electroencephalogram recordings, evaluation of depth of anesthesia according to a clinical scale, and arterial blood samples for plasma propofol determination. Median and spectral edge frequencies were analyzed for single-scale permutation entropy and composite multiscale permutation entropy, approximate entropy, index of consciousness, and the spectral parameters. The spectral parameters and single-scale and multiscale permutation entropies were corrected for the presence of burst suppression. Performance of the indexes was compared by prediction probability and pharmacodynamic analysis. RESULTS: The single-scale and composite multiscale permutation entropies with a burst suppression correction showed better prediction probabilities than did the other electroencephalogram-derived parameters but not better than the electromyographic activity. CONCLUSION: Single-scale and multiscale permutation entropies may be promising measures of propofol anesthetic depth when corrected for burst suppression. Additional studies should investigate the information measured by electromyography algorithms from commercial monitors of anesthetic depth. The rabbit may be a promising animal model for electroencephalographic studies because it provides a good-quality signal.

[Roland Morris disability questionnaire - adaptation and validation for the Portuguese speaking patients with back pain]. / Questionário de incapacidade de Roland Morris - adaptação e validação para os doentes de língua Portuguesa com lombalgia.

The objective of the current study was to adapt and validate the Roland Morris disability questionnaire (RMDQ) to the Portuguese patients because there are no European Portuguese psychometric instruments to evaluate patients suffering from low back pain. After translation and back translation the Portuguese version of the RMDQ was tested in 112 patients with low back pain (30 males and 82 females) to analyse psychometric characteristics. Analysis of measures obtained points to high levels of internal consistency (Cronbach's alpha: 0.81) and temporal stability (test-retest: r = 0.86). External validity was assessed by association with numerical pain rating scale (END), Schöber test (TS) and fingertip floor measurement (GFA). The results revealed a large correlation between the RMDQ and END (r = 0.73) and a medium correlation with TS and GFA (in this order, r = -0,52 and r = 0,42). The psychometric analysis showed that the RMDQ gives reliable measures for the disability of patients with back pain and was successfully adapted and validated to the European Portuguese patients.