Modelos de resposta à interação entre fármacos anestésicos : análise de regressão e análise de Clusters

Os avanços tecnológicos e científicos, na área da saúde, têm vindo a aliar áreas como a Medicina e a Matemática, cabendo à ciência adequar de forma mais eficaz os meios de investigação, diagnóstico, monitorização e terapêutica. Os métodos desenvolvidos e os estudos apresentados nesta dissertação resultam da necessidade de encontrar respostas e soluções para os diferentes desafios identificados na área da anestesia. A índole destes problemas conduz, necessariamente, à aplicação, adaptação e conjugação de diferentes métodos e modelos das diversas áreas da matemática. A capacidade para induzir a anestesia em pacientes, de forma segura e confiável, conduz a uma enorme variedade de situações que devem ser levadas em conta, exigindo, por isso, intensivos estudos. Assim, métodos e modelos de previsão, que permitam uma melhor personalização da dosagem a administrar ao paciente e por monitorizar, o efeito induzido pela administração de cada fármaco, com sinais mais fiáveis, são fundamentais para a investigação e progresso neste campo. Neste contexto, com o objetivo de clarificar a utilização em estudos na área da anestesia de um ajustado tratamento estatístico, proponho-me abordar diferentes análises estatísticas para desenvolver um modelo de previsão sobre a resposta cerebral a dois fármacos durante sedação. Dados obtidos de voluntários serão utilizados para estudar a interação farmacodinâmica entre dois fármacos anestésicos. Numa primeira fase são explorados modelos de regressão lineares que permitam modelar o efeito dos fármacos no sinal cerebral BIS (índice bispectral do EEG – indicador da profundidade de anestesia); ou seja estimar o efeito que as concentrações de fármacos têm na depressão do eletroencefalograma (avaliada pelo BIS). Na segunda fase deste trabalho, pretende-se a identificação de diferentes interações com Análise de Clusters bem como a validação do respetivo modelo com Análise Discriminante, identificando grupos homogéneos na amostra obtida através das técnicas de agrupamento. O número de grupos existentes na amostra foi, numa fase exploratória, obtido pelas técnicas de agrupamento hierárquicas, e a caracterização dos grupos identificados foi obtida pelas técnicas de agrupamento k-means. A reprodutibilidade dos modelos de agrupamento obtidos foi testada através da análise discriminante. As principais conclusões apontam que o teste de significância da equação de Regressão Linear indicou que o modelo é altamente significativo. As variáveis propofol e remifentanil influenciam significativamente o BIS e o modelo melhora com a inclusão do remifentanil. Este trabalho demonstra ainda ser possível construir um modelo que permite agrupar as concentrações dos fármacos, com base no efeito no sinal cerebral BIS, com o apoio de técnicas de agrupamento e discriminantes. Os resultados desmontram claramente a interacção farmacodinâmica dos dois fármacos, quando analisamos o Cluster 1 e o Cluster 3. Para concentrações semelhantes de propofol o efeito no BIS é claramente diferente dependendo da grandeza da concentração de remifentanil. Em suma, o estudo demostra claramente, que quando o remifentanil é administrado com o propofol (um hipnótico) o efeito deste último é potenciado, levando o sinal BIS a valores bastante baixos.

Cardiovascular response to beta-adrenergic blockade or activation in 23 inbred mouse strains.

We report the characterisation of 27 cardiovascular-related traits in 23 inbred mouse strains. Mice were phenotyped either in response to chronic administration of a single dose of the beta-adrenergic receptor blocker atenolol or under a low and a high dose of the beta-agonist isoproterenol and compared to baseline condition. The robustness of our data is supported by high trait heritabilities (typically H(2)>0.7) and significant correlations of trait values measured in baseline condition with independent multistrain datasets of the Mouse Phenome Database. We then focused on the drug-, dose-, and strain-specific responses to beta-stimulation and beta-blockade of a selection of traits including heart rate, systolic blood pressure, cardiac weight indices, ECG parameters and body weight. Because of the wealth of data accumulated, we applied integrative analyses such as comprehensive bi-clustering to investigate the structure of the response across the different phenotypes, strains and experimental conditions. Information extracted from these analyses is discussed in terms of novelty and biological implications. For example, we observe that traits related to ventricular weight in most strains respond only to the high dose of isoproterenol, while heart rate and atrial weight are already affected by the low dose. Finally, we observe little concordance between strain similarity based on the phenotypes and genotypic relatedness computed from genomic SNP profiles. This indicates that cardiovascular phenotypes are unlikely to segregate according to global phylogeny, but rather be governed by smaller, local differences in the genetic architecture of the various strains.

Fitting models for the joint action of two drugs using SAS(R)

Combinations of drugs are increasingly being used for a wide variety of diseases and conditions. A pre-clinical study may allow the investigation of the response at a large number of dose combinations. In determining the response to a drug combination, interest may lie in seeking evidence of synergism, in which the joint action is greater than the actions of the individual drugs, or of antagonism, in which it is less. Two well-known response surface models representing no interaction are Loewe additivity and Bliss independence, and Loewe or Bliss synergism or antagonism is defined relative to these. We illustrate an approach to fitting these models for the case in which the marginal single drug dose-response relationships are represented by four-parameter logistic curves with common upper and lower limits, and where the response variable is normally distributed with a common variance about the dose-response curve. When the dose-response curves are not parallel, the relative potency of the two drugs varies according to the magnitude of the desired effect and the models for Loewe additivity and synergism/antagonism cannot be explicitly expressed. We present an iterative approach to fitting these models without the assumption of parallel dose-response curves. A goodness-of-fit test based on residuals is also described. Implementation using the SAS NLIN procedure is illustrated using data from a pre-clinical study. Copyright © 2007 John Wiley & Sons, Ltd.

A fuzzy logic controller for intestinal levodopa infusion in Parkinson’s disease

The aim of this work is to evaluate the fuzzy system for different types of patients for levodopa infusion in Parkinson Disease based on simulation experiments using the pharmacokinetic-pharmacodynamic model. Fuzzy system is to control patient’s condition by adjusting the value of flow rate, and it must be effective on three types of patients, there are three different types of patients, including sensitive, typical and tolerant patient; the sensitive patients are very sensitive to drug dosage, but the tolerant patients are resistant to drug dose, so it is important for controller to deal with dose increment and decrement to adapt different types of patients, such as sensitive and tolerant patients. Using the fuzzy system, three different types of patients can get useful control for simulating medication treatment, and controller will get good effect for patients, when the initial flow rate of infusion is in the small range of the approximate optimal value for the current patient’ type.

Implementation of a medication guideline to improve medication safety for patients

Although the incidence of medication error remains unknown, in Australian hospitals, they are thought to occur in 5-20 % of drug administrations 1. Not surprisingly, international debate has focused on the mechanisms to improve the safety of patients. Thus a new National Inpatient Medication Chart (NIMC) was endorsed to improve communication and reduce medication errors 2. This study aimed to investigate the documentation practices of clinicians following the implementation of a medication guideline and NIMC.
A pre and post-test design was used to evaluate the adoption of and adherence to the medication guideline at Western Health, an 850 bed healthcare network in Australia. Audits of inpatient medication charts (N=265) were conducted at 3 months prior to and repeated 4 months (N=290) after implementation. The pre-test data was used to formulate an interdisciplinary organizational strategy that included mandatory education for all clinical staff, practice reminders, decision prompts, a telephone hotline for support, an intranet information website and electronically distributed Frequently Asked Questions.
Pre and post implementation audits highlighted areas of potential medication error. The post-test showed an overall trend towards improvement in documentation. There were significant improvements in 4 critical practices: Drug name clear (p=0.0003); Drug dose clear (p=0.0002); Prescribed frequency equals documented frequency (p=0) and; No signature by administrator (p=0).
The majority of documentation errors showed poor attention to detail and would be considered a slip or lapse in skill based judgment 3. Although this study was designed to evaluate documentation practices, future research should include observation methods to increase our understanding of the context behind the judgments such as work place interruptions, skill mix and knowledge levels. While evidence based guidelines enable work, they are not the actual work or substance of patient care. Organisational systems can assist in preventing unconscious aberrations that lead to error.

Effects of 15d-PGJ(2)-loaded poly(D,L-lactide-co-glycolide) nanocapsules on inflammation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Uso de la cefalexina en infecciones piogenas de la piel: comparacion de dos esquemas terapeuticos

50 patients with pyogenic infections of the skin were divided into 2 groups and treated with cephalexin. Group A, 26 patients, received 500 mg/12 hours; Group B, 24 patients, 250 mg/6 hours. Clinical diagnosis was substantiated by bacteriologic study of cultures to identify the organism and determination of its susceptibility to the drug. Group A showed 91%, group B 95%; satisfactory results. No side-effects were noted. Either form of dosage was effective in the treatment of pyogenic infections of the skin.

Envolvimento do sistema dopaminérgico na sensibilização comportamental ao femproporex

The effects of repeated administration of fenproporex (FEN) on motor activity of rats were studied. FEN-treated group (5.0 mg/kg, i.p., single dose, 7 consecutive days), showed a marked increase in the motor activity of rats, indicating that the drug induced behavioral sensitization. Repeated coadministration of haloperidol prevented the development of sensitization to repeated administration of FEN. Repeated administration of FEN increased also locomotor activity measured in the open field, ratifying the occurence of sensitization. These findings indicated development of sensitization to repeated FEN administration and that the dopamine system might be involved in the mechanism of sensitization.

Evaluation of cardiac rhythm in dogs treated with levamisole hydrochloride using 24-hour ambulatory electrocardiography

The objective of this study was to evaluate the electrocardiographic alterations in the cardiac rhythm in dogs treated with levamisole hydrochloride over a period of 24 hours. Thirty-six mixed-breed dogs, both male and female, all clinically healthy, were used in the experiment. The dogs were divided into 6 groups with 6 dogs in each group, according to dosage and route of administration. The Holter test was initiated immediately after the treatment, and was maintained for 24 hours. In the group treated with 10 mg/kg by way of subcutaneous injection, one of them showed ventricular premature complexes, sometimes isolated and other times in pairs, and ventricular tachycardia, concentrated mainly in the first hour after administration of the drug. In the group of 6 animals treated subcutaneously with 25mg/kg, four showed isolated ventricular premature complexes, ventricular bigeminy and trigeminy, mainly during the first 2 hours after administration of the drug. All the animals in the other groups showed sinus arrhythmia followed by sinus arrest. The disturbances in the cardiac rhythm observed in clinically healthy animals treated with levamisole hydrochloride, indicate that it is preferable to avoid subcutaneous administration of levamisole hydrochloride and that the oral administration of the drug should be done with caution. © 2003 Elsevier B.V. All rights reserved.

Sildenafil for pulmonary hypertension treatment after cardiac surgery

Objective: To report on the use of sildenafil for pulmonary hypertension treatment of a newborn patient after cardiac surgery. Description: A female, full term newborn infant with diagnosis of double outlet right ventricle, pulmonary hypoplasia and subaortic ventricular septal defect, was submitted to Blalock surgery in the first week of life. In postoperative the newborn had pulmonary hypertension and persistent hypoxia, without response to nitric oxide, but with improved oxygenation after continuous intravenous infusion of prostaglandin E1. After several failed attempts to discontinue prostaglandin E1, oral sildenafil was used. There was a decrease in pulmonary vascular resistance with consequent oxygenation improvement and 48 hours later it was possible to discontinue prostaglandin E1 infusion. Comments: Sildenafil can be an alternative therapy for pulmonary hypertension, especially when there is no response to conventional therapy. Copyright © 2005 by Sociedade Brasileira de Pediatria.

La última palabra en dosis mínima

In this article we rewiewed the indications of the low-dose hormone replacement therapy in post menopausal women. We evaluate the effects of this therapy on menopausal symptoms bone metabolism, cardiovascular risk and endometrial cancer. The low-dose hormone replacement therapy is satisfactory to relief menopausal symptoms and improves lipid profile preventing atherosclerosis. It does not increase the risk of hyperplasia or endometrial cancer when is associate with progestagens. The low dose hormone replacement therapy is also associate to improve bone mineral density but to have better comprehension about the effective action of the low dose hormone replacement therapy on bone, more studies evaluating the risk of fractures are necessary.

Comparison of xylazine and medotomidine as premedicants for cats being anaesthetised with propofol-sevoflurane

The effects of premedicating cats with saline, xylazine or medetomidine before anaesthetising them with propofol-sevoflurane were compared. Twenty-four cats were randomly assigned to three groups of eight to receive either 0.25 ml of saline, 0.50 mg/kg of xylazine or 0.02 mg/kg of medetomidine intravenously, and anaesthesia was induced with propofol and maintained with sevoflurane. Medetomidine produced a greater reduction in the induction dose of propofol and fewer adverse postoperative effects than saline or xylazine. Hypoxaemia was observed after induction with propofol in the cats premedicated with saline and xylazine, but not in the cats given medetomidine. The cats treated with medetomidine and xylazine developed profound bradycardia. The blood pressure of the cats premedicated with saline and xylazine decreased, but the blood pressure of the cats premedicated with medetomidine was maintained. The cats premedicated with saline took longer to recover from anaesthesia than the other two groups.

Evaluation of Strychnos pseudoquina St. Hil. leaves extract on gastrointestinal activity in mice

Strychnos pseudoquina St. Hil. (Loganiaceae) was investigated for its ability to protect the gastric mucosa against injuries caused by non-steroidal anti-inflammatory drugs (piroxicam) and a necrotizing agent (HCl/EtOH) in mice. The MeOH extract and enriched alkaloidic fraction (EAF) provided significant protection in experimental models wheer used at doses of 250 and 1000 mg/kg. In vivo tests were carried out to evaluate for possible toxic effects and no mortality was observed up to the 5 g/kg dose level. Phytochemical investigation led to the isolation of a new indole alkaloid, which elucidated the observed pharmacological effects. © 2005 Pharmaceutical Society of Japan.

Eficácia e segurança da atorvastatina no tratamento de pacientes com hipercolesterolemia primária

Introduction: Hypercholesterolemia is an important risk factor for cardiovascular disease, the first cause of death and third reason for hospital admissions in Brazil. The reduction of serum cholesterol levels reduces morbidity and mortality from cardiovascular disease. The present study evaluated the efficacy and safety of atorvastatin in the treatment of Brazilian patients with primary hypercholesterolemia (types IIA and IIB dyslipidemias). Patients and methods: After a 4-week wash-out period, 152 patients were treated with atorvastatin at the initial dose of 10 mg/day. According to treatment efficacy within the first 8 weeks this dose could be increased to 20 mg/day. Treatment lasted for a total of 16 weeks, and its efficacy was evaluated by the reduction of serum levels of LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglycerides, as well as by the propotion of patients that achieved the target levels recommended by the National Cholesterol Education Program - Adult Treatment Panel II (NCEP ATP II) Results: The analysis of efficacy was conducted in 145 patients. Atorvastatin led to significant reductions in the levels of LDL-cholesterol after 8 and 16 weeks of treatment (P<0.001 for both comparisons). The relative reduction of such levels was 38% (P<0.001 after 8 and 16 weeks). Atorvastatin also led to significant reductions of total cholesterol and triglycerides. At the end of the study, 81% of patients achieved the target LDL-cholesterol levels recommended by NCEP ATP II. Treatment was well tolerated, and was interrupted due to creatine phosphokinase elevation in only one patient. Conclusion: Atorvastatina is efficacious and safe in the treatment of patients with primary hypercholesteromia. © Copyright Moreira Jr. Editora. Todos os direitos reservados.