Diabetes is a leading cause of death and disability in the United States. Diabetes requires a lifetime medical treatment. Some diabetes drugs could be taken orally, while others require daily injection or inhalation to maximize bioavailability and minimize toxicity. Parenteral delivery is a group of delivery routes which bypass human gastrointestinal track. Among all the parenteral methods, we chose subcutaneous implant based on its fast act and high patient compliance. When using subcutaneous implant, drug release needs to be strictly controlled. There are three major groups of controlled release methods. Solvent controlled system is already used as osmotic implant. Matrix controlled system is used in Zoladex® implant to treat cancer. Membrane controlled systems is widely used in coating tablets, but not that popular as an implant. Based on the research reported by previous scientists, we decided to build a hybrid system using both matrix and membrane control to delivery human insulin and other small molecule drugs. Subcutaneous environment is different from human GI track. It has less tolerance for external materials so many polymers cannot be used. From the FDA safe excipient database, we selected albumin as our primary polymer and gelatin as secondary choice. In our preliminary insulin diffusion study, we successfully found that insulin mixed with albumin provided a slower diffusion rate compared with control. In addition, we added zinc chloride, a metal salt that can precipitate albumin. The insulin diffusion rate is further reduced. The preliminary study proved that matrix control using albumin is definitely feasible and we might add zinc chloride as another factor. In order to fabricate an implant with appropriate size, we use lyophilisation technology to produce uniformly mixed matrix. Apart from albumin and human insulin, we added sucrose as protectant and plasticizer. The fine powder after freeze-dry was pressed as a form of tablet. The tablets were sealed in Falcon® cell culture insert. Cell culture insert provide a cylinder shape and 0.3 cm2 surface area for drug release. Insulin release study provided a zero order kinetics from prototypes with zinc chloride or 0.4 micron pore size membrane. Caffeine was used as a model drug to investigate the releasing mechanism. Three pore size membranes (0.4, 3 and 8 micron) were tested with same formulation. While 0.4 micron prototypes provided the slowest release, 3 micron ones surprisingly released caffeine faster than 8 micron implants. We calculated the porosity with pore size and concluded that the percentage of open area on a membrane is the key point to control caffeine release. 0.4 micron membranes were used for future research. We increased the percentage of albumin in our excipient, and achieved a slower caffeine release. However, the zero order release could only last for 3 days. After we replaced sucrose with gelatin, a 5 day zero order release of caffeine was achieved. With all the results, we proposed our “Three Phase” drug release mechanism controlled by both membrane and matrix. Seven other small molecule drugs were tested using our prototype. Cloudy suspension was observed with slightly soluble drugs. We updated our “Three Phase” drug release mechanism with the influence of drug solubility. Data shows that releasing rate with same formulation and membrane follows the solubility in pH 7.4. This result proves that our prototype might be used for different drugs based on their solubility. Finally, with all the information of our prototype, we decided to build a “smart insulin implant” with dose adjustment. We proposed an electrical controlled implant with different porosity membranes. Solenoid was used as the mechanical arm to control membrane porosity. 3-D printing technology was used to produce the first real prototype of our implant. Finally, insulin implant with clinically effective insulin release rate was achieved. / Pharmaceutical Sciences

INTRODUÇÃO: Relatos conflitantes têm dificultado para se estabelecer o potencial benefício da glutamina (GLN) no tratamento de condições inflamatórias agudas. Nós avaliamos o efeito da infusão parenteral de GLN, prévia à pancreatite aguda (PA) experimental, nos mediadores inflamatórios, morbidade e mortalidade. MÉTODOS: Ratos Lewis (n = 131) receberam glutamina parenteral (grupo GG), solução salina (grupo SS ou controle), ou permaneceram sem infusão parenteral (grupo Sham) por 48h. Após este período, foi induzida PA por meio da injecção retrógrada de taurocolato de sódio no ducto pancreático. Sangue, amostras de pulmão, fígado, pâncreas e líquido ascítico foram colhidos a partir de 2, 12 e 24 horas após PA para avaliação das variáveis propostas (citocinas, hsp, histologia, amilase). Sessenta animais permaneceram vivos após PA para a análise da mortalidade em sete dias. RESULTADOS: A análise entre grupos não mostrou diferenças significativas nos níveis de citocinas (p > 0,05). Análise cinética dentro de cada grupo ao longo do tempo mostrou maior INF-y no grupo Sham e SS às 2h do que em 12h e 24h, maior IL-2 e inferior IL-10 no Sham, às 24h do que em 2h e 12h, e menor IL-10 no SS e GG em 24 h do que no tempo de 2h (p <= 0.05). O grupo GG exibiu maior expressão de HSP 90 no pulmão e no fígado do que no grupo Sham nos tempos de 2h e 12h, respectivamente; e maior expressão no fígado de HSP90 e HSP70 no grupo SS no tempo 12 horas (p < 0,01). O grupo Sham apresentou maior expressão de HSP 70 no pulmão e HSP 90 no fígado do que os outros grupos no tempo de 24h. Não ocorreram alterações na taxa de mortalidade. CONCLUSÕES: Em modelo de PA experimental induzida por taurocolato de sódio, o pré-tratamento com GLN parenteral melhorou o perfil dos mediadores inflamatórios, sem afetar a mortalidade / INTRODUCTION: Conflicting reports have hindered establish the potential glutamine (GLN) benefit in treating acute inflammatory conditions. We evaluated the effect of parenteral GLN infusion before experimental acute pancreatitis (AP), as systemic inflammation-reproducing model, on inflammatory mediators and mortality. METHODS: Lewis rats (n=131) received parenteral glutamine (GG group), saline (SS or Control group), or remained without parenteral infusion ( Sham group) for 48h. Thereafter, AP was induced by retrograde injection of sodium taurocholate into pancreatic duct. Blood, lung, liver and pancreas samples were collected from 2, 12 and 24h post-AP to assess serum cytokines levels, tissue HSP expression, histology and amylase. Sixty animals remained alive post-PA for seven-day mortality analysis. RESULTS: Punctual between-groups analysis did not show differences in cytokine levels (p > 0.05). Intragroup analysis over time showed higher INF-y in Sham and SS at 2h than at 12h and 24h, higher IL-2 and lower IL-10 in Sham at 24h than at 2h and 12h, and lower IL-10 in SS and GG at 24h than at 2h timepoint (p <= 0.05). GG group exhibited higher lung and liver HSP90 than Sham at 2h and 12h timepoints, respectively; and higher liver HSP90 and HSP70 than SS at 12h timepoint (p < 0.01). Sham group presented higher lung HSP70 and liver HSP90 than the others at 24h timepoint (p < 0.02). No changes occurred on mortality rate. CONCLUSIONS: In sodium taurocholate-induced PA model, pretreatment with parenteral GLN improved inflammatory mediator\'s profile, without affecting mortality

INTRODUÇÃO: Emulsão lipídica parenteral composta por óleo de peixe, rica em ácidos graxos ômega-3, é infundida associada a emulsões lipídicas convencionais, como parte da terapia nutricional parenteral. Em pacientes cirúrgicos, a infusão perioperatória de emulsão lipídica de óleo de peixe se associa à preservação de funções imunológicas e modulação favorável de mediadores inflamatórios pós-operatórios, com redução na frequência de complicações infecciosas e no tempo de internação em unidade de terapia intensiva e hospitalar. Os benefícios descritos encorajam a infusão parenteral isolada de emulsão lipídica de óleo de peixe, como fármaconutriente adjuvante no tratamento de pacientes cirúrgicos, independente da indicação de terapia nutricional parenteral. OBJETIVO: O presente estudo avaliou o efeito da infusão parenteral pré-operatória, por curto prazo, de emulsão lipídica de óleo de peixe isolada sobre a resposta imunológica pósoperatória e a evolução clínica imediata de pacientes com câncer gastrintestinal. MÉTODOS: Estudo prospectivo, aleatório, duplo-cego e controlado em 63 pacientes cirúrgicos eletivos com câncer gastrintestinal. Os doentes receberam infusão por veia periférica (0,2g gordura/kg de peso corpóreo/dia) de emulsão lipídica parenteral de óleo de peixe (Omegaven® 10% - Fresenius-Kabi) ou emulsão lipídica parenteral controle (Lipovenos MCT® 10% - Fresenius-Kabi) durante os 3 últimos dias pré-operatórios. Amostras de sangue foram coletadas antes e após a infusão parenteral das emulsões lipídicas e nos 3º e 6º (apenas para citocinas) dias pósoperatórios. Analisou-se a concentração plasmática de IL-6 e IL-10 e a migração, fagocitose, explosão oxidativa e expressão de moléculas HLA-DR e CD32 leucocitárias. A frequência de complicações infecciosas e tempo de internação na unidade de terapia intensiva e hospitalar também foram avaliados no período pós-operatório imediato. RESULTADOS: No período pós-operatório, pacientes tratados com emulsão de óleo de peixe tiveram aumento de IL-10 (dia 3, p < 0,0001), diminuição de IL-6 (dia 3, p = 0,029) e IL-10 (dia 6 p < 0,0001), menor diminuição da explosão oxidativa leucocitária (p = 0,028), manutenção da porcentagem de monócitos exprimindo HLA-DR (p = 0,046) e CD32 (p = 0,025) e aumento da intensidade da expressão de CD32 por neutrófilos (p=0,010), em comparação a pacientes tratados com emulsão lipídica controle. A migração leucocitária não foi influenciada. Não foram encontradas diferenças na frequência de infecções e no tempo de permanência na unidade de terapia intensiva e hospitalar. CONCLUSÕES: A infusão pré-operatória, por curto prazo, de emulsão lipídica parenteral de óleo de peixe isolada, como fármaco-nutriente, melhora a resposta imunológica pós-operatória de pacientes com câncer gastrintestinal sem estar associada à melhora significativa na frequência de infecções e tempo de permanência na unidade de terapia intensiva e hospitalar. / BACKGROUND: Parenteral lipid emulsion composed by fish oil, rich in omega-3 fatty acids, is infused in addition to other standard lipid emulsions, as part of parenteral nutrition therapy. In surgical patients, the perioperative infusion of fish oil lipid emulsion is associated with immune functions preservation and favorably modulation of postoperative inflammatory mediators, with decreased infectious complications and length of intensive care unit and hospital stay. These reported benefits encourage the use of fish oil lipid emulsion alone, as a pharmacological adjuvant agent for the treatment of surgical patients, independent of parenteral nutritional therapy indication. AIM: This clinical trial assessed the effect of short-term preoperative infusion of fish oil lipid emulsion alone on postoperative immune response and immediate clinical outcomes of patients with gastroenterological cancer. METHOD: In a prospective, randomized, controlled and double-blind design, elective surgical patients with gastrointestinal cancer (n= 63) received, for the last 3 pre-operative days, peripheral infusion (0.2g fat/kg of body weight./d) of fish oil lipid emulsion (Omegaven® 10% - Fresenius-Kabi) or control lipid emulsion (Lipovenos MCT® 10% - Fresenius-Kabi). Peripheral blood samples were collected before and after lipid emulsion infusion at the 3rd and 6th (only for cytokines) postoperative days to analyze plasma concentration of IL-6 and IL-10, as well as leukocyte migration, phagocytosis, oxidative burst and expression of HLADR and CD32 molecules. Postoperative infections, length of intensive care unit and hospital stay were also measured. RESULTS: At postoperative period, patients treated with fish oil lipid emulsion had increase of IL-10 (day 3, p < 0.0001), decrease of IL-6 (day 3, p = 0.029) and IL-10 (day 6, p<0.0001), lower decrease of leukocyte oxidative burst (p=0.023), maintenance of the percentage of monocytes expressing HLA-DR (p=0.046) and CD32 (p=0,025) and increase of the intensity of CD32 expression on neutrophil surface (p=0,010), when compared to patients treated to control lipid emulsion. The leukocyte chemotaxis was not affected. No changes were observed on postoperative infections and length of intensive care unit and hospital stay. CONCLUSION: Short-term preoperative infusion of fish oil lipid parenteral emulsion alone improves postoperative immune response of patients with gastrointestinal cancer without benefit on infections frequency and length of intensive care unit and hospital stays.

INTRODUÇÃO: Indicadores de qualidade em terapia nutricional (IQTN) são importantes ferramentas de avaliação e monitoramento de qualidade da terapia nutricional (TN). No Brasil, além da escassez de recursos humanos e materiais, a aplicação dos IQTNs,disponíveis para prática clínica, tem sido limitada devido ao seu elevado número. O presente estudo procurou identificar os dezIQTNs mais pontuados, dentre aqueles disponíveis no Brasil, através da avaliação da opinião de especialistas em TN. MÉTODOS: Todos os IQTNs disponíveis para aplicação clínica no Brasil (n=36) foram avaliados em duas fases distintas. Na fase 1 (seleção), especialistas em TN (n=26) pontuaramos IQTNs de acordo com quatro atributos (utilidade, simplicidade, objetividade, e baixo custo), utilizando a escala de Likert com 5 pontos. Os IQTNs foram classificadosem ordem da maior para menor pontuação e a confiabilidade da opinião de especialistas para cada indicador foi avaliada poralfa de Cronbach. Na fase 2, os dez IQTNs selecionados com maior pontuaçãoforam submetidos ànova análise dos especialistas, por meio de duas perguntas fechadas. RESULTADOS: Os dez IQTNs selecionadoscom maior pontuação, em ordem do mais para o menos pontuado, foram 1.) Frequência de realização de triagem nutricional em pacientes hospitalizados, 2.) Frequência de diarreia em pacientes em Terapia Nutricional Enteral, 3.) Frequência de saída inadvertida de sonda de nutrição em pacientes em Terapia Nutricional Enteral, 4.) Frequência de obstrução de sonda de nutrição em pacientes em Terapia Nutricional Enteral, 5.) Frequência de jejum digestório por mais de 24 horas em pacientes em Terapia Nutricional Enteral ou Oral, 6.) Frequência de pacientes com disfunção da glicemia em Terapia Nutricional Enteral e Parenteral, 7.) Frequência de medida ou estimativa do gasto energético e necessidades proteicas em pacientes em Terapia Nutricional, 8.) Frequência de infecção por Cateter Venoso Central em pacientes em Terapia Nutricional Parenteral, 9.) Frequência de conformidade de indicação da Terapia Nutricional Enteral, 10.) Frequência de aplicação de Avaliação Subjetiva Global (ASG) em pacientes em Terapia Nutricional. As opiniões dos especialistas entrevistados foram significantemente consistentes. Durante a fase 2, 96% dos especialistas informaram estar satisfeitos com os 10 IQTNs selecionados, e 100% manifestaram que esta seleção refletiu a mesma opinião anteriormente emitida,na primeira fase do estudo. CONCLUSÃO: A avaliação da opinião de especialistas em TN, com o uso de técnicas psicométricas e ferramentas estatísticas, possibilitou a identificação dedezIQTNsmais pontuados,com consistência e representatividade de opiniões entre eles.A redução do número de trinta e seis IQTNs para os dez presentemente identificados pode contribuir para sua aplicação clínica / BACKGROUND: Quality indicators in nutritional therapy (QINT) are central tools to evaluate and monitor the quality of nutritional therapy. In addition to the scarcity of human and material resources, the application of the QINT available for clinical practice in Brazil has been limited also due to its elevated number. This study attempted to identify the ten more scored QINT that suit in the clinical practice, among those available in Brazil, through evaluating experts in Nutritional Therapy (NT). METHODS: All the 36 available QINTs to the clinical application in Brazil were evaluated in two distinct phases. In the phase 1 (selection), 26 experts in NT rated the QINTs following four attributes (utility, simplicity, objectivity and low cost), on a 5- point Likert scale. The top 10 QINTs were identified from the top 10 scores; and the reliability of the experts opinion to each indicator were evaluated by Cronbachs alpha. In phase 2, the top 10 selected QINTs were subjected in a new experts analysis following two closed questions. RESULTS: The top 10 selected QINTs, from the biggest to the least scored order, were: 1) Frequency of carrying out nutrition screening of hospitalized patients, 2) Frequency of diarrhea in patients on Enteral Nutrition (EN), 3) Frequency of involuntary withdrawal of enteral feeding tubes, 4) Frequency of tube feeding occlusion in patients on EN, 5) Frequency of digestive fasting for more than 24 hours in patients on oral nutrition or EN, 6) Frequency of patients with glycemic dysfunction on NT, 7) Frequency of measurement or estimation of energy expenditure and protein needs in patients on NT, 8) Frequency of Central Venous Catheter infection in patients on Parenteral Nutrition, 9) Frequency of indication compliance of NT 10) Frequency of application of Subjective Global Assessment in patients on NT. The opinions of the experts interviewed were significantly consistent. During the phase 2, 96% of the experts were found to be satisfied with the top 10 selected QINTs, and 100% expressed that the selection of the top 10 QINTs interfered the same opinion in the first phase of the study. CONCLUSION: The evaluation of the experts opinion in NT using psychometrics techniques and statistical tools, allowed the identification of the 10 most scored QINTs, with good applicability in NT and representativeness of opinions among them. The reduction of QINT number from 36 to ten, may contribute to their clinical application

A Síndrome do Intestino Curto (SIC) é uma doença complexa que ocorre após extensa ressecção do intestino delgado, levando a uma má absorção de nutrientes e fluidos, uma condição que pode causar diarreia, desnutrição e perda de peso graves com alto risco para o desenvolvimento da osteoporose. Estudos recentes mostram existir ampla interação fisiológica do esqueleto com os diversos sistemas, incluindo o metabolismo energético e o trato digestório. Peptídeos originados não só no tecido adiposo, mas também no intestino como as incretinas [GIP (polipeptídeo trópico insulínico dependente de glicose) e GLP1 (peptídeo 1 tipo glucagon)] modulam a atividade de remodelação óssea. O objetivo principal do atual estudo foi avaliar a relação entre os tecidos adiposos subcutâneo (TAS), visceral (TAV), lipídeos intra-hepáticos (LIH), tecido adiposo da medula óssea (TAMO), bem como do GIP, GLP1, e grelina com a densidade mineral óssea (DMO) em pacientes com SIC. Tratase de um estudo observacional prospectivo composto por dois grupos experimentais pareados por altura, idade e sexo: a) o grupo controle (GC) (n = 18; 9M,9F) e b) o grupo de pacientes com SIC, o qual foi avaliado em 2 ocasiões, com intervalo de um ano entre as análises, sendo denominados SIC0 (n = 14; 7M,7F) e SIC1 (n = 11; 6M,5F). Em comparação com o GC, pacientes com SIC ao longo do estudo apresentaram menor DMO e maior LIH e GIP (p< 0,05). Os valores de TAMO, GLP1 e grelina foram similares entre os grupos. O TAMO teve correlação negativa e significativa com DMO de L3 no GC (r= -0,6; p< 0,05), porém, no grupo SIC esta correlação foi positiva, mas sem significância estatística ao longo do estudo: SIC0 (r= 0,45; p= 0,13) e SIC1 (r= 0,45; p= 0,17). LIH associou-se negativamente com DMO do colo do fêmur (R²= 0,16; p< 0,05) e quadril total (R²= 0,27; p< 0,05). Existe alta prevalência de osteoporose em pacientes com SIC. No entanto, não se observou nem expansão de TAMO e nem relação negativa da DMO com o TAMO. O acesso a calorias parece afetar positivamente a relação entre TAMO e massa óssea. A deposição hepática de lipídeos parece afetar negativamente a massa óssea de pacientes com SIC. / Short bowel syndrome (SBS) is a complex disease that occurs after extensive resection of the small intestine leading to malabsorption of nutrients and fluids, a condition that can cause severe watery diarrhea, dehydration and acute weight loss, developing high risk for the appearance of osteometabolic disease. Studies have shown the progress on the physiological interaction of the skeleton with the various systems, including energetic metabolism and the gastrointestinal tract. Peptides originated not only in adipose tissue but also in the intestine such as incretin [GIP (Glucose-dependent insulinotropic polypeptide) and GLP1 (glucagonlike peptide 1) modulate bone remodeling activity. The main objective of the current study was to evaluate the influence of subcutaneous (SAT), visceral (VAT) adipose tissue, intrahepatic lipids (IHL), bone marrow fat adipose tissue (MAT), as well as the influence of GIP, GLP1, and ghrelin on the bone mineral density (BMD) of SBS patients. It is a prospective observational study composed by two experimental groups matched by height, age and sex: a) the control group (CG) (n = 18; 9M,9F) and b) the SBS group which were evaluated in two occasions with a period between analyzes of one year: named SBS0 (n = 14; 7M,7F) and SBS1 (n = 11; 6M,5F). Compared to CG, SBS patients throughout the study had significantly lower BMD and elevated IHL and GIP (p< 0.05). Values of MAT, GLP1 and ghrelin were similar between groups. MAT was negatively and significantly correlated with L3 BMD in the CG (r = -0.6; p< 0.05) and positively correlated, but not significant with L3 BMD in the SBS group throughout the study: SBS0 (r= 0.45; p= 0.13) and SBS1 (r= 0.45; p= 0.17). IHL was negatively and significantly associated with femoral neck BMD (R²= 0.16; p< 0.05) and total hip BMD (R²= 0.27; p< 0.05). The occurrence of osteoporosis is frequent in SBS patients, but MAT is not increased in these patients and had positive correlation with BMD, although not significant. Access to calories seems to positively affect the relationship between MAT and bone mass. IHL appear to negatively affect bone mass in SBS patients.

Introduction: Medical advances have resulted in reduced mortality of pediatric patients with Intestinal Failure. Consequently, more patients go home on parenteral nutrition (PN) for extended durations. This time-consuming and complicated therapy necessitates persistent vigilance in monitoring and response to potential life-threatening side effects. These issues may impact quality of life (QOL) for patients, caregivers and families. Methods: This observational, cross-sectional, mixed-methods analysis of multidimensional QOL used a quantitative battery assessment and a qualitative focus group. Questionnaire results were compared to published norms, published small bowel transplant (SBTx), and institutional SBTx patients. Results: Home PN proxy assessments scored children lower than published norms but similar to SBTx. The child self-reports were similar to both normative and SBTx populations, except lower general and overall health. Generic questionnaires did not capture disease-specific issues. Conclusion: QOL is compromised in children on home PN and caregivers compared to norms but is similar to SBTx.

Introduction: Medical advances have resulted in reduced mortality of pediatric patients with Intestinal Failure. Consequently, more patients go home on parenteral nutrition (PN) for extended durations. This time-consuming and complicated therapy necessitates persistent vigilance in monitoring and response to potential life-threatening side effects. These issues may impact quality of life (QOL) for patients, caregivers and families. Methods: This observational, cross-sectional, mixed-methods analysis of multidimensional QOL used a quantitative battery assessment and a qualitative focus group. Questionnaire results were compared to published norms, published small bowel transplant (SBTx), and institutional SBTx patients. Results: Home PN proxy assessments scored children lower than published norms but similar to SBTx. The child self-reports were similar to both normative and SBTx populations, except lower general and overall health. Generic questionnaires did not capture disease-specific issues. Conclusion: QOL is compromised in children on home PN and caregivers compared to norms but is similar to SBTx.

Except for tyrosine, the amino acid requirement of parenterally fed (PN) human neonates has not been derived. Methionine and cysteine are indispensable and dispensable sulphur amino acids respectively. Cysteine is synthesized from methionine. Cysteine is unstable in solution, and is left out or added in very small amounts to amino acid solutions. Methionine is added to compensate for the lack of cysteine, assuming that the neonate will convert methionine to cysteine to meet the body’s metabolic demand. Methionine is hepatotoxic and there is evidence that the neonate has limited ability for its conversion to cysteine. To determine the requirement of the neonate for methionine, PN-fed, stable, post-surgical neonates received graded intakes of methionine. The mean methionine requirement was estimated to be 49 mg.kg-1.day-1, which is 48 to 90% of the methionine content of current commercial amino acid solutions. Because cysteine is the rate limiting substrate for glutathione (GSH) synthesis and current methods of determining amino acid requirement measure requirement for protein synthesis, SAA requirements for maintenance of GSH status was deleniated in healthy adult males and in PN-fed human neonates. GSH kinetics was measured in healthy men receiving the mean methionine requirement and graded intakes of cysteine. GSH synthesis did not change with the addition of cysteine. Additionally, PN-fed post-surgical neonates recieved a methionine-adequate cysteine-free PN followed by cysteine supplemented PN for two 3-day periods and GSH kinetics measured on days 3 and 6. There was no change in GSH synthesis in response to cysteine supplementation. It is concluded that the PN-fed human neonate is capable of synthesizing enough cysteine from methionine not only for protein synthesis but for GSH synthesis. For both healthy men and stable post-surgical neonates, the requirement for GSH synthesis is met at the sulphur amino acid requirement derived using the indicator amino acid technique

Except for tyrosine, the amino acid requirement of parenterally fed (PN) human neonates has not been derived. Methionine and cysteine are indispensable and dispensable sulphur amino acids respectively. Cysteine is synthesized from methionine. Cysteine is unstable in solution, and is left out or added in very small amounts to amino acid solutions. Methionine is added to compensate for the lack of cysteine, assuming that the neonate will convert methionine to cysteine to meet the body’s metabolic demand. Methionine is hepatotoxic and there is evidence that the neonate has limited ability for its conversion to cysteine. To determine the requirement of the neonate for methionine, PN-fed, stable, post-surgical neonates received graded intakes of methionine. The mean methionine requirement was estimated to be 49 mg.kg-1.day-1, which is 48 to 90% of the methionine content of current commercial amino acid solutions. Because cysteine is the rate limiting substrate for glutathione (GSH) synthesis and current methods of determining amino acid requirement measure requirement for protein synthesis, SAA requirements for maintenance of GSH status was deleniated in healthy adult males and in PN-fed human neonates. GSH kinetics was measured in healthy men receiving the mean methionine requirement and graded intakes of cysteine. GSH synthesis did not change with the addition of cysteine. Additionally, PN-fed post-surgical neonates recieved a methionine-adequate cysteine-free PN followed by cysteine supplemented PN for two 3-day periods and GSH kinetics measured on days 3 and 6. There was no change in GSH synthesis in response to cysteine supplementation. It is concluded that the PN-fed human neonate is capable of synthesizing enough cysteine from methionine not only for protein synthesis but for GSH synthesis. For both healthy men and stable post-surgical neonates, the requirement for GSH synthesis is met at the sulphur amino acid requirement derived using the indicator amino acid technique

INTRODUÇÃO: Emulsão lipídica parenteral composta por óleo de peixe, rica em ácidos graxos ômega-3, é infundida associada a emulsões lipídicas convencionais, como parte da terapia nutricional parenteral. Em pacientes cirúrgicos, a infusão perioperatória de emulsão lipídica de óleo de peixe se associa à preservação de funções imunológicas e modulação favorável de mediadores inflamatórios pós-operatórios, com redução na frequência de complicações infecciosas e no tempo de internação em unidade de terapia intensiva e hospitalar. Os benefícios descritos encorajam a infusão parenteral isolada de emulsão lipídica de óleo de peixe, como fármaconutriente adjuvante no tratamento de pacientes cirúrgicos, independente da indicação de terapia nutricional parenteral. OBJETIVO: O presente estudo avaliou o efeito da infusão parenteral pré-operatória, por curto prazo, de emulsão lipídica de óleo de peixe isolada sobre a resposta imunológica pósoperatória e a evolução clínica imediata de pacientes com câncer gastrintestinal. MÉTODOS: Estudo prospectivo, aleatório, duplo-cego e controlado em 63 pacientes cirúrgicos eletivos com câncer gastrintestinal. Os doentes receberam infusão por veia periférica (0,2g gordura/kg de peso corpóreo/dia) de emulsão lipídica parenteral de óleo de peixe (Omegaven® 10% - Fresenius-Kabi) ou emulsão lipídica parenteral controle (Lipovenos MCT® 10% - Fresenius-Kabi) durante os 3 últimos dias pré-operatórios. Amostras de sangue foram coletadas antes e após a infusão parenteral das emulsões lipídicas e nos 3º e 6º (apenas para citocinas) dias pósoperatórios. Analisou-se a concentração plasmática de IL-6 e IL-10 e a migração, fagocitose, explosão oxidativa e expressão de moléculas HLA-DR e CD32 leucocitárias. A frequência de complicações infecciosas e tempo de internação na unidade de terapia intensiva e hospitalar também foram avaliados no período pós-operatório imediato. RESULTADOS: No período pós-operatório, pacientes tratados com emulsão de óleo de peixe tiveram aumento de IL-10 (dia 3, p < 0,0001), diminuição de IL-6 (dia 3, p = 0,029) e IL-10 (dia 6 p < 0,0001), menor diminuição da explosão oxidativa leucocitária (p = 0,028), manutenção da porcentagem de monócitos exprimindo HLA-DR (p = 0,046) e CD32 (p = 0,025) e aumento da intensidade da expressão de CD32 por neutrófilos (p=0,010), em comparação a pacientes tratados com emulsão lipídica controle. A migração leucocitária não foi influenciada. Não foram encontradas diferenças na frequência de infecções e no tempo de permanência na unidade de terapia intensiva e hospitalar. CONCLUSÕES: A infusão pré-operatória, por curto prazo, de emulsão lipídica parenteral de óleo de peixe isolada, como fármaco-nutriente, melhora a resposta imunológica pós-operatória de pacientes com câncer gastrintestinal sem estar associada à melhora significativa na frequência de infecções e tempo de permanência na unidade de terapia intensiva e hospitalar. / BACKGROUND: Parenteral lipid emulsion composed by fish oil, rich in omega-3 fatty acids, is infused in addition to other standard lipid emulsions, as part of parenteral nutrition therapy. In surgical patients, the perioperative infusion of fish oil lipid emulsion is associated with immune functions preservation and favorably modulation of postoperative inflammatory mediators, with decreased infectious complications and length of intensive care unit and hospital stay. These reported benefits encourage the use of fish oil lipid emulsion alone, as a pharmacological adjuvant agent for the treatment of surgical patients, independent of parenteral nutritional therapy indication. AIM: This clinical trial assessed the effect of short-term preoperative infusion of fish oil lipid emulsion alone on postoperative immune response and immediate clinical outcomes of patients with gastroenterological cancer. METHOD: In a prospective, randomized, controlled and double-blind design, elective surgical patients with gastrointestinal cancer (n= 63) received, for the last 3 pre-operative days, peripheral infusion (0.2g fat/kg of body weight./d) of fish oil lipid emulsion (Omegaven® 10% - Fresenius-Kabi) or control lipid emulsion (Lipovenos MCT® 10% - Fresenius-Kabi). Peripheral blood samples were collected before and after lipid emulsion infusion at the 3rd and 6th (only for cytokines) postoperative days to analyze plasma concentration of IL-6 and IL-10, as well as leukocyte migration, phagocytosis, oxidative burst and expression of HLADR and CD32 molecules. Postoperative infections, length of intensive care unit and hospital stay were also measured. RESULTS: At postoperative period, patients treated with fish oil lipid emulsion had increase of IL-10 (day 3, p < 0.0001), decrease of IL-6 (day 3, p = 0.029) and IL-10 (day 6, p<0.0001), lower decrease of leukocyte oxidative burst (p=0.023), maintenance of the percentage of monocytes expressing HLA-DR (p=0.046) and CD32 (p=0,025) and increase of the intensity of CD32 expression on neutrophil surface (p=0,010), when compared to patients treated to control lipid emulsion. The leukocyte chemotaxis was not affected. No changes were observed on postoperative infections and length of intensive care unit and hospital stay. CONCLUSION: Short-term preoperative infusion of fish oil lipid parenteral emulsion alone improves postoperative immune response of patients with gastrointestinal cancer without benefit on infections frequency and length of intensive care unit and hospital stays.