M. Mulieri

Bio: M. Mulieri is an academic researcher. The author has contributed to research in topics: Anorexia & Cancer. The author has an hindex of 7, co-authored 9 publications receiving 316 citations.

Effects of administration of oral branched-chain amino acids on anorexia and caloric intake in cancer patients

Abstract: Anorexia, with its attendant reduction of food intake and progressive depletion of body stores, is among the major causes of the anorexia-cachexia syndrome occurring in cancer patients (J). Results from a number of studies (2-6) suggest that the enhanced brain availability of the amino acid precursor of serotonin, tryptophan, may play a role in the pathogenesis of cancer anorexia by increasing brain serotoninergic activity. During tumor growth, plasma-free tryptophan concentrations, one of the major determinants of brain tryptophan concentrations and serotonin synthesis, are significantly increased (2-4). Tryptophan entry into the brain is regulated by a specific transport system, which is competitively shared by the other large neutral amino acids (i.e., branchedchain amino acids [BCAAs], tyrosine, phenylalanine, and methionine). Thus, it is conceivable that entry of tryptophan into the brain may be reduced by increasing the plasma levels of competitors of tryptophan (7). We therefore hypothesized that the oral administration of BCAAs to cancer patients with anorexia would lead to decreased brain tryptophan concentrations and reduced serotoninergic activity, eventually resulting in an improvement of food intake. To test this hypothesis, 28 anorexic, not weight-losing patients, who had been admitted to our institutions in Italy with newly diagnosed, resectable cancers and who were undergoing surgical resection of the tumors, were enrolled in the study. None of the patients received radiotherapy and/or chemotherapy during the study or in the previous 4 weeks. The research protocol, double-blinded and placebo-controlled, was approved by the ethics committees at our institutions in Italy. After giving written, informed consent prior to surgery, patients were randomly assigned to receive either 4.8 g three times per day of a BCAA mixture (leucine, 2.36 g; isoleucine 1.28 g, and valine 1.16 g; BCAA group; n = 15 patients) or a placebo (isonitrogenous dose of glycine; placebo group; n = 13 patients), both obtained from Bracco Industria Chimica, Milan, Italy. BCAAs and a placebo, in powder form, were dissolved in tap water, and patients were required to take them orally three times per day, 60 minutes before each meal, for 7 consecutive days. Nutritional status prior to and at the end of the study was investigated by means of biochemical indices (serum levels of C3, prealbumin, transferrin, and ceruloplasmin). Daily caloric intake was evaluated in each patient throughout the study by carefully weighing food before and after each meal. The presence of anorexia was investigated prior to and at the end of the study, using a previously described questionnaire (4). On days 0 (base line), +3, and +7, blood samples were collected from all patients immediately before dinner (i.e., 1 hour after the drug, either BCAAs or a placebo, was taken) for the determination of plasma amino acids, including tryptophan, as previously described (4). Student's / test and chi-squared test were used to statistically analyze the results. A two-sided P value of <.05 was considered to indicate statistical significance. Data are expressed as mean value ± standard error. Only 25 patients completed the study, since three patients (one in the placebo group and two in the BCAA group) underwent surgery earlier than anticipated for reasons not related to the trial. Assessable patients in the placebo (n = 12) and BCAA (n = 13) groups were comparable for sex (male to female ratio = 7:5 and 7:6, respectively), age (64.6 ± 3.1 years [range, 41-81 years] and 65.0 ± 3.1 years [range, 47-83 years], respectively), and tumor origin (lung/gastrointestinal tract/urinary bladder/pancreas/ breast/neck; 4/4/1/1/1/1 and 5/5/1/1/1/0, respectively). In all patients, the biochemical indices of nutritional status were within the normal range prior to and at the end of the study (data not shown). In the placebo group, plasma amino acid patterns did not change throughout the study period (Fig. 1, A and B). In the BCAA group, plasma large neutral amino acids (LNAAs) increased significantly (Fig. 1, A), mainly as a consequence of an increase in BCAA concentrations (104.7 ± 14.4 |imol/dL on day +7; +121% versus base line; P<.0\\). Consequently, the free tryptophan/LNAA ratio, which closely predicts brain tryptophan concentrations (5), decreased significantly in patients receiving BCAA (Fig. 1, B). The incidence of anorexia decreased significantly among patients in the BCAA group when compared with the base line (100% prior to and 45% at the end of the study; P<.05), while it did not change among patients in the placebo group (100% versus 84%, respectively). When compared with the base line, caloric intake by the patients increased significantly in the BCAA group but remained unchanged in the placebo group (Fig. 2). Cancer anorexia impinges significantly on quality of life, reduces the benefits of antineoplastic therapy, and ultimately

Plasma and CSF tryptophan in cancer anorexia

Abstract: Eighteen untreated cancer patients and ten sex- and age-matched healthy volunteers were studied. In all patients eating behavior was investigated by means of a specific questionnaire from which the presence of anorexia and anorexia-related symptoms was assessed. To investigate the role of tryptophan in cancer anorexia, fasting plasma and CSF levels of tryptophan and other neutral amino acids were assayed in patients and controls. Cancer patients showed abnormally high plasma free tryptophan levels. In case of patients with cancer anorexia a significant rise of the ratio in plasma between free and tryptophan/large neutral amino acids, competing with tryptophan for its brain entry, was observed. This increase was correlated to a consistent rise of CSF tryptophan levels suggesting a specific role of the serotoninergic system in the pathogenesis of cancer anorexia.

Cytokines, tryptophan and anorexia in cancer patients before and after surgical tumor ablation.

Abstract: Serotoninergic system activity and cytokine production have been both implicated in the pathogenesis of cancer anorexia. To verify the existence of relationships between tryptophan, cytokines and anorexia, twenty cancer and six non-neoplastic patients were studied. Plasma amino acid concentration, including tryptophan, and spontaneous and LPS stimulated tumor necrosis factor and interleukin-1 release from peripheral blood mononuclear cells were determined before and after surgery in both groups of patients. A close relationship between plasma free tryptophan concentration and anorexia was observed, whereas no relationship between cytokine production and either anorexia or plasma tryptophan was found in cancer patients.

Increased plasma free tryptophan levels in human cancer: a tumor related effect?

Abstract: High free tryptophan (F-TRP) plasma levels are found in cancer patients (CP). F-TRP plasma concentrations are affected by the levels of its carrier, albumin (ALB), and free fatty acids (FFA) competing with TRP for ALB binding sites. The lack of correlation between F-TRP, ALB and FFA in CP suggests a tumor-dependent effect on the rise in F-TRP. To verify this hypothesis, F-TRP, ALB and FFA levels were assayed in 12 lung and 16 breast CP susceptible to radical surgery, before and 15 days after surgical removal of the tumor. F-TRP levels significantly decreased after tumor ablation. Since no correlation was found between F-TRP, ALB and FFA variations, it is conceivable that the tumor itself may be responsible for the high F-TRP levels in CP.

Cachexia in cancer patients

Abstract: Cachexia — the massive (up to 80%) loss of both adipose tissue and skeletal muscle mass — is a significant factor in the poor performance status and high mortality rate of cancer patients. Although this metabolic defect has been known since cancer was first studied, it is only recently that major advances have been made in the identification of catabolic factors that act to destroy host tissues during the cachectic process. Although anorexia is frequently present, depression of food intake alone seems not to be responsible for the wasting of body tissues, as nutritional supplementation or pharmacological manipulation of appetite is unable to reverse the catabolic process — particularly with respect to skeletal muscle. However, recent clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors and modifiers of the central effects on appetite might also show promise.