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C Cangiano

Publications and source records attributed to C Cangiano.

At least 19 recordsLinked to original sources
PubMed2004

Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications.

RATIONALE: To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. OBJECTIVES: The aim of this study is to compare the occupancy of striatal D2 receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D2 occupancy by dopamine as a result of these treatments. METHODS: Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [123I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V3") after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]-1. D2 receptor occupancy was calculated by comparing V3" measured in treated patients to an age-corrected V3" value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1-(V3" treated/V3" drug free). RESULTS: V3" was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23+/-0.06 versus 0.34+/-0.08, P=-0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69+/-8% versus 55 +/-11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D2 receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D2 receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D2 receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D2 receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required. CONCLUSIONS: These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D2 receptors to levels slightly lower than those found in unmedicated healthy subjects.

Adult↗
PubMed2000

Effects of intra-VMN mianserin and IL-1ra on meal number in anorectic tumor-bearing rats.

BACKGROUND: Tumor growth in animals and humans is associated with the onset of anorexia and reduced food intake. We previously demonstrated that the ventromedial nucleus of hypothalamus (VMN) plays a contributory role in mediating cancer anorexia. Because serotonin and interleukin-1 (IL-1) are putative mediators of cancer anorexia, we hypothesized that their influence on food intake during tumor growth might occur via their action within the VMN. METHODS: To test this hypothesis, 12 Fischer rats injected subcutaneously with 10(6) viable MCA sarcoma cells (TB rats) and their nontumor-bearing controls (NTB, n = 13) were studied. When anorexia developed, TB and NTB rats received bilateral intra-VMN microinjections of the serotonin antagonist mianserin (200 nmol) or the IL-1 receptor antagonist (IL-1ra, 25 ng). Food intake and its determinants of meal number and size were continuously recorded via a computerized device. RESULTS: In NTB rats, intra-VMN mianserin did not affect food intake, whereas after IL-1ra or vehicle a momentary decrease in food intake due to a predominant reduction of meal size occurred. In TB rats, intra-VMN mianserin or IL-1ra selectively increased meal number, leading to improved food intake. CONCLUSIONS: Data suggest that intra-VMN serotonin and IL-1 are involved in influencing cancer related anorexia.

Animals↗
PubMed1999

Peripherally injected IL-1 induces anorexia and increases brain tryptophan concentrations.

Interleukin-1 is an anorexigenic cytokine, and is involved in the pathogenesis of cancer anorexia. Interleukin-1 induced anorexia is mediated by direct action within the hypothalamus, and by peripheral mechanism(s) yet to be determined. Here we present evidence showing that in an animal model the peripheral injection of interleukin-1 is followed by a significant rise in brain tryptophan concentrations. Tryptophan is the precursor of the neurotransmitter serotonin, known to mediate the onset of satiety under normal and pathological conditions. By inference, we conclude that interleukin-1 induced anorexia is mediated by at least two different mechanism: i) interleukin-1 direct action within the hypothalamus; ii) increased brain serotonergic activity, secondary to interleukin-1 induced increased brain availability of the serotonin precursor, tryptophan.

Animals↗
PubMed1999

Effect of cisplatin and paclitaxel on plasma free tryptophan levels. An in vitro study.

UNLABELLED: Emesis is a common side effect of some antineoplastic drugs. Cisplatin (CP) induces a biphasic pattern of emesis referred to as acute (AE) and delayed (DE) emesis. The serotonergic system plays a major role in the pathogenesis of CP-induced AE, as suggested by the therapeutic efficacy of 5HT3 receptor antagonists. The pathogenesis of CP-induced DE are not clear. To date, there are no pharmacological agents which satisfactorily control DE. We hypothesize that increased availability of tryptophan (TRP) for the synthesis of brain serotonin (5-HT) could, at least in part, contribute to CP-induced DE. In fact, within 2-4 hrs of administration, CP is largely bound to albumin (ALB) with consequent possible displacement of TRP which circulates in plasma mostly (90% of total plasma TRP) bound to its natural carrier, ALB. To test this hypothesis, we studied in vitro the effect of increasing doses of cisplatin on F-TRP in plasma obtained from healthy volunteers. We also tested the effects of therapeutic amounts of paclitaxel, an antineoplastc agent which does not cause emesis. RESULTS: F-TRP concentrations increased in a dose-dependent manner following incubation with cisplatin, in contrast to paclitaxel (PTX). CONCLUSIONS: The preliminary data obtained suggest that CP, but not PTX, at therapeutic doses, increases plasma F-TRP concentrations. This increase has likely negligible relevance in CP-induced AE, which is induced by the 5-HT released by the enterochromaffin cell system, while it might play a role in the pathogenesis of CP-induced DE. In fact, CP binding to ALB is stable for 4-5 days following administration, thus suggesting long-term TRP displacement from ALB and enhanced brain 5-HT synthesis and release. Whether increased TRP availability for 5-HT synthesis might be the pathogenic mechanism for CP-induced DE in vivo, is currently being tested.

Cisplatin↗
PubMed1999

Effect of kynurenine on tryptophan-albumin binding in human plasma.

Increased plasma free tryptophan levels have been reported in cancer patients and causally associated to the presence of anorexia. The pathogenesis of this occurrence is yet to be completely understood. Kynurenine is a metabolite of tryptophan, and has been reported increased in plasma during tumor growth. Because of the similarities between tryptophan and kynurenine we speculate that their rise in the presence of a tumor might be causally related. To test this hypothesis, we performed a series of in-vitro studies, showing that kynurenine supplementation reduces the amount of tryptophan bound to albumin, and thus, by competition, increases free tryptophan levels. The likely clinical consequences of these findings are discussed.

Humans↗
PubMed1998

Clinical and metabolic effects of different parenteral nutrition regimens in patients undergoing allogeneic bone marrow transplantation.

BACKGROUND: Nutrients may interfere with physiological and pathophysiologic mechanisms. The present study was aimed at evaluating whether the differences in the quality of energy substrates administered with total parenteral nutrition (TPN) after cytoreductive therapy may influence the clinical outcome of patients undergoing bone marrow transplantation (BMT). METHODS: Sixty-six consecutive allogeneic BMT patients with hematologic malignancies were randomized to receive either a glucose-based (100% glucose) or a lipid-based (80% lipid, using an omega-6 long-chain triacylglycerol emulsion + 20% glucose) TPN, providing 146.3 kJ/kg body weight, 1.4 g of protein/kg of body weight, administered from day +1 to day +15 after BMT. Time to engraftment (EGT), incidence of sepsis and metabolic complications (hyperglycemia and hypertriglyceridemia), incidence of acute graft-versus-host-disease (A-GVHD) and relapse, survival at 18 months, incidence of deaths for A-GVHD and relapse were evaluated. RESULTS: Six patients dropped out before completing the study period. Thirty-one patients in the glucose-based TPN group and 29 patients in the lipid-based TPN group were evaluated. The incidence of hyperglycemia was significantly lower in the lipid-based TPN group than in the glucose-based TPN group (3.4% vs. 32%, respectively; P=0.004). Five patients in the glucose group and none in the lipid group died for A-GVHD (P<0.05). Survival at 18 months tended to be higher in the lipid group than in the glucose group (62% vs. 42%, P=NS). Rate of bone-marrow EGT, time to EGT, incidence of sepsis and fungal infections during TPN, incidence of A-GVHD, and rate of relapse at 18 months were not different in the two groups. CONCLUSIONS: The results obtained suggest that the use of lipid-based TPN after allogeneic BMT is associated with lower incidence of lethal A-GVHD and hyperglycemia, without negatively affecting the EGT of infused cells. Intravenously administered lipids might have influenced the severity of A-GVHD likely via modulation of immune response and synthesis of cytokines, prostaglandins, and leukotrienes that participate in the pathogenesis of graft-versus-host disease.

Adolescent↗
PubMed1998

Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients.

OBJECTIVE: In obese patients, brain serotonergic stimulation via orally administered 5-hydroxy-tryptophan (5-HTP), the precursor of serotonin, causes decreased carbohydrate intake and weight loss. Since diabetes mellitus is associated with depressed brain serotonin, hyperphagia and carbohydrate craving, we hypothesized that in diabetic patients, orally administered 5-HTP stimulates brain serotonergic activity and thus normalizes eating behaviour. To test this hypothesis, we investigated whether in diabetic patients: 1) predicted brain serotonin concentrations are depressed as a result of decreased availability of the precursor, tryptophan; and 2) oral 5-HTP is effective in reducing energy and carbohydrate intake. SUBJECTS AND METHODS: 25 overweight non-insulin dependent diabetic outpatients were enrolled in a double-blind, placebo-controlled study, and randomized to receive either 5-HTP (750 mg/d) or placebo for two consecutive weeks, during which no dietary restriction was prescribed. Energy intake and eating behaviour, as expressed by macronutrient selection, were evaluated using a daily diet diary. Plasma amino acid concentrations and body weight, as well as serum glucose, insulin and glycosylated haemoglobin were assessed. RESULTS: 20 patients (nine from the 5-HTP group and 11 from the Placebo group) completed the study. Brain tryptophan availability in diabetic patients was significantly reduced when compared to a group of healthy controls. Patients receiving 5-HTP significantly decreased their daily energy intake, by reducing carbohydrate and fat intake, and reduced their body weight. CONCLUSIONS: These data confirm the role of the serotonergic system in reducing energy intake, by predominantly inhibiting carbohydrate intake, and suggest that 5-HTP may be safely utilized to improve the compliance to dietary prescriptions in non-insulin dependent diabetes mellitus.

5-Hydroxytryptophan↗
PubMed1997

Plasma tryptophan levels and anorexia in liver cirrhosis.

OBJECTIVE: Increased brain tryptophan (TRP) availability for serotonin synthesis may play a role in the pathogenesis of anorexia. Since in chronic liver failure, increased plasma and cerebrospinal fluid TRP concentrations are characteristically reported, we hypothesize that also in liver cirrhosis increased brain TRP availability may constitute the pathogenic mechanism of anorexia. To test this hypothesis, the association between anorexia and plasma TRP was investigated. METHODS: Anorexia and plasma amino acid concentrations were evaluated in 16 patients with liver cirrhosis and compared with those obtained in 13 healthy volunteers. RESULTS: According to a questionnaire, 11 cirrhotic patients were considered as anorectic. In these patients, brain TRP availability was significantly higher than in nonanorectic patients and controls. DISCUSSION: Increased brain TRP availability is also associated with anorexia in liver cirrhosis, and supports the hypothesis that increased serotonergic activity may constitute the common pathogenic mechanism for anorexia associated with different diseases.

Adult↗
PubMed1996

Mechanism of early tumor anorexia.

Whether in tumor-bearing rats a temporal relationship exists between an increase in plasma free tryptophan (FTRP), an increase in brain serotonin (5-HT), and onset of anorexia was studied. Rats were assigned to three groups: tumor-bearing (TB), pair fed (PF), and controls. Food intake was recorded daily. In TB rats anorexia developed on Day 18 and thereafter food intake decreased progressively until end of study. After tumor inoculation, tumor became palpable on Day 10 and continued to grow exponentially until end of study. Rats were killed on Days 6, 10, 16, 18, 22, and 26 to determine plasma FTRP, FTRP/LNAA, and brain 5HT and compared to PF and controls. On Day 6, before tumors became detectable, FTRP and FTRP/LNAA were increased (P < 0.05) in TB rats vs controls. Both continued to increase so that by Day 18 when food intake had started to decrease (P < 0.05), brain 5-HT increased and correlated with the onset of anorexia (R2 = 0.6, P < 0.05). Increases in plasma FTRP the precursor to brain 5-HT occurred in TB rats before physical appearance of tumor and increased until an increase in brain 5-HT occurred, leading to anorexia.

Amino Acids↗
PubMed1996

Cancer anorexia: new pathogenic and therapeutic insights.

During tumor growth, anorexia and reduced food intake markedly contribute to the development of malnutrition, thus worsening overall patients' survival. A better understanding of the pathophysiology of eating behavior may lead to new and more effective therapies, aiming at counteracting the detrimental effects of anorexia and reduced food intake on nutritional status and survival in cancer patients. Brain tryptophan and serotonin concentrations seem to play a pivotal role in the regulation of eating behavior. Increased brain serotonin activity is indeed associated with a reduction of food intake. It has been recently hypothesized that increased availability of tryptophan to the brain and the consequent increased serotonin activity may represent the pathogenic mechanism for cancer-associated anorexia. According to this hypothesis, the modulation of brain serotonin activity may result in an improvement of anorexia. Reducing brain tryptophan availability represents a possible mechanism to restore brain serotonin activity to normal. There is evidence that the oral administration of neutral amino acids competing with tryptophan for brain entry results in a significant improvement of cancer anorexia. The same treatment may also be effective in improving secondary anorexia, which is associated with other chronic illnesses, including renal and liver failure, sepsis, and so forth, sharing a similar pathogenic mechanism.

Animals↗
PubMed1996

Cracking the riddle of cancer anorexia.

During tumor growth, anorexia and reduced food intake are among the major causes leading to malnutrition and eventually cachexia, which negatively affect patients' outcome. Consistent evidence from our laboratories in rats and humans indicates a key role for ventromedial hypothalamic (VMH) serotonergic system in the development of cancer anorexia. Thus, we postulated that during cancer, increased plasma tryptophan levels (the precursor of serotonin) lead to increased cerebrospinal fluid tryptophan concentrations and increased VMH serotonin synthesis, which then mediates the occurrence of anorexia. However, recent data strongly suggest that factors other than tryptophan supplied to the central nervous system might be involved in the pathogenesis of reduced food intake during tumor growth. Particularly, a significant role appears to be played by interleukin-1 (IL-1). We recently showed that IL-1 infusion in normal rats causes changes in food intake and its determinants, meal number and meal size, similar to those characterizing cancer anorexia, thus supporting the involvement of this cytokine in the development of anorexia. Interestingly, IL-1 and the VMH serotonergic system appear to be closely linked: peripherally infused IL-1 increases brain tryptophan and serotonin concentrations, while intracerebrally infused IL-1 increases neuronal firing rate and serotonin release. We therefore hypothesize that during tumor growth, increased production/secretion of IL-1 occurs, which facilitates the tryptophan supply to the brain. IL-1 can then also act on the VHM itself, where IL-1 receptors exist, to increase its neuronal activity and serotonin release. In other words, we believe that centrally acting IL-1 increases hypothalamic neuronal firing rate and serotonin release, while peripherally acting IL-1 is critical in supplying the hypothalamus with the precursor, tryptophan, in order to maintain the high rate of serotonin synthesis. Also, additional factors recently proposed as mediators of anorexia (including neuropeptide Y and nitric oxide) appear to be part of the hypothesized pathogenic mechanism.

Animals↗
PubMed1992

Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan.

Previous observations have shown that oral administration of 5-hydroxytryptophan (5-HTP) without dietary prescriptions causes anorexia, decreased food intake, and weight loss in obese subjects. To confirm these data over a longer period of observation and to verify whether adherence to dietary restriction could be improved by 5-HTP, 20 obese patients were randomly assigned to receive either 5-HTP (900 mg/d) or a placebo. The study was double-blinded and was for two consecutive 6-wk periods. No diet was prescribed during the first period, a 5040-kJ/d diet was recommended for the second. Significant weight loss was observed in 5-HTP-treated patients during both periods. A reduction in carbohydrate intake and a consistent presence of early satiety were also found. These findings together with the good tolerance observed suggest that 5-HTP may be safely used to treat obesity.

5-Hydroxytryptophan↗
PubMed1991

Effect of energy substrate manipulation on tumour cell proliferation in parenterally fed cancer patients.

The effects of isocaloric carbohydrate-based vs. fat-based total parenteral nutrition (TPN) regimens on cancer cell proliferation and host nutritional status were evaluated in 27 patients with tumours of the gastro intestinal tract consecutively assigned to receive for 14 days: a glucose-based (A) or a lipid-based (B) TPN formula, or an oral diet (C) isocaloric and isonitrogenous to A and B. Cancer cell replication rate was evaluated by thymidine labelling index (LI) on tumour samples before and at the end of each nutritional regimen. The number of replicating cells increased by 32.2% in patients receiving regimen A. LI decreased by 24.3% in patients given regimen B. LI values were slightly increased (+15%) in patients maintained on regimen C. Nutritional status remained within normal limits. None of the LI changes observed between and within the three arms of the trial were found to be statistically significant. Thus we failed to prove that glucose consistently stimulates or lipids inhibit tumour proliferation despite a trend in this sense.

Journal Article↗