Role of alpha-lipoic acid in counteracting paclitaxel- and doxorubicin-induced toxicities: a randomized controlled trial in breast cancer patients.

BACKGROUND AND OBJECTIVE: Paclitaxel and doxorubicin are associated with neurotoxicity and cardiotoxicity respectively. This study aimed at investigating the role of alpha-lipoic acid (ALA) in counteracting paclitaxel-induced neuropathy and doxorubicin-associated cardiotoxicity in women with breast cancer. PATIENTS AND METHODS: This randomized double-blind placebo-controlled prospective study included 64 patients with breast cancer who were randomized into control group (n = 32) which received 4 cycles of doxorubicin plus cyclophosphamide (every 21 days) followed by weekly doses of paclitaxel for 12 weeks plus placebo tablets once daily and ALA group (n = 32) which received the same chemotherapeutic regimen plus ALA 600 once daily for 6 months. Patients were assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0) for grading of neuropathy and by 12-item neurotoxicity questionnaire (Ntx-12). The assessment included also echocardiography and evaluation of serum levels of brain natriuretic peptide (BNP), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), and neurotensin (NT). Data were analyzed by paired and unpaired t-test, Mann-Whitney U test, and chi-square test. RESULTS: As compared to placebo, ALA provoked significant improvement in NCI-CTCAE neuropathy grading and Ntx-12 score after the end of 9th and 12th weeks of paclitaxel intake (p = 0.039, p = 0.039, p = 0.03, p = 0.004, respectively). At the end of the chemotherapy cycles, ALA resulted in significant decline in serum levels of BNP, TNF-α, MDA, and neurotensin (p < 0.05) as compared to baseline data and placebo. CONCLUSION: Alpha-lipoic acid may represent a promising adjuvant therapy to attenuate paclitaxel-associated neuropathy and doxorubicin-induced cardiotoxicity in women with breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03908528.

Release of avian neurotensin in response to intraluminal contents in the duodenum of chickens.

Peripheral and hepatic-portal plasma levels of neurotensin (NT) in fed and fasted chickens were determined using RIA. Portal levels of NT(1-13) (fed = 61.3 ± 3.9 fmol/mL; fasted = 44.5 ± 3.9 fmol/mL) were significantly higher than peripheral levels (fed = 8.2 ± 3.3 fmol/mL; fasted = 7.8 ± 3.0 fmol/mL) collected from the wing vein, indicating that some NT is metabolized in the liver. Portal plasma levels of NT collected from fed birds were also significantly higher than portal plasma levels of NT collected from fasted birds. Neurotensin, as identified by HPLC, exhibited a 2-fold increase in plasma extracts following perfusion of the proximal ileum with a 10-mg sample of oleic acid, as compared with control samples of plasma collected before oleic acid perfusion. In whole-animal studies, the injection of a micellar solution of oleic acid into isolated segments of the duodenum resulted in elevated plasma immunoreactive NT in blood collected from the pancreaticoduodenal vein. Injection of a 1,000 mOsm sodium chloride solution had a slightly lesser and delayed effect compared with oleic acid, but a greater effect than 0.1 N hydrochloric acid in isotonic saline solution. Injection of an amino acid solution (10% Travasol), 300 mOsm glucose solution, or pure corn oil had no effect. These results demonstrate that intraduodenal oleic acid is a potent stimulus for the release of NT from the duodenum into the hepatic-portal circulation of chickens.

Gut hormone levels in neonates under phototherapy.

Gastrin, vasoactive intestinal peptide (VIP) and neurotensin plasma levels were measured in three groups of healthy term newborn infants, on the 3rd, 4th and 5th days of life. Group A consisted of 15 babies without jaundice. Group B comprised of 15 babies with mild jaundice (bilirubin levels < 256 mumol/l) and group C included 15 babies with marked jaundice (bilirubin levels > 256 mumol/l) who received phototherapy for at least 24 h. There was no significant difference in gut hormone levels between groups A and B. Infants in group C had significantly lower gastrin levels compared to infants in groups A and B, on both days 4 and 5. VIP levels on the 4th day of life were significantly higher in group C in comparison to groups A and B. Neurotensin levels in the three groups did not differ significantly. Increased stool number was noted in infants in group C. Increased VIP levels in jaundiced infants under phototherapy may be the cause of increased stool frequency, through stimulation of intestinal water and electrolyte secretion.

Opposite influence of carbohydrates and fat on hypothalamic neurotensin in Long-Evans rats.

Neurotensin inhibits food intake when injected in the central nervous system and is released after fat ingestion. The aim of the present study was to measure it in different brain areas and to determine if it is involved in the long-term variations in food intake induced by the ingestion of a high-fat (HF) diet. We compared the results with those obtained with 2 low-fat [high-carbohydrates (HC)] diets and a well-balanced diet. For this purpose, weanling male Long-Evans rats were fed ad libitum for 14 weeks either on a control diet, a HF diet or a HC diet. The rats with the HC (high-starch) diet were divided into 2 subgroups: the first (HC) drank water and the second (HCS) drank a 25% sucrose solution. During the last week of the experiment, energy intake of the HCS rats was significantly greater than that of the 3 other groups of rats (+17.2%; p < 0.01; +27.1%; p < 0.001 and +34.6%; P < 0.001 vs the control, HC and HF rats respectively). NT did not vary in the midbrain and particularly in the ventral tegmental area. Its concentrations were significantly higher in the 2 HC groups than in the HF rats both in the paraventricular (PVN; p < 0.02) and dorsomedial nuclei (DMN; p < 0.03). In the DMN, they were positively correlated with energy intake (r = 0.39; p = 0.027). These results indicate that hypothalamic neurotensin is indeed involved in the long-term modulation of feeding behavior by diet composition and that fat is the more potent macronutrient for its regulation.

Changes in hypothalamic neurotensin concentrations and food intake in rats fed a high fat diet.

Neurotensin (NT), a peptide present both in the brain and in the gastrointestinal tract, has potent anorexigenic effects when centrally injected in rats and is secreted after fat ingestion. High fat diets are often associated with increased energy intake. The aim of this study was therefore to evaluate the role of neurotensin in the feeding behaviour of rats fed on a high fat (HF) diet. Adult Long-Evans rats were fed for two weeks either a control (C) well-balanced diet (n = 10) or a fat-rich diet containing about two-thirds of its energy as fat (margarine and peanut oil; n = 10). Neurotensin was measured by a specific radioimmunoassay in the plasma and in several microdissected brain nuclei involved in the regulation of feeding behaviour. Ingestion of the HF diet induced an increased body weight gain (47.6 +/- 7.7 g (HF) vs. 37.6 +/- 9.3 g (C); P less than 0.05) and an increased energy intake (+ 7.2%; P less than 0.05). Plasma fasting NT concentrations were not affected by the HF diet. In the hypothalamus, significant decreases in NT concentrations were measured in the HF rats in two nuclei important in the regulation of food intake, i.e. the paraventricular nucleus (1.72 +/- 0.16 (HF) vs. 2.27 +/- 0.15 (C) ng/mg protein; P less than 0.05) and the lateral hypothalamus (1.87 +/- 0.16 (HF) vs. 2.37 +/- 0.19 (C) ng/mg protein; P less than 0.05). On the other hand, no variations were measured in the ventral tegmental area, an important site for the metabolism and regulatory action of neurotensin and in other hypothalamic nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of oral fat on plasma levels of neurotensin and neurotensin fragments in humans. Characterization by high-pressure liquid chromatography.

The effect of ingestion of fat (Lipomul 1 g/kg) on the circulating levels of neurotensin (NT1-13) and amino-terminal fragments (NT1-8, NT1-11) and carboxy-terminal fragment (NT8-13) of NT were investigated in six healthy male volunteers. NT and NT fragments were extracted from plasma collected at 0, 15, 30, and 60 min after ingestion of fat, and the plasma levels of NT1-13 and NT fragments were characterized using high-pressure liquid chromatography and radioimmunoassay techniques. Significant elevations of plasma levels of NT1-8, NT1-11, and NT1-13 were observed at 15, 30, and 60 min after fat ingestion. The maximum elevations were 273% for NT1-8, 234% for NT1-11, and 54% for NT1-13. NT8-13 levels failed to rise significantly when compared to basal levels. These findings indicate that both the amino-terminal and carboxy-terminal fragments of NT are either released along with intact NT or are formed as metabolites from NT1-13 in response to ingestion of fat in man.

Neurotensin in hypothalamo-hypophyseal portal blood.

The control of hypothalamo-hypophyseal neurotensin secretion was studied using a modification of the Worthington-Fink portal sampling technique. Portal concentrations of neurotensin were significantly greater than the concentrations found in peripheral plasma, and HPLC characterisation demonstrated that both portal and peripheral plasma neurotensin were very similar. Two different anaesthetic agents, urethane and althesin, did not differ in the resulting portal concentrations of neurotensin. Electrical stimulation of the median eminence resulted in a very marked increase in portal neurotensin concentration.

Importance of the ileum in neurotensin released by fat.

Neurotensin is a potent stimulant of pancreatic exocrine secretion. Ileal mucosa is the storage site for about 90% of total neurotensin. Release occurs rapidly after a fatty meal and during perfusion of the duodenum and jejunum with fat but not during perfusion of the ileum with fat. To determine the origin of neurotensin released after fat stimulation, we studied the pattern of release of neurotensin before and after resection of the distal two thirds of the small bowel. Six dogs with gastric and duodenal fistulas were studied on different days. All dogs received infusions (in random order) of intraduodenal corn oil (Lipomul) (3 ml/kg/hr) and intravenous calcium chloride (0.36 mmol/kg intravenous bolus, followed by 0.36 mmol/kg/hr infusion) before and 6 weeks after resection of the distal two thirds of the small bowel with preservation of the ileocecal valve. Plasma levels of neurotensin were measured by specific radioimmunoassay. We found that release of neurotensin, in response to both intraduodenal Lipomul and intravenous calcium chloride stimulation, was abolished by resection of the distal small bowel. Before surgery, Lipomul-stimulated release of neurotensin rose to a peak concentration of 51 +/- 17 pg/ml at 30 minutes. After surgery there was no release (the levels were unchanged from basal). Before surgery, intravenous calcium chloride produced a peak release of neurotensin (52 +/- 15 pg/ml) 2 minutes after bolus injection. After surgery, neurotensin was not released by intravenous calcium. We conclude that the source of neurotensin released by perfusion of the proximal gut and by intravenous calcium infusion is the ileum. The release of neurotensin from the distal gut appears to be dependent on a signal from proximal to distal gut. The identity of the signal is unknown but is either a nerve reflex or a peptide agent.

The role of neurotensin in human gallbladder motility.

Gallbladder contraction in response to a fatty meal is thought to be caused by release of cholecystokinin (CCK). We have previously demonstrated a close correlation between circulating concentrations of CCK and contraction of the gallbladder in normal humans and in gallstone patients. Recent studies in animals, however, have shown that other potentially cholecystokinetic hormonal agents are released by a fatty meal, which suggests that other hormones may be involved in postprandial gallbladder contraction. Neurotensin, a 13-amino acid peptide, is released by fat; we have shown it to cause gallbladder contraction in dogs. In the present study, we measured release of neurotensin in seven normal adult volunteers. We determined the effects of infused neurotensin (4 pmol/kg-min) on gallbladder contractility, measured by ultrasonography in 10 adult volunteers, and we evaluated release of neurotensin in eight patients with gallstones. After ingestion of fat, we found significant release of neurotensin in normal volunteers from a mean basal concentration of 15.9 +/- 3.5 pg/ml to a maximum of 34.7 +/- 0.2 pg/ml. In the gallstone patients after fat ingestion, neurotensin rose from a basal of 16.8 +/- 3.1 pg/ml to a maximum of 53.4 +/- 28.1 pg/ml, which was a significantly greater release than in controls. Intravenous infusion of neurotensin produced dilatation of the gallbladder (from a mean basal volume of 13.7 +/- 2.3 cc to 20.0 +/- 1.8 cc). Neurotensin causes relaxation of the gallbladder in humans and, by contributing to stasis, may be involved in the formation of gallstones.

Role of neurotensin in pancreatic secretion.

The objective of this study was to examine the effect of neurotensin (NT) on pancreatic exocrine secretion in awake dogs (n = 5) with chronic gastric and pancreatic fistulas. Intravenous (IV) infusion of NT (1 microgram/kg/hr) alone significantly stimulated pancreatic secretion of protein and bicarbonate without causing release of secretin or cholecystokinin-33 (CCK-33). IV NT potentiated the secretory response of pancreatic bicarbonate to the intraduodenal (ID) infusion of HCl alone and to ID infusions of the amino acids, phenylalanine and tryptophan (AA) alone, as well as to an ID mixture of AA plus HCl. IV NT acted in an additive manner with ID AA, ID HCl, or ID AA plus HCl in the stimulation of pancreatic protein output. The addition of IV NT to each luminal secretagogue (ID AA, ID HCl, or ID AA plus HCl) failed to elevate plasma concentrations of CCK-33 or secretin over those observed during ID infusion of each secretagogue alone. ID corn oil (Lipomul) stimulated the simultaneous release of CCK-33, NT, and secretin significantly; IV infusion of NT (0.5 microgram/kg/hr) resulted in plasma NT levels that were similar to levels observed after ID Lipomul. These studies provide evidence that endogenous NT, CCK, and secretin may interact in the physiologic regulation of pancreatic exocrine secretion.