Massimo D'Amato

The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans

BACKGROUND AND AIMS The mechanism of intraduodenal fat induced inhibition of food intake is still unclear. Therefore, we tested the ability of duodenal fatty acids to suppress food intake at a lunchtime meal; in addition, we were interested to test if these effects were mediated by cholecystokinin (CCK) A receptors. SUBJECTS AND METHODS Three sequential double blind, three period crossover studies were performed in 12 healthy males each: (1) subjects received intraduodenal fat with or without 120 mg of tetrahydrolipstatin, an inhibitor of gastrointestinal lipases, or saline; (2) volunteers received intraduodenal long chain fatty acids, medium chain fatty acids, or saline; (3) subjects received long chain fatty acids or saline together with concomitant intravenous infusions of saline or loxiglumide, a specific CCK-A receptor antagonist. The effect of these treatments on food intake and feelings of hunger was quantified. RESULTS Intraduodenal fat perfusion significantly (p<0.05) reduced calorie intake. Inhibition of fat hydrolysis abolished this effect. Only long chain fatty acids significantly (p<0.05) decreased calorie intake, whereas medium chain fatty acids were ineffective. Infusion of loxiglumide abolished the effect of long chain fatty acids. CONCLUSIONS Generation of long chain fatty acids through hydrolysis of fat is a critical step for fat induced inhibition of food intake; the signal is mediated via CCK-A receptors.

Inhibition of food intake in response to intestinal lipid is mediated by cholecystokinin in humans

Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but it is not clear whether the effects are mediated by cholecystokinin (CCK) in humans. Here, we tested whether CCK-A receptors mediate the inhibition of fat on food intake. Two sequential, double-blind, crossover studies were performed in 24 male subjects. First, subjects received either intraduodenal fat or saline together with a preload of either water or banana shake. Second, 12 subjects received either intraduodenal fat or saline perfusion plus a concomitant infusion of saline or loxiglumide, a specific CCK-A receptor antagonist, together with a preload of banana shake. In both studies, subjects were free to eat and drink as much as they wished. Fat induced a reduction in calorie intake ( P < 0.05) compared with controls. Furthermore, a decrease in hunger feelings was observed. Infusion of loxiglumide abolished the effects of fat. Duodenal fat interacts with an appetizer to modulate energy intake in humans. This effect is mediated by CCK-A receptors.

Abnormalities of GI transit in bloated irritable bowel syndrome: effect of bran on transit and symptoms

OBJECTIVES:Bloating is an important but poorly understood symptom in irritable bowel syndrome (IBS) that is often aggravated by bran. The aim of our study was to determine whether IBS patients with bloating responded to bran differently from healthy controls.METHODS:A total of 12 patients with IBS (according to Rome I criteria), all with moderate to severe bloating, and 12 healthy controls participated in a two way, double blind, randomized, cross-over trial of bran versus placebo (crushed biscuits) 15 g b.i.d. An average daily pain index and bloating score were derived from daily symptom diaries. On day 14, gastric emptying, small bowel transit, percent remaining in ascending colon, and geometric center of a meal marker at 24 h were calculated from scintigraphic images obtained after ingesting a Tc99m-labeled rice pudding meal with 15 g of either placebo or coarse bran.RESULTS:Results are given as median (range). Bran significantly increased the pain index and bloating (p < 0.02) in IBS patients but not controls. The most striking finding was that the small bowel transit time of the meal without bran was markedly faster in IBS patients than in controls, being 203 min (range 109–313) versus 367 min (219–543), p < 0.001. Although in controls bran accelerated small bowel transit time to 262 min (180–380), p = 0.03, and significantly reduced % remaining in the ascending colon from 22% (0–46) to 3% (0–25), p = 0.03, this was not seen in the IBS patients. Bran accelerated whole gut transit as assessed by geometric center at 24 h in both IBS patients and controls.CONCLUSIONS:Bran accelerates small bowel transit and ascending colon clearance without causing symptoms in controls. Small bowel transit is rapid in IBS patients with bloating and, unlike in healthy control subjects, cannot be further accelerated by bran, which nevertheless aggravates symptoms of pain and bloating. We speculate that bran-induced bloating may originate in the colon rather than the small bowel.

A randomised, double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations differing by their molecular weight in symptomatic knee osteoarthritis

Objectives To compare the effects of an intermediate molecular weight (MW) intra-articular hyaluronic acid (HA) with a low MW product on knee osteoarthritis (OA) symptoms. Methods Patients with symptomatic knee OA were enrolled inarandomised, controlled, double-blind, parallel-group, non-inferiority trial with the possibility to shift to superiority. Patients were randomised to GO-ON(MW 800–1500 kD, 25 mg/2.5 ml) or Hyalgan(MW 500–730 kD, 20 mg/2 ml) injected at 3-weekly intervals. The primary outcome was 6-month change in the WOMAC pain subscale (0–100 mm). Sample size was calculated on a non-inferiority margin of 9 mm, lower than the minimum perceptible clinical improvement. Secondary endpoints included OARSI-OMERACT responder rates Results The intention-to-treat (ITT) and per-protocol (PP) populations consisted of 217 and 209 patients and 171 and 172 patients in the GO-ON and Hyalgan groups, respectively. ITT WOMAC pain of 47.5±1.0(SE) and 48.8±1.0 mm decreased by 22.9±1.4 mm with GO-ON and 18.4±1.5 mm with Hyalgan after 6 months. The primary analysis was conducted in the PP population followed by the ITT population.Mean (95% CI) differences in WOMAC pain change were 5.2 (0.9 to 9.6)mm and 4.5 (0.5 to 8.5)mm, respectively,favouring GO-ON, satisfying the claim for non-inferiority (lower limit>−9 mm) and for statistical superiority (95% CI all>0, p=0.021). Ahigher proportion of OARSI/OMERACT responders was observed with GO-ONthan with Hyalgan (73.3% vs58.4%, p=0.001). Both preparations were well tolerated. Conclusions Treatment with 3-weekly injections of intermediate MW HA may be superior to low MW HA on knee OA symptoms over 6 months, with similar safety.

Cholecystokinin-A receptor antagonists: therapies for gastrointestinal disorders

Cholecystokinin (CCK) is a peptide that exerts several regulatory functions in the periphery, as well as in the brain. The biological functions attributed to CCK are mediated by two receptor subtypes, termed CCKA and CCKB, located predominantly in the gastrointestinal (GI) tract and in the brain, respectively. Several selective and potent non-petide CCKA receptor antagonists have been synthesised and fully characterised in preclinical studies. A few of them have been, and continue to be tested in humans. This paper focuses on the data available on the effect of CCKA receptor antagonist administration in humans, and shows how, in addition to allowing a more exact definition of the role of CCK in the regulation of some GI functions, these drugs may also possess therapeutic potential in GI disorders.

Small bowel transit of a bran meal residue in humans: sieving of solids from liquids and response to feeding

Background—Ileal motor patterns are adapted to the propulsion of viscous meal residue, such as bran, which accumulates in the distal ileum postprandially. Aims—To examine the effects of a second liquid/solid meal on ileal emptying. Subjects and methods—Eleven healthy fasting subjects consumed a 1.47 MJ pancake containing 15 g bran and 5 MBq Technetium-99m labelled amberlite resin (meal A). Gastric emptying and transit through the left upper quadrant (proximal) and right lower quadrant (distal) small bowel regions and colon were assessed scintigraphically. Transit was compared with and without a second Indium-111 liquid/solid DTPA labelled 2.28 MJ meal (B) given three hours after the first meal. Results—Gastric emptying of meal A was slower than meal B (the time for 50% of the activity to leave the stomach (T50) being 113 (11) minutes versus 48 (3) minutes respectively, p<0.01, n=11). Both meals passed rapidly through the proximal small bowel (T50 meal A = 57 (14) minutes versus T50 meal B = 42 (11) minutes). Transit of meal A through the distal small bowel was much slower (T50 more than 390 minutes versus 176 (29) minutes for meal B, p<0.01), resulting in meal B overtaking meal A and entering the colon earlier. Ingestion of the second meal (B) resulted in significantly less meal A marker entering the colon (5 (3)%) at 11 hours than when meal A was taken alone (18 (4)%) (p<0.05, n=8). Conclusions—The distal small bowel selectively retains bran, allowing liquid phase markers through to the colon. Consuming a second liquid/solid meal does not stimulate ileal transit of bran which seems to be propelled quicker by fasting motor patterns.

Regulation of Fat-Stimulated Neurotensin Secretion in Healthy Subjects

CONTEXT Cholecystokinin (CCK) and neurotensin are stimulated during meal intake by the presence of fat in the small intestine. The sequence of events suggests that fat hydrolysis is crucial for triggering the release. OBJECTIVE The aim of this study was to investigate whether CCK mediated the effect of intraduodenal (ID) fat on neurotensin secretion via CCK-1 receptors. SETTING This was a single center study; 34 male volunteers were studied in consecutive, randomized, double-blind, cross-over studies. SUBJECTS AND METHODS CCK and neurotensin release were quantified in: 1) 12 subjects receiving an ID fat infusion with or without 60 mg orlistat, an irreversible inhibitor of gastrointestinal lipases, in comparison to vehicle; 2) 12 subjects receiving ID long chain fatty acids (C18s), ID medium chain fatty acids, or ID vehicle; and 3) 10 subjects receiving ID C18 with and without the CCK-1 receptor antagonist dexloxiglumide or ID vehicle plus iv saline (placebo). Hormone concentrations were measured by specific RIA systems. RESULTS ID fat induced a significant increase in CCK and neurotensin concentrations (P < 0.001-0.002). Inhibition of fat hydrolysis by orlistat abolished both effects. C18 stimulated CCK and neurotensin release (P < 0.001, respectively), whereas medium chain fatty acid was ineffective. Dexloxiglumide administration partially blocked the effect of C18 on neurotensin; the effect was only present in the first phase of neurotensin secretion. CONCLUSIONS Generation of C18 through hydrolysis of fat is a critical step for fat-induced stimulation of neurotensin in humans; the signal is in part mediated via CCK release and CCK-1 receptors.

Antiviral activity and safety profile of silibinin in HCV patients with advanced fibrosis after liver transplantation: a randomized clinical trial.

Response to interferon‐based therapies in HCV recurrence after liver transplantation (LT) is unsatisfactory, and major safety issues aroused in preliminary experience with boceprevir and telaprevir. As transplant community identified HCV viral clearance as a critical matter, efficacious and safe anti‐HCV therapies are awaited. The aim of this study was to assess efficacy and safety of intravenous silibinin monotherapy in patients with established HCV recurrence after LT, nonresponders to pegylated interferon and ribavirin. This is a single center, prospective, randomized, parallel‐group, double‐blind, placebo‐controlled, phase 2 trial including 20 patients randomly assigned (3:1) to receive daily 20 mg/kg of intravenous silibinin or saline as placebo, for 14 consecutive days. On day 14 of treatment, viral load decreased by 2.30 ± 1.32 in silibinin group versus no change in the placebo group (P = 0.0002). Sixteen days after the end of the treatment, viral load mean values were similar to baseline. Treatment resulted well tolerated apart from a transient and reversible increase in bilirubin. Neither changes in immunosuppressant through levels nor dosage adjustments were necessary. Silibinin monotherapy has a significant antiviral activity in patients with established HCV recurrence on the graft not responding to standard therapy and confirms safety and tolerability without interaction with immunosuppressive drugs (ClinicalTrials.gov number: NCT01518933).

Effect of selective CCK1 receptor antagonism on accommodation and tolerance of intestinal gas in functional gut disorders.

Participants with functional gut disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. To determine the role of cholecystokinin (CCK1) receptors on gas transit and tolerance in women with functional gut disorders.

Selective CCK1 receptor antagonism enhances accommodation and tolerance of intestinal gas in functional gut disorders

Participants with functional gut disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. To determine the role of cholecystokinin (CCK1) receptors on gas transit and tolerance in women with functional gut disorders.