Photochemical internalization and gemcitabine combined with first-line chemotherapy in perihilar cholangiocarcinoma: observations in three patients.

Photochemical internalization (PCI) is a technology to induce a localized, intracellular enhancement of therapeutics that are processed through endosomal pathways, including gemcitabine in malignant cells. In addition to a direct phototoxic and tumoricidal effect, PCI specifically disrupts endosomal membranes and, thereby, the compartmentalization of certain cytotoxic compounds to enhance a drug's intended intracellular target reach within the tissue treated. Non-resectable extrahepatic cholangiocarcinoma (eCCA) is a common primary tumor and gemcitabine/cisplatin chemotherapy is widely considered standard of care for it. PCI is well suited as an endoscopic intervention, and clinical observations in three subjects participating in a phase I/IIa dose escalation safety trial are described. The trial included patients with perihilar, non-resectable CCA suitable for standard-of-care chemotherapy. Per protocol, a single endoscopic PCI procedure with gemcitabine was conducted at the initiation of standard gemcitabine/cisplatin therapy. Sixteen patients enrolled in the initial dose escalation phase of the trial, which later was extended to explore the safety of a second PCI procedure during chemotherapy. While limited to a case series, the various clinical observations described here serve to illustrate the effects of localized, perihilar tumor targeting in appropriate patients by any safe methodology, including PCI. As previously indicated by clinical data using other localized treatment modalities, adding a directed, tumor-targeting treatment to systemic therapy to ameliorate the progressively expanding extrahepatic tumor burden can have important effects on the overall outcome of systemic treatment in many patients who have incurable eCCA.

Effect of glucagon-like peptide-1 receptor antagonism on appetite and food intake in healthy men.

BACKGROUND: Exogenous glucagon-like peptide-1 (GLP-1) inhibits eating in healthy, overweight, and diabetic subjects. OBJECTIVE: The GLP-1 receptor antagonist exendin(9-39)NH2 (ex9-39) was used to further explore the role of GLP-1 as an endogenous satiation signal. DESIGN: Two double-blind, 4-way crossover studies were performed, each of which included 10 healthy men. In study A, subjects received an intravenous infusion of ex9-39 or saline plus an oral glucose preload and an intraduodenal infusion of saline or glucose for 60 min. In study B, intravenous infusions were identical, but an oral mixed-liquid meal preload and a 60-min intraduodenal infusion of saline or oleic acid were administered. Thirty minutes after oral preloads, subjects ate and drank ad libitum, and amounts ingested and the time to meal completion were quantified. In addition, appetite and plasma GLP-1, peptide YY (PYY), insulin, glucagon, and blood glucose concentrations were measured. RESULTS: In both studies, GLP-1, PYY, and glucagon were substantially higher with intravenous ex9-39 than with intravenous saline (P ≤ 0.001). Insulin was lower with intravenous ex9-39 during intraduodenal glucose (P ≤ 0.05). The decrease in prospective food consumption and desire to eat during ad libitum eating after glucose ingestion was slightly attenuated (P ≤ 0.05 and P ≤ 0.01, respectively) with ex9-39. However, with intravenous ex9-39, food and fluid intakes and eating duration were not changed in either study. CONCLUSIONS: GLP-1 receptor antagonism slightly modulates appetite during ad libitum eating, but food and fluid intakes and meal duration remain unchanged, suggesting that endogenous GLP-1 is a weak satiation signal. However, concomitant substantial increases in plasma PYY and glucagon may counteract a desatiating effect of ex9-39. The effect of ex9-39 on PYY secretion supports an autoinhibitory feedback mechanism that controls L cell secretion; the effect on insulin and glucagon confirms the role of GLP-1 in glycemic control through its action on pancreatic α and ß cells.

Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion.

CONTEXT: Glucagon-like peptide-1 (GLP-1) is produced by specialized cells in the gut and secreted in response to carbohydrates and lipids. The mechanisms regulating fat-stimulated GLP-1 release have, however, not been clarified in detail. AIM: We aimed to investigate the effect of intraduodenal (ID) fat hydrolysis on GLP-1 release and test whether the signal is mediated through cholecystokinin (CCK)-1 receptors. DESIGN AND SETTING: Thirty-four healthy, male ambulatory volunteers were studied in three consecutive, randomized, double blind, crossover studies. INTERVENTION: There were three interventions: 1) 12 subjects received an ID fat infusion with or without orlistat, an irreversible inhibitor of gastrointestinal lipases, in comparison with vehicle; 2) 12 subjects received ID sodium oleate (C18:1), ID sodium caprylate (C8:0), or ID vehicle; and 3) 10 subjects received ID sodium oleate with and without the CCK-1 receptor antagonist dexloxiglumide or ID vehicle plus iv saline (placebo). The effect of these treatments on GLP-1 concentrations and CCK release was quantified. RESULTS: The following results were reached: 1) ID fat induced significant increase in GLP-1 concentrations (P < 0.004), and inhibition of fat hydrolysis by orlistat abolished this effect; 2) sodium oleate significantly stimulated GLP-1 release (P < 0.008), whereas sodium caprylate was ineffective compared with controls; and 3) dexloxiglumide administration abolished the effect of sodium oleate on GLP-1. ID fat or sodium oleate significantly stimulated plasma CCK (P < 0.006 and P < 0.004) compared with saline, whereas sodium caprylate did not. CONCLUSION: Generation of long-chain fatty acids through hydrolysis of fat is a critical step for fat-induced stimulation of GLP-1 in humans; the signal is mediated via CCK release and CCK-1 receptors.

Impaired hyperglycemia-induced delay in gastric emptying in patients with type 1 diabetes deficient for islet amyloid polypeptide.

OBJECTIVE: Slowing of gastric emptying by hyperglycemia, a physiological response to minimize postprandial hyperglycemia, may be impaired in patients with type 1 diabetes. The causes and consequences on glucose homeostasis are unknown. RESEARCH DESIGN AND METHODS: Consequences of euglycemia- and hyperglycemia-induced changes in gastric emptying on postprandial glucose fluxes and excursions were studied in 10 healthy subjects and 15 type 1 diabetic subjects after ingestion of a mixed meal using the double isotope approach ([6,6-(2)H(2)] and [1-(13)C]glucose) and scintigraphic measurements of gastric emptying. RESULTS: Gastric emptying was greater in type 1 diabetic subjects (90-120 min, P < 0.03), and 50% retention times were comparable in healthy subjects and type 1 diabetic subjects (167 +/- 8 vs. 152 +/- 10, P = 0.32). Hyperglycemia markedly delayed gastric emptying in healthy subjects but did not alter it in type 1 diabetic subjects (50% retention time 222 +/- 18 vs. 167 +/- 8 min, P = 0.003 and 148 +/- 9 vs. 152 +/- 10 min, P = 0.51). Plasma islet amyloid polypeptide (IAPP) increased approximately fourfold in healthy subjects (P < 0.001), whereas it was undetectable in type 1 diabetic subjects. IAPP replacement, using the analog pramlintide, in type 1 diabetic subjects slowed gastric emptying to a comparable extent, as did hyperglycemia in healthy subjects (P < 0.14), and greatly reduced postprandial hyperglycemia (P < 00.1). Meal-derived glucose appearance in plasma (10.7 +/- 0.5 vs. 6.8 +/- 0.7 mumol . kg(-1) . min(-1), P < 0.001) was reduced, and splanchnic glucose sequestration increased (14.0 +/- 3.0 vs. 25.0 +/- 6.0%, P = 0.04). CONCLUSIONS: In patients with type 1 diabetes the ability to delay gastric emptying in response to hyperglycemia is impaired. This impairment contributes to exaggerated rates of meal-derived glucose appearance and, ultimately, postprandial glucose excursions.

Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes Importance of postprandial glycemia to achieve target HbA1c levels.

OBJECTIVE: HbA1c values reflect overall glycemic exposure over the past 2-3 months and are determined by both fasting (FPG) and postprandial plasma glucose (PPG) levels. Cross-sectional studies suggest that attainment of HbA1c goals requires specific targeting of postprandial hyperglycemia. RESEARCH DESIGN AND METHODS: We undertook a prospective intervention trial to assess the relative contribution of controlling FPG and PPG for achieving recommended HbA1c goals. One hundred and sixty-four patients (90 male and 74 female) with unsatisfactory glycemic control (HbA1c >/=7.5%) were enrolled in an individualized forced titration intensified treatment program. RESULTS: After 3 months HbA1c levels decreased from 8.7+/-0.1 to 6.5+/-0.1% (p<0.001); FPG decreased from 174+/-4 to 117+/-2mg/dl (p<0.001); PPG decreased from 224+/-4 to 159+/-3mg/dl (p<0.001) and daylong hyperglycemia (average of premeal, postprandial and bedtime plasma glucose excluding FPG) decreased from 199+/-4 to 141+/-2mg/dl (p<0.0001). Patients' weight remained unchanged (84.0+/-1.4kg versus 82.9+/-1.5kg, p=0.36). No severe hypoglycemia occurred. Only 64% of patients achieving FPG targets of <100mg/dl achieved an HbA1c target of <7% whereas 94% of patients achieving the postprandial target of <140mg/dl did. Decreases in PPG accounted for nearly twice as much for the decreases in HbA1c as did decreases in FPG. PPG accounted approximately 80% of HbA1c when HbA1c was <6.2% and only about 40% when HbA1c was above 9.0%. CONCLUSIONS: Control of fasting hyperglycemia is necessary but usually insufficient for achieving HbA1c goals <7%. Control of postprandial hyperglycemia is essential for achieving recommended HbA1c goals.

Are gap junctions truly involved in inhibitory neuromuscular interaction in mouse proximal colon?

1. Gap junctions exist between circular muscle cells of the colon and between interstitial cells of Cajal (ICC) in the myenteric plexus of the gastrointestinal tract. They also probably couple intramuscular ICC with smooth muscle cells. Recent functional evidence for this was found in dye-coupling and myoelectrical experiments. 2. In the present study, we tested the hypothesis of gap junctions putatively being involved in neuromuscular interaction in mouse colon by using different classes of gap junction blockers. 3. Electrical field stimulation of the myenteric plexus elicited tetrodotoxin-sensitive and hexamethonium-independent fast and slow inhibitory junction potentials (fIJP and sIJP, respectively) in circular smooth muscle cells, as evaluated by intracellular recording techniques in impaled smooth muscle cells. Heptanol produced a time-dependent hyperpolarization of the membrane potential (MP) and abolished fIJP and sIJP. Octanol had no effect on the MP and abolished fIJP and sIJP. Carbenoxolone produced a time-dependent depolarization of the MP without any effect on fIJP or sIJP. The connexin 43 mimetic gap junction blocker GAP-27 had no effect on MP, fIJP or sIJP. 4. Based on the presently available gap junction blockers we found no evidence that gap junctions are involved in neuromuscular transmission in mouse colon, as suggested by morphological studies.