Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects.

BACKGROUND/OBJECTIVE: The sweet-taste receptor (T1r2+T1r3) is expressed by enteroendocrine L-cells throughout the gastrointestinal tract. Application of sucralose (a non-calorific, non-metabolisable sweetener) to L-cells in vitro stimulates glucagon-like peptide (GLP)-1 secretion, an effect that is inhibited with co-administration of a T1r2+T1r3 inhibitor. We conducted a randomised, single-blinded, crossover study in eight healthy subjects to investigate whether oral ingestion of sucralose could stimulate L-cell-derived GLP-1 and peptide YY (PYY) release in vivo. METHODS: Fasted subjects were studied on 4 study days in random order. Subjects consumed 50 ml of either water, sucralose (0.083% w/v), a non-sweet, glucose-polymer matched for sweetness with sucralose addition (50% w/v maltodextrin+0.083% sucralose) or a modified sham-feeding protocol (MSF=oral stimulation) of sucralose (0.083% w/v). Appetite ratings and plasma GLP-1, PYY, insulin and glucose were measured at regular time points for 120 min. At 120 min, energy intake at a buffet meal was measured. RESULTS: Sucralose ingestion did not increase plasma GLP-1 or PYY. MSF of sucralose did not elicit a cephalic phase response for insulin or GLP-1. Maltodextrin ingestion significantly increased insulin and glucose compared with water (P<0.001). Appetite ratings and energy intake were similar for all groups. CONCLUSIONS: At this dose, oral ingestion of sucralose does not increase plasma GLP-1 or PYY concentrations and hence, does not reduce appetite in healthy subjects. Oral stimulation with sucralose had no effect on GLP-1, insulin or appetite.

Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents.

OBJECTIVE: To determine the efficacy of a long-acting oxyntomodulin (OXM) analogue, OXM6421, in inhibiting food intake and decreasing body weight in lean and diet-induced obese (DIO) rodents. RESEARCH DESIGN AND METHODS: The glucagon-like peptide-1 (GLP-1) receptor binding affinity and efficacy, sensitivity to enzymatic degradation in vitro and persistence in the circulation after peripheral administration were investigated for OXM6421 and compared with native OXM. The chronic effect of OXM6421 on food intake, body weight and energy expenditure was examined in lean rats, and its anti-obesity potential was evaluated in DIO mice. RESULTS: OXM6421 showed enhanced GLP-1 receptor binding affinity and cyclic adenosine monophosphate (cAMP) stimulation, and higher resistance to enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) compared with native OXM. OXM6421 persisted longer in the circulation than OXM after peripheral administration. Acute administration of OXM6421 potently inhibited food intake in lean rodents, with cumulative effects lasting up to 24 h. In lean rats, daily subcutaneous (s.c.) administration of OXM6421 caused greater weight loss than the pair-fed animals, and a higher rate of oxygen consumption than both the pair-fed and the saline controls. In DIO mice, continuous s.c. infusion of OXM6421 resulted in a significant weight loss, accompanied by an improvement in glucose homeostasis and an increase in circulating adiponectin levels. Once-daily s.c. administration of OXM6421 for 21 days caused sustained weight loss in DIO mice. CONCLUSION: OXM6421 induces negative energy balance in both lean and obese rodents, suggesting that long-acting OXM analogues may represent a potential therapy for obesity.

The palliative benefits of MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in patients with malignant mesothelioma.

BACKGROUND: With the rising incidence of malignant mesothelioma (MM), it is important to optimise treatment to control symptoms, maintain quality of life and, if possible, prolong life. We have analysed prospectively collected data to evaluate a frequently used palliative chemotherapy regimen. PATIENTS AND METHODS: Between October 1986 and May 2002 all patients with inoperable pleural mesothelioma were considered for treatment with MVP (mitomycin C 8 mg/m2 every 6 weeks, vinblastine 6 mg/m2 every 3 weeks and cisplatin 50 mg/m2 every 3 weeks) chemotherapy. Symptoms were assessed by physician assessment at baseline and after each cycle of chemotherapy. RESULTS: One hundred and fifty patients were treated with MVP for mesothelioma. Forty-three per cent had a performance status (PS) 2 or worse. The response rate was 15.3%, with 68.6% having stable disease. Sixty-nine per cent reported an improvement in symptoms; in particular there were good responses for pain (71%), cough (62%) and dyspnoea (50%). The most common grade 3/4 toxicity was neutropenia (22%). Median overall survival was 7 months, with 1-year survival 31% and 2-year survival 11%. Median survival for patients with PS 0/1 was 10 months, and was 6 months for patients with PS 2/3. Poor prognostic factors in univariate analysis included poor PS, weight loss, mixed or sarcomatoid histology, low haemoglobin and high white blood cell count. Excluding pathological subtype, the prognostic significance of poor PS and weight loss were retained in multivariate analysis. CONCLUSIONS: Palliation of symptoms in MM is achievable with current cisplatin-based treatments.

Phase I study of irinotecan and raltitrexed in patients with advanced gastrointestinal tract adenocarcinoma.

To determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of irinotecan and raltitrexed given as sequential short infusions every 3 weeks, 33 patients with pretreated gastrointestinal adenocarcinoma (31 colorectal, 2 oesophagogastric) entered this open label dose-escalation study. For the first five dose levels patients received irinotecan 175-350 mg m(-2) followed by raltitrexed 2.6 mg m(-2). Level VI was irinotecan 350 mg m(-2) plus raltitrexed 3.0 mg m(-2), level VII was irinotecan 400 mg m(-2) plus raltitrexed 2.6 mg m(-2); 261 courses were administered. Only one patient at dose levels I-V experienced DLT. At level VI, 5/12 patients experienced DLT: one had grade 3 diarrhoea and lethargy, one had grade 4 diarrhoea and one had lethargy alone. Two others had lethargy caused by disease progression. There was no first-cycle neutropenia. At level VII, 3/6 patients experienced dose-limiting lethargy, one also had grade 3 diarrhoea. Dose intensity fell from over 90% for both drugs at level VI to 83% for irinotecan and 66% for raltitrexed at level VII. Lethargy was therefore the DLT, and level VII the MTD. Pharmacokinetic data showed no measurable drug interaction; 6/30 patients (20%) had objective responses. This combination is active with manageable toxicity. Recommended doses for further evaluation are irinotecan 350 mg m(-2) and raltitrexed 3.0 mg m(-2).

Combination of raltitrexed with other cytotoxic agents: rationale and preclinical observations.

Agents for use in combination therapy should be effective as monotherapy in the tumour type of interest, have different mechanisms of action or pharmacology, and preferably non-overlapping toxicity profiles. Raltitrexed is effective as monotherapy in a number of tumour types, but it is hoped that combining it with other cytotoxic agents will lead to enhanced efficacy. Raltitrexed and 5-fluorouracil (5-FU) are specific and non-specific inhibitors, respectively, of thymidylate synthase, a critical enzyme in the de novo synthesis of DNA. Preclinical studies have indicated that raltitrexed and 5-FU have an incompletely overlapping spectrum of antitumour activity and may have additive or synergistic effects on colon carcinoma cells. These interactions are schedule-dependent (raltitrexed should precede 5-FU). Pre-treatment of colon carcinoma cells with raltitrexed has also been shown to increase intracellular levels of phosphoribosyl pyrophosphate resulting in increased incorporation of 5-FU nucleotides into RNA. Raltitrexed has a different mechanism of action from two other new agents active in colorectal cancer, irinotecan and oxaliplatin, and tumours are therefore not necessarily cross-resistant. Short pre-exposure of colon carcinoma cells to the irinotecan active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), prior to exposure to raltitrexed has consistently resulted in synergistic cell kill, whereas the reverse sequence is antagonistic. Preliminary results indicate that equitoxic doses of raltitrexed and cisplatin, or oxaliplatin, are antagonistic in two colon carcinoma cell lines. However, because there are major difficulties in translating preclinical drug combination results to the clinical settings, these results should be interpreted with caution.

Peri-radicular inflammation related to dens invaginatus treated without damaging the dental pulp: a case report.

A 12-year-old boy was referred with a discharging sinus tract related to the maxillary left lateral incisor, and with a non-vital maxillary left central incisor. The lateral incisor gave a positive response to sensitivity testing. The lesion did not heal after disinfection of the root canal of the central incisor, but healed subsequently after 'endodontic' treatment of an invagination in the lateral incisor. After 2 years the lateral incisor continued to give a positive response to sensitivity testing.

Surgical repair of a resorptive defect in an anterior tooth of an adolescent: a case report.

A case is described in which a 14-year-old girl was referred with external inflammatory resorption in the middle third of the root of her maxillary left lateral incisor; the resorptive defect was in continuity with the root canal and the prognosis was considered poor. After controlling the infection in the root canal and then repairing the defect surgically, the resorption ceased, and healing occurred, enabling the tooth to be retained.

A rare translocation (4;11)(q21;p14-15) in an acute lymphoblastic leukemia expressing T-cell and myeloid markers.

A 21-year-old male presented with a large mediastinal mass and a white cell count of 420 x 10(9)/L. A diagnosis of acute lymphoblastic leukemia (ALL) was made, with 90% of cells in the bone marrow (BM) and 99% in the peripheral blood (PB) being lymphoblasts (FAB L1). Cytogenetic analysis of these cells revealed a rare variant of the t(4;11) translocation involving chromosome arm 11p rather than 11q, namely t(4;11)(q21;p14-15). The standard form of the (4;11) translocation has been associated with leukemias with mixed-lineage phenotypes. Three cases of ALL with t(4q;11p) have previously been reported. One of these cases showed phenotypic heterogeneity involving myeloid and lymphoid lineages. The leukemia reported here also exhibits lymphoid/myeloid features. Immunophenotyping of the blasts showed that most of the cells were positive for CD2, CD5, CD7, CD10 (CALLA), CD34, and HLA-DR. A significant proportion of the cells expressed CD33. These results suggest a biphenotypic rather than a biclonal disease. Molecular analysis showed rearrangement of both immunoglobulin heavy-chain genes (JH) and of a single allele of the T-cell receptor (TCR) gamma 1 gene, while retaining germline TCR beta genes.

Effect of lactose or its component sugars on jejunal calcium absorption in adult man.

The effect of lactose vs glucose plus galactose on jejunal calcium absorption was studied in 10 subjects using a triple-lumen perfusion technique. In each, 30 cm of jejunum was perfused with two test solutions. The comparisons made were lactose (Lac) vs mannitol (Man), Lac vs glucose and galactose (GG), and Man vs GG. Compared with Man, Lac, and GG caused a significant increase in net water and sodium absorption and luminal calcium concentration. In subjects receiving both Lac and GG, water and sodium absorption were greater with GG. The only statistically significant increase in net calcium absorption occurred with Man vs GG in which water absorption increased from 16 to 350 mL.h-1.30 cm-1. However, by use of data from all test solutions, water and sodium absorption were found to be significantly correlated with calcium absorption (p less than 0.05). These results suggest that lactose or its component sugars enhance jejunal calcium absorption in proportion to their effect on fluid absorption.

Erythema multiforme associated with trazodone therapy: case report.

A 63-year-old woman with treatment-resistant depression was started on trazodone and subsequently developed erythema multiforme (EM), with lesions predominant on the distal parts of the limbs and involvement of the hands and feet, as well as her palms and soles. The patient's treatment course and subsequent remission are described. It is suggested that trazodone therapy be discontinued immediately upon notice of EM. This patient was also taking lithium, which has not been implicated in erythema multiforme.