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Biomedical subjects

C Richardson

Publications and source records attributed to C Richardson.

At least 19 recordsLinked to original sources
PubMed2007

High-resolution MRI in evaluation of the surgical anatomy of the esophagus and posterior mediastinum.

OBJECTIVE: The purpose of this study was to use high-resolution MRI to evaluate the surgical anatomy of the posterior mediastinum, in particular the esophagus and its relation to the surrounding structures. The aim was to familiarize radiologists with the appearance of structures considered important in planning surgical resection of the esophagus. MATERIALS AND METHODS: The thoraces of two cadavers were imaged with a 1.5-T magnet using a high-resolution T2-weighted sequence. Axial cadaveric sections of the posterior mediastinum were cut with a band saw at levels determined from the MR images, and histologic whole-mount sections of the esophagus and surrounding tissue were prepared from the cadaveric sections. The appearance of structures identified on the MR images was compared with the findings on corresponding gross anatomic and histologic whole-mount sections. RESULTS: The MR images depicted the esophagus and structures in close anatomic relation: the pleural reflections and pericardium. The technique enabled visualization of structures to our knowledge not previously described on cross-sectional imaging: the individual layers of the esophageal wall, the thoracic duct, a connective tissue layer attaching the esophagus to the anterior wall of the aorta, and a fascial plane passing between layers of the right and left parietal pleura posterior to the esophagus. CONCLUSION: High-resolution MRI of the posterior mediastinum provides detailed anatomic information, delineating structures not visible on other forms of cross-sectional imaging. It can provide important information for planning surgical intervention.

Aged↗
PubMed2006

The appearances of oesophageal carcinoma demonstrated on high-resolution, T2-weighted MRI, with histopathological correlation.

This paper describes the spectrum of imaging features of oesophageal adenocarcinoma seen using high-resolution T2-weighted (T2W) magnetic resonance imaging (MRI). Thirty-nine patients with biopsy-proven oesophageal adenocarcinoma were scanned using an external surface coil. A sagittal T2W sequence was used to localise the tumour and to plan axial images perpendicular to the tumour. Fast spin-echo (FSE) T2W axial sequence parameters were: TR/TE, 3,300-5,000 ms/120-80 ms; field of view (FOV) 225 mm, matrix 176x512(reconstructed) mm to 256x224 mm, giving an in-plane resolution of between 1.28x0.44 mm and 0.88x1.00 mm, with 3-mm slice thickness. Thirty-three patients underwent resection and the MR images were compared with the histological whole-mount sections. There were four T1, 12 T2, and 17 T3 tumours. The T2W high-resolution MRI sequences produced detailed images of the oesophageal wall and surrounding structures. Analysis of the imaging appearances for different tumour T stages enabled the development of imaging criteria for local staging of oesophageal cancer using high-resolution MRI. Our study illustrates the spectrum of appearances of oesophageal cancer on T2W high-resolution MRI, and using the criteria established in this study, demonstrates the potential of this technique as an alternative non-invasive method for local staging for oesophageal cancer.

Adenocarcinoma↗
PubMed2006

Etoposide and illegitimate DNA double-strand break repair in the generation of MLL translocations: new insights and new questions.

Faithful repair of chromosomal double-strand breaks (DSBs) is central to genome integrity and the suppression of genome rearrangements including translocations that are a hallmark of leukemia, lymphoma, and soft-tissue sarcomas [B. Elliott, M. Jasin, Double-strand breaks and translocations in cancer, Cell. Mol. Life Sci. 59 (2002) 373-385; D.C. van Gent, J.H. Hoeijmakers, R. Kanaar, Chromosomal stability and the DNA double-stranded break connection, Nat. Rev. Genet. 2 (2001) 196-206]. Chemotherapy agents that target the essential cellular enzyme topoisomerase II (topo II) are known promoters of DSBs and are associated with therapy-related leukemias. There is a clear clinical association between previous exposure to etoposide and therapy-related acute myeloid leukemia (t-AML) characterized by chromosomal rearrangements involving the mixed lineage leukemia (MLL) gene on chromosome band 11q23 [C.A. Felix, Leukemias related to treatment with DNA topoisomerase II inhibitors, Med. Pediatr. Oncol. 36 (2001) 525-535]. Most MLL rearrangements initiate within a well-characterized 8.3 kb region that contains both putative topo II cleavage recognition sequences and repetitive elements leading to the logical hypothesis that MLL is particularly susceptible to aberrant cleavage and homology-mediated fusion to repetitive elements located on novel chromosome partners. In this review, we will discuss the findings and implications of recent attempts to confirm this hypothesis.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Survey of the prevalence, diagnosis and treatment of dermatological conditions in small animals in general practice.

A survey was made of the prevalence, diagnosis and treatment of dermatological conditions in small animals in general practice in the UK. Out of 3707 small animal consultations in general practice that were observed and recorded, 795 (21.4 per cent) involved animals that had a dermatological problem. In dogs and exotic species, pruritus was the most common presenting sign, accounting for 30 to 40 per cent of the dermatological consultations. In cats, cutaneous swellings were the most common presentation (36 per cent). A diagnosis or recommendation for treatment was made on the basis of the presenting clinical signs and physical examination alone in 576 (72 per cent) of the cases, and various diagnostic tests were performed in the other cases. In dogs, parasitic infestations, bacterial infections and neoplasia accounted for the majority of the diagnoses. In cats, parasites and bacterial infections were the most common. In exotic species, parasites accounted for over 80 per cent of the dermatological diagnoses. In dogs, the most common final diagnoses were otitis, pyoderma, anal sac impaction, flea infestation and atopic dermatitis. In cats, abscesses, flea infestation, and otitis were the most common diagnoses. In exotic species, the most common diagnosis was an unspecified mite infestation. Systemic antibiotics were prescribed in 196 cases (25 per cent), systemic glucocorticoids were prescribed in 162 cases (20 per cent) and treatment with an ectoparasiticide was prescribed in 167 cases (21 per cent).

Animals↗
PubMed2006

An intranasal vaccine targeting both the Bacillus anthracis toxin and bacterium provides protection against aerosol spore challenge in rabbits.

An intranasal vaccine targeting the Bacillus anthracis toxin and vegetative bacterium was tested for the ability to protect immunized rabbits against aerosol B. anthracis spore exposure. Rabbits were vaccinated intranasally with PA-based vaccines formulated as dry powders with or without chitosan (ChiSys, Archimedes Development Limited), a compound that exhibits muco-adhesive properties, or as a liquid. Formulations also contained MPL adjuvant and PA. Some vaccines contained PA conjugated to a 10-mer peptide of the poly-d-glutamic acid capsule of B. anthracis. Rabbits were immunized on days 0 and 28 and aerosol challenged with an average 250LD50 Ames spores on day 85. Serum antibody was measured before and after challenge. Significant anti-PA serum IgG levels were obtained, particularly with use of ChiSys based formulations. PA-Conj induced significant anti-capsule responses, although a formulation containing free capsule peptide did not. All immunized rabbits survived the challenge, but differences in morbidity, as evidenced by anorexia, between vaccine groups were observed. Only rabbits immunized with PA+PA-Conj appeared normal throughout the post-challenge observation period (14 days), while all that received PA with the free capsule peptide appeared ill at times as evidenced by a failure to eat normally. One negative control rabbit received a lower inhaled spore dose (183LD50) and survived the challenge, although it was anorexic post-challenge. It also had a high level of anti-LF antibodies in its convalescent serum (5400 U/ml), indicating an extensive infection. In contrast, 75% of the immunized rabbits had no LF-specific antibody in their post-challenge sera, and the rest had low levels (< or = 138 U/ml), indicating that infections resulting in toxin production were avoided or greatly reduced. Thus, intranasal immunization with a chitosan-based powder vaccine combining PA and capsule epitopes provided superior protection against B. anthracis infection compared to a single antigen (PA) vaccine, as evidenced by a reduction in morbidity and prevention of death.

Adjuvants, Immunologic↗
PubMed2006

Fludarabine phosphate and melphalan: a reduced intensity conditioning regimen suitable for allogeneic transplantation that maintains the graft versus malignancy effect.

Reduced intensity conditioning (RIC) for allogeneic stem cell transplantation allows stable donor cell engraftment with the maintenance of a graft versus malignancy effect. Many different regimens exist employing various combinations of chemotherapy, radiotherapy and T-cell depletion. We examined the role of non-T-cell depleted RIC regimens in 56 patients with haematological malignancies. Patients received fludarabine phosphate for 5 days (30 mg/m2 in 35 patients, 25 mg/m2 in 21 patients) and melphalan for 1 day (140 mg/m2 in 36 patients, 100 mg/m2 in 20 patients). Immunosuppression was with CyA alone in 33 patients and CyA/MTX in 23 patients. Twenty-four of the 26 patients with chimerism data showed >95% donor chimerism at 3 months post transplant. aGVHD occurred in 18% of patients receiving CyA/MTX compared to 53% of patients receiving CyA. The 100-day mortality rate was 0.16 (95%CI 0.08-0.28) and 1-year nonrelapse mortality was 0.24 (95%CI 0.13-0.38). Thirty-three patients remained alive and in CR at a median of 19 months post transplant (range 3-38 months). We have shown that patients transplanted with fludarabine phosphate, melphalan 100 mg/m2 and with CyA/MTX as post transplant immunosuppression can achieve good disease control with an acceptable level of toxicity. Further studies are required to confirm these findings.

Adult↗
PubMed2006

Highly demanding resistive vibration exercise program is tolerated during 56 days of strict bed-rest.

Several studies have tried to find countermeasures against musculoskeletal de-conditioning during bed-rest, but none of them yielded decisive results. We hypothesised that resistive vibration exercise (RVE) might be a suitable training modality. We have therefore carried out a bed-rest study to evaluate its feasibility and efficacy during 56 days of bed-rest. Twenty healthy male volunteers aged 24 to 43 years were recruited and, after medical check-ups, randomised to a non-exercising control (Ctrl) group or a group that performed RVE 11 times per week. Strict bed-rest was controlled by video surveillance. The diet was controlled. RVE was performed in supine position, with a static force component of about twice the body weight and a smaller dynamic force component. RVE comprised four different units (squats, heel raises, toe raises, kicks), each of which lasted 60 - 100 seconds. Pre and post exercise levels of lactate were measured once weekly. Body weight was measured daily on a bed scale. Pain questionnaires were obtained in regular intervals during and after the bed-rest. Vibration frequency was set to 19 Hz at the beginning and progressed to 25.9 Hz (SD 1.9) at the end of the study, suggesting that the dynamic force component increased by 90 %. The maximum sustainable exercise time for squat exercise increased from 86 s (SD 21) on day 11 of the BR to 176 s (SD 73) on day 53 (p = 0.006). On the same days, post-exercise lactate levels increased from 6.9 mmol/l (SD2.3) to 9.2 mmol/l (SD 3.5, p = 0.01). On average, body weight was unchanged in both groups during bed-rest, but single individuals in both groups depicted significant weight changes ranging from - 10 % to + 10 % (p < 0.001). Lower limb pain was more frequent during bed-rest in the RVE subjects than in Ctrl (p = 0.035). During early recovery, subjects of both groups suffered from muscle pain to a comparable extent, but foot pain was more common in Ctrl than in RVE (p = 0.013 for plantar pain, p = 0.074 for dorsal foot pain). Our results indicate that RVE is feasible twice daily during bed-rest in young healthy males, provided that one afternoon and one entire day per week are free. Exercise progression, mainly by progression of vibration frequency, yielded increases in maximum sustainable exercise time and blood lactate. In conclusion, RVE as performed in this study, appears to be safe.

Adult↗
PubMed2006

Leukocyte count as a predictor of death during remission induction in acute myeloid leukemia.

Acute myeloid leukemia (AML) presenting with a high leukocyte count has been associated with an increase in induction mortality and poor results in a number of other survival measures. However, the level at which an elevated leukocyte count has prognostic significance in AML remains unclear. In this report on a series of 375 adult (non-M3) AML patients undergoing induction chemotherapy at a single institution, leukocyte count analyzed as a continuous variable is shown to be a better predictor of induction death (ID) and overall survival (OS) than a leukocyte count of > or = 100 x 10(9)/L, a value characteristically associated with "hyperleukocytosis" (HL). In this patient cohort, a presenting leukocyte count of > or = 30 x 10(9)/L had high sensitivity and specificity for predicting ID, and both performance status (PS) and leukocyte count more accurately predicted for ID than age. Considering these parameters in newly-diagnosed AML patients may facilitate the development of strategies for reducing induction mortality.

Adolescent↗
PubMed2006

Smoking enhances absorption of insulin but reduces glucodynamic effects in individuals using the Lilly-Dura inhaled insulin system.

AIM: To quantify the pharmacokinetic (PK) and glucodynamic (GD) impact of smoking on inhaled and subcutaneous (SC) insulin administration in healthy subjects. METHODS: This study employed the euglycemic clamp procedure in a four-period, four-way randomized crossover design. Eight smoking and eight non-smoking healthy males were given SC insulin on two occasions and human insulin inhalation powder (HIIP) on two other occasions. RESULTS: Smokers exhibited greater insulin exposure (AUC(0-t')) than non-smokers, following both routes of insulin administration (HIIP, P = 0.003, 58% increase; SC, P = 0.006, 24% increase). The maximum insulin concentration (C(max)) following HIIP was greater in smokers by 172% (P = 0.001) compared with non-smokers. The glucodynamic effects were greater in smokers following HIIP, consistent with the insulin concentration difference observed. However, maximum glucose response (R(max)) following SC was decreased by 36% (P = 0.001) and obtained later [time of maximum glucose response (TR(max)); P < 0.001] in smokers than in non-smokers. Smokers appeared less sensitive to insulin [total glucose infused during the clamp procedure normalised by total insulin exposure (G(tot))/AUC(0-t')] than non-smokers following both SC (P = 0.001) and inhaled (P = 0.011) routes of administration. CONCLUSION: Smokers had substantially increased peak HIIP insulin concentration, but the glucodynamic effect was partially offset, most likely because of increased insulin resistance.

Absorption↗
PubMed2006

The development and optimization of high spatial resolution MRI for imaging the oesophagus using an external surface coil.

This paper describes the development and optimization of an innovative technique using an external surface coil to obtain high resolution, thin section MR images of the oesophagus using volunteers. T2 weighted fast spin echo sequences were performed with and without cardiac gating. The field of view (FOV), matrix size, slice thickness, number of signal averages (NSA), and repetition time (TR)/echo time (TE) were altered to optimize signal to noise ratio (SNR) whilst maintaining spatial resolution. The effect of cardiac gating was also investigated. Workstation images were evaluated on the ability to visualize: individual oesophageal wall layers; perioesophageal fat; the azygos vein and wall of the descending aorta, giving qualitative assessment of image clarity. The optimum sequence enabled the layers of the oesophageal wall and perioesophageal tissues to be demonstrated in an acceptable scan time of 7.07 min. A FOV of less than 250 mm degraded image quality so that individual oesophageal wall layers could not be depicted and noise within the image impaired visualization of posterior mediastinal structures. The results indicate that high resolution imaging of the oesophagus using an external surface coil can depict anatomic structures clearly and that the use of cardiac gating improves image clarity. The technique offers an alternative, non-invasive method of detailed imaging of the oesophagus.

Esophageal Neoplasms↗
PubMed2005

Efficacy of antidepressants in child and adolescent depression: a meta-analytic study.

OBJECTIVES: To examine whether antidepressant drugs are superior to placebo in the treatment of juvenile depression. METHOD: Extensive literature search was done to retrieve all randomised controlled and all uncontrolled trials describing children and adolescents with a diagnosis of depression who underwent any antidepressant drug treatment. In order to combine results, separate analyses using random effect models were conducted first for controlled and then for both controlled and open studies. RESULTS: 18 controlled and 23 open trials were submitted to meta-analysis. Tricyclics showed no significant benefit over placebo. Odds ratios for SSRIs were 1.84 (95% CI 1.35-2.50) for controlled and 1.83 (95% CI 1.40-2.40) for controlled and uncontrolled studies suggesting a significant benefit over placebo. Combining all antidepressants also gave confidence interval excluding the value one. CONCLUSIONS: Despite some promising data concerning the use of SSRIs in the treatment of adolescent depression, caution is warranted until the long-term safety of these agents can be demonstrated. Insufficient data are available to judge even the short term merits of these agents in prepubertal children. There is no evidence to support the use of tricyclics in this population.

Adolescent↗
PubMed2005

Study of apoptosis and heat shock protein (HSP) expression in hepatocytes following radiofrequency ablation (RFA).

BACKGROUND: Radiofrequency ablation (RFA) of the liver produces necrosis of the hepatocytes. Histological examination shows a sharp demarcation between ablated and normal liver tissue. This experiment was carried out to study the cellular injury produced by RFA in area surrounding the ablated tissue and effect of reperfusion on this zone. MATERIAL AND METHODS: Five pigs underwent RFA of liver parenchyma. Four pigs were sacrificed 30 min after RFA and one pig was sacrificed 5 days later. Ablated lesions including surrounding liver parenchyma was examined for apoptosis and HSP 70 expression. RESULTS: There was a zone of transition surrounding the necrotic ablated area that showed apoptosis as well as increased HSP 70 expression. This was more prevalent in the pig that was sacrificed 5 days later. CONCLUSION: RFA produces sub lethal injury in the zone of transition causing apoptosis and increase in HSP 70 expression. Increased HSP expression enhances immunogenicity of these cells that can have therapeutic implications for the treatment of liver.

Animals↗
PubMed2005

Creation of porcine liver tumor using human hepatoma cell lines: experimental study.

BACKGROUND: Pig is an ideal animal to study the efficacy of surgical and ablative treatment options available for the treatment of liver tumors. But there is no liver tumor model available in pig. This experiment was carried out to create liver tumors in the pig using immunosuppression and portal tolerance. MATERIAL AND METHODS: Two mini pigs (specific pathogen free) were immunosupressed using cyclosporine, azathioprine and prednisolone immunotherapy. Human hepatoma cell line (HepG2) was delivered into the liver through portal vein injection. Engraftment of the tumor cell was monitored using regular measurement of serum alfa- fetoprotein level (AFP). Pigs were sacrificed at the end of six weeks to confirm any evidence of tumor in the liver. RESULT: Although there was rise in serum AFP level in the first week, tumor cells did not engraft in the liver and there was no evidence of liver tumor at the end of experiment. CONCLUSION: Effect of immunosuppression and portal tolerance does not prevent rejection of human hepatoma cells by porcine immune system.

Animals↗
PubMed2005

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells.

AIMS/HYPOTHESIS: Troglitazone was the first thiazolidinedione (TZD) approved for clinical use, exerting hypoglycaemic effects related to its action as a ligand of the peroxisome proliferator-activated receptor gamma receptor in adipocytes. However, emerging evidence suggests that mitochondrial function may be affected by troglitazone, and that skeletal muscle cells acutely respond to troglitazone by enhancing glucose uptake. The aim of the present study was to determine the cellular mechanisms by which troglitazone acutely stimulates glucose utilisation in skeletal muscle cells. METHODS: L6 cells overexpressing GLUT4myc were incubated with troglitazone. Glucose uptake, transport and phosphorylation as well as AMP-activated protein kinase (AMPK) signalling and insulin signalling were examined. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye JC-1. AMPK signalling was interfered with using AMPK alpha1/alpha2 siRNA. RESULTS: Troglitazone acutely (in 10 min) reduced the mitochondrial membrane potential in L6GLUT4myc myotubes and robustly stimulated AMPK activity. Following 30 min of incubation with troglitazone or insulin, 2-deoxyglucose uptake was stimulated 1.5- and 2.1-fold respectively, and in cells treated with troglitazone, a 1.8-fold increase in the 2-deoxyglucose-6-phosphate:2-deoxyglucose ratio was observed. Moreover, contrary to insulin, troglitazone did not significantly stimulate 3-O-methylglucose uptake. Unlike insulin, troglitazone did not increase surface GLUT4myc content and did not increase IRS1-associated phosphatidylinositol 3-kinase activity or Akt phosphorylation on T308 and S473. Interestingly, interfering with troglitazone-induced activation of AMPK by decreasing the expression of the enzyme using siRNA inhibited the stimulation of 2-deoxyglucose uptake by the TZD. CONCLUSIONS/INTERPRETATION: We propose that troglitazone acutely increases glucose flux in muscle via an AMPK-mediated increase in glucose phosphorylation.

AMP-Activated Protein Kinases↗
PubMed2005

Ocular motility findings in chronic progressive external ophthalmoplegia.

AIMS: To characterise the ocular motility features of chronic progressive external opthalmoplegia by quantitative and semiquantitative means. To assess the prevalence of diplopia and the binocular adaptations to nonaligned visual axes. METHOD: We studied 25 patients with chronic progressive external ophthalmoplegia. In each case muscle biopsies were consistent with mitochondrial myopathy. All patients underwent cover test in the primary position, assessment of binocular status, and measurement of uniocular fields of fixation using the Goldmann perimeter. RESULTS: A total of 23 (92%) patients had an exo-deviation, with six (26%) of those having an associated vertical deviation: 12 patients were binocular. Of the 13 patients with a manifest deviation seven had diplopia and six had suppression. Of all paired extra-ocular muscles (EOM), 68% had symmetry of movement within 5 degrees of each other. CONCLUSION: Almost all patients had an exo-deviation. Diplopia was more common than expected. The majority of patients had symmetry of EOM limitation.

Adult↗
PubMed2005

Long-term effects of pioglitazone and metformin on insulin sensitivity in patients with Type 2 diabetes mellitus.

AIM: Despite their comparable glycaemic effects in patients with Type 2 diabetes mellitus (T2DM), pioglitazone and metformin may have different effects on insulin sensitivity because they have different mechanisms of action. We studied the changes in insulin sensitivity, as assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), in patients with T2DM who used metformin or pioglitazone as monotherapy or in combination therapy with sulphonylurea. METHODS: Data in this report are from two multicentre, randomized, double-blind, double-dummy studies conducted in Europe (monotherapy) or in Europe and Canada (combination therapy study). Patients were randomized to 52 weeks of treatment consisting of a 12-week forced titration period and a 40-week maintenance period. HbA(1c), fasting plasma glucose (FPG) and fasting serum insulin (FSI) were quantified from a single blood sample at weeks 0, 8, 16, 24, 32, 42 and 52. Insulin sensitivity was assessed with QUICKI, which is calculated from FSI and fasting blood glucose (FBG) concentrations using the formula 1/(log(10) FSI + log(10) FBG). Time course effects of the treatments were compared by repeated measures analysis of covariance. RESULTS: As monotherapy, pioglitazone and metformin increased QUICKI compared with baseline (baseline vs. end point [mean +/- sem]; pioglitazone [0.303 +/- 0.001 vs. 0.321 +/- 0.001; P < 0.001] and metformin [0.304 +/- 0.001 vs. 0.315 +/- 0.001; P < 0.001]). Pioglitazone increased insulin sensitivity more than metformin from week 4 through week 52. There were significant increases in QUICKI from baseline in both combination therapy groups (baseline vs. end point; pioglitazone + sulphonylurea [0.305 +/- 0.001 vs. 0.319 +/- 0.001; P < 0.001] and metformin + sulphonylurea [0.306 +/- 0.001 vs. 0.317 +/- 0.001; P < 0.001]). Overall, pioglitazone + sulphonylurea significantly increased insulin sensitivity more than metformin + sulphonylurea. CONCLUSION: Pioglitazone differed from metformin in its effects on insulin sensitivity despite both drugs having comparable glycaemic effects.

Adult↗
PubMed2005

Techniques and trouble-shooting in high spatial resolution thin slice MRI for rectal cancer.

MRI is increasingly advocated as an optimal method of staging rectal cancer. The technique enables depiction of the relationship of tumour to the mesorectal fascia and may thus identify tumours at risk of positive circumferential margin involvement at surgery. Depth of extramural spread may also be accurately measured and tumour deposits within the mesorectum are shown. It is important that a high spatial resolution technique is used in order to accurately depict these features and care should be taken in ensuring that images acquired cover the entire rectal tumour and mesorectum. This paper describes the technique of high spatial resolution rectal cancer imaging and the potential technical pitfalls in acquiring good quality images. Important factors to consider include: adequate scan duration to achieve high spatial resolution images with sufficient signal to noise ratio, careful positioning of the pelvic phased array coil, use of T2 weighted turbo spin-echo rather than T1 weighted imaging and careful planning of scans to ensure that images are obtained perpendicular to the rectal wall.

Humans↗
PubMed2004

The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo.

1 Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 receptor agonist activity. 2 Tegaserod had significant binding affinity for human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi=7.5, 8.4 and 7.0, respectively). The 5-HT2B receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT4(c) receptors (mean pKi=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor. 3 Tegaserod (0.1-3 microm) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA2=8.3), consistent with 5-HT(2B) receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3',5' cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT4(c) receptor (mean pEC50=8.6), as well as 5-HT4) receptor-mediated relaxation of the rat isolated oesophagus (mean pEC50=8.2) and contraction of the guinea-pig isolated colon (mean pEC50=8.3). 4 Following subcutaneous administration, tegaserod (0.3 or 1 mg kg(-1)) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of alpha-methyl 5-HT (0.03 mg kg(-1)) and BW 723C86 (0.3 mg kg(-1)), selective 5-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(-1) subcutaneously) evoked a 5-HT4 receptor-mediated increase in colonic transit in conscious guinea-pigs. 5 The data from this study indicate that tegaserod antagonizes 5-HT2B receptors at concentrations similar to those that activate 5-HT4 receptors. It remains to be determined whether this 5-HT2B receptor antagonist activity of tegaserod contributes to its clinical profile.

Animals↗