Reversal of dopamine neurons and locomotor ability degeneration in aged rats with smilagenin.

The purpose of this paper is to study the effect of smilagenin (SMI) (PYM50028), a sapogenin compound originally identified from Chinese medicinal herb, on dopamine neurons and locomotor ability in aged rats. Experiments were carried out on young and aged Sprague-Dawley rats, which were daily administered with either SMI (18mg/kg/day) or vehicle (0.5% sodium carboxymethycellulose [CMCNa]). Open-field and rotarod performance tests revealed that behavioral ability was impaired in aged rats and was improved by oral administration of smilagenin. Immunohistochemical data showed that tyrosine hydroxylase (TH)-positive neuron numbers in the substantia nigra pars compacta (unbiased stereological counting) were altered with aging and were increased by smilagenin treatment. Likewise, the dopamine receptor density and the striatal dopamine transporter (DAT) density ((125)I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane [(125)I-FP-CIT] autoradiography) were significantly lowered in aged rats as compared to young rats, and treatment with smilagenin significantly elevated the dopamine receptor and DAT density in aged rats. Furthermore, smilagenin enhances glial cell-derived neurotrophic factor (GDNF) release both in the striatum and midbrain. These results indicate a possible role of smilagenin in the treatment of age-related extrapyramidal disorders.

Determining the direction to a sound source in air using vector sound-intensity probes.

This paper is concerned with probes for measuring vector sound intensity in air using the minimum number of sound-pressure sensors. The probes consist of an arrangement of four small microphones at the vertices of a regular tetrahedron. They are connected to a digital signal processor, which determines the sound-intensity vector, using the cross-spectral formulation based on finite-difference approximations. Determining the direction of a sound source is an obvious application. To do this accurately the probes should be omnidirectional. This implies that the microphones in the probe have to be omnidirectional and to have the same response. Results in the paper show that the direction of a sound source can be determined with an accuracy of a few degrees. Two types of probes are described. One measures the sound-intensity vector in three-dimensional space. The other measures the vector in a half space such as would occur above the ground or in front of a wall.

Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation - a double-blind, randomized, placebo-controlled, study.

BACKGROUND: Renzapride, a 5-hydroxytryptamine type-4 (5-HT(4)) receptor agonist and 5-HT(3) receptor antagonist, has been proposed as a new treatment of irritable bowel syndrome with constipation (IBS-C). AIM: To assess the efficacy and safety of renzapride in women with IBS-C. METHODS: Women with IBS-C were randomized to renzapride 4 mg daily, 2 mg b.d. or placebo for 12 weeks. The primary outcome measure was global relief of IBS symptoms. A subset of patients were enrolled in a 12-month, open-label study of renzapride 4 mg daily. RESULTS: A total of 1798 patients were included in the efficacy analysis and 971 patients entered the long-term study. The mean (S.E.M.) number of months with relief of overall IBS symptoms was 0.55 (0.04), 0.60 (0.04) and 0.44 (0.04) in the renzapride 4 mg daily, 2 mg b.d. and placebo groups (P = 0.027 and P = 0.004 respectively). Small yet statistically significant differences in favour of renzapride were observed on stool consistency and frequency, and bloating/abdominal distension scores. Renzapride was generally well tolerated; however, three episodes of ischaemic colitis were reported in the long-term study. CONCLUSION: Given the limited increase in efficacy over placebo and the incidence of ischaemic colitis observed, our data suggest that the benefit/risk ratio of renzapride is not sufficient to warrant further study in IBS-C.

Treatment of oral mucositis after peripheral blood SCT with ATL-104 mouthwash: results from a randomized, double-blind, placebo-controlled trial.

ATL-104 is a potent mitogen for epithelial cells of the gastrointestinal tract. In animal models, ATL-104 aids regeneration of the gastrointestinal tract after treatment with chemotherapeutic agents. The effect of ATL-104 on mucositis in patients requiring high-dose melphalan or BEAM before peripheral blood SCT (PBSCT) was investigated in a randomized, placebo-controlled, double-blind, two-part study. Patients were randomized to ATL-104 (50, 100 or 150 mg) or placebo once daily for 3 days before chemotherapy and 3 days after PBSCT. Part one of the study was a dose-escalation design; part two was a parallel group design using all three ATL-104 doses. Patients were followed up for 28 days post-treatment. Severity of signs and symptoms were assessed and used to calculate scores for standard toxicity rating scales (WHO, Western Consortium for Cancer Nursing Research (WCCNR)). Sixty-three patients were treated. Treatment with ATL-104 substantially reduced the median duration of severe oral mucositis (WHO grade 3 or 4) compared with placebo (median duration: ATL-104 groups 2 or 3 days, placebo 10.5 days). The effect of ATL-104 on the incidence of severe oral mucositis was inconclusive. Similar results were obtained using the WCCNR Scale. Adverse events (AEs) were predominantly mild or moderate in intensity. Gastrointestinal AE were most common.

Identification of patients with non-d, non-C irritable bowel syndrome and treatment with renzapride: an exploratory, multicenter, randomized, double-blind, placebo-controlled clinical trial.

This was an exploratory study of renzapride in 168 male and female patients with non-D, non-C irritable bowel syndrome (IBS). Patients were randomized to placebo or renzapride (1, 2, or 4 mg/day) for 8 weeks. The primary efficacy variable was patient-reported satisfactory relief of IBS symptoms. Secondary variables included relief of abdominal pain/discomfort. The proportion of patients reporting satisfactory relief of their IBS symptoms for at least 50% of the time did not differ significantly from those on placebo. However, post hoc analysis in women showed differences in responder rate on renzapride versus placebo of 18.2% (95% CI -5% to 42%; P = 0.066) during weeks 1-4 and 6% (95% CI -21% to 33%; P = 0.339) during weeks 5-8. Renzapride was well tolerated and most adverse events were mild to moderate in intensity. Further studies are warranted to determine whether renzapride is beneficial in this patient population.

Clinical trial: renzapride therapy for constipation-predominant irritable bowel syndrome--multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting.

BACKGROUND: Relatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required. AIM: To identify an appropriate dosage of renzapride (a 5-HT(4) receptor full agonist/5-HT(3) receptor antagonist) to treat abdominal pain/discomfort in patients with constipation-predominant irritable bowel syndrome. METHODS: In this randomized, placebo-controlled, phase IIb study in the primary care setting, men and women were randomized to placebo or renzapride (1, 2 or 4 mg/day) for 12 weeks. The primary outcome measure was patient self-assessed relief of abdominal pain/discomfort during weeks 5-12. Secondary efficacy measures included patients' assessment of their bowel habits, stool consistency and quality of life. RESULTS: Although there were no statistically significant differences between renzapride and placebo for relief from abdominal pain/discomfort, responder rates in the renzapride treatment groups increased dose dependently, with the 4 mg/day group being consistently numerically greater than placebo. Importantly, a larger numerical treatment difference vs. placebo was observed in women (8% and 12% respectively). Statistically significant improvements in bowel movement frequency and stool consistency were observed in the 4 mg/day group relative to placebo. Renzapride was well tolerated at all doses. CONCLUSIONS: This study confirms the gastrointestinal prokinetic effects of renzparide. The data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome.

The cardiovascular safety profile of renzapride, a novel treatment for irritable bowel syndrome.

The cardiac safety of renzapride, a novel benzamide currently under clinical development for the treatment of irritable bowel syndrome, was investigated in a four-way randomized crossover electrocardiographic clinical study in healthy human subjects and also in an in vitro cardiac conductivity study in sheep isolated Purkinje fibres. The primary endpoint in the clinical study was prolongation of the individually corrected QT interval (QTci). No clinically or statistically significant prolongation of QTci after 4 or 20 mg renzapride compared with placebo was observed. The relative effects of renzapride and cisapride in the in vitro study showed that the cardiac action potential duration was unaltered by 0.2 and 2 microM renzapride, shortened by 20 microM renzapride, and prolonged by 1 microM cisapride. Cisparide was also a 1000-fold more potent inhibitor of human ether-a-go-go related gene (hERG) channels in HEK293 cells than renzapride. These studies indicate that therapeutic doses of renzapride are unlikely to prolong cardiac action potentials and, therefore, are also unlikely to cause cardiac arrhythmias in clinical use.

Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients.

OBJECTIVE: To determine the efficacy, safety and tolerability of cetilistat (ATL-962), a novel inhibitor of gastrointestinal (GI) lipases, in obese patients. DESIGN: Phase II, multicentre, randomized, placebo-controlled, parallel group study. Enrolled patients (N=442) were advised a hypocaloric diet (deficient by 500 kcal per day, 30% of calories from fat) for a 2-week run-in period. Patients who satisfied the entry criteria (N=371) continued on the hypocaloric diet and were randomized to either placebo or one of three different doses of cetilistat (60 mg three times daily t.i.d., 120 mg t.i.d. and 240 mg t.i.d.) for 12 weeks, followed by a 4-week post-treatment follow-up. Safety, tolerability and body weight were assessed, together with other parameters associated with obesity. OUTCOME MEASURES: The primary outcome measure was absolute change in body weight from baseline. Secondary outcomes included the proportion of patients achieving pre-defined weight loss targets, changes from baseline in waist circumference and in blood lipids. GI tolerability criteria were specifically assessed, as was safety. RESULTS: Treatment with cetilistat reduced mean body weight to similar extents at all doses, which were statistically significant compared with placebo (60 mg t.i.d. 3.3 kg, P<0.03; 120 mg t.i.d. 3.5 kg, P=0.02; 240 mg t.i.d. 4.1 kg, P<0.001). Total serum and low-density lipoprotein cholesterol levels were likewise significantly reduced by 3-11% at all doses of cetilistat. Cetilistat was well tolerated. The frequency of withdrawal owing to treatment-emergent adverse events was similar between cetilistat-treated groups (5.3-7.6%) and placebo (7.6%). Adverse events were generally mild to moderate in intensity, occurred on only one occasion and were mostly GI in nature. The incidence of GI adverse events was increased in the cetilistat-treated groups compared to placebo. However, those GI adverse events, such as flatus with discharge and oily spotting, only occurred in 1.8-2.8% of subjects in the cetilistat-treated groups. CONCLUSIONS: Cetilistat produced a clinically and statistically significant weight loss in obese patients in this short-term 12-week study. This was accompanied by significant improvements in other obesity-related parameters. Cetilistat treatment was well tolerated. The risk-benefit demonstrated in this study in terms of weight loss vs intolerable GI adverse effects shows that cetilistat merits further evaluation for the pharmacotherapy of obesity and related disorders.

Analysis of acoustic communication by ants.

An analysis is presented of acoustic communication by ants, based on near-field theory and on data obtained from the black imported fire ant Solenopsis richteri and other sources. Generally ant stridulatory sounds are barely audible, but they occur continuously in ant colonies. Because ants appear unresponsive to airborne sound, myrmecologists have concluded that stridulatory signals are transmitted through the substrate. However, transmission through the substrate is unlikely, for reasons given in the paper. Apparently ants communicate mainly through the air, and the acoustic receptors are hairlike sensilla on the antennae that respond to particle sound velocity. This may seem inconsistent with the fact that ants are unresponsive to airborne sound (on a scale of meters), but the inconsistency can be resolved if acoustic communication occurs within the near field, on a scale of about 100 mm. In the near field, the particle sound velocity is significantly enhanced and has a steep gradient. These features can be used to exclude extraneous sound, and to determine the direction and distance of a near-field source. Additionally, we observed that the tracheal air sacs of S. richteri can expand within the gaster, possibly amplifying the radiation of stridulatory sound.

An evaluation of some statistical methods for analysing numbers of abnormalities found amongst litters in teratology studies.

Skeletal abnormalities in rabbit, rat and mouse foetuses are found to follow closely beta-binomial distributions rather than simple binomial distributions, i.e., foetuses from the same litter are found to have closer chances of being abnormal than foetuses from different litters. Control and treated groups of 12 litters were simulated using beta-binomial distributions and were used to compare the performances of three types of analysis on two-group teratological studies: Student's t test on the litter proportions, transformed or weighted where necessary; the Wilcoxon distribution-free on ranked litter proportions; and likelihood ratio tests assuming a beta-binomial distribution of abnormalities. It was found that the likelihood ratio tests do not have Type I errors equal to the nominal level and are not more powerful than the Student's t test or the Wilcoxon test. The latter two tests produce similar results but the Student's t test is marginally more powerful.