Manometric evaluation of the motilin receptor agonist camicinal (GSK962040) in humans.

BACKGROUND: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. METHODS: In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial. KEY RESULTS: The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH. CONCLUSIONS AND INFERENCES: Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848.

The effects of camicinal, a novel motilin agonist, on gastro-esophageal function in healthy humans-a randomized placebo controlled trial.

BACKGROUND: A proportion of patients with foregut dysmotility fail to respond to standard interventions. Motilin agonists may be beneficial in this group. We aimed to determine the effect of camicinal, a novel motilin agonist, on gastrointestinal physiology in healthy volunteers. METHODS: Healthy male subjects were randomly assigned to receive a single dose of 125 mg camicinal or placebo in a double-blind cross-over design. Esophageal function and reflux indices were assessed using high-resolution manometry (pre and 1.5-h post dose) and 24-h ambulatory multichannel intraluminal impedance/pH. After a standardized meal, subjects ingested a wireless motility capsule from which compartmental transit times and motility indices were derived. Subjects were restudied with the alternate intervention after 7 days. KEY RESULTS: The study subjects (12 male, mean age 47.4 years, range 22-55) tolerated the drug well, except one who exhibited mild abdominal pain on both placebo and camicinal. In comparison to placebo, gastric emptying time (GET) was accelerated following camicinal (-115.4 min, 95% confidence interval -194.4, -36.4, p = 0.009). No effect was demonstrable on esophageal function, small bowel, colonic, or whole bowel transit times and motility indices. With camicinal, as part of a post hoc analysis, there was a trend association between the percentage reduction in GET and total number of acidic reflux events (r = 0.56, p = 0.09). CONCLUSIONS & INFERENCES: Camicinal decreases GET and was generally well-tolerated. In health, the direct effects of camicinal are on accelerating GET with a potential secondary benefit of reducing reflux events, which warrant further exploration in patient cohorts.

Modulation of LPS-induced pulmonary neutrophil infiltration and cytokine production by the selective PPARbeta/delta ligand GW0742.

OBJECTIVE: To define the anti-inflammatory effects of PPARbeta/delta activation by use of the selective PPARbeta/delta ligand (GW0742) in a model of lipopolysaccharide (LPS)-induced pulmonary inflammation. METHODS: Male BALB/c mice were pretreated for three days with the PPARbeta/delta agonist, GW0742, prior to induction of LPS-mediated pulmonary inflammation. Bronchial alveolar lavage fluid (BALF) was analyzed for inflammatory cell influx and for levels of pro-inflammatory mediators. BALF-derived inflammatory cells were also collected for mRNA analysis. RESULTS: Pretreatment with GW0742 resulted in a significant decrease in leukocyte recruitment into the pulmonary space. Protein and mRNA levels of the pro-inflammatory cytokines IL-6, IL-1beta and TNFalpha in BALF were found to be significantly decreased in GW0742-treated animals (30 mg/kg). A significant decrease in granulocyte macrophage-colony stimulating factor (GM-CSF), a major regulator of neutrophil chemotaxis (via its downstream actions on TNFalpha and other cytokines/chemokines), activation and survival, was also noted in the BALF levels of GW0742-treated animals. CONCLUSIONS: The present study demonstrates that activation of PPARbeta/delta attenuates the degree of inflammation in a model of LPS-induced pulmonary inflammation and may therefore represent a novel therapeutic approach for the treatment of inflammation-mediated pathologies.

The seizure-related phenotype of brain-derived neurotrophic factor knockdown mice.

The present investigation focused on the seizure-related phenotype of mice lacking one allele of brain-derived neurotrophic factor. Thresholds for producing seizures in brain-derived neurotrophic factor wild-type and brain-derived neurotrophic factor heterozygous mice were compared in several seizure models, including thresholds for electrically-induced clonic, tonic-clonic and 6 Hz limbic seizures, as well as seizures induced chemically by kainate, pilocarpine and pentylenetetrazol. In addition, the rate of amygdala kindling, as well as pre- and post-kindling seizure thresholds was determined. Seizure thresholds for clonic and tonic-clonic electrically induced seizures did not differ between brain-derived neurotrophic factor wild-type and heterozygous mice. However, heterozygous mice had higher thresholds for 6 Hz limbic seizures compared with wild-type mice. Heterozygous mice also required larger doses of kainate to produce limbic seizures. Somewhat surprisingly, heterozygous mice required significantly lower doses of pilocarpine to produce limbic seizures. However, heterozygous mice required a higher dose of pentylenetetrazol to induce twitches, but not clonic seizures, compared with wild-type mice. In addition, heterozygous mice required more current to elicit focal afterdischarges in the amygdala both pre- and post-kindling than did wild-type mice, and, heterozygous mice kindled more slowly than wild-type mice. The present findings provide additional support for the hypothesis that brain-derived neurotrophic factor is involved not only in normal excitability, but may also be involved in abnormal excitability such as occurs in seizure disorders and epileptogenesis.

Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy.

Originally described as a model of 'psychomotor seizures' (J. Pharmacol. Exp. Ther. (1953) 107-273), the 6 Hz corneal stimulation model was abandoned shortly after its description because of its lack of sensitivity to phenytoin. This observation is the basis for the present study designed to validate the 6 Hz seizure as a model of therapy-resistant epilepsy. The pharmacological profile of the 6 Hz seizure was determined at varying current intensities using seven established AEDs (phenytoin, carbamazepine, clonazepam, phenobarbital, ethosuximide, trimethadione, valproic acid) and five second-generation AEDs (lamotrigine, levetiracetam, felbamate, tiagabine, topiramate). The immediate early gene c-Fos was used as a marker of seizure-induced neuronal activation to help define those brain structures that were activated by 6 Hz corneal stimulation. At the current intensity required to produce a seizure in 97% of the population (CC97=22 mA), the 6 Hz seizure did not discriminate between clinical classes of AEDs tested. Increasing the current intensity by 50% (i.e. 32 mA) decreased the sensitivity of the 6 Hz seizure to phenytoin and lamotrigine. At a current intensity of 2 x CC97 (i.e. 44 mA), only two AEDs, levetiracetam and valproic acid, displayed complete protection against the 6 Hz seizure, though the efficacy of these drugs was reduced when compared to the lower stimulation intensities. Intense c-Fos staining from 6 Hz seizures induced by 22 and 32 mA stimulus intensities remained localized to the amygdala and piriform cortex. Increasing the stimulus intensity to 44 mA resulted in additional heavy staining of the dentate gyrus. This recruitment of the dentate gyrus may account for the decrease in potency of levetiracetam and valproic acid at 44 mA. The pharmacological results combined with the c-Fos immunohistochemistry suggest that the 6 Hz stimulation may provide a useful model of therapy-resistant limbic seizures.

Conversational patterns of two-year-old twins in mother-twin-twin triads.

This study investigated the general nature of conversational interaction in mother-twin-twin triads. Four sets of firstborn twins (2;3) were videotaped during 15 minutes of free play with their mothers. Analyses revealed that triadic conversations were approximately five times longer, and elicited more turns from all speakers, than dyadic conversations between mother and a single twin. Twins also responded as often to comments and requests made to another person as to those directed to themselves, but responded more often to questions directly to them than to others, indicating reliable monitoring of language not addressed to them. These results largely parallel those reported for mother-infant-sibling triads and indicate the unique effects of triadic exchanges are not due to the relative linguistic levels of the child partners.

Intermittent vertical supranuclear ophthalmoplegia and ataxia.

A 6-year-old girl is described with a history of episodes of severe ataxia precipitated by fever since the age of 11 months and in whom mental and physical development was otherwise normal. The ataxia was associated with a complete vertical supranuclear ophthalmoplegia and normal horizontal eye movements. After resolution of the attack she had no abnormal movement of her limbs or clinical evidence of ophthalmoplegia, though electro-oculograms showed a persistent mild deficit of vertical saccades. In between the attacks hyperglycinuria, an elevated plasma glycine level (687 mumol L(-1], and negative screening for organic aciduria suggest that she may have nonketotic hyperglycinaemia. To our knowledge, intermittent vertical supranuclear ophthalmoplegia and ataxia in a normally developing child has not been reported previously.