Sildenafil relieves symptoms and normalizes motility in patients with oesophageal spasm: a report of two cases

Oesophageal spasm presents with dysphagia and chest pain. Current treatments are limited by poor efficacy and side effects. Studies in health and oesophageal dysmotility show that sildenafil reduces peristaltic pressure and velocity; however the clinical efficacy and tolerability in symptomatic oesophageal spasm remains uncertain. We provided open-label sildenafil treatment to two patients with severe, treatment resistant symptoms associated with oesophageal spasm. The effects of sildenafil on oesophageal function and symptoms were documented by high resolution manometry (HRM). Patients were followed up to assess the efficacy of maintenance treatment with sildenafil b.i.d. HRM revealed focal and diffuse spasm in the smooth muscle oesophagus that were associated with symptoms in both cases, especially on swallowing solids. Lower oesophageal sphincter function was normal. A therapeutic trial of 25-50 mg sildenafil suppressed oesophageal contraction almost completely for water swallows; however effective, coordinated peristalsis returned with reduced frequency of spasm for solid swallows. Dysphagia and chest pain resolved during the therapeutic trial and efficacy was maintained on maintenance treatment with 25-50 mg sildenafil b.i.d. without troublesome side effects. This report shows that sildenafil can improve oesophageal function and relieve dysphagia and chest pain in patients with oesophageal spasm in whom other treatments have failed.     

Electrophysiological and morphological properties of submucosal neurons in the mouse distal colon

Abstract  The pathophysiology of intestinal secretion is increasingly studied using transgenic mouse models of colonic inflammation, but little is known about the properties of single submucosal neurons regulating epithelial secretion in the mouse. Therefore, these neurons were characterized in the mouse distal colon submucosal plexus using electrophysiological and morphological techniques. Action potentials and synaptic responses in single neurons were recorded in submucosal preparations in vitro using intracellular electrodes filled with neurobiotin, enabling subsequent morphological examination. Most neurons (∼90%) were classified as S-type neurons based on the presence of fast excitatory postsynaptic potentials (EPSPs), absence of prolonged after-hyperpolarizations, and uni-axonal morphology. These neurons rarely fired more than one action potential in response to intracellular depolarization but spontaneous fast EPSPs were observed. Fibre tract stimulation (20 Hz) elicited slow EPSPs in many neurons (37%) and slow inhibitory potentials were also observed in a subset of neurons (18%). None of these cells exhibited electrophysiological features suggestive of AH neurons. However, morphological studies demonstrated that 12% of neurons had two axons, and an immunohistochemical marker of mouse AH neurons, calcitonin gene-related peptide, was co-localized with the pan-neuronal marker HuD in 9% of neurons. Cell counts indicated that mouse distal colon ganglia were much smaller (>80% contain one to five neurons) compared to guinea-pig distal colon ganglia (∼30% contain >10 neurons). This study has shown that mouse distal colon submucosal ganglia are relatively small and, based on combined morphological and electrophysiological features, most neurons exhibit S-type characteristics.     

Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation

Abstract  Velusetrag (TD-5108) is a potent, selective high intrinsic activity serotonin 5-HT₄ receptor agonist. We assessed effects of Velusetrag on gastrointestinal transit and compared its pharmacokinetics in healthy volunteers (HV) and chronic constipation (CC) patients. Sixty HV were randomly assigned, double-blind to placebo, 5, 15, 30 or 50 mg Velusetrag (single and 6-day dosing). Primary endpoints were colonic transit (geometric centre at 24 h, GC24) and ascending colon emptying (ACE) T _1/2 after first dose. Secondary endpoints included gastric emptying (GE) T _1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T _1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T _1/2 at 15–50 mg. Pharmacokinetics studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of Velusetrag. Stimulation of bowel function after15 mg Velusetrag was similar in CC and controls. There were no serious adverse events; notable adverse events were the predictable gastrointestinal effects such as diarrhoea or altered bowel movements. Velusetrag significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted.     

Effect of a κ-opioid agonist, i.v. JNJ-38488502, on sensation of colonic distensions in healthy male volunteers

Abstract  Kappa-opioid receptors are located on visceral pain fibres. JNJ-38488502 is a highly selective tetrapeptide κ-opioid agonist with little access to the central nervous system and low risk of central nervous system side effects. The aim of the study was to evaluate the effects of i.v. JNJ-38488502 on sensations, including pain, during colonic distension. In a single-centre study, 23 healthy adult males underwent a single-dose, randomized, double-blind crossover study of JNJ-38488502 (0.42 mg kg⁻¹ i.v. infusion) vs placebo on left colon compliance, sensory thresholds and ratings during standard distensions. One participant could not undergo sensation studies. In the other 22, JNJ-38488502 increased colonic compliance (pressure at half-maximum volume 17.9 ± 0.8 mmHg) compared to placebo (21.6 ± 0.9 mmHg, P  = 0.007). There was no significant effect on sensory thresholds which, however, were not reached by 44 mmHg in >50% of participants in both treatment phases. There were no significant treatment effects on sensory ratings to distensions at 8, 16, 24, 32 and 36 mmHg above baseline operating pressure. JNJ-38488502 was associated with increased urine output and plasma prolactin, consistent with κ-opioid receptor activation. This study concluded that i.v. JNJ-38488502 induced κ-opioid effects, but did not attenuate colonic sensations following random order colonic distension. Further studies of effects on pain sensations in health and disease are required.     

The impact of FDG positron emission tomography imaging on the management of lymphomas

The role of 2-(F-18)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging in the management of patients with lymphoma has been evaluated. 29 patients (12 Hodgkin's disease, 17 non-Hodgkin's lymphoma (NHL)) who underwent FDG-PET imaging during their lymphoma treatment programme were reviewed retrospectively. Correlation between FDG-PET and CT was evaluated, together with the impact upon clinical management of the findings on FDG-PET imaging. FDG-PET added extra information to the findings on clinical examination and CT in 12 patients (41%). This was seen both in patients with negative and positive CT scan. Two false positive FDG-PET scans were seen, reflecting FDG uptake in extranodal sites. Information from FDG-PET imaging resulted in a change in clinical management in 10 patients (34%); in two, initial management was altered, and in eight consolidation therapy after completion of initial chemotherapy was influenced. These changes in clinical management occurred in six patients with high grade NHL, two with low grade NHL and two with Hodgkin's disease. No specific subgroup was identified in whom FDG-PET was particularly discriminant.