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Biomedical subjects

A V Emmanuel

Publications and source records attributed to A V Emmanuel.

18 recordsLinked to original sources
PubMed2007

Faecal incontinence.

BACKGROUND: Faecal incontinence is a life style-limiting condition with multiple aetiologies. Surgical cure is not often possible. METHODS AND RESULTS: A review of the literature was undertaken using Medline, Cochrane database and standard textbooks. Advanced imaging techniques now inform the treatment algorithm and objectively assess success. The long-term outcome of anal surgery is uncertain. Modern approaches favour conservative measures, such as biofeedback, and less invasive surgical procedures. Stoma formation is a definitive option for some patients. CONCLUSION: Current treatment of faecal incontinence is evolving from a sphincter-focused view to a more holistic one, recognizing the influence of the pelvic floor and psyche in maintaining continence. Modern imaging modalities direct treatment strategies.

Adult↗
PubMed2006

Ghrelin augments afferent response to distension in rat isolated jejunum.

Ghrelin has been shown to decrease firing of gastric vagal afferents at doses comparable with circulating levels in the fasted state. This raises the possibility that ghrelin may have a hormonal action on other vagal afferent populations. The aim of this study was to determine the effects of ghrelin on jejunal afferent activity; including responses to distension, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) and cholecystokinin (CCK) in both naïve and vagotomized rats. Ghrelin significantly augmented the afferent response to distension. No effect was observed on baseline afferent discharge, or the response to 2-methyl-5-HT and CCK. The effect of ghrelin was more pronounced at lower ramp distending pressures (0-30 mmHg). Similarly, ghrelin augmented the jejunal afferent responses to phasic distension at 10-30 mmHg, but had no effect at higher pressures. Chronic subdiaphragmatic vagotomy and administration of the growth hormone secretagogue receptor (GHS-R) antagonist [D-Lys3]-GHRP-6 prevented the augmentation of the afferent responses to distension indicating ghrelin is acting through the GHS-R on vagal afferent fibres. Ghrelin augments the mechanosensation of jejunal vagal afferents and hence may lead to increased perception of hunger contractions.

Animals↗
PubMed2005

Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study.

BACKGROUND: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. METHODS: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)-3). RESULTS: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p < 0.05) but did not correlate with GER. CONCLUSIONS: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.

Adult↗
PubMed2004

Azathioprine dose escalation in inflammatory bowel disease.

BACKGROUND: Forty per cent of patients with inflammatory bowel disease fail to respond to standard dose azathioprine (2 mg/kg/day). AIMS: To evaluate the efficacy and safety of increasing the azathioprine dose according to a fixed schedule and guided by clinical response and adverse effects. METHODS: We reviewed the records of all patients with inflammatory bowel disease treated by a single clinician over 6 years, unresponsive to at least 3 months treatment with standard dose azathioprine, and whose dose was subsequently increased. RESULTS: Forty patients (27 male; 24 Crohn's, 16 ulcerative colitis) with chronic active disease or recurrent flares despite standard dose azathioprine for a median 8 months (range 3-114) increased their dose from a median 2.02 (1.61-3.19) mg/kg/day to 2.72 (2.37-3.99) mg/kg/day in one to four increments of 0.5 mg/kg/day, and were followed over a median 6 (0.5-54) months. Eleven of the 40 patients (seven Crohn's, four ulcerative colitis) responded or had reduced frequency of flare-ups at the end of follow-up, while 17 of the 40 patients had no benefit. Response was more likely for maximum doses < or =2.5 mg/kg/day (six of 11 patients) than for doses >2.5 mg/kg/day (five of 29 patients) (P = 0.042). Twelve patients (11 of whom received maximum doses >2.5 mg/kg/day) were unable to maintain an increased azathioprine dose because of leukopenia in eight, nausea in three, and raised liver enzymes in one (all transient and reversible). CONCLUSIONS: Increasing the azathioprine dose up to 2.5 mg/kg/day appears beneficial in patients who have not responded to 2 mg/kg/day. Further increase above 2.5 mg/kg/day is less likely to be efficacious, and is associated with a substantial risk of adverse reactions.

Adult↗
PubMed2004

Erythromycin for the treatment of chronic intestinal pseudo-obstruction: description of six cases with a positive response.

BACKGROUND: Chronic intestinal pseudo-obstruction, due to intestinal myopathy or neuropathy, is characterized by the signs and symptoms of intestinal obstruction in the absence of true obstruction. Episodes are resistant to medical therapy. AIM: To determine the value of erythromycin treatment in chronic intestinal pseudo-obstruction. METHODS: All patients with proven chronic intestinal pseudo-obstruction treated with erythromycin were reviewed. Patients with symptomatic benefit are described in detail. Responders were compared with non-responders to identify the factors associated with benefit. RESULTS: Fifteen consecutive patients (nine females; median age, 37 years; median follow-up, 41 months) were treated with oral erythromycin, 1.5-2.0 g/day. Six patients (three primary visceral myopathy, two normal histology on light microscopy, one visceral myopathy secondary to scleroderma) responded, with decreased pain and vomiting, normalized bowel dysfunction and decreased episodes of ileus. Five of the six patients (83%) who responded to erythromycin were male, compared with two of the nine non-responders (22%) (P = 0.04). Four of the six responders (67%) had histological or immunohistological visceral myopathy, compared with three of the nine patients (33%) who failed to respond. Responders were less likely than non-responders to be taking long-term opiates. CONCLUSIONS: Erythromycin is effective for acute episodes of ileus and chronic symptoms in some patients with chronic intestinal pseudo-obstruction.

Adult↗
PubMed2004

Behavioural therapy (biofeedback) for solitary rectal ulcer syndrome improves symptoms and mucosal blood flow.

AIMS: The aim of the study was to determine if there is a permanent disorder of mucosal blood flow in patients with solitary rectal ulcer syndrome (SRUS) or a disorder related to autonomic gut innervation and physiological function that is reversible concomitant with successful treatment. Rectal mucosal blood flow was used as a validated measure of extrinsic autonomic nerve function. METHODS: Sixteen consecutive patients with SRUS (12 women; mean age 35 years) and 26 healthy controls (17 women; mean age 36 years) were studied. Laser Doppler mucosal flowmetry was performed before and after biofeedback treatment. Symptoms were documented before and after biofeedback treatment using a standardised prospectively applied questionnaire. RESULTS: Twelve of 16 patients (75%) reported subjective symptomatic improvement after treatment. Five of the 16 patients (31%) had sigmoidoscopic ulcer resolution. Pretreatment rectal mucosal blood flow was significantly lower in patients with SRUS compared with controls (163 (27) v 186 (14) flux units (FU) (mean (SD)); p<0.01). Biofeedback resulted in a significant improvement in rectal mucosal blood flow in subjects who felt subjectively better after biofeedback (p = 0.001), from 165 (30) FU to 190 (40) FU. CONCLUSION: Gut directed biofeedback is an effective behavioural treatment for the majority of patients with SRUS. Mucosal blood flow is reduced to a similar level seen in normal transit constipation, suggesting similar impaired extrinsic autonomic cholinergic nerve activity. Successful outcome following biofeedback is associated with increased rectal mucosal blood flow, suggesting that improved extrinsic innervation to the gut may be partially responsible for the response to treatment.

Adult↗
PubMed2003

Long-term results of low-dose intravenous ciclosporin for acute severe ulcerative colitis.

BACKGROUND: Intravenous ciclosporin for acute, severe colitis is usually administered in a dose of 4 mg/kg/day, with concurrent intravenous steroids. This is associated with considerable morbidity. We have been using a low-dose regimen, most commonly without concurrent steroids, for seven years, and present the outcome. METHODS: Records of all patients admitted for severe ulcerative colitis, treated by one physician over seven years, were reviewed. RESULTS: Thirty-one patients received low-dose intravenous ciclosporin (2 mg/kg/day) for a median 8 days. Eleven early patients received concurrent intravenous corticosteroids. Three patients had hypertension requiring dose reduction, one elevated creatinine and one elevated liver enzymes (all transient), and four experienced infection (two arm cellulitis, one perianal abscess, one post-operative wound infection). Twenty-four patients (77%) avoided urgent colectomy, and were discharged on oral ciclosporin and azathioprine. After a median 18 months (range 3-77), 14 patients (45% of total) avoided colectomy, of whom eight had flares responding to medical therapy and two had persistent, mildly active disease. CONCLUSIONS: Low-dose intravenous ciclosporin (2 mg/kg/day), usually used as a monotherapy and followed by azathioprine, achieves similar long-term efficacy to higher dose ciclosporin combined with steroids in severe acute ulcerative colitis. Morbidity appears to be low.

Acute Disease↗
PubMed2002

Prucalopride, a systemic enterokinetic, for the treatment of constipation.

BACKGROUND: Laxatives are frequently ineffective in treating constipation. An alternative therapeutic approach is to target serotonin-4 receptors, which are involved in initiating peristalsis. AIM: In a double-blind, placebo-controlled trial, to assess the efficacy and safety of a systemically active serotonin-4 agonist, prucalopride. METHODS: Seventy-four women with constipation were stratified into slow or normal transit groups, and each group was randomized to receive either placebo or 1 mg prucalopride daily for 4 weeks. A bowel function diary was maintained. Whole-gut and orocaecal transit, visceral sensitivity, quality of life and psychological state were assessed before and after treatment. RESULTS: Prucalopride, not placebo, increased spontaneous stool frequency (P=0.008) and reduced time to first stool (P < 0.001). Prucalopride reduced the number of retained markers in all patients compared to placebo (P=0.004). Prucalopride reduced the mean number of retained markers in slow transit (P=0.069), but did not alter the marker count in normal transit (P=0.86). Orocaecal transit was accelerated by prucalopride, not placebo (P=0.004). Prucalopride, notplacebo, increased rectal sensitivity to distension (urge volume, P=0.01) and electrical stimulation (P=0.001). Prucalopride significantly improved several domains of the Short Form Health Status Survey and the disease-specific quality of life. Adverse effects were similar for prucalopride and placebo. CONCLUSIONS: Prucalopride improves symptoms, upper gut transit and gut sensitivity in constipated patients with both slow and normal transit. It improves transit in patients with slow transit. These changes are associated with improved well-being.

Adult↗
PubMed2002

Gut mucosal response to food antigens in Crohn's disease.

BACKGROUND: Food antigens may contribute to gut inflammation in Crohn's disease. AIM: To assess in vivo sensitization to food antigens, ascertain whether sensitivity is gut specific, assess food sensitization in vitro, and correlate in vivo changes with histological and blood changes. METHODS: Skin testing and rectal exposure to six food antigens (cereal, cabbage, citrus, milk, yeast and peanut) and control saline were assessed double-blind by immediate and 3.5-h laser Doppler blood flowmetry, and rectal biopsies were taken. Peripheral blood lymphocyte proliferation was measured in response to the same antigens. RESULTS: Ten patients with Crohn's disease and 10 healthy controls were studied. Blood flow increased in 24 of 60 antigen sites in Crohn's disease patients and six of 60 antigen sites in controls (P < 0.0001) after 3.5 h. The Crohn's disease group demonstrated higher rectal blood flow than controls in response to all food antigens, and this was significantly different for the responses to yeast (P = 0.036) and citrus fruits (P = 0.038). Lymphocyte proliferation occurred in 32 of 60 tests in Crohn's disease patients and eight of 60 tests in controls (P < 0.0001). There were no skin responses. Submucosal oedema corresponded to increased mucosal flow. CONCLUSIONS: Crohn's disease patients demonstrate in vivo and in vitro sensitization to food antigens, which is gut specific. Mucosal flowmetry allows the identification of sensitization to gut antigens.

Adult↗
PubMed2001

Relationship between psychological state and level of activity of extrinsic gut innervation in patients with a functional gut disorder.

BACKGROUND: Anxiety and depression are known to be associated with alterations in central autonomic activity, and this may manifest as a functional gut disturbance. However, the final expression of motility disturbance is non-specific and non-quantifiable. This study examines the relationship between psychological state and psychosocial functioning with a new direct measure of the level of activity of extrinsic autonomic gut innervation, rectal mucosal Doppler blood flow. MATERIALS AND METHODS: Thirty four female patients (mean age 36 years, range 19--45) with constipation for greater than five years and 19 healthy women (mean age 38 years, range 21--60) were studied. They completed the general health questionnaire-28 point scale (GHQ-28; psychosocial functioning) and the Bem sex role inventory (BSRI; an index of women's psychological feelings about their own femininity). On the same day they underwent measurement of rectal mucosal Doppler blood flow, a new validated measure of the activity of gut extrinsic nerve innervation. Measurements were made during the follicular phase and in the fasted state. RESULTS: Women with constipation scored higher on the total GHQ-28 score and the somatisation (p=0.05) and anxiety (p=0.05) subscales of the GHQ-28. There was a negative correlation between mucosal blood flow and GHQ somatisation subscale (r=-0.45, p<0.005), anxiety (r=-0.38, p<0.05), and depression (r=-0.40, p<0.01) scores in women with constipation. Although constipated women scored no higher than controls on the BSRI, there was a significant negative correlation between blood flow and BSRI score (r=-0.49, p<0.005) for constipated women. CONCLUSIONS: General psychosocial function, somatisation, anxiety, depression, and feelings about female role are impaired in women with constipation and associated with altered rectal mucosal blood flow, a measure of extrinsic gut innervation. These findings suggest that psychological factors are likely to influence gut function via autonomic efferent neural pathways.

Adult↗
PubMed2001

Response to a behavioural treatment, biofeedback, in constipated patients is associated with improved gut transit and autonomic innervation.

BACKGROUND: Although behavioural treatment (biofeedback) successfully treats the pelvic floor abnormalities in patients with idiopathic constipation, many patients also normalise their impaired bowel frequency. We postulated that a response may be associated with altered cerebral outflow via extrinsic autonomic nerves to the gut. We investigated whether treatment changes extrinsic innervation, using mucosal laser Doppler flowmetry, whether autonomic changes are gut specific, and whether it changes gut transit. MATERIALS AND METHODS: Forty nine patients (44 female, mean age 39 years) with idiopathic constipation were studied before and after biofeedback treatment (mean five sessions). Rectal mucosal blood flow was measured by laser Doppler flowmetry to assess direct extrinsic gut nerve autonomic activity. To assess general autonomic activity, RR (interval between successive R waves on the electrocardiogram) variability, Valsalva ratio, orthostatic adjustment ratio, and phase II:IV blood pressure ratio (II:IV) of the Valsalva manoeuvre were measured. All autonomic tests were compared with those of 26 healthy volunteers (19 female, mean age 37 years). RESULTS: Twenty nine of 49 patients were symptomatically improved. Treatment reduced those with < or =3 bowel actions per week (27 v 9, pre v post), need to strain (26 v 9), and laxative or suppository use (34 v 9). Biofeedback reduced retained markers by 32% in those with slow transit and by 20% in those with normal transit. Twenty two had slow transit before treatment-14 felt symptomatic improvement of whom 13 developed normal transit. There was a significantly greater increase in rectal mucosal blood flow in patients who subjectively improved compared with those who did not (29% v 7%; p<0.03) and in those with improved bowel frequency (33% v 9%, increased v unchanged bowel frequency; p<0.05). Thirty five patients had abnormal RR variability and 33 an abnormal Valsalva ratio; one had an abnormal orthostatic adjustment ratio and one an abnormal II:IV ratio. None of the general cardiorespiratory autonomic reflexes was changed by treatment. CONCLUSIONS: Biofeedback treatment affects more than the pelvic floor. Successful outcome after biofeedback treatment is associated with improved activity of the direct cerebral innervation to the gut and improved gut transit. This effect is gut specific; cardiovascular autonomic reflexes were not altered.

Adolescent↗
PubMed2000

Behavioural treatment (biofeedback) for constipation following hysterectomy.

BACKGROUND: Constipation after hysterectomy has been postulated to be due to pelvic nerve damage, but there may be emotional or reversible physical factors of pathophysiological relevance. The aim of this study was to determine whether such constipation is responsive to behavioural treatment. METHODS: Three groups of patients who had completed a course of biofeedback treatment were compared: women with no history of abdominal or pelvic surgery (n = 25), women for whom a hysterectomy had led to no change in bowel function (n = 27) and women who stated that their constipation was precipitated (n = 18) or severely worsened (n = 8) by hysterectomy. Pretreatment and post-treatment details about bowel function and symptoms were assessed using structured interview, and pretreatment whole-gut transit time and anorectal physiology testing were assessed for prognostic relevance. RESULTS: Follow-up after completing treatment was a median of 28 (range 12-44) months. Forty-eight of 78 patients considered that their constipation had improved with treatment; the proportion in each group was similar (P = 0.73). Biofeedback reduced the need to strain, reduced abdominal pain, improved bowel frequency, and reduced laxative use to a similar degree in all three groups. Thirty-three of 53 patients with slow transit considered there was an improvement, compared with 15 of 22 with measured normal transit. Physiological testing did not predict outcome and did not differ between the three groups. CONCLUSION: The majority of patients complaining of constipation induced or worsened by hysterectomy respond subjectively to behavioural treatment, in a similar proportion to those with idiopathic constipation. In contrast to the widely held view that nerve damage is responsible for symptoms, reversible factors are likely to be important in many patients.

Adult↗
PubMed2000

Laser Doppler flowmetry as a measure of extrinsic colonic innervation in functional bowel disease.

BACKGROUND: In functional disorders it is unknown whether disturbed function is due to an intrinsic gut abnormality or altered extrinsic innervation. AIMS: To study whether measurement of mucosal blood flow could be used as a quantitative direct measure of gut extrinsic nerve autonomic activity in patients with idiopathic constipation. METHODS: Seventy two patients with idiopathic constipation and 26 healthy volunteers had rectal mucosal blood flow measurements by a laser Doppler flowmetry probe applied 10 cm from the anus. Measurements were made at rest and after inhaled placebo and ipratropium 40 microg. RESULTS: Constipated subjects had lower baseline rectal blood flow than controls. Patients with slow transit had lower mucosal blood flow than normal transit. The number of retained markers on x-ray was inversely correlated with blood flow. Ipratropium reduced blood flow compared with placebo, reduced it less in constipated patients than controls, and reduced it less in patients with slow compared with normal transit. Constipated patients, not controls, showed a significantly attenuated RR interval (the interval between successive R waves on the ECG) variability, and blood flow correlated with vagal function. CONCLUSIONS: Laser Doppler mucosal flowmetry is a gut specific, quantitative measure of extrinsic autonomic nerve activity. The technique has shown that patients with idiopathic constipation have impaired extrinsic gut nerve activity, and this is more notable in those with slow transit. The degree of slow transit correlates with the degree of impaired extrinsic innervation.

Adolescent↗
PubMed2000

Reproducible assessment of vaginal and rectal mucosal and skin blood flow: laser doppler fluximetry of the pelvic microcirculation.

Pelvic venous congestion is a common cause of chronic pelvic pain in women of reproductive age. Although this condition represents a functional disturbance of the pelvic circulation which is related to the menstrual cycle, its aetiology remains unknown. Indirect techniques demonstrate that the vasoconstrictive reflex response of the microcirculation of the foot to a rise in venous pressure is attenuated throughout the menstrual cycle. We wished to develop a simple and non-invasive direct measure of pelvic blood flow to aid diagnosis of this condition. Laser doppler blood flux measurements of the skin of the big toe and of the vaginal and rectal mucosa in the follicular and luteal phases of the menstrual cycle in 12 healthy asymptomatic premenopausal women (mean age 30 years) with regular cycles and in four healthy asymptomatic postmenopausal women (mean age 59 years) were carried out both in the supine position and in response to 40 degrees head-up tilt. The coefficient of variation of resting vaginal flux was lower for measurements in postmenopausal women (0.04) and in premenopausal women in the follicular phase (0. 07) compared with those in the luteal phase (0.16). At rest, vaginal blood flow was higher than rectal and skin flux in both premenopausal and postmenopausal women. In the follicular phase a decrease in flow was observed in response to head-up tilt in the skin (-32.0%), vagina (-34.3%) and rectum (-9.4%). In the luteal phase this reflex was attenuated at these three sites (-8.6%, +6.7% and +7.4% respectively). There were no significant reflex changes in postmenopausal women. Thus laser doppler fluximetry is a reproducible method for comparing the flux of blood in the microcirculation of the skin and of the vaginal and rectal mucosa. The skin is the least sensitive site for testing vascular reactivity in response to cyclical changes. The vaginal and rectal microcirculations are the most sensitive sites for testing visceral cyclical reactivity, and have the advantage of direct anatomical relevance. The follicular phase of the menstrual cycle is associated with greatest vascular reactivity and is the most appropriate phase during which to test for abnormal vascular responses.

Adult↗
PubMed1999

Laser Doppler measurement of rectal mucosal blood flow.

BACKGROUND: Gut mucosal blood flow measurement is used to study a variety of disorders and possibly extrinsic neural function. AIMS: To determine optimal measurement criteria and validate this technique as a measure of level of activity of extrinsic autonomic gut innervation. METHODS: In 26 healthy volunteers a laser Doppler mucosal probe was applied 10 cm from the anus. Response to inhaled salbutamol 200 microgram and ipratropium 40 microgram, intravenous metoprolol 2.5 mg, and direct sacral nerve electrostimulation (in nine incontinent patients) was also studied. RESULTS: The coefficient of variation for subjects studied under identical conditions on two, three, and four days was 0.06, 0.05, and 0.06, respectively. Mean mucosal blood flow increased after a standard meal. Blood flow decreased for 15 minutes after smoking and returned to baseline at 30 minutes. Fasted measurements at 0900, 1200, 1600, and 2200 were similar. There was a negative correlation between blood flow and body size but not age. Follicular phase mucosal flow was less and more reproducible than luteal. Mucosal blood flow was highest in men and lowest in postmenopausal women. Inhaled salbutamol did not change blood flow; ipratropium significantly reduced, and metoprolol and sacral nerve stimulation increased flow. CONCLUSIONS: Measurement of gut mucosal blood flow by laser Doppler flowmetry is highly reproducible. Eating, smoking, body size, sex, ovulatory status, and menstrual phase influence blood flow. Changes in mucosal blood flow induced by autonomically active drugs and nerve stimulation confirm the role of the mucosal microcirculation as a measure of extrinsic nerve activity.

Adolescent↗
PubMed1998

Solitary rectal ulcer syndrome.

BACKGROUND: Solitary rectal ulcer syndrome is a rare disorder characterized by erythema or ulceration of the rectal wall, associated with typical histological features, and disturbed defaecatory behaviour with the passage of blood and mucus. METHODS: This is a review based on a literature search using a computer database (Medline) and manual cross-referencing. RESULTS: The pathogenesis is likely to vary in different patients; it includes trauma from straining, direct digital trauma and possibly primary neuromuscular pathology. The histological findings of extension of the muscularis mucosa between crypts and muscularis propria disorganization on full-thickness specimens are characteristic. Biofeedback defaecation retraining, including habit training, can lead to symptom improvement and return to work in a majority of patients. Abdominal rectopexy offers long-term symptom improvement in approximately 50 per cent of patients. Rectal ulceration may persist after any treatment, even if symptoms improve. CONCLUSION: Behavioural therapy and carefully considered operations offer the best treatment results. Further work on psychological factors and neuromuscular and vascular pathology is required.

Humans↗
PubMed1998

Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers.

BACKGROUND: Stronger prokinetic agents which specifically enhance transit in different parts of the gut are required. R093877 is a novel 5-HT4 agonist prokinetic compound which is chemically related to cisapride but believed to have greater effect on colonic activity. AIMS: To evaluate the effects of R093877 on bowel function, upper and lower gut transit, visceral sensitivity, and sphincter function in healthy volunteers in a double blind, placebo controlled, crossover study. METHODS: The study consisted of five consecutive one week periods: no drug treatment; active drug treatment with either 1 or 2 mg daily or placebo; washout; active drug or placebo; no treatment. Seventeen male subjects maintained a detailed dairy of bowel function for the entire study. Orocaecal transit (breath hydrogen), whole gut transit (radio-opaque markers), and anorectal function were assessed at the end of each of the two treatment periods. Blood testing was performed to confirm compliance and for safety analysis. RESULTS: One subject withdrew from the study due to side effects while on placebo. Eight subjects completed the study on 1 mg and a further eight on 2 mg. Blood testing showed non-compliance in one subject on the 2 mg dose, and he was excluded from analysis of all diary and physiological data. Treatment increased the number of stools per week (placebo versus 1 mg, 7.8 versus 13.6, p = 0.003; placebo versus 2 mg, 8.9 versus 11.3, p = 0.15) and the percentage of loose or watery stools (24.2% versus 61.5%, p < 0.04; 9.9% versus 40.0%, p < 0.02). Stool frequency and consistency reverted to normal immediately after treatment. Treatment shortened orocaecal and whole gut transit in all subjects on both doses. Treatment accelerated orocaecal (76 versus 51 minutes, p = 0.007; 63 versus 47 minutes, p = 0.07) and whole gut (38.2 versus 27.0 hours, p = 0.05; 44.8 versus 24.0 hours, p < 0.04) transit, and decreased the number of retained markers ingested 36 hours previously (4.8 versus 1.8, p = 0.016; 7.0 versus 4.3, p = 0.033). Gut sensitivity to distension and electrical stimulation, and anal manometry, were unchanged. Transient headache occurred in seven subjects on R093877 and one subject had mild elevation of liver aminotransferases which resolved on drug cessation. CONCLUSIONS: R093877 is well tolerated by healthy subjects and has a marked and consistent effect on stool frequency and consistency, and upper gut and colonic transit. It does not affect visceral sensitivity or sphincter function. It holds promise for patients with large bowel symptoms or slow gut transit.

Cross-Over Studies↗