A randomised, controlled, crossover study to investigate the safety and response of 1R,2S-methoxamine hydrochloride (NRL001) on anal function in healthy volunteers.

AIMS: This study aimed to assess the dose and volume effects of suppository preparations and safety of NRL001 (one of four possible stereoisomers of methoxamine hydrochloride) on anal sphincter tone using rectal suppositories in healthy adult volunteers. METHODS: This was a Phase I, single-centre, randomised, double-blind, three-way crossover study during which subjects received three single doses of 1 g rectal suppositories (containing 5 or 10 mg NRL001 or matching placebo) or 2 g rectal suppositories (containing 10 or 15 mg NRL001 or matching placebo) on three separate dosing days. The outcome measures were mean anal resting pressure (MARP) variables (monitored continuously for 20-30 min before and up to 6 h after dosing), pharmacokinetics (PK) and safety assessments. RESULTS: Twenty-six subjects were dosed with study medication. Two subjects were withdrawn prematurely and were not included in the main analysis. There was a dose-dependent increase in anal sphincter tone (MARP) when comparing the 5 and 10 mg doses of NRL001; however, the 15 mg dose did not have a significantly greater effect than the 10 mg dose. Suppository size (1 or 2 g) did not appear to have an effect on sphincter tone. There was no evidence against dose proportionality for the PK variables, but the mean maximum plasma concentration (Cmax ) for the 1 g suppository group was higher than for the 2 g group. Twenty-one adverse events were reported in 8 (30.8%) subjects. A dose dependent decrease in heart rate was noted; however, there were no adverse events reported that were related to this reduction in heart rate. CONCLUSIONS: The increase in anal sphincter tone supports the potential therapeutic use of NRL001 in treating faecal incontinence, with further studies in patients required. NRL001 was well tolerated in single doses of up to 15 mg.

Use of a gentamicin-impregnated collagen sheet (Collatamp(®) ) following implantation of a sacral nerve stimulator for faecal incontinence.

AIM: Gentamicin-impregnated collagen (Collatamp(®) ) is well described for the prevention of infection in surgery. This technical note describes its intraoperative use as a prophylactic measure to prevent infection following implantation of a sacral nerve stimulator for faecal incontinence. METHOD: Following implantation of the Interstim II Neurostimulator (Medtronic Neuromodulation, 710 Medtronic Parkway, Minneapolis, USA) in a subcutaneous pocket overlying the gluteal muscle, a single sheet of 10cm × 10cm gentamicin-impregnated collagen is placed within the wound covering the implant. The subcutaneous tissue and skin are then closed in separate layers. RESULTS: To date eight patients [median age 46.5 (30-59) years] have received prophylactic cover with gentamicin-impregnated collagen following permanent sacral nerve stimulator implantation. At a median interval of 89.5 (51-128) days, none of these patients developed a wound infection at the site of the neurostimulator implant. CONCLUSION: Gentamicin-impregnated collagen (Collatamp(®) ) used in the implantation of a sacral nerve stimulator may be a useful addition to the technique.

Fibrin glue for the treatment of fistulae in ano--a method worth sticking to?

OBJECTIVE: The current evidence for fibrin glue as a treatment for anal fistulae is mixed. This study reviews the experience of fibrin glue as a treatment for anal fistulae in a single tertiary referral centre and attempts to identify factors related to failure of therapy and the length of follow-up required. METHOD: Patients with fistulae in ano that were treated with fibrin glue between February 2004 and August 2008 were analysed. All procedures were performed by two colorectal consultants based at the Queens Medical Centre, Nottingham. All patients were followed-up to assess the outcome of this treatment. RESULTS: Forty patients (21 male, 19 female) with a mean age of 46.5 years were studied. The mean duration of symptoms prior to presentation was 39 months (range 4-240 months). Presenting symptoms included perianal discharge (72.5%), perianal abscess (57.5%), pain (12.5%), PR bleeding (7.5%), itching (5%) and urgency (2.5%). Patients had a minimum of two follow-up appointments and the median follow-up period was 5.2 months (range 1-16 months). Following MRI and operative assessment, 28 (70%) of the 40 fistulae were considered complex (high trans-sphincteric, extra-sphincteric, pouch-vaginal). Patients who had inflammatory bowel disease were classified as simple tracts but all failed to heal (three patients). Twenty of the complex fistulae failed to heal. Three patients who had repeat application of glue for their complex fistulae failed to heal on follow-up. Of the remaining 12 patients who had simple fistulae in ano, five (41.7%) healed completely. There were no complications such as abscess, related to treatment. All patients who were asymptomatic at 3 months did not develop any further recurrence. CONCLUSION: Fibrin glue is a simple treatment strategy, preserves sphincter function with minimal adverse side effects. It should therefore be considered as possible first line treatment in simple fistulae but it is less likely to be successful in complex or those fistulae associated with inflammatory bowel disease. Repeat gluing is unlikely to be successful. Fistulae that have failed to heal by 3 months will need further treatment.

The effect of an oral glucose load on sodium and water excretion after rapid intravenous infusion of 0.9% (w/v) saline.

BACKGROUND & AIMS: Previous studies have suggested that oral or intravenous glucose enhances salt and water retention following a saline load. To test this, we studied the effects of an oral glucose load on urinary sodium and water excretion and serum biochemistry in response to a 2l intravenous infusion of 0.9% saline in normal subjects. METHODS: A crossover study was conducted on six male volunteers. On one occasion, they received 2l 0.9% saline intravenously over 1h. A week later, they were given 100ml 50% dextrose orally prior to the same infusion. Subjects passed urine before start of the infusion. Body weight, haematocrit and serum biochemistry were recorded preinfusion and hourly for 6h. Urine was collected for 6h postinfusion and analysed for sodium, potassium and osmolality. RESULTS: The six subjects had a mean (SE) age of 20.9 (0.4) years and BMI of 22.7 (0.2). Median (IQR) water balance over 6h was 1462 (1005-1650)ml after saline and 1203 (989-1735)ml after glucose and saline (NS). Urinary sodium and potassium excretion on the two occasions over 6h were 76 (69-111) vs 74 (92-174)mmol and 31 (29-40) vs 30 (20-36)mmol, respectively (NS). Using repeated measures testing, there was no significant difference in body weight, haematocrit, serum albumin, sodium, potassium, chloride, osmolality and blood glucose measured at hourly intervals on the two occasions. CONCLUSIONS: In contrast to previous literature, in normal subjects, an additional oral glucose load does not appear to have an effect on urinary sodium excretion or serum biochemistry after a rapid 2l infusion of 0.9% saline. This does not preclude an effect under conditions of prior starvation or injury.

Dual effects of α2 -adrenoceptors in modulating myogenic tone in sheep isolated internal anal sphincter.

BACKGROUND: The role of α-adrenoceptors in promoting continence through modulation of sphincter tone has focused primarily on the effects of α1 -adrenoceptors. We have used three clinically available agents, which are selective for α2 -adrenoceptors, to investigate their role in contractile and neurogenic responses on the internal anal sphincter (IAS). METHODS: IAS strips, which had spontaneously generated tone, were used to investigate the contractile effect of lofexidine, brimonidine, and dexmedetomidine on muscle tone in the presence or absence of subtype selective antagonists. The effect of brimonidine on the magnitude and time course of neurogenic responses generated by electrical field stimulation (EFS) was also examined. The affinity of test compounds at α1 - and α2 -adrenoceptors was established by competition binding with [3H]-prazosin and [3H]-RX821002. KEY RESULTS: All agonists caused concentration-dependent contraction of the IAS and lofexidine demonstrated an enantiomeric difference in potency with a 10-fold difference between the (-) and (+) isomers. Responses to lofexidine and dexmedetomidine were inhibited in the presence of the α1 -adrenoceptor selective antagonist prazosin, but not in the presence of RX811059 (α2 -adrenoceptor selective antagonist); brimonidine responses were inhibited by RX811059 and, to a lesser extent, by prazosin. Brimonidine affected both magnitude and duration of neurogenic responses, which was reversed in the presence of RX811059. CONCLUSIONS & INFERENCES: We conclude that α2 -adrenoceptors can mediate contraction of IAS, although this effect is most evident with efficacious imidazoline agonists rather than the most selective ligand. In addition, this receptor subtype can directly inhibit noradrenergic contractile responses to EFS and, indirectly, enhance nitrergic relaxatory responses.

Investigation of the distribution and function of alpha-adrenoceptors in the sheep isolated internal anal sphincter.

BACKGROUND AND PURPOSE: We have investigated the distribution of alpha-adrenoceptors in sheep internal anal sphincter (IAS), as a model for the human tissue, and evaluated various imidazoline derivatives for potential treatment of faecal incontinence. EXPERIMENTAL APPROACH: Saturation and competition binding with (3)H-prazosin and (3)H-RX821002 were used to confirm the presence and density of alpha-adrenoceptors in sheep IAS, and the affinity of imidazoline compounds at these receptors. A combination of in vitro receptor autoradiography and immunohistochemistry was used to investigate the regional distribution of binding sites. Contractile activity of imidazoline-based compounds on sheep IAS was assessed by isometric tension recording. KEY RESULTS: Saturation binding confirmed the presence of both alpha(1)- and alpha(2)-adrenoceptors, and subsequent characterization with sub-type-selective agents, identified them as alpha(1A)- and alpha(2D)-adrenoceptor sub-types. Autoradiographic studies with (3)H-prazosin showed a positive association of alpha(1)-adrenoceptors with immunohistochemically identified smooth muscle fibres. Anti-alpha(1)-adrenoceptor immunohistochemistry revealed similar distributions of the receptor in sheep and human IAS. The imidazoline compounds caused concentration-dependent contractions of the anal sphincter, but the maximum responses were less than those elicited by l-erythro-methoxamine, a standard non-imidazoline alpha(1)-adrenoceptor agonist. Prazosin (selective alpha(1)-adrenoceptor antagonist) significantly reduced the magnitude of contraction to l-erythro-methoxamine at the highest concentration used. Both prazosin and RX811059 (a selective alpha(2)-adrenoceptor antagonist) reduced the potency (pEC(50)) of clonidine. CONCLUSIONS AND IMPLICATIONS: This study shows that both alpha(1)- and alpha(2)-adrenoceptors are expressed in the sheep IAS, and contribute (perhaps synergistically) to contractions elicited by various imidazoline derivatives. These agents may prove useful in the treatment of faecal incontinence.

From small acorns--developing a laparoscopic colorectal surgical service.

INTRODUCTION: Randomised controlled trials have shown that laparoscopic colorectal surgery is equal in terms of safety to open surgery. Benefits have been seen for length of stay, blood loss, immune suppression and analgesia requirements. The aim of this study was to assess the safety and feasibility of introducing laparoscopic colorectal surgery to our unit. PATIENTS AND METHODS: Prospectively collected cases of all patients undergoing laparoscopic colorectal surgery between July 2003 and July 2007 were reviewed. RESULTS: A total of 143 patients (75 males and 68 females) with a mean age of 65.8 years (range, 21-95 years) underwent surgery. Laparoscopic resection for colorectal malignancy was performed in 93 patients (65%). The conversion rate for all cases was 14.7%. Mean operative time was 203 min (range, 100-400 min), with a mean blood loss of 180 ml. The mean number of lymph nodes in malignant cases was 13.8 with clear resection margin in all but one case. The mean postoperative stay was 5.6 days (median, 4 days; range, 2-35 days). UKCCR standard for lymph node retrieval was achieved in 62.6% of cases. There were four postoperative deaths. The overall 30-day morbidity rate was 21.7%. The service is consultant-led with 9.8% of cases performed by senior trainees and 37% of procedures performed by two consultants. CONCLUSIONS: Laparoscopic colorectal surgery is technically feasible and safe in our hands. Although operative time is longer, this is counterbalanced by shorter hospital stay. The results from this series support the findings of others and continuing development of this service.