Nicotine enemas for active Crohn's colitis: an open pilot study.

BACKGROUND: Smoking has a detrimental effect in Crohn's disease (CD), but this may be due to factors in smoking other than nicotine. Given that transdermal nicotine benefits ulcerative colitis (UC), and there is a considerable overlap in the treatment of UC and CD, the possible beneficial effect of nicotine has been examined in patients with Crohn's colitis. AIMS: To assess the efficacy and safety of nicotine enemas in active Crohn's colitis. Patients. Thirteen patients with active rectosigmoid CD; 3 patients were excluded because they received antibiotics. METHODS: Subjects were given 6 mg nicotine enemas, each day for 4 weeks, in an open pilot study. At the beginning and end of the trial, a Crohn's disease activity index (CDAI) score was calculated, sigmoidoscopy was performed, and haematological inflammatory markers measured. RESULTS: Mean CDAI decreased from 202 to 153-the score was reduced in 6 patients, unchanged in 3, and increased in one. Frequency of bowel movements decreased in 8 patients and the sigmoidoscopy grade was reduced in 7. Mean C-reactive protein decreased from 22.0 to 12.3 mg/L. There were no withdrawals due to adverse events. CONCLUSIONS: In this relatively small study of patients with active Crohn's colitis, 6 mg nicotine enemas appeared to be of clinical benefit in most patients. They were well tolerated and safe.

Comparative study of enema retention and preference in ulcerative colitis.

BACKGROUND: Therapeutic enemas are often used to treat active colitis but their retention may be limited because of urgency to defecate. Some preparations may be better retained and tolerated than others because of their physical properties. AIM: To compare patient preference and retention of four therapeutic enemas, including a nicotine enema, in patients with ulcerative colitis (UC). METHODS: Twenty four patients with active UC received the four trial enemas-corticosteroid, 5-amino salicylate (5-ASA), and nicotine liquid enemas and a corticosteroid foam, in a randomised order, taking one enema on each of four successive nights. Patients scored them 1 to 4 for ease of administration and retention, degree of abdominal bloating, and for their overall preference. RESULTS: Fifteen patients rated nicotine their overall favourite or second favourite, compared with 14 for corticosteroid foam and 11 for 5-ASA and corticosteroid liquids, but this was not significant (p = 0.302). Overall, there was no significant difference in overnight retention. However, the nicotine enema tended to be less well retained in patients with milder urgency but a higher proportion retained it overnight with more severe urgency (p = 0.031 compared with 5-ASA enema). CONCLUSION: There was no significant difference in patient preference or overall duration of retention for the four enemas.

Nicotine enemas for treatment of ulcerative colitis: a study of the pharmacokinetics and adverse events associated with three doses of nicotine.

BACKGROUND: Transdermal nicotine is of value in active ulcerative colitis but causes adverse events because of systemic absorption. Nicotine enemas may give rise to fewer adverse events. AIM: To assess the pharmacokinetics of nicotine enemas in three doses. METHODS: Thirteen volunteers, all non-smokers but three ex-smokers, were given enemas on separate occasions containing 3, 6 and 9 mg of nicotine, in ascending dose order. Adverse events were recorded and blood samples taken over 8 h for measurement of serum nicotine and cotinine. RESULTS: Enemas were retained by most subjects. Eleven of 14 adverse events were 'early'--30-105 min after the enema, corresponding to maximum plasma nicotine concentrations; three events were later, 4-8 h after the enema and unrelated to the tmax. 'Early' adverse events occurred in eight subjects--six with 9 mg. The three highest plasma nicotine concentrations were with 9 mg and associated with headache, nausea and sweating. Only one had adverse events with 3 mg and withdrew from the study. Nicotine Cmax with 6 and 9 mg doses were respectively two and three times the value with 3 mg. Peak nicotine concentrations occurred 44-50 min after the enema. CONCLUSION: The 6 mg dose of nicotine probably represents the dose to use in clinical practice - for the highest therapeutic dose with a low risk of adverse events.

Plasma glucocorticoid concentrations in free-ranging platypuses (Ornithorhynchus anatinus): response to capture and patterns in relation to reproduction.

Energy demands in the platypus are likely to increase in the breeding season, which occurs from winter to early spring. Glucocorticoids, which play a major role in energy mobilisation, were measured in consecutive blood samples from free-ranging adults at approximately monthly intervals throughout the year. Glucose and free fatty acids were also measured in some samples. Plasma concentrations of glucocorticoids rose significantly during the first 30 min after capture, accompanied by a rise in free fatty acids, but no corresponding increase in glucose concentrations. We observed a strong pattern in plasma glucocorticoids in samples collected within 15 min of capture (indicative of pre-disturbance concentrations) in different phases of the annual reproductive cycle, with significantly higher levels in both males and females in the breeding season compared to the non-breeding season. These data, and the decline in tail fat stores that occur towards the end of the mating period (around October), suggest that platypus experience high-energy demands during this phase of reproduction. Plasma glucocorticoid concentrations in females sampled during the lactation period (October-February) were relatively low, and similar to those in females sampled in the non-breeding, non-lactation period (March-June). The latter requires further investigation as results may have been influenced by sampling limitations.

Naloxone treatment for irritable bowel syndrome--a randomized controlled trial with an oral formulation.

BACKGROUND: Opioids change gut motility and secretion, causing delayed intestinal transit and constipation. Endorphins play a role in the constipation troubling some patients with irritable bowel syndrome; hence naloxone, an opioid antagonist, may have a therapeutic role. AIM: To assess the efficacy and safety of an oral formulation of naloxone in irritable bowel syndrome patients with constipation. METHODS: A randomized, double-blind, placebo-controlled trial was performed. Patients fulfilling the Rome II criteria for irritable bowel syndrome (constipation-predominant and alternating types) were randomized to receive 8 weeks of treatment with naloxone capsules, 10 mg twice daily, or identical placebo. RESULTS: Twenty-eight patients entered the study, which was completed by 25. 'Adequate symptomatic relief' was recorded in six of 14 on naloxone and three of 11 on placebo. Whilst the differences were not significant, improvements in severity gradings and mean symptom scores for pain, bloating, straining and urgency to defecate were greater with naloxone than placebo for all parameters. In addition, quality of life assessments improved to a greater extent in patients taking naloxone. CONCLUSIONS: Preliminary results suggest that naloxone is well tolerated and beneficial in patients with irritable bowel syndrome and constipation. A larger clinical trial is needed to provide sufficient statistical power to assess efficacy.

Enteric-release glyceryl trinitrate in active Crohn's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Mucosal ischaemia may contribute to the pathogenesis of Crohn's disease. Microvascular abnormalities have been found in colonic resection specimens, and mucosal levels of constitutive nitric oxide synthase are reduced. AIM: To assess the efficacy of a novel, enteric-release formulation of the nitric oxide donor, glyceryl trinitrate, aimed at increasing the mucosal circulation and relaxing smooth muscle in the affected bowel. METHODS: The trial was randomized, double-blind and placebo-controlled. Baseline disease activity was assessed by a structured symptom diary, with blood tests and a quality of life assessment. Patients with a Crohn's disease activity index of > or = 150 and < 450 were randomized to receive 12 weeks of either glyceryl trinitrate (initially 6 mg twice daily, increasing to 9 mg twice daily after 6 weeks) or an identical placebo. Assessments were repeated at 6 and 12 weeks. RESULTS: Seventy patients (22 male) entered the study; 34 were given glyceryl trinitrate and 36 placebo. At 12 weeks, there were no differences between the treatment groups in terms of Crohn's disease activity index, pain, stool frequency, inflammatory markers or quality of life scores. CONCLUSIONS: Enteric-release glyceryl trinitrate did not benefit patients with mild to moderately active Crohn's disease. Whilst ischaemia may contribute to the pathogenesis of Crohn's disease, our results fail to provide supportive evidence for this hypothesis.

Effect of an enteric-release formulation of naloxone on intestinal transit in volunteers taking codeine.

INTRODUCTION: Constipation is a common side-effect of opioid therapy; in addition to their analgesic effect, opioids reduce intestinal secretion and motility with an increase in whole-gut transit time. Naloxone, a specific opioid antagonist, reverses these effects but may also cause symptoms of opioid withdrawal in patients on long-term therapy. AIM: To use an enteric-release formulation, designed to produce a topical effect in the gut, with minimum systemic effects. METHODS: Naloxone 10 mg b.d. and codeine 30 mg b.d. were used with identical placebo capsules in four sets of studies; 12 male volunteers were given the drugs alone and in combination, with a control study involving double placebo, during each of four study periods. Whole-gut transit time was calculated and compared for each treatment period. RESULTS: Naloxone, both alone and with codeine, significantly shortened the mean whole-gut transit time compared with the control period, respectively, from 53.1 to 42.1 h (P=0.005) and to 40.7 h (P=0.024). Urgency to defecate was reported by two volunteers on naloxone alone and by three on combination therapy. CONCLUSIONS: The results show that the naloxone formulation counteracts the effect of codeine on intestinal transit, suggesting that it may have useful clinical applications.

An oral formulation of nicotine for release and absorption in the colon: its development and pharmacokinetics.

AIMS: Ulcerative colitis is predominantly a disease of nonsmokers and transdermal nicotine has therapeutic value in active disease; however side-effects are troublesome. The aim of this study was to develop an oral formulation of nicotine which would be slowly released in the colon over 6 h, and to examine its pharmacokinetic profile in 12 healthy volunteers, with measurements of serum nicotine and cotinine, its principal metabolite. METHODS: Nicotine was combined with a polyacrylic carbomer, Carbopol 974P which was incorporated into 13 different vehicles and their release profiles examined in vitro. The polyglycolized glyceride, Gelucire 50/13, was chosen for subsequent kinetic studies because it consistently produced a suitable release pattern which was linear. Capsules containing 3 mg nicotine, combined with carbomer in Gelucire 50/13, were coated with an acrylic resin Eudragit L; this ensured the capsule would remain intact until the ileum. On 2 separate days, 6 and 15 mg nicotine, contained in 2 and 5 capsules, respectively, were administered to 12 subjects, all nonsmokers, mean age 28 years. Serial blood measurements were taken for 36 h, serum nicotine and cotinine concentrations were measured by gas liquid chromatography. RESULTS: There was considerable intersubject variability in the nicotine and cotinine values. Plasma nicotine levels began to rise about 4 h after ingestion of the capsules, corresponding with the oro-caecal transit time. Cmax nicotine values were 2.2 and 5 ng ml-1, obtained 7 h after the ingestion of 6 and 15 mg, respectively, of the formulation. The corresponding Cmax values for cotinine were 37 and 94.4 ng ml-1, occurring after 9-10 h. The mean for elimination half-lives in the 24 studies, including the 6 and 15 mg doses, for nicotine were 4.3+/-2.7 h and for cotinine 16.8+/-7.5 h. With 6 mg nicotine-carbomer, only 1 of 12 volunteers had possible side-effects, but with the 15 mg dose 11 out of the 12 reported adverse effects which were systemic or gastrointestinal in nature-their timing corresponded with peak serum concentrations of nicotine. CONCLUSIONS: An oral formulation of nicotine has been developed; in the ileum and colon, this becomes available for slow linear release over 6 h and delivers high concentrations of nicotine for topical effect on the colon. 6 mg Nicotine was well tolerated, whilst 15 mg gave both systemic and gastrointestinal side-effects. High concentrations of topical nicotine in the colon are achieved with relatively low systemic bioavailablity-reflected by the Cmax and AUC values for nicotine. This, or comparable formulations, may be of therapeutic value in ulcerative colitis.

Intra-luminal nicotine reduces smooth muscle tone and contractile activity in the distal large bowel.

BACKGROUND: Nicotine may be of therapeutic value in ulcerative colitis (UC), although its mechanism of action has not been established. OBJECTIVE: To examine the effect of a solution of nicotine on sustained resting pressure (tone) and contractile activity in the human colon. METHODS: Ten healthy volunteers, and seven with UC in symptomatic remission took part; all were non-smokers. All 17 subjects were given nicotine or placebo solution on two separate occasions in a randomized sequence. A water-perfused manometry catheter, with openings at 5, 10 and 15 cm from the tip, was placed by rigid sigmoidoscopy in the recto-sigmoid region. Baseline tone and activity were measured for 15 min prior to instillation of 20 ml of saline alone or with nicotine, 1.2 mg, at pH 4.5. Observations were made over the subsequent 15-20 min. RESULTS: Baseline spontaneous activity in all subjects showed both high- and low-frequency components; in three patients with UC, the low-frequency activity was of high amplitude. The nicotine reduced both tone and activity in all subjects, with reduction or abolition of the large contractions in UC. Tone in all 17 subjects was reduced significantly at 3 min after nicotine (P = 0.000015, sign test); the rate of recovery varied in individuals. Results from normals and UC did not differ significantly from each other. No significant change in tone or activity was observed with the saline solution. CONCLUSION: Intra-luminal nicotine significantly reduces both smooth muscle tone and contractile activity in the recto-sigmoid colon in both normal subjects and patients with UC.

Topical diltiazem and bethanechol decrease anal sphincter pressure without side effects.

BACKGROUND: Topical nitrates lower anal sphincter pressure and heal anal fissures, but a majority of patients experience headache. The internal anal sphincter has a calcium dependent mechanism to maintain tone, and also receives an inhibitory extrinsic cholinergic innervation. It may therefore be possible to lower anal sphincter pressure using calcium channel blockers and cholinergic agonists without side effects. AIMS: To investigate the effect of oral and topical calcium channel blockade and a topical cholinomimetic on anal sphincter pressure. METHODS: Three studies were conducted, each involving 10 healthy volunteers. In the first study subjects were given oral 60 mg diltiazem or placebo on separate occasions. They were then given diltiazem once or twice daily for four days. In the second and third studies diltiazem and bethanechol gels of increasing concentration were applied topically to lower anal pressure. RESULTS: A single dose of 60 mg diltiazem lowered the maximum resting anal sphincter pressure (MRP) by a mean of 21%. Once daily diltiazem produced a clinically insignificant effect but a twice daily regimen reduced anal pressure by a mean of 17%. Diltiazem and bethanechol gel produced a dose dependent reduction of the anal pressure; 2% diltiazem produced a maximal 28% reduction, and 0.1% bethanechol a maximal 24% reduction, the effect lasting three to five hours. CONCLUSIONS: Topical diltiazem and bethanechol substantially reduce anal sphincter pressure for a prolonged period, and represent potential low side effect alternatives to topical nitrates for the treatment of anal fissures.

Topical phenylephrine increases anal sphincter resting pressure.

BACKGROUND: Phenylephrine is an alpha1-adrenergic agonist which causes contraction of human internal anal sphincter muscle in vitro. Its intra-arterial administration in animals has been shown to increase resting sphincter pressure in vivo. In this study the effect of topical application of phenylephrine on resting anal pressure in healthy human volunteers was investigated. METHODS: Twelve healthy volunteers had measurements of maximum resting sphincter pressure (MRP) and anodermal blood flow taken before and after topical application of increasing concentrations of phenylephrine gel to the anus. To determine the duration of effect of the agent, readings were taken throughout the day after a single application. RESULTS: There was a dose-dependent rise in the resting anal sphincter pressure, with a small 8 per cent rise after 5 per cent phenylephrine (P = 0.012) and a larger 33 per cent rise with 10 per cent phenylephrine (mean(s.d.) MRP 85(12) cmH2O before versus 127(12) cmH2O after treatment, P < 0.0001). Thereafter no additional response was noted with higher concentrations of phenylephrine. The median duration of action of a single application of 10 per cent phenylephrine was 7 (range from 6 to more than 8) h. CONCLUSION: Topical application of 10 per cent phenylephrine gel to the anus produces a significant rise in the resting anal sphincter pressure in healthy human volunteers. This represents a potential novel therapeutic approach to the treatment of passive faecal incontinence associated with a low resting anal sphincter pressure.

Nicotine carbomer enemas--pharmacokinetics of a revised formulation.

AIMS: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine has therapeutic benefit but causes frequent side-effects. We have previously developed a topical enema combining nicotine with a polyacrylic carbomer; pharmacokinetic parameters were similar in healthy volunteers and patients with active ulcerative colitis. This enema was reformulated to reduce and delay nicotine absorption, thereby improving tolerance. METHOD: Pharmacokinetic observations and side-effects with both formulations are compared in the same 8 healthy volunteers--all non-smokers, 3 male, mean age 33 years. Six milligrams of nicotine were complexed with 400 mg of carbomer in a 100 ml liquid enema. The original formulation was buffered with potassium/phosphate to pH 5.5, kinematic viscosity was 3 mNm; the revised preparation incorporated trometamol 1% solution to buffer to pH 4.2, viscosity 5 mNm. All subjects had the two formulations on separate occasions at least a month apart, with serial blood measurements and side-effect profile recorded for 8 hours. RESULTS: The revised enema formulation significantly reduced Cmax for nicotine from 8.3 +/- 2.7 to 6.6 +/- 2.1, p = 0.03 with some reduction in nicotine absorption and improved tolerance. Although there was considerable intersubject variation in profiles for nicotine and cotinine, they were similar for each subject on both occasions. CONCLUSIONS: The lower pH and greater viscosity reduced the amount of free nicotine in its unionised form available for absorption, but made it possible to expose colonic mucosa to the same nicotine dose. In other drug formulations where side-effects are a limiting factor these modifications may also be relevant.

The effects of environmental temperature, hypoxia, and hypercapnia on the breathing pattern of saltwater crocodiles (Crocodylus porosus).

This study aimed to describe the effects of change in environmental temperature, hypoxia, and hypercapnia on the breathing pattern of Crocodylus porosus. Increased environmental temperature, hypoxia, and hypercapnia each caused an increase in minute ventilation and changes in breathing pattern. Breathing frequency increased and the duration of the nonventilatory period decreased in response to all three conditions. Under hypercapnia tidal volume also increased, with no change in rate of inspiration. The number of breaths per breathing burst decreased with increased temperature but remained unaltered under hypoxia. Hypercapnia reduced the number of breaths per burst at 20 degrees C, but the number did not decrease further at 30 degrees C. The results support the idea that the responses to increased temperature, hypoxia, and hypercapnia are under separate control but that some effects of hypercapnia and temperature may involve a common regulatory pathway.

Nicotine enemas for active ulcerative colitis--a pilot study.

BACKGROUND: Since transdermal nicotine is of value in the treatment of active ulcerative colitis but is often associated with side-effects, an alternative in the form of topical therapy with nicotine enemas has been developed. METHODS: In an open study, 22 patients with active colitis, all non-smokers, were asked to take a 100 mL enema containing 6 mg of nicotine every night for 4 weeks. Pre-trial treatment using mesalazine (n = 16), oral prednisolone (8), cyclosporin (1) and azathioprine (1) was kept constant for the month prior to assessment and during the study period. Symptoms, with stool frequency, were recorded on a diary card and an endoscopy was performed with rectal biopsy at the beginning of the study and after 4 weeks. RESULTS: Seventeen of the 22 patients completed 1 month of treatment. Mean duration of relapse was 29 weeks, range 3-94. Sixteen of 17 improved their St Mark's score. Urgency and stool frequency improved in 12 patients, sigmoidoscopic and histological scores in 10. Three patients had a full remission of symptoms with normal sigmoidoscopy. Six of 10 with a partial response continued with the enemas for a second month and five showed further improvement with full remission in two. The enema appeared effective when added to conventional treatment and produced few side-effects. CONCLUSION: Topical nicotine therapy for ulcerative colitis may have a place in future management, but controlled studies are needed.

A dose-ranging pharmacokinetic study of nicotine tartrate following single-dose delayed-release oral and intravenous administration.

BACKGROUND: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine is therapeutic but often results in side-effects. Administration of nicotine tartrate as a liquid enema decreases systemic nicotine absorption and may be effective for treatment of active distal ulcerative colitis. Ileocolonic delivery of nicotine tartrate via a delayed release oral capsule would be the preferred route to deliver nicotine to the colon. AIM: To determine the bioavailability and pharmacokinetic parameters of delayed-release oral nicotine tartrate capsules (Eudragit S100 coated) at doses of 3 mg and 6 mg nicotine. METHODS: Twenty healthy human subjects received delayed-release oral nicotine tartrate at one of two doses (each group n = 10): 3 mg and 6 mg nicotine. All subjects also received intravenous nicotine tartrate (at a dose of 15 micrograms nicotine base/kg) during a separate study period. Serum nicotine concentrations were determined by gas chromatography-mass spectrometry. In addition, concentrations of serum cotinine (major nicotine metabolite) were determined by high-performance liquid chromatography in all samples for two subjects (both given 6 mg nicotine). Adverse reactions were determined by questionnaire. RESULTS: The mean bioavailabilities of nicotine after ileocolonic nicotine tartrate administration via delayed-release oral capsules at doses 3 mg and 6 mg nicotine were 41% and 42%, respectively. The ratios (after adjusting for nicotine dose) of cotinine area under the curve (AUC) for delayed-release oral nicotine to cotinine AUC for intravenous nicotine were 1.5 and 1.6 for the two subjects undergoing cotinine pharmacokinetics, demonstrating significant first-pass metabolism. Serum nicotine concentrations did not predict adverse reactions. CONCLUSIONS: Nicotine tartrate delivered to the ileocolon as a delayed-release oral capsule at doses of 3 mg and 6 mg nicotine considerably reduced systemic nicotine bioavailability. This reduction in bioavailability appears to be a result of first-pass hepatic metabolism rather than poor mucosal absorption of nicotine. The therapeutic potential of an ileocolonic delivery formulation of nicotine tartrate, which can potentially limit toxicity by local delivery of high doses of nicotine, should be investigated in patients with ulcerative colitis.

Pharmacokinetics of nicotine carbomer enemas: a new treatment modality for ulcerative colitis.

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers, and transdermal nicotine is of therapeutic value in the active disease. Because side effects are common, we developed a topical enema formulation of nicotine. OBJECTIVE: To study the pharmacokinetics of nicotine complexed with a polyacrylic carbomer and administered by enema to eight healthy volunteers and to eight patients with active ulcerative colitis, verified sigmoidoscopically. PATIENTS AND METHODS: All 16 subjects were nonsmokers. The mean age for normal subjects was 33 years; the mean for patients with ulcerative colitis was 60 years. Median stool frequency for patients with ulcerative colitis was four daily. Patients were taking 5-amino salicylic acid compounds and five were taking oral prednisolone (median dose, 12 mg daily). Nicotine, 6 mg, complexed with carbomer 974P, 400 mg, was administered in a 100 ml enema after an overnight fast, with serial blood measurements taken over 8 hours. Serum nicotine and cotinine were measured by gas liquid chromatography. Area under the concentration-time curves were calculated by the trapezoidal method, and the terminal elimination half-life was derived by extrapolation of the log-linear terminal phase. RESULTS: With the exception of nicotine time to reach peak concentration, which was longer in patients (median of 60 minutes compared with 45 minutes; p < 0.005), other comparisons between normal subjects and patients showed no statistically significant difference, although there was considerable inter-subject variation. Maximum concentration of nicotine, 8.1 +/- 3.5 ng/ml, in the 16 subjects occurred after a median of 60 minutes (range, 30 to 180 minutes); maximum cotinine concentrations of 60.4 +/- 11.5 ng/ml occurred after 4 hours. Side effects in five subjects were mild (four subjects) or moderate (one subject) and included lightheadedness, nausea, and headache; these five subjects were female lifelong nonsmokers of low body weight. CONCLUSION: Because most of the active ingredient of nicotine is converted to continine on the first pass through the liver, substantial concentrations can be achieved at the site of disease with only modest rises in serum nicotine, which are responsible for side effects; cotinine has low pharmacologic activity. Topical administration of nicotine may be useful treatment for distal ulcerative colitis.

Inflammatory bowel disease management. Some thoughts on future drug developments.

This article is intended to stimulate thought and focus on those areas where we feel advances in drug therapy for inflammatory bowel disease may occur. It is not an extensive review of current practice, although this is considered where it is thought to be pertinent to future developments. There are several excellent reviews of current practice which we do not attempt to repeat, nor do we give a comprehensive set of references, but cite well referenced reviews where necessary. New therapeutic developments should ideally stem from an understanding of the cause of pathogenesis of a condition; alternatively, established therapies may be modified or used as a basis for progress. Since the causes of both ulcerative colitis and Crohn's disease remain unknown, most forward thinking on drug development must come from current practice, but remain open to novel approaches. Our thoughts on possible future treatments for inflammatory bowel disease are somewhat selective, and because of their speculative nature are unlikely to coincide with those of others-only the future will reveal genuine advances as they become incorporated into established practice.