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.

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.

HTLV-I-associated myelopathy and polymyositis in a US native.

A patient who had always lived in the United States had an HTLV-I infection and a chronic myelopathy clinically mimicking amyotrophic lateral sclerosis. Needle EMG and nerve conduction studies were consistent with anterior horn cell disease but muscle biopsy showed denervation and an inflammatory myopathy. Serum HTLV-I antibody tests were positive and HTLV-I DNA was present in peripheral leukocytes. This is the 1st reported US native with HTLV-I-associated myelopathy and polymyositis.

Paraneoplastic motor neuron disease and renal cell carcinoma: improvement after nephrectomy.

A 74-year-old man had a paraneoplastic motor neuron disease mimicking amyotrophic lateral sclerosis. He had an elevated erythrocyte sedimentation rate, other laboratory abnormalities, and a previously undiagnosed renal cell carcinoma. Four months after nephrectomy, his strength had improved and he had no fasciculations. Seven other patients with cancer and motor neuron disease improved or stabilized after tumor treatment. Even though it is rare, paraneoplastic motor neuron disease is important to diagnose because it may be treatable.

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.

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.

A pharmacokinetic study of sulphasalazine and two new formulations of mesalazine.

We have examined the pharmacokinetics of enteric coated sulphasalazine compared with two new formulations of mesalazine. These consisted of microgranules of mesalazine coated with Eudragit S in a concentration of either 20 or 25% dry lacquer substance; these in turn were enclosed in capsules coated with Eudragit L. In-vitro dissolution studies of coated microgranules showed that drug release was pH dependent. Studies in 7 normal volunteers showed median peak concentrations of 5-amino-salicylic acid and N-acetyl-5-amino-salicylic acid occurred at about 6 hours with both microgranular preparations, compared with sulphasalazine at 15 h. The microgranule formulation coated with 20% Eudragit S gave serum levels and overall systemic absorption similar to values with sulphasalazine. This new formulation may be of value for delivering mesalazine and other therapeutic agents to the colon.

Tripotassium dicitrato bismuthate enemas in the treatment of ulcerative proctitis.

Eleven patients with active proctitis or proctosigmoiditis completed one month's treatment with tripotassium dicitrato bismuthate enemas administered at night. Symptoms, sigmoidoscopic appearances, and the histological grade of acute inflammation were assessed at the commencement of therapy and after one month. An overall score of these features showed improvement in 9 of 11 patients, which encourages further investigation of bismuth in controlled trials for patients with inflammatory bowel disease.

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.

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.

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.

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.

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.

Effects of chronic bretylium treatment on the sympathetic neuron and the smooth musculature of the rat.

The effects of chronic i.p. injection of high doses of bretylium on sympathetic nerves on the smooth musculature of the vas deferens of adult and newborn rats were examined using fluorescence histochemistry, light and electron microscopy and organ bath physiological techniques. Bretylium treatment caused mitochondrial swelling, loss of cristae and the formation of electron-dense inclusions in the mitochondria of sympathetic neurons. However, neuron degeneration was not observed and fluorescent histochemical appearance of adrenergic neurons was normal. A small transient supersensitivity of the isolated vas deferens of bretylium-treated rats to noradrenaline, but not to acetylcholine, occurred. There was, however, considerable increase in the maximal contractile response to both noradrenaline and acetylcholine. In high calcium concentrations acetylcholine-induced contractions of vasa deferentia from bretylium-treated rats were significantly greater than control; there was no difference in magnitude of noradrenaline-induced contractions.

Evidence for direct vasoconstrictor activity of melatonin in "pressurized" segments of isolated caudal artery from juvenile rats.

Responses of isolated, 60 mmHg 'pressurized' segments of the distal caudal artery of adult and juvenile Wistar rats to melatonin and the selective alpha 2-adrenoceptor agonist 5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate (UK-14304) were examined using the Halpern pressure myograph. Melatonin showed no direct vasoconstrictor activity in vessels from adult rats, whereas UK-14304 produced moderate vasoconstriction (pD2-7.43 +/- 0.09). In the presence of phenylephrine-induced tone, melatonin produced a variable but small constrictor response (less than 10 microns reduction in diameter) in some vessels; the response to 1 mumol/l UK-14304 was less than in the absence of tone. In vessels isolated from juvenile rats, melatonin caused concentration-dependent vasoconstriction with a maximum response about 70% of the maximum response elicited by UK-14304. Vessels from juvenile rats were more sensitive to melatonin (pD2-9.40 +/- 0.07) than they were to UK-14304 (pD2-8.12 +/- 0.14). In the presence of phenylephrine-induced tone, the vasoconstrictor responses to both melatonin and IK-14304 were markedly less; the sensitivity to melatonin was not different from that seen in the absence of tone. These findings indicate that 'pressurized' segments of the isolated distal caudal artery may provide a simple and convenient, functional model of melatonin receptors. The findings also appear to implicate melatonin in thermoregulatory processes in juvenile rats.

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.

Quantitative structure--activity relationships and carminative activity II: steric considerations.

The unexplained variation in the relationships between carminative activities and octanol--water distribution coefficients of various classes of compounds was explained. The steric substituent constant (Es) value, van der Waals volume, and molecular connectivity were introduced into a previously derived correlation. Each parameter brought about an improvement, and molecular connectivity was the most successful. Correlations containing molecular connectivity was the most successful. Correlations containing molecular connectivity terms explained the excess variation. The results were in agreement with a mechanism in which carminative activity depended on the availability of the oxygen atom in the functional group of the molecule and was reduced when the substituent attached to the oxygen hindered the interaction between the oxygen atom and the receptor.

Quantitative structure-activity relationships and carminative activity.

Carminative activities of 34 alcohols, esters, ethers, phenols, and carbonyl compounds were determined using the guinea pig isolated ileum preparation and are expressed as the ability to produce a 50% inhibition (ID50) of a standard response to carbachol. Aqueous solubilities were measured at 37 degrees using either UV absorption or GLC. The ratios of solubility to ID50 were reasonably constant, suggesting nonspecific biological activity, similar to that previously observed with general anesthetics. Hansch analysis indicated that carminative activities were largely controlled by solubility, as indicated by octanol-water distribution coefficients. The principal remaining factor appeared to be the steric availability of the oxygen atom in the functional group of the compound.

Intracranial injections of 6-OHDA. Comparison of catecholamine-depleting effects of different volumes and concentrations.

Fluorescence histochemistry was used to assess monoamine depletion after injections of 6-OHDA into selected brain areas. Two volumes (2 and 4 mul) and 4 concentrations (1, 2, 4 and 8 mug/mul) of 6-OHDA were injected into the olfactory tubercle, the posterior lateral hypothalamus and the lateral hyopthalamus. Selective destruction of catecholamine-containing neurons resulted from all injections of 6-OHDA with the exception of the 2 lowest doses (2 and 4 mul of 1 mug/mul) and the highest dose (4 mul of 8 mug/mul) which produced nonspecific damage of brain parenchyma. The results indicate that, in addition to the selection of an effective dose, it is also possible to choose a site of injection which will produce a maximal area of specific depletion. In cases where injections into terminal areas caused limited specific depletion the same dose injected into preterminal axons often caused a more widespread loss of fluorescence. With volume, concentration and anatomical location being important variables to consider, caution is needed in the interpretation of behavioural experiments. When using 6-OHDA it is necessary to show that specific depletion of catecholamines has been achieved.

Intracranial injection of drugs: comparison of diffusion of 6-OHDA and guanethidine.

Marked differences in extent of diffusion have been shown with the fluorescence histochemical method between guanethidine and 6-OHDA(64 mug in 2 mul) when injected acutely or chronically into the lateral hypothalamus, the substantia nigra or the amygdala of the rat brain. Cannulation damage up to 1 mm in diameter and attributed to the implantation of cannulae and placebo injection was observed. A further area of generalized damage occurred following the injection of drugs and was far greater for 6-OHDA (2 mm) than for guanethidien (0.3 mm). Guanethidine, but not 6-OHDA, caused specific damage to catecholamine-containing nerurons up to a distance of at least 3 mm and more from the cannula tip. These striking differences between the effects of intracranial injection of 6-OHDA and guanethidine are discussed in terms of the uptake and degradation of the two drugs and the anatomical features of the injection site; they are not explicable in terms of experimental conditions such as concentration, volume of injection, molecular weight or lipid solubility. The different patterns of damage would not easily be distinguished by biochemical analyses and the catecholamine specificity of 6-OHDA in studies of the central nervous system must be seriously questioned. Vascularization of chronically implanted cannula tracks and the presence of anatomical diffusion barriers are also discussed in relation to the diffusion of drugs injected intracranially.