Are short-chain fatty acid enemas effective for left-sided ulcerative colitis?
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Colitis, Ulcerative↗
Biomedical subjects
W J Sandborn
Publications and source records attributed to W J Sandborn.
Dialysis of the rectum for sampling drug concentrations in the luminal extracellular fluid of the gut: technique and precision.
BACKGROUND: It is useful to measure the luminal concentration of drugs which act in the gut. Dialysis of the rectum has not previously been used or validated for this purpose. AIM: To determine the precision of rectal dialysis for measuring rectal drug concentrations. METHODS: To establish the duration of dialysis required to approach equilibrium, the rate of methotrexate diffusion into dialysis bags was first determined in vitro. The precision of rectal dialysis for sampling the methotrexate concentration of colonic lumen extracellular fluid was determined in seven subjects who underwent two consecutive dialysis procedures. Subjects treated with subcutaneous methotrexate for refractory inflammatory bowel disease were studied. RESULTS: Methotrexate crossed the dialysis membrane by a first-order process, and after a 2 h in vitro dialysis, equilibration was 74 +/- 2% (mean +/- s.d.) complete. Rectal dialysis was well tolerated by all subjects. The mean +/- s.e. methotrexate concentration of 3.6 +/- 1.1 nmol/L in the first dialysate was not significantly different from 3.6 +/- 0.9 nmol/L in the second dialysate. P = 0.99 (paired two-tailed t-test). Similar precision was obtained for an endogenous molecule, potassium, secreted by the rectal mucosa. CONCLUSIONS: Dialysis of the rectum is a well tolerated and precise technique for sampling the colonic lumen extracellular fluid for quantitative analyses of exogenous and endogenous substances.
Antirheumatic Agents↗
Azathioprine: state of the art in inflammatory bowel disease.
INTRODUCTION: The use of 6-mercaptopurine (6MP) and its prodrug azathioprine (AZA) for inflammatory bowel disease (IBD) has increased in recent years. The pharmacology, patient response in controlled trials, new formulations and routes of administration and safety for these agents are reviewed. PHARMACOLOGY: AZA is rapidly converted to 6MP, which is then further metabolized to the active metabolites, the 6-thioguanine nucleotides (6TGN). The half-life of 6TGN in erythrocytes is prolonged and weeks to months may be required to reach steady state. This prolonged time to 6TGN steady state may help explain the clinical observation that prolonged treatment (3-4 months) with 6MP/AZA for IBD is required before a therapeutic response occurs. CLINICAL RESPONSE: Controlled trials of 6MP (1.5 mg/kg/d) or AZA (1.0-3.0 mg/kg/d) support the following treatment indications for 6MP/AZA: inflammatory Crohn's disease; fistulizing Crohn's disease; steroid-sparing; and remission maintenance. Controlled trials of AZA (1.5-2.5 mg/kg/d) in UC have suggested efficacy for the indications of steroid sparing and remission maintenance, as well as a possible effect in chronically active disease. A therapeutic response appears to require > or = 17 weeks for most patients, and it has been suggested that a greater cumulative dose of AZA may result in increased likelihood of response to AZA. A recent pilot study suggested that administration of an i.v. loading dose of AZA (20-44 mg/kg over 36 h) may decrease the time to response in Crohn's disease patients treated with AZA, perhaps by administering a portion of the necessary cumulative dose more rapidly. Two recent pharmacokinetic studies demonstrated that use of a delayed release oral AZA formulation which delivers AZA directly to the ileocolon markedly reduces systemic absorption of AZA. This 'topical' or 'local' approach to AZA treatment of IBD holds the promise of equal or improved efficacy with a significant reduction in toxicity, and dose-ranging clinical trials with delayed release oral AZA are planned in the near future. SAFETY: Side effects of AZA/6MP include pancreatitis, fever, nausea, leukopenia, infection, and hepatitis. It appears that the risk of malignancy during or following monotherapy with AZA/6MP for IBD is not increased relative to the general population. CONCLUSIONS: AZA/6MP therapy is efficacious and reasonably safe for selected patients with IBD. Indications for treatment with AZA/6MP include refractory Crohn's disease, fistulizing Crohn's disease, steroid-dependent Crohn's disease, Crohn's disease remission maintenance, and possibly refractory UC, steroid dependent UC, and UC remission maintenance. The use of these immune modifier drugs in patients with IBD represents a significant therapeutic advance.
Azathioprine↗
Antineutrophil cytoplasmic antibody subtypes in children and adolescents after ileal pouch-anal anastomosis for ulcerative colitis.
BACKGROUND: Perinuclear antineutrophil cytoplasmic antibodies occur frequently in adult patients with chronic pouchitis after colectomy and ileal pouch-anal anastomosis for ulcerative colitis. The purpose of the study was to determine the prevalence of perinuclear antineutrophil cytoplasmic antibodies and cytoplasmic antineutrophil cytoplasmic antibody in children and adolescents who undergo colectomy and ileal pouch-anal anastomosis for ulcerative colitis and familial adenomatous polyposis. METHODS: Five groups of children and adolescents (age, <20 years) were studied, with the following histories: acute pouchitis and history of ulcerative colitis; chronic pouchitis and history of ulcerative colitis; pouchitis with Crohn's disease features and a history of ulcerative colitis; no pouchitis and a history of ulcerative colitis; and familial adenomatous polyposis, with or without pouchitis. Antineutrophil cytoplasmic antibody levels and titers were detected in postoperative sera by enzyme-linked immunosorbent assay, and positive results were subtyped by indirect immunofluorescence. RESULTS: The frequency of perinuclear antineutrophil cytoplasmic antibodies and cytoplasmic antineutrophil cytoplasmic antibody in patients with a history of ulcerative colitis were 67% and 15%, compared with a 0% presence in patients with familial adenomatous polyposis (p < 0.001). There was no significant correlation between the frequency of perinuclear antineutrophil cytoplasmic antibodies and ulcerative colitis patient subgroups (patients with and without pouchitis, 66% and 75%). Similarly, there was no significant correlation between the frequency of cytoplasmic antineutrophil cytoplasmic antibodies among ulcerative colitis patient subgroups (patients with and without pouchitis, 19% and 8%). The frequency of cytoplasmic antineutrophil cytoplasmic antibody in patients with Crohn's disease features (50%), was increased, but this difference was not significant. CONCLUSIONS: There is a high frequency of perinuclear antineutrophil cytoplasmic antibodies in children and adolescents who undergo ileal pouch-anal anastomosis for ulcerative colitis, whether or not they have pouchitis. The frequency of cytoplasmic antineutrophil cytoplasmic antibody is lower in this patient population. Additional studies will be required to determine whether the presence of cytoplasmic antineutrophil cytoplasmic antibody is associated with the postoperative development of features of Crohn's disease.
Adenomatous Polyposis Coli↗
Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn's disease with intravenous cyclosporine.
OBJECTIVE: To determine outcome following treatment of refractory Crohn's disease with intravenous (i.v.) cyclosporine (CYA). METHODS: The medical records of 18 patients with refractory Crohn's disease treated with i.v. CYA were reviewed. Nine patients had refractory inflammatory Crohn's disease and nine patients had complex fistulizing Crohn's disease. All patients were initially treated with i.v. CYA (4 mg/kg/day). Patients who responded were converted to standard oral CYA. Patient outcomes were classified as complete response, partial response, or nonresponse. RESULTS: Four of nine patients with severe inflammatory Crohn's disease and seven of nine patients with fistulizing Crohn's disease had a partial response to i.v. CYA. Four of four responding patients in the inflammatory group and four of six responding patients in the fistulizing group (plus one initial nonresponder) maintained or improved their response during oral CYA therapy. After discontinuing oral CYA, all four patients in the inflammatory group and five of seven patients in the fistulizing group relapsed despite 1-17 wk of concomitant treatment with azathioprine or 6-mercaptopurine (AZA/6MP). Two patients who received overlapping CYA and AZA/6MP for 17 and 23 wk maintained long-term responses. CYA toxicity was minimal: reversible nephrotoxicity (n = 2), headache (n = 2), oral candidiasis (n = 1), paresthesia (n = 2). CONCLUSIONS: I.v. CYA appears to benefit both refractory inflammatory and fistulizing Crohn's disease. Most patients who respond to i.v. CYA will maintain their response during oral CYA therapy. However, the majority of these patients relapse when oral CYA is discontinued, probably because of inadequate duration of overlap with the slow acting maintenance drugs, AZA/6MP.
Administration, Oral↗
Renal and urologic complications of inflammatory bowel disease.
Renal and urologic complications are not uncommon in patients with inflammatory bowel disease, and can be directly or indirectly related to the underlying disease process or its treatment. Many of these patients have asymptomatic disease, or the urinary symptoms are nonspecific or overshadowed by bowel symptoms. By the time a urinary complication is considered, significant disease progression or renal damage may have occurred. These risks necessitate a high degree of diligence and periodic urologic evaluation as part of the long-term management of patients with inflammatory bowel disease.
Amyloidosis↗
Drug therapy of inflammatory bowel disease.
The drugs that are effective in inflammatory bowel disease (IBD) act by inhibiting the chronic unregulated intestinal inflammation in these patients. The mainstays of the drug therapy of IBD are a variety of formulations of 5-aminosalicylic acid (5-ASA), the conventional and newer low bioavailability glucocorticoids, the nitroimidazole antibiotic metronidazole, and certain immunomodulating agents. Increased understanding of the mechanisms of inflammation in IBD has permitted the development of effective designer drugs. These agents are products of the biotechnology industry and include antibodies to tumor necrosis factor (TNF)-alpha, antisense oligonucleotides and recombinant human interleukin (IL)-10. In addition, a number of other agents such as nicotine and n-3 fatty acids are useful in certain patients. This review first focuses on the pharmacology and mechanism of action of these drugs in IBD, followed by an approach to the treatment of patients with ulcerative colitis (UC) and Crohns disease (CD). The recommendations consider type and activity of IBD and are based largely on data from controlled trials and systematic reviews in the IBD literature.
Journal Article↗
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.
Acrylic Resins↗
Transdermal nicotine for mildly to moderately active ulcerative colitis. A randomized, double-blind, placebo-controlled trial.
BACKGROUND: Ulcerative colitis is predominantly a disease of nonsmokers. Transdermal nicotine may help control clinical manifestations of this condition. OBJECTIVE: To determine the efficacy of transdermal nicotine for controlling clinical disease activity in active ulcerative colitis. DESIGN: Randomized, double-blind, placebo-controlled, single-center clinical trial. SETTING: Multispecialty group serving as an academic tertiary referral center. PATIENTS: 64 nonsmoking patients with mildly to moderately active ulcerative colitis despite the use of medication. INTERVENTION: Patients were stratified on the basis of smoking history, extent of disease, and concomitant medical therapy. After stratification, patients were randomly assigned to daily treatment with transdermal nicotine (n = 31) at the highest tolerated dose (11 mg for 1 week and then < or = 22 mg for 3 weeks) or placebo (n = 33). MEASUREMENTS: Clinical features were assessed at baseline and 4 weeks by endoscopy, physician assessment, and a patient diary of daily symptoms. Serum concentrations of nicotine were determined by using gas chromatography and mass spectrometry, and plasma concentrations of cotinine were measured by using high-performance liquid chromatography. RESULTS: At 4 weeks, 12 of 31 patients (39%) who received nicotine showed clinical improvement compared with 3 of 33 patients (9%) who received placebo (P = 0.007). Four patients receiving nicotine discontinued therapy because of side effects (contact dermatitis [n = 2], nausea [n = 1], and acute pancreatitis [n = 1]). At week 4, the nicotine group had a mean (+/-SD) trough serum nicotine concentration of 11.3 +/- 8.4 ng/mL and a mean trough plasma cotinine concentration of 192 +/- 95 ng/mL. CONCLUSIONS: Transdermal nicotine administered at the highest tolerated dosage (< or = 22 mg/d) for 4 weeks is efficacious for controlling clinical manifestations of mildly to moderately active ulcerative colitis.
Administration, Cutaneous↗
Pharmacokinetics of nicotine tartrate after single-dose liquid enema, oral, and intravenous administration.
Ulcerative colitis is predominantly a disease of nonsmokers, and transdermal nicotine is therapeutic but often results in adverse reactions. Colonic administration of nicotine tartrate as a liquid enema could decrease systemic nicotine absorption and adverse reactions. The purpose of the current study was to determine the bioavailability and pharmacokinetic parameters of nicotine after administration by hydrophilic liquid enema (acidic and basic), hydrophobic liquid enema (acidic and basic), and by oral and intravenous routes. Thirty healthy volunteers received 45 micrograms nicotine base/kg (as nicotine tartrate) in one of five formulations (each n = 6): hydrophilic acidic liquid enema, hydrophilic basic liquid enema, hydrophobic acidic liquid enema, hydrophobic basic liquid enema, and oral solution. All participants also received 15 micrograms nicotine base/kg (as nicotine tartrate) intravenously during a separate study period. Serum concentrations of nicotine were determined by gas chromatography with mass spectrometry. The mean (+/-SD) bioavailabilities of nicotine after administration in the liquid enema formulations (hydrophilic acidic 17 +/- 18%, hydrophilic basic 16 +/- 16%, hydrophobic acidic 25 +/- 17%, hydrophobic basic 15 +/- 12%) were similar to the bioavailability of nicotine after administration by oral solution (20 +/- 25%). The bioavailabilities of nicotine for all five nonintravenous formulations were significantly less than for intravenous nicotine (100%). Serum concentrations of nicotine did not predict adverse reactions. Nicotine tartrate administered as either a liquid enema or as an oral solution had low bioavailability and was well tolerated. The therapeutic potential of nicotine tartrate liquid enemas, which can potentially limit toxicity by local (colonic) delivery of high doses of nicotine should be investigated in patients with left-sided ulcerative colitis.
Administration, Oral↗
Lymphoma of the pouch after ileal pouch-anal anastomosis: report of a case.
The most common cause of pouch dysfunction after ileal pouch-anal anastomosis is pouchitis. Although low-grade dysplasia in the mucosa of the pouch has been recently described in the presence of pouchitis, there has been no report of carcinoma arising in the pouch itself. We describe a patient who developed a large-cell lymphoma of the ileal pouch after ileal pouch-anal anastomosis.
Aged↗
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.
Acrylic Resins↗
A controlled trial of anti-tumor necrosis factor alpha antibody for Crohn's disease.
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Antibodies↗
A new syndrome of Crohn's disease and pachydermoperiostosis in a family.
Few syndromic associations with Crohn's disease are described. The aim of this study was to characterize a new syndrome of Crohn's disease associated with pachydermoperiostosis in 3 brothers. Three probands, 6 siblings, both parents, 20 of 21 third-generation relatives, and 9 spousal controls were evaluated. Serological evaluation for antineutrophil cytoplasmic antibodies and human leukocyte antigens as well as genetic testing for tumor necrosis factor microsatellites, intercellular adhesion molecule 1 polymorphisms, the interleukin 1 receptor antagonist gene, and the interleukin 1 beta gene were performed. Only the 3 probands were affected and developed pachydermoperiostosis between ages 14 and 17 years. Pachydermoperiostosis preceded Crohn's ileocolitis by 6 and 20 years in two probands, excluding secondary hypertrophic osteoarthropathy. Two probands were antineutrophil cytoplasmic antibody positive vs. 1 of 27 unaffected relatives (P < 0.001, chi 2). Haplotypes for human leukocyte antigen and tumor necrosis factor microsatellites were discordant. The probands' generation was homozygous for the common allele 1 of the interleukin 1 receptor antagonist and interleukin 1 beta genes. Two probands carried a rare polymorphism of the intercellular adhesion molecule 1 gene. A new syndrome of Crohn's disease and pachydermoperiostosis associated with antineutrophil cytoplasmic antibodies is described. Inheritance is most likely autosomal recessive by pedigree. No clear association was found between this syndrome and the gene regions evaluated.
Adolescent↗
Dexpanthenol enemas in ulcerative colitis: a pilot study.
OBJECTIVE: To test the hypothesis that topical administration of pantothenic acid, a precursor of coenzyme A, might result in increased tissue levels of coenzyme A, improvement of fatty acid oxidation, and amelioration of ulcerative colitis. MATERIAL AND METHODS: In an open-label pilot study, three patients with active left-sided ulcerative colitis received nightly enemas that contained 1,000 mg of dexpanthenol for 4 weeks. Before and after the study, patients submitted stool specimens for short-chain fatty acid analysis and urine collections for measurement of pantothenic acid and dicarboxylic acids; they also underwent flexible sigmoidoscopy for procurement of biopsy specimens for histologic examination and measurement of colonic coenzyme A activity. A clinical disease activity index and histologic disease activity index were used to assess response. RESULTS: Despite increases in urinary pantothenic acid, no significant changes were found in colonic tissue coenzyme A concentrations, fecal short-chain fatty acid concentrations, or urinary dicarboxylic acid concentrations. Moreover, no significant changes in clinical or histologic disease activity were noted. Although stool frequency and rectal bleeding remained unchanged, all patients noted increased abdominal cramping, and one patient had an increased extent of disease. CONCLUSION: Topically administered dexpanthenol seems to be absorbed, but at the dose used in this study, it did not influence concentrations of colonic coenzyme A activity, fecal short-chain fatty acids, or clinical response in patients with active left-sided ulcerative colitis.
Administration, Topical↗
Nicotine tartrate liquid enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy: a pilot study.
BACKGROUND: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine is therapeutic but often results in side-effects. Administration of nicotine as a liquid rectal enema results in less systemic nicotine absorption. AIM: To determine the safety and clinical response of nicotine tartrate liquid enemas for active left-side ulcerative colitis in a pilot study. METHODS: Ten non-smoking patients with mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy were treated in an open protocol with nightly nicotine tartrate liquid enemas at a dose of 3 mg nicotine base for 1 week then 6 mg for 3 weeks. Clinical assessments were determined at baseline and 4 weeks by endoscopy, physician assessment and a patient diary of daily symptoms. Peak and trough serum nicotine and trough plasma cotinine were determined by gas chromatography/mass spectrometry and high performance liquid chromatography, respectively. RESULTS: After 4 weeks of treatment, 5/7 patients (71%) showed clinical and sigmoidoscopic improvement (per protocol analysis). The other three patients discontinued therapy within 7 days because of inability to retain the liquid enemas. No patients showed histologic improvement. Six of the patients who completed the 4-week study had peak and trough serum nicotine concentration determined, only 1 of 6 patients had a detectable peak nicotine concentration (value 2.3 ng/mL), and all six patients had undetectable trough nicotine concentrations. The mean trough plasma cotinine concentration was 13 +/- 10 ng/mL. Transient and mild adverse events occurred in 4/10 patients (nausea, lightheadedness, tremor, sleep disturbance). Given the low or undetectable serum nicotine concentrations, these adverse events are not likely to be related to the nicotine enemas. CONCLUSIONS: Nicotine tartrate liquid enemas administrated at a dose of 3 mg nicotine base/day for 1 week and then 6 mg/day for 3 weeks are safe and appear to result in clinical improvement in some patients with mildly to moderately active, left-sided ulcerative colitis unresponsive to first-line therapy. Placebo-controlled trials are warranted to confirm these preliminary findings.
Adult↗
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.
Adult↗
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.
Administration, Oral↗