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.

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.

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.

A dose-ranging study of azathioprine pharmacokinetics after single-dose administration of a delayed-release oral formulation.

6-Mercaptopurine and its prodrug azathioprine are an effective treatment for inflammatory bowel disease, but widespread use has been limited by concern about toxicity. Ileocolonic delivery of azathioprine as a 50-mg delayed-release oral capsule has been shown to decrease bioavailability, thus potentially decreasing toxicity. This study aimed to determine the bioavailability and pharmacokinetic parameters of delayed-release oral azathioprine capsules at doses of 200 mg, 400 mg, and 600 mg relative to 100 mg of standard oral azathioprine tablets. Thirty healthy human volunteers each received delayed-release oral azathioprine at one of the three doses (n = 10 for each group). All participants also received a 100-mg tablet of standard oral azathioprine. Plasma concentrations of 6-mercaptopurine were determined by high-pressure liquid chromatography. The relative bioavailabilities of 6-mercaptopurine after ileocolonic azathioprine administration via delayed-release oral capsules at doses of 200 mg, 400 mg, and 600 mg (means of 15%, 15%, and 12%, respectively) were all significantly less than 100% compared with standard oral azathioprine at a 100-mg dose. Ileocolonic delivery of azathioprine by a delayed-release oral capsule formulation at doses up to 600 mg considerably reduces 6-mercaptopurine bioavailability, relative to standard oral azathioprine tablets. The therapeutic potential of this ileocolonic delivery formulation, which can limit toxicity by local delivery of azathioprine, should be investigated in patients with inflammatory bowel disease.

Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration.

BACKGROUND: 6-Mercaptopurine and its prodrug azathioprine are effective medications for refractory inflammatory bowel disease. However, use of these drugs has been limited by concerns about their toxicity. Colonic delivery of azathioprine may reduce its systemic bioavailability and limit toxicity. AIM: To determine the bioavailability of 6-mercaptopurine after administration of azathioprine via three colonic delivery formulations. METHODS: Twenty four healthy human subjects each received 50 mg of azathioprine by one of four delivery formulations (each n = 6): oral; delayed release oral; hydrophobic rectal foam; and hydrophilic rectal foam. All subjects also received a 50 mg dose of intravenous azathioprine during a separate study period. Plasma concentrations of 6-mercaptopurine were determined by high pressure liquid chromatography. RESULTS: The bioavailabilities of 6-mercaptopurine after colonic azathioprine administration via delayed release oral, hydrophobic rectal foam, and hydrophilic rectal foam (7%, 5%, 1%; respectively) were significantly lower than the bioavailability of 6-mercaptopurine after oral azathioprine administration (47%) by Wilcoxon rank sum pairwise comparison. CONCLUSIONS: Azathioprine delivered to the colon by delayed release oral and rectal foam formulations considerably reduced systemic 6-mercaptopurine bioavailability. The therapeutic potential of these colonic delivery methods, which can potentially limit toxicity by local delivery of high doses of azathioprine, should be investigated in patients with inflammatory bowel disease.

Simultaneous determination of azathioprine and 6-mercaptopurine by high-performance liquid chromatography.

A specific, sensitive, single-step solid-phase extraction and reversed-phase high-performance liquid chromatographic method for the simultaneous determination of plasma 6-mercaptopurine and azathioprine concentrations is reported. Following solid-phase extraction, analytes are separated on a C18 column with mobile phase consisting of 0.8% acetonitrile in 1 mM triethylamine, pH 3.2, run on a gradient system. Quantitation limits were 5 ng/ml and 2 ng/ml for azathioprine and 6-mercaptopurine, respectively. Peak heights correlated linearly to known extracted standards for 6-mercaptopurine and azathioprine (r = 0.999) over a range of 2-200 ng/ml. No chromatographic interferences were detected.

An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn's disease.

BACKGROUND & AIMS: Azathioprine, an effective therapy for Crohn's disease, is limited by a prolonged time to response. The aim of this study was to determine the safety and utility of a loading dose of azathioprine to decrease the time to response in patients with Crohn's disease. METHODS: Twelve patients were studied: 6 with 13 fistulae and 6 with inflammatory disease. All patients received an intravenous infusion of azathioprine (50 mg/h for 36 hours). Response was determined by physical and radiographic examination for fistulae and by the Crohn's Disease Activity Index for inflammatory disease. Erythrocyte concentrations of azathioprine metabolites were measured by chromatography. RESULTS: Seven of 13 fistulae closed by week 4, and three had a temporary decrease in drainage. One fistula improved at week 16. Two fistulae failed to improve. Four of 6 patients with inflammatory disease achieved remission, and 1 improved temporarily. Improvement was rapid (< or = 4 weeks). Peak concentrations of azathioprine metabolites occurred within 3 days. Clinical response did not correlate with azathioprine metabolite concentrations at the azathioprine dose studied. No adverse events occurred. CONCLUSIONS: An 1800-mg intravenous loading dose of azathioprine is safe and may decrease the time to response to < or = 4 weeks in patients with Crohn's disease. Correlation between clinical response and azathioprine metabolite concentrations at larger azathioprine doses should be determined.

Pouchitis disease course after orthotopic liver transplantation in patients with primary sclerosing cholangitis and an ileal pouch-anal anastomosis.

OBJECTIVE: Primary sclerosing cholangitis is associated with the development of pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. This study determined the effect of liver transplantation for primary sclerosing cholangitis on the disease course of pouchitis. METHODS: Seven patients with an ileal pouch-anal anastomosis for ulcerative colitis underwent liver transplantation for primary sclerosing cholangitis. The medical record was reviewed to determine the pouchitis activity and pattern (no pouchitis, single acute, recurrent acute, chronic) before and after transplantation. RESULTS: Five of seven patients had pouchitis before transplant [recurrent acute (n = 3), chronic (n = 2)], and four of those five continued to have pouchitis after transplant (all chronic). Pretransplant sera were positive for antineutrophil cytoplasmic antibody in 6/6 patients, compared to 5/6 patients posttransplant. One patient with pouchitis pretransplant became negative for antineutrophil cytoplasmic antibody posttransplant but continued to have pouchitis. CONCLUSION: Pouchitis occurs frequently in patients with primary sclerosing cholangitis and an ileal pouch-anal anastomosis for ulcerative colitis. Liver transplantation does not alter the disease course of pouchitis for most of these patients.

Collagenous and lymphocytic colitis: subject review and therapeutic alternatives.

OBJECTIVE: To review the published studies on collagenous and lymphocytic (microscopic) colitis with specific emphasis on clinical features, investigational studies, characteristic histology, possible pathogenesis, disease course, and empirical treatment. DESIGN: Comprehensive synopsis of the stated objective, prepared for the physician treating patients with collagenous or lymphocytic colitis. MATERIALS AND METHODS: The medical literature on collagenous and lymphocytic colitis. RESULTS: Collagenous and lymphocytic colitis are chronic diarrheal illnesses of indeterminate etiology that typically present in the late sixth or early seventh decade of life. These disorders may be distinct entities, although some data support the idea that they are only different manifestations of the same disease. The pathogenesis is unknown but may be on an inflammatory, possibly autoimmune, basis. Physical examination and investigational studies are normal or nonspecific, with fecal leukocytosis the only abnormality found in the majority of patients tested. Association with various gastrointestinal, autoimmune, and rheumatologic conditions has been observed in some patients. Clinical and occasional histologic response has been observed after treatment with anti-inflammatory agents such as 5-aminosalicylate and corticosteroids, and should be used when there is no response to symptomatic therapy. CONCLUSIONS: Collagenous and lymphocytic colitis are uncommon but important causes of chronic diarrhea which are important to diagnose and treat.

Collagenous colitis: mucosal biopsies and association with fecal leukocytes.

OBJECTIVE: To determine the frequency of patchy colonic involvement, fecal leukocytosis, and association with celiac sprue in a large cohort of patients with collagenous colitis. DESIGN: We conducted a retrospective review of the medical records of 172 consecutive Mayo Clinic patients in whom collagenous colitis had been diagnosed between 1982 and 1993. METHODS: For each of the 172 patients, the medical record was reviewed to determine the frequency of (1) fecal leukocytosis; (2) characteristic histologic findings in the rectum and the sigmoid, descending, and ascending colon; and (3) small bowel biopsy findings consistent with celiac sprue. RESULTS: The presence of fecal leukocytes was noted in 64 of 116 patients (55%) who had undergone assessment for fecal leukocytosis. On analysis of histologic findings, 113 of 123 rectal, 116 of 121 sigmoid, and 68 of 70 descending colon biopsy specimens were diagnostic of collagenous colitis. Small bowel biopsies were performed in 45 patients who did not have a history of small intestinal disease: 1 had celiac sprue and 44 had normal findings. Two other patients had previously diagnosed celiac sprue. CONCLUSION: The finding of fecal leukocytes in 55% of patients with collagenous colitis confirms the inflammatory basis of this disease. Biopsy specimens obtained by flexible sigmoidoscopy seem sufficient to establish the diagnosis in most patients, and colonoscopic biopsy of the more proximal area of the colon is usually unnecessary. Celiac sprue infrequently accompanies collagenous colitis; thus, routine small bowel biopsy is not warranted.