Bradley J. Zins

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

BACKGROUND & AIMS Azathioprine, an effective therapy for Crohns 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 Crohns 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 Crohns 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 Crohns disease. Correlation between clinical response and azathioprine metabolite concentrations at larger azathioprine doses should be determined.

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.

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.

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.

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 μg 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 μg 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.

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.

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

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.

A comparison of standard and induction interferon therapy with and without initial ribavirin in treatment na

A COMPARISON OF STANDARD AND INDUCTION INTERFERON THERAPY WITH AND WITHOUT INITIAL RIBAVIRIN IN TREATMENT NA. Craig J. Peine, Jeffrey H. Albrecht, Joseph P. Roel, Betty A. Gundersen, John P. Kirchner, Bradley Zins, Daniel McKee, Samuel B. Ho, Theresa Smith, Hennepin County Med O r, Minneapolis, MN; Marshfield Clin, Marshfield, WI; Billings Clin, Billings, MT; St Lukes Hosp, Duluth, MN; Veterans Affairs Med Ctr, Minneapolis, MN; Duluth Clin, Duluth, MN.