Cyclosporine therapy in inflammatory bowel disease: short-term and long-term results.

Intravenous cyclosporine therapy followed by oral cyclosporine therapy reduce the need for urgent surgery in steroid-refractory inflammatory bowel disease (IBD). Our objective is to report short- and long-term results of cyclosporine therapy in IBD patients. Thirteen patients with steroid-refractory IBD, seven patients with ulcerative colitis (UC), and six patients with Crohn's disease (CD) were treated with intravenous cyclosporine (4 mg/kg/day) for a mean period of 11.4+/-2.8 days (range, 4-15 days). Subsequently the patients were started on oral cyclosporine (8 mg/kg/day) and followed for a mean of 10.3+/-10 months (range, 1-30 months). Twelve patients responded to intravenous cyclosporine therapy. One patient with UC developed sepsis on the fourth day of intravenous cyclosporine therapy and needed urgent colectomy. Nine of 12 initial responders (6 patients with UC and 3 patients with CD) relapsed during follow-up despite oral cyclosporine and underwent elective surgery. One patient with CD relapsed 3 months after discontinuation of oral cyclosporine. Only two patients with CD are in long-term remission. There were no long-term side effects in any of the 13 treated patients. In conclusion, intravenous cyclosporine was effective in inducing remission or significant improvement in 12 of 13 patients with steroid-refractory IBD. However, with subsequent oral cyclosporine the remission could be maintained only for a short while. Each of the six patients with UC needed colectomy and three of the five patients with CD had intestinal resection within 12 months despite oral cyclosporine therapy.     

Long-term treatment of Crohn's disease with cyclosporine: the effect of a very low dose on maintenance of remission

Low-dose oral cyclosporine was used to maintain remission in patients with Crohn's disease. In seven patients, cyclosporine was used as a steroid-sparing agent; in 14 it was given for refractory active disease as an adjunct to conventional treatment, and then continued as maintenance treatment. Cyclosporine was given at an initial dose of 5 mg/kg reduced by 1 mg/kg at 2-month intervals until a maintenance dose of 2 mg/kg was reached. Of the seven patients in whom cyclosporine was used as a steroid-sparing agent, six had a relapse. Remission was achieved in seven of the refractory active group, but cyclosporine was withdrawn because of side effects in six of the patients in this group. Of the seven patients who had achieved remission, six subsequently had a relapse. Therefore, 12 of 14 patients (86%) in remission had a relapse despite cyclosporine maintenance. Ten of these (83%) had a relapse at a cyclosporine dose of 2 or 3 mg/kg. Cyclosporine levels at relapse (median, 74 ng/ml) were lower than the mean levels over the first 6 weeks of treatment (median, 130 ng/ml; p = 0.02). Our data do not support the use of cyclosporine to maintain remission in Crohn's disease.     

Clinical outcome and pharmacokinetics after addition of low-dose cyclosporine to methotrexate: a case study of five patients with treatment-resistant inflammatory bowel disease

INTRODUCTION: This study reports the clinical outcome, toxicity, and methotrexate pharmacokinetics after the addition of low-dose cyclosporine to methotrexate in patients with ulcerative colitis or Crohn's disease. METHODS: Three patients with steroid-refractory ulcerative colitis and two patients with steroid refractory Crohn's disease who failed monotherapy with subcutaneous methotrexate 25 mg/week for 16 weeks were treated with the combination of methotrexate and low-dose oral cyclosporine (3 mg/kg/day) for an additional 16 weeks. Clinical response was measured with the Inflammatory Bowel Disease Questionnaire (IBDQ) score. Concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate were also determined. RESULTS: Both patients with Crohn's disease withdrew from the study for toxicity (headaches, seizure). The three patients with ulcerative colitis experienced clinical improvement with a mean increase in the IBDQ score from 164 to 190 points, p = 0.01. The mean serum creatinine in the three patients who completed the study increased from 0.9 mg/dL at baseline to 1.2 mg/dL at week 16. p = 0.04. One patient developed hypertension. There was no significant change from baseline in the concentrations of erythrocyte methotrexate, plasma methotrexate, and plasma 7-hydroxymethotrexate. CONCLUSIONS: Combination therapy with methotrexate and low-dose oral cyclosporine did not alter methotrexate pharmacokinetics and resulted in high rates of cyclosporine-associated toxicity.     

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.     

Cyclosporine Enemas for Treatment-Resistant, Mildly to Moderately Active, Left-Sided Ulcerative Colitis

Ten patients with treatment-resistant left-sided ulcerative colitis were treated in an open protocol with 350 mg cyclosporine enemas nightly for 4 wk. A 12-point clinical disease activity index (DAI) score was calculated at baseline and after 4 wk. Whole blood and colonic tissue cyclosporine concentrations were determined by HPLC at the end of the study. Five of 10 patients responded to treatment, defined as a decrease in the clinical DAI score ≥3 points. Responders retained the enemas longer than nonresponders (7.5 ± 1.3 vs. 3.3 ± 2.2 h, p = 0.01), and there was a positive correlation between decrease in the clinical DAI score and enema retention time ( r = 0.64, p = 0.05). The mean colonic tissue cyclosporine concentration was not significantly higher in responders than in nonresponders (2884 ± 1635 vs. 2359 ± 576 ng/g, p = 0.52), and the correlation between decrease in the clinical DAI score index and colonic tissue cyclosporine was weak ( r = 0.39, p = 0.26). Cyclosporine was undetectable in whole blood samples from all patients, and there were no apparent side effects with treatment. In conclusion, 50% of patients with treatment-resistant left-sided ulcerative colitis significantly improved during therapy with cyclosporine enemas for 4 wk. Patients with longer enema retention times were more likely to respond. A controlled trial is underway to investigate these findings further.     

Cyclosporine therapy in patients with steroid resistant autoimmune hepatitis

Autoimmune hepatitis is a form of chronic liver disease characterized by progressive hepatocellular inflammation, which usually responds to treatment with corticosteroids. However, 10% of patients with autoimmune hepatitis are refractory to corticosteroids and develop progressive liver disease and cirrhosis. We describe five patients with autoimmune hepatitis who did not respond to conventional corticosteroids and azathioprine therapy who were then treated with cyclosporine A. Cyclosporine A was started at 2–3 mg/kg/day and induced biochemical remission in four of five patients within 3 months. One of the four responders relapsed within 1 month of discontinuing cyclosporine on two occasions. Each time, liver tests promptly normalized after reinitiation of cyclosporine. Two responders were managed with cyclosporine alone. The single patient who did not respond to cyclosporine developed progressive liver failure, underwent orthotopic liver transplantation, and subsequently died of disseminated cytomegalovirus infection. Cyclosporine was generally well tolerated and none of the patients developed renal insufficiency. These data and review of 11 cases in the literature show that cyclosporine can induce remission of liver disease in patients with autoimmune hepatitis who are refractory to corticosteroids.     

Efficacy of cyclosporine in treatment of fistula of crohn's disease

Sixteen Crohn's disease patients with active fistula who had failed standard medical therapy were treated with intravenous cyclosporine. Ten patients had perirectal disease, four had enterocutaneous fistula, and two had rectovaginal fistula. Patients were initially treated with intravenous cyclosporine, 4 mg/kg/day, and then switched to oral cyclosporine, 6–8 mg/kg/day. Improvement was graded using the Present-Korelitz criteria, and success was defined as moderate to total closure of the fistula. Fourteen of 16 patients (88%) responded in the acute phase to parenteral cyclosporine. Closure of fistula occurred in seven (44%) with moderate improvement in the remaining seven (44%). Subsequently, five patients (36%) relapsed to some degree on oral cyclosporine (three severe and two mild relapses). Nine (64%) patients maintained their improvement in the chronic phase. Chronic steroids could be discontinued in 6/8 (75%) of patients. Mild side effects were common [paresthesias (75%) and hirsuitism (19%)]. A single patient had severe paresthesias requiring discontinuation of therapy. Mild hypertension was noted in four (25%) and one patient (6%) had to be withdrawn because of nephrotoxicity, which reversed after stopping cyclosporine. We conclude that intravenous cyclosporine is effective therapy for perianal, rectovaginal, and enterocutaneous fistula in Crohn's disease. Its future role awaits controlled trials as well as determination of the risk-benefit ratio.     

Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients

Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n=25), renal dysfunction (n=3), hepatic dysfunction (n=2), and hypertension (n=2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n=4), hyperbilirubinemia (n=2), and hypertension (n=2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.     

Cyclosporine for the treatment of fulminant ulcerative colitis in children

PURPOSE: Emergency surgery for fulminant colitis is often complicated by high-dose steroid therapy, poor nutrition, and psychologic maladjustment. Cyclosporine is effective for fulminant ulcerative colitis in adults, resulting in avoidance of immediate surgery in 75 percent of patients and a 55 percent long-term remission rate. Over the last five years, we studied the effectiveness of cyclosporine in children with fulminant colitis. METHODS: Fourteen patients with ulcerative colitis (age, 7–20 years) received cyclosporine after satisfying the following criteria: 1) greater than five bloody diarrheal stools per day; 2) severe abdominal pain; 3) no improvement after ten days of bowel rest, 4) intravenous methylprednisolone (1–2 mg/kg/day); and 5) parenteral nutrition. Treatment was begun with oral cyclosporine (4.6–9.6 mg/kg/day), and the dose was adjusted to achieve whole blood trough levels measured with a monoclonal radioimmunoassay between 150 and 300 ng/ml. If improved, patients were discharged on oral cyclosporine, prednisone, and a regular diet. RESULTS: Eleven of 14 patients (78 percent) responded within two to nine days and were able to consume a normal diet, had three or less soft stools per day, and had no pain. One did not respond after ten days and underwent an ileal pouch-anal anastomosis procedure. Two patients elected surgery after 20 days of therapy and a partial response. Of 11 patients who left the hospital, 4 had recurrent symptoms after 2 to 11 months of taking therapeutic doses of cyclosporine and 3 flare ups while weaning from cyclosporine after 4 to 8 months. Three patients have been weaned from cyclosporine after 8 to 13 months and have remained in remission from six months to five years. One patient is about to complete a six-month course of cyclosporine. Overall ten (72 percent) have undergone surgery, including 7 of 11 who responded initially to cyclosporine and left the hospital. Weight (P<0.001), albumin (P <0.01), erythrocyte sedimentation rate (P>0.05), and prednisone dose (P<0.001) improved significantly in the seven patients on cyclosporine who responded initially, left the hospital, and subsequently underwent surgery. CONCLUSIONS: Cyclosporine is effective in achieving clinical remission in 80 percent of children with refractory fulminant colitis; however, within one year, most initial responders will require colectomy because of a flare up of the disease. In a majority of patients, the role of cyclosporine therapy is to rapidly ameliorate symptoms and prevent precipitous colectomy, improve nutrition and psychologic adaptation, and reduce the steroid dose leading to surgery in a well-prepared patient.Read in part at the meeting of the American Society of Gastrointestinal Endoscopy, New Orleans, Louisiana, May 15 to 18, 1994. Winner of the Midwest Society of Colon and Rectal Surgeons William C. Bernstein, M.D. Award.     

High-dose intravenous cyclosporine in steroid refractory attacks of inflammatory bowel disease.

BACKGROUND/AIMS: To determin whether cyclosporine is effective in inducing remission in patients with severe active inflammatory bowel disease, refractory to steroids. METHODOLOGY: Twenty-three patients with severe and steroid-refractory inflammatory bowel disease (15 ulcerative colitis and 8 Crohn's disease) were included. The Mayo Clinic Score and the CDAI were used to evaluate activity. Cyclosporine (4 mg/kg/day) was administered for a maximum of ten and a minimum of 7 days. RESULTS: Ten of the 15 ulcerative colitis patients achieved remission with a mean response lag time to onset improvement of 8 days. Seven of these patients remained stable with mesalazine 4 months after cyclosporine treatment. Two patients relapsed and underwent colectomy on the 50th and 200th day after treatment. Five patients presented no response and required urgent colectomy. Six of the 8 Crohn's disease patients achieved remission with a mean response lag time to onset improvement of 7 days. The 6 patients remained stable with mesalazine four months after cyclosporine treatment. The other 2 developed reversible renal failure and had to be released from the study. CONCLUSIONS: Intravenous high dose cyclosporine is effective and can be used as a rapid onset treatment for acute steroid refractory IBD.     

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of 相似文献   

Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of inflammatory bowel disease

In the past decade, immunosuppressive drugs have come to play an integral role in the treatment of patients with inflammatory bowel disease. Cyclosporine, microemulsion cyclosporine, tacrolimus, and mycophenolate mofetil can be considered for the treatment of patients with refractory inflammatory Crohn's disease, fistulizing Crohn's disease, and severe ulcerative colitis. This article reviews the use of cyclosporine, tacrolimus, and mycophenolate mofetil in patients with inflammatory bowel disease, with emphasis on pharmacology, results in controlled clinical trials, and safety, and issues related to dosing and toxicity monitoring.     

Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease

BACKGROUND: Pyoderma gangrenosum complicates inflammatory bowel disease in 2-3% of patients and often fails to respond to antibiotics, steroids, surgical debridement or even colectomy. METHODS: We performed a retrospective chart analysis of 11 consecutive steroid-refractory pyoderma patients (5 ulcerative colitis, 6 Crohn's disease) referred to our practice and then treated with intravenous cyclosporine. Pyoderma gangrenosum was present on the extremities in 10 patients, the face in 2, and stomas in 21. At initiation of intravenous cyclosporine, bowel activity was moderate in 3 patients, mild in 4, and inactive in 4. All patients received intravenous cyclosporine at a dose of 4 mg/kg/d for 7-22 days. They were discharged on oral cyclosporine at a dose of 4-7 mg/kg/d. RESULTS: All 11 patients had closure of their pyoderma with a mean time to response of 4.5 days and a mean time to closure of 1.4 months. All seven patients with bowel activity went into remission. Nine patients were able to discontinue steroids, and nine were maintained on 6-mercaptopurine or azathioprine. One patient who could not tolerate 6-mercaptopurine had a recurrence of pyoderma. No patient experienced significant toxicity. CONCLUSION: Intravenous cyclosporine is the treatment of choice for pyoderma gangrenosum refractory to steroids and 6-mercaptopurine should be used as maintenance therapy.     

Cyclosporine in rheumatoid arthritis.

The efficacy and toxicity of cyclosporine in the treatment of patients with rheumatoid arthritis (RA) are reviewed. Most of the early trials were restricted to patients with intractable RA. The initial daily dose of cyclosporine was 5 to 10 mg/kg, which is now considered high. Of 283 cyclosporine-treated patients in nine studies, 8% discontinued the drug prematurely because of inefficacy and 17% because of adverse reactions. Cyclosporine improves clinical parameters but does not influence the erythrocyte sedimentation rate. The most important side effects are gastrointestinal intolerance and nephrotoxicity. The former is of minor importance with the present dosage schedule (starting daily dose, 2.5 mg/kg), and increments should follow the principle "go low, go slow." Guidelines are given to avoid or reduce nephrotoxicity. It may be beneficial to administer cyclosporine early in the course of RA.     

Combination immunomodulatory therapy with cyclosporine and azathioprine in corticosteroid-resistant severe ulcerative colitis: the Edinburgh experience of outcome

BACKGROUND: Cyclosporine is a fungal metabolite and a powerful immunosuppressant. While response to intravenous steroids in severe ulcerative colitis is in excess of 60%, the remainder of patients are left with the options of curative panproctocolectomy or administration of intravenous rescue therapy with cyclosporine. There have been conflicting reports on the efficacy of intravenous cyclosporine in acute ulcerative colitis, and there are serious concerns about potential toxicity and opportunistic infections such as Pneumocystis carnii pneumonia. There are also concerns about early relapse and colectomy following cyclosporine rescue. To date there has been a paucity of data available to help guide the gastroenterologist in the use of cyclosporine and the maintenance of remission once achieved. METHODS: Between 1994 and 2001, a total of sixteen patients who had received intravenous cyclosporine for acute exacerbation of their known UC (seven females, nine males, mean age 33 years) whose records were available for analysis. All patients were refractory to intravenous methylprednisolone (60 mg/24 h). Patients who responded to cyclosporine were discharged on a regimen of oral cyclosporine, oral steroids oral azathioprine and 5-aminosalicylate. RESULTS: Median disease duration was 5.4 years (range 0.9-25 years). All sixteen patients were initially treated with cyclosporine at a dose of 4 mg/kg/day. Nine patients were started on oral azathioprine (median dose 1.8 mg/kg). Seven patients underwent surgery (panproctocolectomy), although none had surgery after 6 months. Comparisons were made between patients with <7 days and >7 days intravenous steroid. Other parameters analysed were stool frequency at 3 days and CRP at 3 days. There were no significant differences between these groups. Median bowel frequency at day 3 was higher in patients who finally underwent surgery. At 3 years follow-up, 56% of the sixteen patients had avoided surgery by using azathioprine immunosuppression. CONCLUSION: The initial response rate to intravenous cyclosporine was high (69%). Side effects were documented in the majority of patients, but none of the patients had to discontinue treatment on account of these. Azathioprine has a useful role in maintaining the remission achieved by i.v. cyclosporine for acute ulcerative colitis patients. More than half the patients will avoid colectomy long-term when using triple immunosuppressive therapy including azathioprine adding support for its relative safety and another role for its use.     

Cyclosporine enhances the growth of carcinogen-induced enzyme-altered foci in rat liver

Cyclosporine, a powerful immunosuppressant, has been used successfully for organ transplantation. Its efficacy on liver transplants of patients with primary hepatic tumors remains controversial because of a high rate of recurrence of the original tumors in the transplanted livers. In this study, we experimentally tested whether cyclosporine exerts any effects on the growth of carcinogen-initiated liver cells using the short-term assays of rat liver carcinogenesis. Dietary cyclosporine, which maintained sufficient levels of blood cyclosporine and suppressed host immune functions, enhanced the development of the glutathione S-transferase, placental form-positive hepatocyte foci in the liver of male F-344 rats treated with a single weekly dose of diethylnitrosamine (75 mg/kg) for 3 wk. Dietary cyclosporine also accelerated the growth of preformed glutathione S-transferase, placental form-positive foci induced by a single dose of diethylnitrosamine (250 mg/kg) followed by the promoting regimen of a choline-deficient diet. It is possible that the enhancement of the size of hepatocyte foci by cyclosporine could be due to stimulation of growth or inhibition of regression. The mechanisms by which cyclosporine modifies the growth of preneoplastic lesions in the liver are not yet fully understood. Possible involvement of immunologically relevant cells in the liver, Kupffer cells and pit cells in the process is suggested.     

Intravenous cyclosporine for inflammatory bowel disease--safe and effective

BACKGROUND/AIMS: Intravenous cyclosporine has been used in the treatment of active inflammatory bowel disease. However, there are serious concerns regarding its toxicity. Cyclosporine's exact place in the treatment of Crohn's disease is yet to be defined. The aims of this study are to assess the safety and efficacy of intravenous cyclosporine in treatment of patients with inflammatory bowel disease. METHODOLOGY: We reviewed the hospital files of all patients who received intravenous cyclosporine in Rambam Medical Center during the period of December 2000 to November 2003. The patients' charts, focusing on clinical outcomes and toxicity were recorded and analyzed. RESULTS: Twenty patients, 10 males, seven with Crohn's disease and 13 ulcerative colitis. Seven patients underwent surgery within one year after cyclosporine therapy. Clinical response was achieved in 77.8% of Crohn's patients' treatment courses and 85.7% of ulcerative colitis patients' treatment courses. Clinical response included significant reduction in bowel movements, amount of blood and improvement in consistency of stool. No major or life-threatening adverse effects of cyclosporine were observed. CONCLUSIONS: Cyclosporine as given was as effective and safe for Crohn's disease patients as for ulcerative colitis patients.     

Combination therapy with oral tacrolimus (FK506) and azathioprine or 6-mercaptopurine for treatment-refractory Crohn's disease perianal fistulae

Our aim was to report the clinical experience with combination treatment using tacrolimus and either azathioprine (AZA) or 6-mercaptopurine (6MP) in patients with Crohn's disease (CD) perianal fistulae. The medical records of all patients with Crohn's disease perianal fistulae seen at the Mayo Clinic from 1996-1998 who were treated with tacrolimus were reviewed. Clinical response was classified as: complete response, partial response, and nonresponse. Eleven patients were treated with oral tacrolimus for a mean duration of 22 weeks. The initial oral dose of tacrolimus ranged from 0.15 to 0.31 mg/kg/day. Azathioprine or 6MP was continued in combination with tacrolimus in seven patients and initiated simultaneously with tacrolimus in four patients. All patients improved clinically, seven had a complete response, and four had a partial response. The mean time to initial improvement was 2.4 weeks, and the mean time to complete response was 12.2 weeks. The most frequent adverse events were nausea, paresthesias, nephrotoxicity, and tremor. Patients with nephrotoxicity had a significantly higher mean initial tacrolimus dose (0.31 mg/kg/day) compared with patients who did not have nephrotoxicity (0.25 mg/kg/day) (p = 0.035); however, there was not a statistically significant association between the starting dose or mean blood level and clinical response. Combination therapy with oral tacrolimus and AZA or 6MP may be effective treatment for CD perianal fistulae. Higher initial tacrolimus doses increase the risk of nephrotoxicity without improving clinical response.     

Cytomegalovirus infection in patients with inflammatory bowel disease

OBJECTIVE: It has been suggested that, in inflammatory bowel disease, cytomegalovirus behaves in the intestine as a nonpathogenic bystander, and even its finding in intestinal mucosa has unclear clinical relevance. We report our experience with a small series of patients with refractory inflammatory bowel disease and cytomegalovirus infection and their clinical outcome. METHODS AND RESULTS: Nine patients with moderate-severe attacks of inflammatory bowel disease did not respond to i.v. prednisone (1 mg/kg/day) for a mean of 24 days. Four of these patients were further treated with i.v. cyclosporine A (4 mg/kg/day). Cytomegalovirus infection was diagnosed in two patients after resection for treatment failure. In the remaining patients, cytomegalovirus infection was diagnosed in endoscopic mucosal biopsies and i.v. ganciclovir was then administered at a dose of 10 mg/kg/day for 2-3 wk. Five of these patients went into clinical remission, allowing corticosteroid and cyclosporine A discontinuation. Follow-up biopsies were performed and in all cases cytomegalovirus could not be detected in the colonic tissue. Two patients needed to be treated with intravenous cyclosporine A after antiviral therapy because of persistence of clinical symptoms despite the elimination of cytomegalovirus infection. CONCLUSIONS: Cytomegalovirus infection may play a role in the natural history of refractory inflammatory bowel disease and in some of its complications. The clearance of cytomegalovirus in colonic mucosa may lead some of these patients to remission.     

Cyclosporine A modulates baroreceptor function in kidney transplant recipients

Cyclosporine has been described to increase the sympathetic tone. Alterations in sympathetic tone may contribute to baroreceptor dysfunction. Therefore, in this study baroreceptor function in 20 kidney transplant recipients was investigated under both low and high cyclosporine whole blood concentrations using the sequence analysis technique. The sympathetic nerve activity was estimated by calculating the low frequency oscillation of heart rate and blood pressure following Fast Fourier Transformation (FFT). Besides cyclosporine, azathioprine and prednisolone no other drugs were used. The increase in cyclosporine whole blood levels (from 101+/-13.4 ng/ml to 469+/-52 ng/ml) did not change mean arterial blood pressure significantly (83.7+/-2.5 vs. 82.2+/-2.0 mm Hg). Baroreflex sensitivity in +PI/+RR (+pulsinterval/+blood pressure) sequences, however, increased from 11.2+/-0.4 to 13.0+/-0.5 ms/mm Hg, whereas it was reduced in -PI/-RR (-pulsinterval/-blood pressure) sequences (14.4+/-0.3 to 12.5+/-1.1 ms/mm Hg). The increase in cyclosporine whole blood concentrations was associated with an increase in low frequency oscillation of heart rate (430+/-12 to 461+/-13) and blood pressure (452+/-9 to 469+/-12), indicating an enhanced sympathetic tone. Our results provide evidence that cyclosporine A by itself alters baroreceptor function. An imbalance between the sympathetic and parasympathetic nervous system due to an enhanced sympathetic tone may explain the reduction in -PI/-RR and the increase in +PI/+RR sequence baroreflex sensitivity.