tacrolimus and Multiple-Sclerosis

Topics: Adult; Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cholangitis; Cyclosporine; Diabetes Mellitus, Type 1; Digestive System Diseases; Disease Models, Animal; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; Kidney Diseases; Male; Mice; Multiple Sclerosis; Nephrotic Syndrome; Psoriasis; Rats; Swine; Tacrolimus

Topics: Anti-Bacterial Agents; Cyclosporins; Humans; Immunosuppressive Agents; Multiple Sclerosis; T-Lymphocytes; Tacrolimus

A randomized concentration-controlled clinical trial (RCCCT) is a trial design in which patients are randomized to predefined blood drug concentrations (low, medium, high). If the concentration ranges are sufficiently separated, this study design can reveal important blood concentration-response relations. Tacrolimus is a potent yet "infant" immunosuppressant for the treatment and prevention of graft rejection and has been shown to exhibit significant clinical activity in some immune-mediated disorders. A tacrolimus artificial intelligence modeling system (AIMS) was used to guide patient dosing to achieve target concentrations specified by the study protocols. In the Multiple Sclerosis study group, we were able to define a concentration range (0.3-0.7 ng/ml) that appeared to show efficacy and minimal tacrolimus toxicity. Patients randomized to the high zone (0.6-1.2 ng/ml) in the Primary Biliary Cirrhosis study group showed significant reduction (approximately 50%) in surrogate efficacy markers [aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT)] compared with patients in the low zone (0.1-0.6 ng/ml). Therefore the RCCCT allowed the detection and delineation of clinically significant concentration-response relations in an ethical and efficient manner.

Topics: Artificial Intelligence; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Multiple Sclerosis; Randomized Controlled Trials as Topic; Research Design; Tacrolimus

We have taken the opportunity of a clinical trial of the potential efficacy and safety of FK 506 (tacrolimus) in chronic progressive multiple sclerosis (MS) to examine the influence of this potent new immunosuppressant on circulating T-lymphocytes in an otherwise healthy non-transplant population. Peripheral blood levels of subsets of CD4+ T lymphocytes expressing the activation molecule interleukin-2 receptor (p55 alpha chain; CD25) or the CD45RA isoform were determined sequentially in 19 patients that were treated continuously with oral FK 506 (starting dose 0.15 mg/kg/day) for 12 months. No significant change in the proportion of circulating CD25+ CD4+ cells was observed over the study period in which the mean trough plasma FK 506 level rose from 0.3 +/- 0.2 to 0.5 +/- 0.4 ng/ml. There was also no significant effect of FK 506 on the percentage of CD45R+ CD4+ cells in the peripheral blood at 12 months compared with pretreatment values. Analysis of a subgroup of 7 patients, who showed a sustained reduction in CD25+ CD4+ cells and a reciprocal increase in CD45RA+ CD4+ cells for at least 6 months after start of treatment, did not reveal any difference in disability at one year compared with the treatment group as a whole. The side effects of FK 506 were mild and the overall degree of disability estimated by the mean Kurtzke expanded disability status scale (EDSS) score or the ambulation index did not deteriorate significantly in the 19 patients studied over the 12 months of FK 506 administration.

Topics: Administration, Oral; Adult; Aged; CD4-Positive T-Lymphocytes; Fatigue; Feeding and Eating Disorders; Female; Humans; Leukocyte Common Antigens; Male; Middle Aged; Multiple Sclerosis; Pilot Projects; Receptors, Interleukin-2; Tacrolimus; Tremor

To alert clinicians to a potential novel adverse drug effect of interferon beta 1a, we herein report a patient with relapsing-remitting multiple sclerosis who developed ulcerative colitis following treatment with interferon beta 1a. Ulcerative colitis persisted despite discontinuation of interferon beta 1a treatment and switching the patient to glatiramer acetate. Tacrolimus (FK506), 6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen. Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease (IBD) and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD.

Topics: Adjuvants, Immunologic; Adult; Colitis, Ulcerative; Female; Glatiramer Acetate; Humans; Immunity, Innate; Immunosuppressive Agents; Interferon beta-1a; Interferon-beta; Mercaptopurine; Multiple Sclerosis; Peptides; Prednisolone; Recurrence; Tacrolimus

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) in which demyelination and axonal loss result in permanent neurologic disability. We examined the neuroprotective property of the immunosuppressant FK506 (tacrolimus), FK1706 (a nonimmunosuppressant FK506 derivative) and cyclosporin A (CsA) in a chronic relapsing experimental autoimmune encephalomyelitis (EAE) model of MS. Female SJL/J mice were immunized by subcutaneous (s.c.) injection with proteolipid protein 139-151 peptide in complete Freund's adjuvant. At the onset of paralysis, 12-14 days after immunization, mice received daily s.c. injections of FK506 (0.2, 1, and 5 mg/kg), FK1706 (5 mg/kg), CsA (2, 10, and 50 mg/kg), saline or vehicle (30% dimethylsulfoxide) for 30 days. FK506 (at a dose of 5 mg/kg) reduced the severity of the initial disease and suppressed relapses. FK1706 did not significantly alter the clinical course and CsA (at a dose of 50 mg/kg) lessened the severity of the initial episode of EAE but did not alter relapses. In the thoracic spinal cord, FK506 (5 mg/kg), FK1706 (5 mg/kg), and CsA (50 mg/kg) significantly (P < 0.001) reduced the extent of damage in the dorsal, lateral, and ventral white matter by a mean of up to 95, 68, and 30%, respectively. A nonimmunosuppressant dose of FK506 (0.2 mg/kg) also significantly (P < 0.001) reduced the extent of damage in the spinal cord by a mean of up to 45%. Other dosages of these compounds were ineffective. FK506 markedly protects against demyelination and axonal loss in this MS model through immunosuppression and neuroprotection.

Topics: Animals; Axons; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Immunophilins; Immunosuppressive Agents; Mice; Multiple Sclerosis; Myelin Sheath; Neuroprotective Agents; Tacrolimus

The effect of liver transplantation on pre-existing multiple sclerosis (MS) has never been reported. We report the three year post-transplant neurological outcome of a patient with MS.. A Caucasian woman with MS received an urgent liver transplant for fulminant liver failure at the age of 59. Her Extended Disability Scale Score (EDSS) pretransplant was 5.0 and clinically she had cerebellar and brainstem dysfunction. Post-transplant immunosuppression consisted of tacrolimus, mycophenolate mofetil and tapering corticosteroids that were discontinued after 1.5 years. Post-transplant her EDSS decreased to 2.0 and after three years she is clinically asymptomatic with only very mild dysarthria on neurologic examination. Long-term maintenance immunosuppression consists of low dose tacrolimus.. Combination immunosuppression with tacrolimus may have a beneficial effect on MS although an effect of donor allograft itself can not be excluded.

Topics: Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Middle Aged; Multiple Sclerosis; Mycophenolic Acid; Prednisone; Remission Induction; Tacrolimus; Treatment Outcome

FK-506 is an immunosuppressive agent used mainly to prevent allograft rejection in organ transplant patients. Recently, it has been applied as a treatment for patients with autoimmune disorders. An entity called posttransplant lymphoproliferative disorder (PTLD) is a well-recognized result of immunosuppression in transplant patients receiving long-term immunosuppression. This disorder is a complication of treatment with FK-506 in 0.7 to 1.6% of transplant patients and is usually of B-cell origin. A majority of patients have serologic evidence of EBV infection. We report a case of a patient receiving long-term FK-506 therapy for multiple sclerosis who developed lymphoproliferative disorder involving the cervix. We will discuss the possible role of FK-506 initiation of this tumor.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Multiple Sclerosis; Tacrolimus; Uterine Cervical Diseases

Topics: Adult; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; Female; Humans; Leukocyte Common Antigens; Male; Middle Aged; Multiple Sclerosis; Receptors, Interleukin-2; Tacrolimus