mna-715 has been researched along with Acute-Disease* in 12 studies
1 trial(s) available for mna-715 and Acute-Disease
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The effects of FK778 in combination with tacrolimus and steroids: a phase II multicenter study in renal transplant patients.
In animal and in vitro models, FK778 inhibits acute rejection, modifies vasculopathy, and shows anti-viral activity. We report first efficacy and safety data of FK778 in human kidney transplant recipients at two concentration-controlled ranges.. In a double-blind manner, 149 patients were randomized to a 12-week treatment with FK778 in combination with tacrolimus (Tac) and corticosteroids (S). Of the high-level group (H), 49 patients received 2 x 600 mg/day FK778 and continued on 150 mg/day, 54 patients of the low-level group (L) got 1 x 600 mg/day followed by 75 mg/day, and 46 patients received placebo (P). Subsequent FK778 doses were adjusted to trough levels of 100-200 microg/mL (H) and 10-100 microg/mL (L). The primary endpoint was the incidence of biopsy proven acute rejection (AR).. In 93% of the patients in group L, targeted plasma trough levels were reached by Day 3; in half of the patients in group H, the targeted levels were reached by Day 9. Graft survival at week 16 was 89.7%, 88.8%, and 91.3%, and the incidences of AR were 26.5%, 25.9%, and 39.1% for groups H, L, and P. For the subgroup of patients in which target levels were reached by week 2, incidences were 7.7%, 27.1%, and 39.1%, respectively. Anemia, the most frequently reported adverse event especially in group H, was reversible. Mean total cholesterol and LDL-cholesterol levels were reduced during FK778 treatment compared with group P.. FK778 is pharmacologically active, well-tolerated, and safe. To fully benefit from this promising new drug, FK778 dosing will be optimized in subsequent studies. Topics: Acute Disease; Adolescent; Adult; Aged; Alkynes; Drug Therapy, Combination; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Isoxazoles; Kidney Transplantation; Male; Middle Aged; Nitriles; Patient Compliance; Prednisolone; Tacrolimus; Treatment Outcome | 2004 |
11 other study(ies) available for mna-715 and Acute-Disease
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Is the malononitrilamide FK778 better for the prevention of acute or chronic rejection?
The aim of this study was to assess the efficacy of FK778 to prevent acute and chronic allograft rejection compared with other immunosuppressive agents.. Heterotopic Brown-Norway (BN)-to-Lewis rat cardiac transplantations and heterotopic BN-to-Lewis tracheal transplantations were performed to study acute heart rejection and the development of chronic obliterative airway disease (OAD), respectively. Recipients were treated with FK778, tacrolimus, MMF, or sirolimus for 10 days (acute rejection study) or 28 days (chronic OAD study) at varying doses.. In untreated recipients, cardiac allograft survival was 6.2 +/- 0.4 days. FK778 (20 mg/kg), tacrolimus (2 or 8 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly prolonged graft survival to 17.0 +/- 2.8, 18.5 +/- 2.7, 25.0 +/- 2.5, 20.7 +/- 3.8, 14.5 +/- 2.2, and 23.2 +/- 1.5 days, respectively (P < .05). Tracheal grafts in untreated recipients showed intense infiltration and complete luminal obliteration by day 28. FK778 (20 mg/kg), tacrolimus (1 or 4 mg/kg), MMF (10 or 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly inhibited tracheal luminal obliteration (19.5% +/- 16.4%, 44.2% +/- 33.6%, 12.3% +/- 3.3%, 61.7% +/- 18.6%, 18.3% +/- 11.3%, 55.0% +/- 30.9%, and 8.5% +/- 3.5% (P < .05). All 4 high-dose groups showed similar efficacy.. When used in therapeutic doses, tacrolimus and sirolimus were more effective than FK778 to prolong cardiac allograft survival. However, with its antiproliferative effects on smooth muscle cells, its good tolerability, and its blockade of cytomegalovirus replication, FK778 proved effective to prevent chronic OAD development. Thus, FK778 may acquire an important role in maintenance therapy for the prevention of long-term fibroproliferative complications. Topics: Acute Disease; Alkynes; Animals; Chronic Disease; Disease Models, Animal; Graft Rejection; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Isoxazoles; Nitriles; Rats; Rats, Inbred BN; Rats, Inbred Lew; Sirolimus; Tacrolimus; Trachea; Transplantation, Homologous | 2007 |
FK778, a novel immunosuppressive agent, reduces early adhesion molecule up-regulation and prolongs cardiac allograft survival.
The adhesion molecules, P-selectin, ICAM-1, and VCAM-1 are important mediators of T-cell adhesion and T-cell co-stimulation. We investigated the effect of the malononitrilamide FK778 on cardiac allograft survival, acute allograft rejection, and adhesion molecule up-regulation in a heterotopic, cardiac transplantation model. Rats received low- or high-dose FK778 or no treatment. Grafts were harvested on the fifth postoperative day for histologic examinations. To assess allograft survival, recipients were treated for a maximum of 10 days and grafts were harvested after cessation of the contractile activity. FK778 low dose showed a mild but significant decrease in mononuclear infiltration but failed to markedly reduce histologic rejection, adhesion molecule up-regulation, or to prolong allograft survival. However, high-dose FK778 treatment significantly reduced early up-regulation of P-selectin, ICAM-1, and VCAM-1, abolished infiltration, reduced histologic rejection and resulted in prolonged cardiac allograft survival. Therefore, FK778 is a novel, highly desirable immunosuppressive drug for transplantation medicine. Topics: Acute Disease; Alkynes; Animals; Graft Rejection; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Isoxazoles; Male; Nitriles; P-Selectin; Rats; Rats, Inbred BN; Rats, Inbred Lew; Transplantation, Homologous; Up-Regulation; Vascular Cell Adhesion Molecule-1 | 2005 |
FK778 attenuates lymphocyte-endothelium interaction after cardiac transplantation: in vivo and in vitro studies.
The malononitrilamide FK778 is a novel derivate of leflunomide and interacts with T- and B-cell function by inhibiting de novo pyrimidine synthesis. We investigated the effects of FK778 upon acute cardiac allograft rejection and upon adhesion molecule upregulation in experimental transplantation and by using in vitro cell culture.. Heterotopic, abdominal cardiac transplantations were performed in the Brown Norway (BN) to Lewis (Lew) rat model. The study groups received daily low- or high-dose FK778 immunosuppression. FK778 plasma levels were quantified by HPLC. Grafts were harvested on the fifth postoperative day for histologic and immunohistologic examinations using computerized morphometry. Purified BN aortic endothelial cell cultures were pretreated with low- or high-dose FK778 according to FK778 plasma levels and were stimulated with tumor necrosis factor (TNF)-alpha. Adhesion molecule expression was quantified by immunofluorescence, FACS analysis, and Western blotting. Lymphocyte-endothelium adhesion assays were performed using purified Lew lymphocytes and radiolabeled TNF-alpha was used for receptor binding assays.. FK778 treatment dose-dependently reduced graft mononuclear infiltration of CD4(+), CD8(+), and ED1(+) cells, but only high-dose FK778 treatment significantly reduced early upregulation of ICAM-1 and VCAM-1 in vivo. FK778 also dose-dependently reduced TNF-alpha-stimulated endothelial adhesion molecule upregulation in vitro, whereas the effect on VCAM-1 was more dominant. We did not find evidence that FK778 interferes with surface receptor binding of TNF-alpha. Lymphocyte adhesion to endothelial cell monolayers was significantly attenuated by FK778.. Besides its inhibitory effect on pyrimidine synthesis, FK778 directly reduces endothelial adhesion molecule upregulation and attenuates lymphocyte-endothelium interaction, which is a critical step in graft rejection. Topics: Acute Disease; Alkynes; Animals; Antineoplastic Agents; Cell Adhesion; Endothelial Cells; Graft Rejection; Heart Transplantation; In Vitro Techniques; Intercellular Adhesion Molecule-1; Iodine Radioisotopes; Isoxazoles; Lymphocytes; Nitriles; Rats; Rats, Inbred BN; Rats, Inbred Lew; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1 | 2004 |
FK778 and FK506 combination therapy to control acute rejection after rat liver allotransplantation.
In organ transplantation, several immunosuppressants are currently used to control graft rejection. Clinically, no single immunosuppressive agent can completely prevent posttransplantation immunoreaction; thus, combination therapy is usually performed. Novel agents with more powerful immunosuppressive activity and less toxicity need to be developed.. Lewis rat livers were orthotopically transplanted into Brown-Norway recipients. FK778 was administered orally from day 0 to day 6 to prevent acute rejection and from day 7 to day 13 to rescue ongoing rejection. To assess the combined effects, recipients were treated with intramuscular injection of FK506 and oral administration of FK778 from day 0 to day 6. Blood chemistry and histopathologic findings were measured to determine the patient's general condition and the graft condition. Allospecific antibodies were measured using enzyme-linked immunosorbent assays. The FK778 trough concentration was examined by using high-performance liquid chromatography.. The acute immune response was suppressed by FK778 alone in a dose-dependent manner. The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day. FK778 treatment from day 7 to day 13 rescued liver grafts from ongoing rejection. The intramuscular FK506 (0.125 mg/kg per day) injection and the oral FK778 (20 mg/kg per day) gavages suppressed acute liver graft rejection effectively and maintained better graft condition compared with monotherapy. CONCLUSIONS.: FK778 treatment effectively prevented acute rejection and rescued ongoing rejection after liver transplantation. The optimal dosage was determined to be 20 mg/kg per day. Combination therapy with FK506 was more beneficial than FK778 monotherapy. Topics: Acute Disease; Alkynes; Animals; Drug Therapy, Combination; Graft Rejection; Immunoglobulin M; Immunosuppressive Agents; Isoxazoles; Liver; Liver Transplantation; Male; Nitriles; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Transplantation, Homologous | 2004 |
Synergistic effects of malononitrilamides (FK778, FK779) with tacrolimus (FK506) in prevention of acute heart and kidney allograft rejection and reversal of ongoing heart allograft rejection in the rat.
The effects of tacrolimus (FK506) and malononitrilamides (MNA) (FK778 and FK779) monotherapy and combination therapy were examined in prevention of acute heart and kidney allograft rejection and reversal of ongoing acute heart allograft rejection in the rat.. Brown Norway (RT1n)-to-Lewis (RT11) and ACI (RT1a)-to-Lewis (RT11) combinations were used, respectively, for heart and kidney transplantation models. Immunosuppressants were administered orally from day 1 to day 14 for preventing acute rejection and from day 4 to day 34 after transplantation for the reversal of ongoing acute rejection.. In the prevention of acute heart rejection model, recipient rats treated with monotherapy of tacrolimus or MNA (FK778, FK779) showed a dose-related prolongation of mean survival time (MST) compared with naive control rats (P<0.01). The mean survival time in combination therapy of tacrolimus (FK506) and FK778 indicated that an additive to synergistic interaction was produced when compared with the respective monotherapies (combination index [CI]=0.631-1.022). These results were reproducible with tacrolimus and FK779 combination therapy (CI=0.572-0.846). Furthermore, similar results were also found in the prevention of acute kidney allograft rejection in the rat (CI=0.137-0.516). In the reversal of ongoing acute heart allograft rejection, combination therapy of tacrolimus and FK778 demonstrated a strong synergistic interaction (CI=0.166-0.970) compared with monotherapy of tacrolimus or FK778.. Combination therapy of tacrolimus and MNA (FK778, FK779) produces synergistic effects in prevention of acute heart and kidney rejection and reversal of ongoing heart allograft rejection in the rat. Topics: Acute Disease; Alkynes; Animals; Drug Synergism; Graft Rejection; Heart Transplantation; Immunosuppressive Agents; Isoxazoles; Kidney; Kidney Transplantation; Male; Myocardium; Nitriles; Rats; Rats, Inbred ACI; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Transplantation, Homologous | 2003 |
Hyperacute skin allograft rejection in presensitized rats is abrogated by malononitrilamides.
Topics: Acute Disease; Alkynes; Animals; Graft Rejection; Immunization; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Isoantigens; Isoxazoles; Leflunomide; Lymphocyte Transfusion; Nitriles; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Skin Transplantation; Structure-Activity Relationship; Time Factors; Transplantation, Homologous | 1998 |
Malononitrilamides reduce IgM and IgG xenoantibodies and prolong skin xenograft survival in a mouse-to rat model.
Topics: Acute Disease; Alkynes; Animals; Antibodies, Heterophile; Antibody Formation; Cyclosporine; Graft Rejection; Graft Survival; Immunosuppressive Agents; Isoxazoles; Mice; Mice, Inbred BALB C; Nitriles; Rats; Rats, Inbred Lew; Skin Transplantation; Time Factors; Transplantation, Heterologous | 1998 |
Malononitrilamides synergistically prevent acute and treat ongoing skin allograft rejection with cyclosporine.
The low molecular weight malononitrilamides (MNAs), a new class of immunosuppressive agents, belong to the derivatives of leflunomide's active metabolite, A771726. They have been shown to bind specifically to dehydroorotate dehydrogenase and inhibit de novo pyrimidine biosynthesis, thereby blocking T- and B-cell proliferation and strongly suppressing IgM and IgG antibody production. Here we evaluated their efficacy together with cyclosporine (CyA) in rat skin allotransplantation models, using different strain combinations. Monotherapy of transplanted animals in these models with the MNAs HMR 1279 and HMR 1715 resulted in a significant and dose-dependent prolongation of the graft survival time. Even a short-term application showed efficacy in the prevention of acute rejection. The MNAs were also effective when treatment was started at the time of expected rejection crisis, demonstrating strong therapeutic activity to reverse ongoing acute rejection, whereas CyA was ineffective for the treatment of ongoing allograft rejection episodes. Combination therapy of MNAs with CyA proved to be very effective for the prevention of acute skin graft rejection. Interestingly, whereas CyA alone was unable to treat ongoing acute rejection episodes, comedication of MNAs and CyA, even after a short-term application, was synergistically effective and significantly suppressed ongoing allogeneic skin graft rejection. These results demonstrate that MNAs are potent and well tolerated immunosuppressants with a potential comparable to that of CyA, but they are superior to CyA in their ability to reverse acute rejection episodes. They represent powerful rescue drugs and demonstrate synergistic activity with CyA to prevent acute and treat ongoing skin allograft rejection. Topics: Acute Disease; Alkynes; Animals; Cyclosporine; Drug Synergism; Graft Rejection; Immunosuppressive Agents; Isoxazoles; Nitriles; Rats; Rats, Inbred F344; Rats, Inbred Lew; Skin Transplantation | 1998 |
Malononitrilamides (MNA 279 and MNA 715) have therapeutic activity in acute and chronic relapsing experimental allergic encephalomyelitis (EAE).
Topics: Acute Disease; Alkynes; Animals; Chronic Disease; Encephalomyelitis, Autoimmune, Experimental; Immunosuppressive Agents; Isoxazoles; Kinetics; Nitriles; Rats; Rats, Inbred Lew; Recurrence | 1997 |
Therapeutic activity of malononitrilamides (MNA 279 and MNA 715) on acute and chronic, relapsing, experimental, allergic encephalomyelitis (EAE).
Due to their immunosuppressive mode of action, we examined the therapeutic effects of the malononitrilamides MNA 279 and MNA 715 in acute EAE, and two models of chronic relapsing EAE in Lewis rats and Biozzi mice. In the first model, sensitization of adult Lewis rats with guinea pig spinal cords results in an acute clinical episode of severe EAE, and by day 15 all animals had died. Treatment of these sensitized rats with the MNAs was most effective in delaying and reducing the onset of clinical symptoms, and mortality of acute EAE was prevented in a dose-dependent manner. The protection afforded by the two MNAs was long-lasting and no subsequent relapse was observed. Similarly, in the chronic relapsing disease, aged Lewis rats were immunized with rabbit myelin basic protein, and all untreated animals developed a disease with up to three relapses. The second and third episodes were both milder and shorter in duration than the first. All animals treated with the MNAs survived the first attack, which also was delayed. Pathological signs were reduced and relapses did not occur. Inhibition of chronic relapsing EAE in aged Lewis rats was observed, even when the MNA-treatment was started after the first appearance of clinical symptoms. All treated animals recovered completely and mortality was prevented. Also in the second model of chronic relapsing EAE in Biozzi AB/H mice, MNA treated animals showed only one acute and delayed episode and no further relapses. All these results qualify both MNA 279 and MNA 715 as powerful immunosuppressants with therapeutic potential in human multiple sclerosis (MS). Topics: Acute Disease; Alkynes; Animals; Chronic Disease; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Guinea Pigs; Immunosuppressive Agents; Isoxazoles; Mice; Mice, Inbred Strains; Nitriles; Rabbits; Rats; Rats, Inbred Lew | 1997 |
Acute skin graft rejection can be prevented and treated in rat models by malononitrilamides.
Topics: Acute Disease; Alkynes; Animals; Cyclosporine; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Graft Rejection; Graft Survival; Immunosuppressive Agents; Isoxazoles; Nitriles; Rats; Rats, Inbred F344; Rats, Inbred Lew; Rats, Inbred Strains; Skin Transplantation; Time Factors | 1996 |