The Use of Mycophenolate Mofetil (Rs-61443) in Human Heart Transplant Recipients

Ensley, Rebecca; Bristow, Michael R.; Olsen, Stephanie L.; Taylor, David O.; Hammond, Elizabeth H.; O’Connell, John B.; Dunn, D; OSBURN, LINDA; Jones, Kent W.; Kauffman, Robert S.; Gay, William A.; Renlund, Dale G.

doi:10.1097/00007890-199307000-00013

Cited by 119 publications

(56 citation statements)

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“…1,2 MMF is an ester prodrug of mycophenolic acid (MPA) which inhibits inosine monophosphate dehydrogenase and thus blocks the de novo pathway of guanosine synthesis in T and B lymphocytes. Following oral administration MMF is rapidly and completely absorbed and hydrolyzed to the active immunosuppressive drug MPA.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Lange

Mueller

Altmann

et al. 2007

Bone Marrow Transplant

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Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 lg/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Lange

Mueller

Altmann

et al. 2007

Bone Marrow Transplant

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“…CyA and FK 506 showed protective effects against the hepatic injury associated with warm ischemia and reperfusion when given prior to ischemia [12,13,151. In most studies, the immunosuppressive compound was given 24 h or more before the operation and induction of ischemia.…”

Section: Discussionmentioning

confidence: 99%

“…Mycophenolate mofetil (MMF) is a new immunosuppressive agent which has been used successfully after kidney and heart transplantation [13,24,32 …”

Section: Introductionmentioning

confidence: 99%

Short-term treatment with mycophenolic acid increases bile flow in continuously perfused and cold-preserved rat livers and does not affect hepatic ischemia-reperfusion injury

Baron¹,

Bilzer²,

Gerbes³

2002

Transplant Int

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Mycophenolate mofetil (MMF) is a new immunosuppressive agent which has been used successfully after kidney and heart transplantation. Experience with MMF after liver transplantation is still limited. In particular, there is no information about influence on ischemia‐reperfusion injury (IRI). Therefore, the aim of this investigation was to assess the effects of mycophenolic acid (MPA), the pharmacologically active metabolite of MMF, in the cold‐preserved or normal rat liver. Livers of male Sprague‐Dawley rats were subjected to cold ischemia in University of Wisconsin (UW) solution (24 h, 4°C) and reperfused for 2 h in the absence or presence of MPA (100 μg/ml, n=5–6 each). Another group received MPA pretreatment for 20 min prior to ischemia (n=7). In further experiments, livers were perfused with a bile salt‐free Krebs‐Henseleit buffer in a continuous fashion (controls, n=5). MPA was infused from 20–40 min after starting perfusion in therapeutic concentrations (5 μg/ml, 10 μg/ml, 40 μg/ml, and 100 μg/ml; n=3–6 each). There was no significant influence of MPA on portal pressure nor on postischemic efflux rates of LDH. MPA pretreatment resulted in a significant improvement of bile flow during reperfusion (0.32±0.05 μl/min × g liver) compared with controls (0.17±0.04 μl/min × g liver, mean±SEM). In contrast, postischemic bile flow was not influenced by continuous administration of MPA during the reperfusion period only (0.18±0.07 μl/min × g liver). In continuously perfused livers, MPA increased bile salt‐independent bile flow (1.00±0.06 μl/min × g liver) in a dose‐dependent manner, reaching half‐maximal effects around 5 μg/ml (1.66±0.15 μl/min × g liver) and maximal effects at 40 μg/ml (2.61±0.28 μl/min × g liver). In conclusion, neither preischemic nor postischemic administration of MPA influences IRI to hepatocytes significantly after hypothermic liver preservation in UW solution. In contrast to other immunosuppressive agents, MPA exhibits strong choleretic effects, which are related to a stimulation of bile salt‐independent bile formation.

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“…312,[482][483][484][485][486]495 3.5.5.1 Toxicity-The elimination half-life of immediate-release MPA is 16 to 18 h, 481,499 and that of delayed-release MPA is 8 to 16 h. 500 Mycophenolate is extensively converted to MPA glucuronide, which is extensively cleared through renal excretion. 481 Adverse reactions associated with MPA administration include cardiovascular effects (systemic hypertension, peripheral edema, tachycardia), 500,501 dermatologic effects (rash, skin neoplasm), 501 endocrinologic effects (hyperglycemia, cushingoid change, hirsutism), 500,501 metabolic effects (hypercholesterolemia, hypophosphatemia, hypokalemia, hyperkalemia), 500,501 GI effects (nausea, anorexia, vomiting, dyspepsia, abdominal pain, diarrhea, constipation), 481,491,497,500,502,503 hematologic effects (anemia, RBC aplasia, leukopenia, thrombocytopenia, leukocytosis), 481,500,501,[503][504][505] opportunistic infection, 481,501,506,507 musculoskeletal effects (bone pain, leg cramps, myalgias, hand cramps), 508 neurologic effects (headache, tremor, insomnia, dizziness, anxiety), 491,500,501,506 ocular changes (blurred vision, cataracts, blepharitis, keratitis, glaucoma, macular abnormalities), 500,506 genitourinary effects (infection, hematuria, tubular necrosis, urinary frequency, burning on urination, kidney stones, vaginal burning, ...…”

Section: Methotrexatementioning

confidence: 99%

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

Baughman

Meyer

Nathanson

et al. 2012

Chest

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Objectives: Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and infl ammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. Methods: Committee members developed and refi ned a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. Conclusions: It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease. CHEST 2012; 142(5):e1S-e111SAbbreviations: ACCP 5 American College of Chest Physicians; ALT 5 alanine aminotransferase; ATG 5 antithymocyte globulin; CHF 5 congestive heart failure; CMV 5 cytomegalovirus; CNI 5 calcineurin inhibitor; COI 5 confl ict of interest; CsA 5 cyclosporin A; FDA 5 US Food and Drug Administration; HBV 5 hepatitis B virus; HMG-CoA 5 b -hydroxy-bmethylglutaryl-coenzyme A; HSP 5 Health and Science Policy Committee; IL2RA 5 IL-2 receptor a ; ILD 5 interstitial lung disease; IPF 5 idiopathic pulmonary fi brosis; ITP 5 idiopathic thrombocytopenia purpura; LAM 5 lymphangioleiomyomatosis; MESNA 5 sodium 2-sulfonylethanesufonate; MPA 5 mycophenolic acid; mTOR 5 mammalian target of rapamycin; PTLD 5 posttransplant lymphoproliferative disease; RCT 5 randomized controlled trial; SIRS 5 systemic infl ammatory response syndrome; TNF 5 tumor necrosis factor; TPMT 5 thiopurine methyltransferase

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The Use of Mycophenolate Mofetil (Rs-61443) in Human Heart Transplant Recipients

Cited by 119 publications

References 0 publications

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Short-term treatment with mycophenolic acid increases bile flow in continuously perfused and cold-preserved rat livers and does not affect hepatic ischemia-reperfusion injury

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

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