tacrolimus and Hemorrhage

Microcystic lymphatic malformations as described in the international literature form a subgroup of low-flow congenital vascular malformations (VM) resulting from irregular embryological development. Microcystic lesions normally manifest as an accumulation of lymph- and blood-filled vesicles that, when externalized, cause skin maceration with consequent pain and potential infection resulting in the impairment of the patient's quality of life. There is no consensus on a standardized algorithm nor clear guidelines for successful treatment of this type of lymphatic malformation, and treatment options employed often result in ambivalent and transient outcomes with a high rate of recurrence. The topical formulation of tacrolimus is a well-known FDAapproved anti-T cell agent that was recently identified as a potent activator of ALK1, which is involved in several processes and functions including angiogenesis. We investigated if topical administration of tacrolimus may be an effective therapy for directly targeting cutaneous microcystic lymphatic malformations as a complement to systemic treatment. The study enrolled four patients with cutaneous microcystic lymphatic malformations: three male (ages: 13,15,18) and one female (age: 30). Two of the patients presented lesions on their backs, one patient on the left hand and one on the left lower limb. All four patients received treatment with topical tacrolimus 0.1% twice a day for 10 weeks on a previously selected area for application. Weekly clinical follow-ups were conducted along with close physician-patient contact. All patients displayed a satisfactory response after treatment. Lymphorrhea and bleeding were stopped in all cases and the esthetic aspect of lesions improved in two patients. To date, all patients presented no clinically significant changes to the size or extension of the lesion. Topical tacrolimus treatment is a promising and reasonable option for microcystic lymphatic malformations. Our results encourage further exploration in larger populations with the consideration that it is a safe and effective alternative or complementary therapy to systemic treatment.

Topics: Adult; Cysts; Female; Hemorrhage; Humans; Lymphatic Abnormalities; Male; Quality of Life; Tacrolimus; Treatment Outcome

Oestrogens could inhibit the metabolism of drugs, such as calcineurin inhibitors, that are substrates for cytochrome P-450 microsomal enzymes. This study assessed the potential tacrolimus interaction with oral conjugated oestrogen in kidney transplant recipients who received conjugated oestrogen as prophylaxis against bleeding, before kidney biopsy.. In this case-control study, 13 kidney transplant recipients who received oral conjugated oestrogen as prophylaxis against uraemic bleeding before allograft biopsy were considered as cases. Thirteen matched kidney transplant recipients with similar immunosuppressive regimen served as controls. In this study, comparisons were made between the groups regarding daily dose, blood trough concentrations and calculated concentration corrected for dose of tacrolimus at three time points of the study.. All patients in the case group received conjugated oestrogen at a dose of 3.75 mg/day for 4.78 ± 0.83 days. Without any change in tacrolimus dose, the blood concentration of tacrolimus increased during concomitant administration of conjugated oestrogen (from 8.10 ± 2.85 to 12.35 ± 4.62 ng/mL; P = .11) and decreased after cessation of conjugated oestrogen (6.07 ± 2.18 ng/mL; P = .015). The calculated concentration corrected for dose of tacrolimus increased from 127.04 ± 79.23 to 211.40 ± 146.38 ngmLmgkg/d after conjugated oestrogen administration (P = .036). Thereafter, it decreased to 108.55 ± 78.61 ngmLmgkg/d after cessation of oestrogen (P = .003). Only one patient experienced nausea while taking oestrogen without any change in her liver enzymes.. Concomitant administration of oral oestrogen increased tacrolimus blood concentration. Hence, it is necessary to monitor tacrolimus blood levels during concomitant oestrogen therapy and for several days after oestrogen withdrawal.

Topics: Adult; Case-Control Studies; Drug Interactions; Estrogens; Female; Hemorrhage; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus

Topics: Administration, Oral; Age Factors; Aging; Anticoagulants; Antipsychotic Agents; Cholinesterase Inhibitors; Drug Monitoring; Geriatrics; Hemorrhage; Humans; Immunosuppressive Agents; Patient Safety; Pharmaceutical Services; Risk Assessment; Risk Factors; Tacrolimus

Topics: Adult; Atrioventricular Block; Bone Marrow Transplantation; Bradycardia; Electrocardiography; Female; Graft vs Host Disease; Heart Block; Hemorrhage; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Liver Diseases; Lung Diseases; Methicillin-Resistant Staphylococcus aureus; Methylprednisolone; Mycophenolic Acid; Pneumonia, Staphylococcal; Skin Diseases; Tacrolimus; Transplantation, Homologous

Pretransplant removal of antiblood group ABO antibodies is the cornerstone of all current ABO-incompatible (ABOi) transplantation programmes. In our protocol, plasmapheresis (PP) is performed with a plasmafilter followed by immunoadsorption (IA) of anti-ABO antibodies. The bleeding complications of this technique are not known. We analysed the data of all 65 consecutive ABOi kidney transplantations between March 2006 and October 2013 and compared these with matched 130 ABO-compatible (ABOc) kidney transplantations. Cases differed from controls in the pre-operative regimen, which included IA-PP and rituximab, tacrolimus, mycophenolate mofetil, prednisone and immunoglobulines. Data on platelet count, blood loss and red blood cell (EC) transfusions during 48 h postoperatively were collected. ABOi patients received EC transfusions more frequently than controls (29% vs. 12%, P = 0.005). Intra-operative blood loss was higher (544 vs. 355 ml, P < 0.005) and they experienced more major bleeding (≥3 EC within 24 h, 15% vs. 2%, P < 0.0005). Platelet count decreased by 28% after the pre-operative IA. In a multivariate model, only the number of pre-operative IAs was associated with the number of ECs given (OR per IA 1.9, P < 0.05). ABOi kidney transplant recipients have a high postoperative bleeding risk, correlating with the number of pre-operative IA sessions performed.

Topics: ABO Blood-Group System; Antibodies; Antibodies, Monoclonal, Murine-Derived; Antigens; Blood Group Incompatibility; Case-Control Studies; Cohort Studies; Erythrocyte Transfusion; Female; Hemorrhage; Humans; Immunoglobulins; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Platelet Count; Prednisone; Rituximab; Tacrolimus

Topics: Aged; Anticoagulants; Cyclosporine; Drug Interactions; Drug Monitoring; Female; Hemorrhage; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Morpholines; Retrospective Studies; Risk Factors; Rivaroxaban; Tacrolimus; Thiophenes

Topics: Adult; Hemorrhage; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Magnetic Resonance Imaging; Male; Retinal Vein; Retinal Vein Occlusion; Risk Factors; Tacrolimus; Vision Disorders; Vision, Ocular

Immunosuppressive drugs are an integral part of therapy in organ transplantation. However, they are not without side effects, and although rare, these agents should be considered in the differential diagnosis of pulmonary complications in patients receiving transplants. We present a case of a patient who developed acute respiratory failure 7 days after orthotopic heart transplantation and who had been on both mycophenolate mofetil (MMF) and tacrolimus agents. Lung biopsy revealed features of pulmonary hemorrhage with capillaritis. Considered as a possible etiology, MMF was withdrawn. There was immediate improvement of the patient's symptoms. The temporal relationship between MMF exposure and onset of pulmonary symptoms in the absence of other possible etiologies strongly suggests a causal relationship. Previously published reports of pulmonary toxicity from MMF included interstitial fibrosis. To the best of our knowledge, this is the first reported case of pulmonary hemorrhage with capillaritis because of administration of MMF.

Topics: Heart Transplantation; Hemorrhage; Humans; Immunosuppressive Agents; Lung Diseases; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Vasculitis

The potent immunosuppressive effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis.. A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected intraperitoneally in other rat groups. The tacrolimus dose was constant in all formulations at 200 μg/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II.. The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC(0-24) after intravesical administration was significantly higher than in the intraperitoneal group (p <0.05). Bladder tacrolimus AUC(0-24) did not differ significantly between the groups.. Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus may be a promising approach as an orphan drug indication for hemorrhagic cystitis.

Topics: Administration, Intravesical; Animals; Cystitis; Hemorrhage; Immunosuppressive Agents; Liposomes; Orphan Drug Production; Rats; Tacrolimus

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Blood Coagulation; Blood Transfusion; Female; Hemorrhage; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Methylprednisolone; Partial Thromboplastin Time; Plasma; Prothrombin Time; Tacrolimus; Treatment Outcome

Many studies have examined the efficacy of tacrolimus in rats and dogs, but few have reported its evaluation in cynomolgus monkeys. The aim of this study was to clarify the efficacy of tacrolimus in a cynomolgus monkey renal transplant model based on the efficacy of various doses. Monkeys that had undergone renal transplant were treated with a vehicle or 0.5, 1.0, or 2.0 mg/kg of tacrolimus by oral administration. Tacrolimus administration prolonged animal survival in a dose-dependent manner, and the median survival time (MST) was 11, 21, and >90 days for the 0.5, 1.0, and 2.0 mg/kg tacrolimus groups, respectively. The MST of the vehicle group was 6 days. Histopathological analyses of all transplanted kidneys were also performed. Typical pathological findings of acute rejection were observed in both the vehicle and tacrolimus (0.5 and 1.0 mg/kg)-treated groups. Only limited mononuclear cell infiltration and hemorrhage were present in the tacrolimus (2.0 mg/kg)-treated group. In conclusion, 2.0 mg/kg was considered to be a therapeutic dose in this model, and 0.5 or 1.0 mg/kg could be used for a study when efficacy of a new compound is evaluated in a combination therapy with tacrolimus.

Topics: Administration, Oral; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Graft Rejection; Graft Survival; Hemorrhage; Immunosuppressive Agents; Kidney; Kidney Transplantation; Leukocytes, Mononuclear; Macaca fascicularis; Male; Survival Rate; Tacrolimus

A 67-year-old woman, suffering from continuous hemoptysis, was admitted to our hospital where she was managed with mechanical ventilation. Computed tomography of the chest demonstrated bilateral massive alveolar hemorrhage without evidence of infectious disease. She was diagnosed with anti-myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated diffuse alveolar hemorrhage because a high titer of MPO-ANCA was found in the serum. Plasmapheresis as well as methylprednisolone pulse therapy were initiated, followed by intravenous administration of cyclophosphamide. Tacrolimus was employed for the maintenance therapy, and the oral prednisolone dosage could successfully be tapered without recurrence, along with the decrement of the titer of MPO-ANCA.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Combined Modality Therapy; Cyclophosphamide; Drug Therapy, Combination; Female; Glucocorticoids; Hemorrhage; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Peroxidase; Plasmapheresis; Prednisolone; Pulmonary Alveoli; Radiography, Thoracic; Tacrolimus; Treatment Outcome

We report a patient with systemic lupus erythematosus (SLE) who developed fulminant pulmonary hemorrhage. This patient also showed liver dysfunction, bicytopenia and hyperferritinemia, with an increase in serum levels of interleukin (IL)-1 beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) at the onset of pulmonary symptoms, probably indicating an associated hemophagocytic syndrome. Despite an acute progressive course temporarily requiring mechanical ventilation the patient was successfully treated with continuous drip infusion of tacrolimus, plasmapheresis and intravenous high-dose immunoglobulin and corticosteroid. In this patient increased inflammatory cytokines ascribable to activation of macrophages and/or helper T cells were considered to play an important role in the pathogenesis of the pulmonary hemorrhage. Because this complication is frequently fatal in SLE, intensive therapy, including immunosuppressants and plasmapheresis, should be actively considered as early as possible after onset.

Topics: Adrenal Cortex Hormones; Adult; Female; Hemorrhage; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Lung Diseases; Lupus Erythematosus, Systemic; Plasmapheresis; Tacrolimus; Treatment Outcome

Topics: Animals; Animals, Newborn; Cyclosporine; Edema; Female; Graft Rejection; Graft Survival; Guanidines; Heart Transplantation; Hemorrhage; Immunosuppressive Agents; Male; Methotrexate; Necrosis; Papio; Splenectomy; Swine; Tacrolimus; Time Factors; Transplantation, Heterologous