tacrolimus and Hypertension--Pulmonary

We contacted and analyzed the data of 18 lung transplant recipients who had had children. The complications we detected included: hypertension (50%), diabetes mellitus (21%), preeclampsia (13%), infection (21%), rejection (30%), loss of graft function (23%) and a lower percentage of live births than in transplant recipients of other organs. Other aspects to keep in mind are: the potential risk for fetal alterations (caused by drugs used as prophylaxis against rejection crossing the placental barrier); greater risk for infection and alterations in drug levels due to changes in metabolism typical of pregnancy and postpartum period. We describe the two cases in Spain of female lung transplant recipients who have had children after transplantation. Although pregnancy in these cases can have a similar evolution as in non-transplanted women, doctors should recommend their transplanted patients to avoid becoming pregnant, while explaining the high risk of both fetal and maternal morbidity and mortality after transplantation.

Topics: Adult; Cardiomyopathies; Female; Graft Rejection; Heart Defects, Congenital; Heart-Lung Transplantation; Humans; Hypertension; Hypertension, Pulmonary; Immunosuppressive Agents; Infant, Newborn; Infant, Premature, Diseases; Lung Diseases, Interstitial; Lung Transplantation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Pregnancy in Diabetics; Pregnancy Outcome; Pregnancy, High-Risk; Spain; Survivors; Tacrolimus

Topics: Adult; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Middle Aged; Tacrolimus; Treatment Outcome

Topics: Animals; Bone Morphogenetic Protein Receptors, Type II; Endothelial Cells; Fibroblasts; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Lung; Rats; Tacrolimus; Transforming Growth Factor beta1; Vascular Remodeling

Topics: Animals; Brain Death; Hypertension, Pulmonary; Lung; Lung Injury; Proto-Oncogene Proteins c-bcl-2; Swine; Tacrolimus

Tacrolimus (TAC) has exhibited promising therapeutic potential in the treatment of pulmonary arterial hypertension (PAH); however, its application is prevented by its poor solubility, instability, poor bioavailability, and negative systemic side effects. To overcome the obstacles of using TAC for the treatment of PAH, we developed nanocomposite microparticles (nCmP) for the pulmonary delivery of tacrolimus in the form of dry powder aerosols. These particles can provide targeted pulmonary delivery, improved solubility of tacrolimus, the potential of penetration through mucus barrier, and controlled drug release. In this system, tacrolimus-loaded polymeric nanoparticles (NP) were prepared via emulsion solvent evaporation and nCmP were prepared by spray drying these NP with mannitol. The NP were approximately 200nm in diameter with narrow size distribution both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were raisin-like spheres. High encapsulation efficacy was achieved both in the encapsulation of tacrolimus in NP and that of NP in nCmP. nCmP exhibited desirable aerosol dispersion properties, allowing them to deposit into the deep lung regions for effective drug delivery. A549 cells were used as in vitro models to demonstrate the non-cytotoxicity of TAC nCmP. Overall, the designed nCmP have the potential to aid in the delivery of tacrolimus for the treatment of PAH.

Topics: Administration, Inhalation; Aerosols; Cell Line, Tumor; Cell Survival; Delayed-Action Preparations; Drug Liberation; Humans; Hypertension, Pulmonary; Nanocomposites; Particle Size; Powders; Solubility; Tacrolimus

Pulmonary arterial hypertension (PAH) is a lethal disease that is characterized by functional and structural abnormalities involving distal pulmonary arterioles that result in increased pulmonary vascular resistance and ultimately right heart failure. In experimental models of pulmonary hypertension, endothelial cell (EC) apoptosis is a necessary trigger for the development of obliterative lung arteriopathy, inducing the emergence of hyperproliferative and apoptosis-resistant vascular cells. However, it has not been established whether EC apoptosis is sufficient for the induction of complex lung arteriolar lesions. We generated a conditional transgenic system in mice to test the hypothesis that lung endothelial cell apoptosis is sufficient to induce a PAH phenotype. The Fas-induced apoptosis (FIA) construct was expressed under the control of endothelial-specific Tie2 promoter (i.e., EFIA mice), and administration of a small molecule dimerizing agent, AP20187, resulted in modest pulmonary hypertension, which was associated with obliterative vascular lesions localized to distal lung arterioles in a proportion of transgenic mice. These lesions were characterized by proliferating cells, predominantly CD68 macrophages. Although endothelial cell apoptosis was also seen in the kidney, evidence of subsequent arteriopathy was seen only in the lung. This model provides direct evidence that lung endothelial cell apoptosis acts as a trigger to initiate a PAH phenotype and provides initial insight into the potential mechanisms that underlie a lung-specific arterial response to endothelial injury.

Topics: Animals; Apoptosis; Disease Models, Animal; fas Receptor; Fas-Associated Death Domain Protein; Gene Expression Regulation; Hypertension, Pulmonary; Lung; Mice; Mice, Transgenic; Plasmids; Promoter Regions, Genetic; Protein Multimerization; Pulmonary Artery; Receptor, TIE-2; Recombinant Fusion Proteins; Respiratory Mucosa; Signal Transduction; Tacrolimus; Tacrolimus Binding Proteins; Transfection

Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

Topics: Animals; Apoptosis; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type II; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Endothelium, Vascular; High-Throughput Screening Assays; Humans; Hypertension, Pulmonary; Inhibitor of Differentiation Protein 1; Male; Mice; Mice, Knockout; Microvessels; Neointima; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Signal Transduction; Smad Proteins; Tacrolimus; Tacrolimus Binding Protein 1A

Topics: Adult; CD4 Lymphocyte Count; Graft Rejection; Heart Transplantation; HIV Infections; HIV-1; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Male; Myocardial Infarction; Myocardial Ischemia; Tacrolimus

Hepatotoxicity, including cholestasis, is a rare but significant complication of treatment with calcineurin inhibitors. Timely life-saving therapy with revision of immunosuppression is mandatory. A 43-year-old woman with pulmonary hypertension was found to have severe cholestasis (serum bilirubin up to 35 mg/dL) after a living-donor lobar lung transplantation. Calcineurin-inhibitor cholestasis markedly improved after withdrawal of the calcineurin inhibitor, initiation of sirolimus, and interleukin-2 receptor blockade. Awareness of the diagnostic criteria of this rare posttransplant complication is important to initiate timely therapy.

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Cholestasis; Disease Progression; Fatal Outcome; Female; Graft Rejection; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Living Donors; Lung Transplantation; Methylprednisolone; Pneumonia, Bacterial; Postoperative Complications; Pseudomonas Infections; Risk Assessment; Sirolimus; Tacrolimus; Transplantation Immunology

The tuberculostatic compound rifampin (INN, rifampicin) induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), cytochromes (cytochrome P450 [CYP] 3A4), uridine diphosphate-glucuronosyltransferases, monoamine oxidases, and glutathione S -transferases. Drugs that depend on these enzymes for their metabolism are prone to drug interactions when coadministered with rifampin. A novel, clinically relevant drug interaction is described between rifampin and mycophenolate mofetil (MMF), a cornerstone immunosuppressive molecule used in solid organ transplantation. Long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout (dose-corrected AUC 0-12 after rifampin withdrawal, 19.7 mg.h.L-1.g -1 versus 6.13 mg.h.L-1.g-1 before rifampin withdrawal [221% change]; dose-uncorrected AUC 0-12 after rifampin withdrawal, 29.6 mg.h/L [daily MMF dose, 3 g] versus 18.4 mg.h/L [daily MMF dose, 6 g] during rifampin administration [60.8% change]). Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.

Topics: Area Under Curve; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Enterohepatic Circulation; Glucuronosyltransferase; Heart-Lung Transplantation; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Pharmacology, Clinical; Respiratory Insufficiency; Rifampin; Tacrolimus; Time Factors; Uridine Diphosphate; Withholding Treatment

A 42-year-old woman who underwent single lung transplantation who received tacrolimus and a 58-year-old woman with pneumonia and multiple comorbidities who received haloperidol both experienced drug-induced prolongation of cardiac repolarization. The second woman also developed torsade de pointes. Critically ill patients are particularly susceptible to developing torsade de pointes due to various comorbidities, electrolyte disturbances, and receipt of numerous drugs. These two case reports illustrate the increased risk for drug-induced cardiotoxicity in the critically ill patient. They also indicate the need for current knowledge derived from basic research and retrospective case reports on drug-induced torsade de pointes to be integrated into the existing body of knowledge. Guidelines can then be developed to help prospectively reduce the frequency of adverse effects in intensive care patients. Research is necessary regarding identification of high-risk patients before drugs are administered, and clarification of the proper role of therapeutic QT monitoring in clinical practice.

Topics: Administration, Oral; Adult; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Electrocardiography; Female; Haloperidol; Heart Conduction System; Humans; Hypertension, Pulmonary; Injections, Intravenous; Long QT Syndrome; Middle Aged; Pneumonia; Tachycardia, Ventricular; Tacrolimus; Torsades de Pointes

A retrospective study involving 13 institutions was performed to assess the efficacy of conversion from cyclosporine (INN: ciclosporin) to tacrolimus.. Data from 244 patients were analyzed. Indications for conversion were recurrent-ongoing rejection (n = 110) and stage 1 to 3 bronchiolitis obliterans syndrome (n = 134).. The incidence of acute rejection decreased significantly within 3 months after versus before the switch from cyclosporine to tacrolimus (P <.01). For patients with recurrent-ongoing rejection, the forced expiratory volume in 1 second decreased by 1.96% of predicted value per month (P =.08 vs zero slope) before and increased by 0.34% of predicted value per month (P =.32 vs zero slope) after conversion (P <.06). For patients with stage 1 to 3 bronchiolitis obliterans syndrome, a significant reduction of rejection episodes was observed (P <.01). In single transplant recipients a decrease of the forced expiratory volume in 1 second averaged 2.25% of predicted value per month (P <.01 vs zero slope) before and 0.29% of predicted value per month after conversion. Corresponding values for bilateral transplant recipients were 3.7% of predicted value per month (P <.01 vs zero slope) and 0.9% of predicted value per month (P = 0.04 vs zero slope), respectively. No significant difference in the incidence of infections within 3 months before and after conversion was observed.. Conversion from cyclosporine to tacrolimus after lung transplantation is associated with reversal of recurrent-ongoing rejection. Conversion for bronchiolitis obliterans syndrome allows short-term stabilization of lung function in most patients.

Topics: Acute Disease; Adult; Australia; Azathioprine; Bronchiolitis Obliterans; Canada; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Europe; Female; Follow-Up Studies; Forced Expiratory Volume; Graft Rejection; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Incidence; Kidney; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Survival after living-donor lobar lung transplantation has been reported to be similar to that after cadaveric lung transplantation. The purpose of this study was to summarize our 5-year experience of living-donor lobar lung transplantation for critically ill patients.. Between October 1998 and April 2004, we performed living-donor lobar lung transplantation in 30 critically ill patients with various lung diseases, including 5 (17%) patients on a ventilator. Mean age was 30.4 years (range, 8-55 years). Postoperative management included slow weaning from a ventilator, relatively low-dose immunosuppressants, and careful rejection monitoring on the basis of radiographic and clinical findings without transbronchial lung biopsy.. The average duration of mechanical ventilation was 15.4 days, intensive care unit stay was 23.5 days, and hospital stay was 64.6 days. Clinically judged acute rejection occurred at an average rate of 1.5 episodes per patient, but infection occurred in only one patient during the first month. In spite of the complicated postoperative course, all patients were discharged without oxygen inhalation. Four patients had unilateral bronchiolitis obliterans syndrome, but the decrease in their forced expiratory volume in 1 second values stopped within 9 months. All 30 recipients are currently alive, with a follow-up period of 1 to 66 months. All donors have returned to their previous lifestyles.. Living-donor lobar lung transplantation can be applied to both pediatric and adult patients with very limited life expectancies. It might provide better survival than conventional cadaveric lung transplantation.

Topics: Adolescent; Adult; Child; Cyclosporine; Female; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Living Donors; Lung Diseases; Lung Diseases, Interstitial; Lung Transplantation; Male; Middle Aged; Patient Selection; Retrospective Studies; Tacrolimus