Gene therapy for β-thalassaemia: the continuing challenge.

The β-thalassaemias are inherited anaemias that form the most common class of monogenic disorders in the world. Treatment options are limited, with allogeneic haematopoietic stem cell transplantation offering the only hope for lifelong cure. However, this option is not available for many patients as a result of either the lack of compatible donors or the increased risk of transplant-related mortality in subjects with organ damage resulting from accumulated iron.

The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats.

Objective: To explore the effect of bortezomib in splenocytes and fibroblast-like synoviocytes (FLS) and its in vivo potency in a rat model of adjuvant-induced arthritis (AIA), which resembles human rheumatoid arthritis (RA).

Methods: AIA was induced with Freund's complete adjuvant. Splenocyte and FLS proliferation and apoptosis were measured by radioactivity incorporation and flow cytometry, respectively.

Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease.

Effective gene therapy for hemoglobinopathies will require high numbers of autologous gene-engineered hematopoetic stem cells to be reintroduced into the patients. Stem cell mobilization using G-CSF is the most convenient and effective approach to achieve this goal, but it can have severe side effects in sickle cell anemia and be potentially harmful in the case of severe thalassemia. Hence, the optimal way of collection of hematopoetic stem cells from patients with thalassemia and sickle cell disease needs to be determined.

The impact of desferrioxamine postallogeneic hematopoietic cell transplantation in relapse incidence and disease-free survival: a retrospective analysis.

Background: Several clinical and preclinical studies have shown that desferrioxamine (DFO), in addition to iron chelation, demonstrates antiproliferative activities against some aggressive malignancies and leukemic cells.

Methods: In this study, we investigated retrospectively the role of early DFO administration postallografting, in terms of relapse incidence (RI) and disease-free survival (DFS) in 143 patients consecutively transplanted for hematological malignancies.

Results: Thirty-seven of 143 patients received DFO.

Mobilization of hematopoietic stem cells in a thalassemic mouse model: implications for human gene therapy of thalassemia.

Granulocyte colony-stimulating factor (G-CSF)-mobilized blood stem cells may become the preferable source of hematopoietic stem cells (HSCs) for gene therapy because of the higher yield of cells compared with conventional bone marrow harvesting. A G-CSF-associated risk of splenic rupture has been recognized in normal donors of HSCs, but limited information is available about the G-CSF effect in the presence of splenomegaly and extramedullary hematopoiesis. We investigated the G-CSF effect in a thalassemic mouse model (HBB(th-3)) as compared with a normal strain (C57BL/6), in terms of safety, mobilization efficacy, and distribution of stem cells among hematopoietic compartments.

Autologous hemopoietic stem cell transplantation for multiple sclerosis: is it worthwile?

High-dose immunosuppressive chemotherapy or total body irradiation followed by autologous transplantation of hemopoietic stem cells (ASCT) was introduced in the treatment of active, progressing, and therapy-resistant multiple sclerosis (MS) in 1995. Since then, more than 300 patients have undergone this sort of treatment worldwide and the European Group for Blood and Marrow Transplantation (EBMT) published on two occasions, in 2002 and in 2006, the results of collective analyses performed in 85 and in 183 cases, respectively. In most communications the results were reported favorable with some cases showing spectacular recoveries and also probabilities of long-lasting disease stability, between 60 and 80% at three years after transplant.

Allografted recipients immunized against hepatitis B virus are at high risk of gradual surface antibody (HbsAb) disappearance post transplant, regardless of adoptive immunity transfer.

Immunized against hepatitis B virus (HBV) recipients are at risk of developing HBV postallogeneic stem cell transplantation because of the potential loss of their HBV immunity. The aim of the study was to evaluate: (1) the HbsAb eradication incidence posttransplant and potential risk factors, (2) the impact of donor's immunity on HbsAb loss, (3) the incidence of hepatitis B in patients with HbsAb disappearance. We studied, retrospectively, in 26 vaccinated and 56 naturally immunized recipients, the posttransplant HbsAb titers for a median period of 36 (6-132) months.

Lasting amelioration in the clinical course of decompensated alcoholic cirrhosis with boost infusions of mobilized peripheral blood stem cells.

For end-stage liver disease, liver transplantation provides the only definite cure; however, many patients die while in the waiting list for donation. Various stem cell populations have been described to contribute to liver regeneration and there is accumulating evidence for the participation of hematopoietic stem cells (HSCs) in this process. We here report two cases treated with boost infusions of autologous mobilized HSCs to regenerate cirrhotic liver.

Development and validation of a high performance liquid chromatographic method for the determination of oxcarbazepine and its main metabolites in human plasma and cerebrospinal fluid and its application to pharmacokinetic study.

An isocratic reversed-phase HPLC-UV procedure for the determination of oxcarbazepine and its main metabolites 10-hydroxy-10,11-dihydrocarbamazepine and 10,11-dihydroxy-trans-10,11-dihydrocarbamazepine in human plasma and cerebrospinal fluid has been developed and validated. After addition of bromazepam as internal standard, the analytes were isolated from plasma and cerebrospinal fluid by liquid-liquid extraction. Separation was achieved on a X-TERRA C18 column using a mobile phase composed of 20 mM KH(2)PO(4), acetonitrile, and n-octylamine (76:24:0.

The use of liposomal daunorubicin (DaunoXome) in acute myeloid leukemia.

Altered pharmacokinetics of liposomal formulations of drugs can diminish toxicity and allow the administration of the encapsulated drug at high doses. The liposomal formulation of daunorubicin (DaunoXome, L-DNR) has been reported to produce high mean area under the plasma curve (AUC) levels due to a slow distribution of the liposomal moiety into the body and also to reduce the conversion of daunorubicin to the toxic, but inactive, daunorubicinol. Animal and in vitro studies have shown increased intratumor and intracellular levels of the drug, resulting in enhanced cytotoxicity, even in multidrug-resistant cell lines, while normal tissue toxicity, including cardiotoxicity, may be reduced.

Frequency distribution of dextromethorphan O-demethylation in a Greek population.

Objective: To determine the CYP2D6 phenotype in a Greek population by using dextromethorphan (DM) as a probe drug.

Methods: DM (30 mg) was given orally to 102 unrelated Greek subjects and 8-hour urine samples were collected. Concentrations of DM and its metabolite dextrorphan (DX) were determined using a validated HPLC assay.

Rituximab is effective for selected patients with chronic steroid-refractory immune thrombocytopenic purpura.

We report results of Rituximab therapy in four patients with chronic immune thrombocytopenic purpura (ITP) refractory to 3-8 prior therapeutic regimens. Rituximab was administered at a dose of 375 mg/m2 once weekly for 4-6 weeks. Three out of four patients achieved a complete remission (rise to platelet count above 100,000/microl).

Stem cell transplantation for autoimmune disorders. Multiple sclerosis.

Autologous transplants for severe and refractory multiple sclerosis (MS) were proposed in 1997 and have been performed on about 200 selected patients worldwide. Phase I/II clinical studies have shown that high-dose immunosuppressive therapy suppresses inflammation in the CNS and may delay the progression of clinical disease. The procedure is associated with toxicity from the high-dose cytotoxic therapy and a risk of serious infections.

Autologous hemopoietic stem cell transplantation in the treatment of multiple sclerosis: rationale and clinical experience.

Based on the encouraging results of transplantation in animals with experimental autoimmune encephalomyelitis (EAE), small-scale phase I/II trials of autologous hematopoietic stem cell transplantation (autoHSCT) were initiated in 1995 for the treatment of severe cases of multiple sclerosis (MS). More than 200 patients with treatment-resistant multiple sclerosis have been transplanted so far, mainly in Europe and the USA. The results of these studies appear promising in terms of impact on MRI disease parameters and, to a lesser extent, clinical stabilization or even improvement.

High-dose immunosuppression and autologous hematopoietic stem cell rescue for severe multiple sclerosis.

Multiple sclerosis is a relatively common and seriously disabling disease of autoimmune pathogenesis, for which there is currently no cure. Available therapies include immunomodulating agents and standard-dose immunosuppressants, which may be helpful but are not curative. Recently, studies in animal models have indicated that control of autoimmune disease can be obtained by high-dose immunosuppression followed by hematopoietic stem cell transplantation (rescue).

Stem cell transplantation for multiple sclerosis: what is the evidence?

Experimental and clinical observations have indicated that high-dose immunosuppression followed by autologous stem cell transplantation (ASCT) can induce remissions in severe, refractory, autoimmune diseases including multiple sclerosis (MS), a T cell-mediated autoimmune disorder against CNS myelin components, causing severe chronic disability. Control of the disease is unsatisfactory in most of the patients, especially those with rapidly evolving relapsing-remitting course and those with chronic progressive disease. The rationale for treating autoimmune diseases with ASCT is based on the immunosuppressive and immunomodulating effects of ASCT which may shift the immunological balance towards disease quiescence, a hypothesis supported by the results of ASCT in animal models of MS and by clinical observations in MS patients transplanted for concurrent malignancies.

Autologous stem cell transplants in treatment of multiple sclerosis: where we stand and future prospects.

Based on experimental and clinical observations, high-dose immunosuppression followed by autologous transplantation may induce remissions in severe, refractory, autoimmune disorders including multiple sclerosis, a disease which, in its progressive form, does not respond to treatment. Phase I/II studies of transplantation in MS published by individual centers as well as a comprehensive analysis of the reports to the EBMT registry have shown that transplantation may positively affect MS by stabilizing the clinical condition of the patients, by improving their disability status, and by completely abrogating the inflammatory process in the brain as evidenced in magnetic resonance imaging. Other available therapies do not appear to be so efficacious as transplantation.

Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study.

Several experimental autoimmune diseases (AID), including allergic encephalomyelitis, ie the multiple sclerosis (MS) model, respond to TBI and chemotherapy followed by BMT. Remissions of AID may also occur in patients with concomitant malignancies treated with allogeneic or autologous BMT. These observations have emphasized the possibility of treating AID with high-dose therapy and haematopoietic stem cell transplantation (HSCT).