Patient-specific in vitro drug release testing coupled with in silico PBPK modeling to forecast the in vivo performance of oral extended-release levodopa formulations in Parkinson's disease patients.

Biorelevant in vitro release models are valuable analytical tools for oral drug development but often tailored to gastrointestinal conditions in 'average' healthy adults. However, predicting in vivo performance in individual patients whose gastrointestinal conditions do not match those of healthy adults would be of great value for optimizing oral drug therapy for such patients. This study focused on establishing patient-specific in vitro and in silico models to predict the in vivo performance of levodopa extended-release products in Parkinson's disease patients.

Monitoring multiple myeloma in the peripheral blood based on cell-free DNA and circulating plasma cells.

With the advent of novel, highly effective therapies for multiple myeloma (MM), classical serologic monitoring appears insufficient for response assessment and prediction of relapse. Moreover, serologic studies in MM are hampered by interference of therapeutic antibodies. The detection of malignant plasma cell clones by next generation sequencing (NGS) or multiparameter flow cytometry (MFC) circumvents these difficulties and can be performed in the peripheral blood (pB) by targeting circulating cell-free DNA (cfDNA) or circulating plasma cells (CPCs), thus also avoiding an invasive sampling procedure.

Review of paediatric gastrointestinal physiology relevant to the absorption of orally administered medicines.

Despite much progress in regulations to improve paediatric drug development, there remains a significant need to develop better medications for children. For the design of oral dosage forms, a detailed understanding of the specific gastrointestinal (GI) conditions in children of different age categories and how they differ from GI conditions in adults is essential. Several review articles have been published addressing the ontogeny of GI characteristics, including luminal conditions in the GI tract of children.

A Biopredictive In Vitro Approach for Assessing Compatibility of a Novel Pediatric Hydrocortisone Drug Product within Common Pediatric Dosing Vehicles.

Purpose: The objective of the present work was to screen whether a novel pediatric hydrocortisone granule formulation can be co-administered with common food matrices and liquids.

Methods: Pediatric hydrocortisone granules were studied using a biopredictive in vitro approach. Experiments included an in situ chemical compatibility study of active ingredient and drug product with liquid dosing vehicles and soft foods commonly ingested by infants, pre-school- and school children.

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With -Internal Tandem Duplication Mutation (SORMAIN).

Purpose: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the like tyrosine kinase 3 gene (ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT.

Patients And Methods: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo).

Outcome of non-mold effective anti-fungal prophylaxis in patients at high-risk for invasive fungal infections after allogenic stem cell transplantation.

Patients who develop severe graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (alloSCT) have a higher risk for invasive fungal infection (IFI). At our center, fluconazole prophylaxis is standard and upfront mold-effective prophylaxis performed only in patients with specific risk constellations. A total of 290 patients undergoing alloSCT between May 2002 and August 2011 were analyzed.

Biorelevant in vitro assessment of dissolution and compatibility properties of a novel paediatric hydrocortisone drug product following exposure of the drug product to child-appropriate administration fluids.

Alkindi® is a novel oral multi-particulate taste-masked formulation of hydrocortisone for use in children with the rare disease adrenal insufficiency. The objective of the present work was to study the biorelevant dissolution and compatibility properties of Alkindi® granules following exposure to administration fluids including breast milk, artificial milk, whole milk and water. To provide in vitro data for a representative patient collective, dosing conditions in neonates, infants and pre-school children were assessed.

[Rare diseases recognizable from blood smears].

The examination of peripheral blood smears is not only essential for the differential diagnostics of hematological diseases but can also provide important indications for general internal diseases, infections, hereditary diseases and poisoning. By the systematic analysis of a blood smear for alterations to thrombocytes, erythrocytes and leukocytes, a blood smear investigation can make a decisive contribution to the formulation of a diagnosis. In this way evidence of rare diseases can also be gained when taking the corresponding clinical findings into consideration.

Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation.

Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available.

A review of patient-specific gastrointestinal parameters as a platform for developing in vitro models for predicting the in vivo performance of oral dosage forms in patients with Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease that presents with visible motor symptoms, but that is accompanied by several additional symptoms, including gastrointestinal symptoms that may affect pharmacokinetics of oral medications. A detailed understanding of the nature of PD-specific gastrointestinal parameters and of how they may affect drug release of orally administered dosage forms seems to be essential information for developing better oral PD medications. The availability of bio-predictive drug release models simulating PD-specific gastrointestinal parameters would also be beneficial for this purpose.

Development and Validation of a Robust and Efficient HPLC Method for the Simultaneous Quantification of Levodopa, Carbidopa, Benserazide and Entacapone in Complex Matrices.

Purpose: A variety of fixed-dose combination products is used in the therapy of Parkinson Disease. However, to date a proper analytical method applicable for comparative screening of different antiparkinson products was not available. The objective of the present work was thus to develop and validate an analytical method for the simultaneous quantification of levodopa, carbidopa, benserazide and entacapone.

[Complications after allogeneic bone marrow and stem cell transplantation].

Since the 1970s there has been an increase in the number of bone marrow and stem cell transplantations as well as a decrease in transplantation-associated fatalities due to improved transplantation techniques and supportive therapy. Annually nearly 50,000 transplantations are conducted worldwide with matched family grafts and matched or sometimes mismatched unrelated donor grafts. The number of long-term survivors is increasing and the late complications of this relatively aggressive therapy are now becoming apparent.

[Side effects of tumor pharmacotherapy. What internists should know].

Cytotoxic drugs have been used in the therapy of malignant tumors for the last 70 years. However, side effects of cytotoxic drugs are very common and often dose-limiting. Although many protocols have been optimized, side effects are still frequently life-threatening.

[Sorafenib in relapsed and refractory FLT3-ITD positive acute myeloid leukemia: a novel treatment option].

Background: The therapeutic options for relapsed or refractory FLT3-ITD positive AML are limited, particularly in case of a prior allogenic stem cell transplantation (SCT) or poor performance status. The clinical value of a targeted intervention using the FLT3-ITD-specific inhibitor sorafenib in this situation is largely unknown.

Patients And Methods: Between 2007 and 2010 eight patients (4 men, 4 women; age 40-75 years) with relapsed or refractory FLT3-ITD positive acute myeloid leukemia (AML) before (n=4) and after allogenic SCT (n=5) were treated off-label with sorafenib.

Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation.

Acute myeloid leukemia (AML) patients with internal tandem duplication (ITD) mutations in the Fms-like tyrosine-3 (FLT3) gene have a dismal prognosis. Here we report compassionate-use results with the multikinase and FLT3-ITD inhibitor sorafenib for the treatment of relapsed or refractory FLT3-ITD-positive AML. Sorafenib induced clinically meaningful and very rapid responses in all 6 patients treated either before (n = 2), after (n = 3), or both before and after (n = 1) allogeneic stem cell transplantation (allo-SCT).

[General and special anaemia diagnostics].

Worldwide, anaemia is one of the most frequent diseases. Its cause is obvious in many cases, especially with overt bleeding. Patients are often referred to many invasive but unnecessary diagnostic procedures.

Local irradiation prior to stem cell harvest has no influence on CD34+ yield: a quantitative analysis.

In patients with multiple myeloma, irradiation of bone marrow prior to mobilization of autologous peripheral blood progenitor cells (PBPCs) may lead to a reduced yield of CD34+ cells. Quantitative effects have not been sufficiently assessed. We retrospectively performed a multivariate analysis in 114 patients (67 men, 47 women) with multiple myeloma, of whom 53 (47%) patients had been irradiated prior to mobilization chemotherapy.

Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer.

Female gender is a significant independent favorable prognostic factor in lung cancer. To study the possible role of sex hormones in lung cancer, the expression of sex-steroid receptors and the glucocorticoid receptor was investigated in 29 lung-cancer cell lines stemming from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) by means of immunocytochemistry, ligand-binding assays and RNA expression via polymerase chain reaction. In at least 2 methods of investigation, NSCLC cell lines showed a low expression of estrogen receptor in 6, progesterone receptor in 13 and androgen receptor in 12 out of 17 cases examined; sex-steroid-receptor expression was virtually absent in SCLC cell lines.

Expression of insulin-like growth factor receptors I and II in normal human lung and in lung cancer.

Insulin-like growth factors are potent mitogenic factors in human lung cancer in vitro, acting via specific receptors. Using monoclonal antibodies we demonstrate the expression of insulin-like growth factor receptor I in bronchial epithelial cells of normal lung and in primary lung cancer (22/24 cases), being most prominent in squamous cell carcinoma. Electron microscopy on lung cancer cell lines reveals a distinct reaction pattern on the plasma membrane.