bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acceptability and characteristics of 124 human bioequivalence studies with active substances classified according to the Biopharmaceutic Classification System
Authors: Ramirez Elena , Laosa Olga , Guerra Pedro , Duque Blanca , Mosquera Beatriz , Borobia Alberto M. , Lei Suhua H. , Carcas Antonio J. , Frias Jesus 
Published: July 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In USA and Europe the classical way to guarantee equivalence between different formulations is the bioequivalence (BE) study based on in vivo bioavailability.• The Biopharmaceutic Classification System (BCS) classifies active substances into four different groups according to their aqueous solubility and intestinal permeability.• Recently the European Medicines Agency (EMA) has released a new bioequivalence guideline for immediate release solid oral dosage forms that includes recommendations on BCS‐based biowaivers. WHAT THIS STUDY ADDS • As far as we know this is the first time that the probability of proving BE of more than one hundred BE studies with 80 active substances categorized according to BCS was evaluated.• Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non‐BE studies.AIMThe aim of this study was to evaluate the acceptability of 124 bioequivalence (BE) studies with 80 active substances categorized according to the Biopharmaceutics Classification System (BCS) in order to establish if there were different probabilities of proving BE between the different BCS classes.METHODSWe evaluated the differences between pharmaceutical products with active substances from different BCS classes in terms of acceptability, number of subjects in the study (n), the point estimates, and intra‐ and inter‐subject coefficients of variation data from BE studies with generic products.RESULTSOut of 124 BE studies 89 (71.77%) were performed with pharmaceutical products containing active substances classified by the BCS. In all BCS classes there were non‐bioequivalent pharmaceutical products: 4 out of 26 (15.38%) in class 1, 14 out of 28 (50%) in class 2, 3 out of 22 (13.63%) in class 3 and 1 out of 13 (7.69%) in class 4. When we removed those pharmaceutical products in which intra‐subject variability was higher than predicted (2 in class 1 active substances, 9 in class 2 and 2 in class 3) there were still non‐BE pharmaceutical products in classes 1, 2 and 3.CONCLUSIONSComparisons between pharmaceutical products with active substances from the four BCS classes have not allowed us to define differential characteristics of each class in terms of n, inter and intra‐subject variability for Cmax or AUC. Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non‐BE studies.
Comparison of the agonist‐antagonist interaction model and the pool model for the effect of remoxipride on prolactin
Authors: Ma Guangli , Friberg Lena E. , Movin‐Osswald Gunilla , Karlsson Mats O. 
Published: July 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Prolactin response is a common side effect of antipsychotic drugs.• The pool model was proposed to describe the effect of remoxipride on prolactin.• The agonist‐antagonist interaction (AAI) model, which incorporated a dopamine‐prolactin feedback loop mechanism and circadian rhythm, was used to depict the effects of risperidone and paliperidone on prolactin.• The pool model could not characterize prolactin response in clinical studies of risperidone and paliperdone.WHAT THIS STUDY ADDS• The AAI model and the pool model were both reconstructed based on the remoxipride data set from which the original pool model was built. The pool model was extended with a circadian rhythm component which was employed in the AAI model.• The objective function values calculated by NONMEM revealed that the pool model with a circadian rhythm component best fitted the data. However, predictive checks of both models were satisfactory and the AAI model was superior in describing the circadian rhythm in healthy male volunteers when compared with earlier studies.• This study shows that the AAI model was superior as it worked well across different populations, study designs and drugs.AIMSThe tolerance to the prolactin response following administration of antipsychotic drugs has been modelled as a depletion of a prolactin pool (pool model) and a model where the tolerance is explained by a feedback loop including the dopamine interaction of prolactin release (agonist‐antagonist interaction model, (AAI model)). The AAI model was superior to the pool model when analyzing data from clinical trials of risperidone and paliperidone. Here we evaluated the two models using the remoxipride data, designed to challenge the short‐term prolactin response, from which the original pool model was built.METHODSThe remoxipride data were collected from a study where eight healthy male subjects received two remoxipride infusions on five occasions. The intervals between the first and second dose on each occasion were 2, 8, 12, 24 and 48 h, respectively. The pool and AAI models were fitted using NONMEM.RESULTSAccording to the objective function values the pool model with a circadian rhythm function fitted the data slightly better, while the AAI model was better in describing the circadian rhythm of prolactin. Visual predictive checks revealed that the models predicted the prolactin profiles equally well.CONCLUSIONSAccording to the analysis performed here, a previous analysis of several clinical studies and literature reports on prolactin concentrations, it appears that the dopamine feedback mechanism included in the AAI model is better than the storage depletion mechanism in the pool model to estimate the bio‐rhythm of prolactin time‐course and the tolerance development across different populations, drugs, treatment schedules and time.
Appropriate infliximab infusion dosage and monitoring: results of a panel meeting of rheumatologists, dermatologists and gastroenterologists
Authors: De Vries Hilbert S. , Van Oijen Martijn G. H. , Driessen Rieke J. B. , De Jong Elke M. G. J. , Creemers Marjonne C. W. , Kievit Wietske , De Jong Dirk J. 
Published: July 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Infliximab is an effective treatment for rheumatoid arthritis, ankylosing spondylitis, Crohn's disease (both adult and paediatric), ulcerative colitis, psoriatic arthritis and plaque psoriasis and national and international guidelines have been developed for each indication. WHAT THIS STUDY ADDS This study is the first study which compared current international, national and local guidelines from the medical specialties involved in the treatment with infliximab on the following topics: indication, dosage, synergy and monitoring of vital signs.AIMS Infliximab, an anti‐TNF biologic agent, is currently indicated and reimbursed for rheumatoid arthritis, ankylosing spondylitis, Crohn's disease (both adult and paediatric), ulcerative colitis, psoriatic arthritis and plaque psoriasis. Development of national and international guidelines for rheumatology, gastroenterology and dermatology, was mostly based on clinical studies and expert opinion. The aim of this study was to compare available guidelines and local protocols for rheumatology, dermatology and gastroenterology, regarding dosage of infliximab, synergy of infliximab with concomitant medication and monitoring of vital signs during infliximab administration, for achieving optimal care.METHODS Current international, national and local guidelines on the use of infliximab were reviewed and compared, differences and shortcomings were identified, and optimal treatment schedules discussed during a meeting (July 2008) of clinical experts and researchers from three departments of a Dutch university hospital.RESULTS Recommended dosages of infliximab are not equal for different indications. Loss of response to infliximab is a common problem encountered within the three medical specialties, but indications for adjustments in treatment schedules are lacking in all of the guidelines. Monitoring of vital signs (blood pressure, pulse, temperature) during infusion with infliximab is common practice and recommended by some guidelines. Routine measurement of vital signs is not of any value in predicting or recognizing acute infusion reactions, in our experience, and this is confirmed by literature on inflammatory bowel disease.CONCLUSION Different indications encompass different dosing schedules. National and internal guidelines do not provide advice regarding loss of response. Routine measurement of vital signs during infusion is not valuable in detecting acute infusion reactions and should only be performed in case of an acute infusion reaction. These topics need to be studied in future studies and covered in future guidelines.
Characterization of Bone Marrow Stromal Cells in Suspension and Monolayer Cultures
Authors: Mendelow B. , Grobicki D. , La Hunt M. de , And J. Katz , Metz J. 
Published: July 2010

Summary. Aspirated marrow fragments from healthy adult baboons were cultured in a simple liquid suspension tissue culture system. During the incubation period, haemopoietic cells were discharged from the fragments and settled to the floor of the culture vessels, thus allowing a separation of marrow stromal elements, retained within the fragments. Cells associated with the marrow stroma in vitro were of four main types: adipocytes, macrophages, plasma cells and unidentified lipid‐laden cells related to fibroblasts. These last cells were capable of DNA synthesis in vitro, and were morphologically and functionally distinguishable from typical marrow macrophages. Macrophages were characterized by their phagocytic properties. Plasma cells were capable of prolonged survival and immunoglobulin output in vitro.In monolayer cultures of disaggregated fragment cell suspensions, the lipid‐laden stromal cells rapidly assumed fibroblast‐like morphology. Fibroblastic proliferation to confluent monolayers was seen within a few days. Plasma cells reorientated themselves around these cells to form rosettes, and bridge communications between the two cell types were seen frequently. Plasma cell immunoglobulin output rate per cell appeared to be potentiated by this association.
Type IIB von Willebrand's disease presenting as thrombocytopenia during pregnancy
Authors: Giles Alan R. , Hoogendoorn Hugh , Benford Kerry 
Published: July 2010

SummaryType IIb von Willebrand's disease has been found to be associated with the development of thrombocytopenia following the infusion of DDAVP (desmopressin). It has also been associated with sporadic thrombocytopenia and evidence of spontaneous platelet aggregation. A family with documented Type IIb von Willebrand's disease is described, where two of the affected females presented with moderate to severe thrombocytopenia developing during pregnancy with reversal to normal or minimally reduced platelet counts in the early post gestational period. In each case, the levels of factor VIII: C, von Willebrand factor antigen and von Willebrand factor ristocetin co‐factor activity rose during pregnancy but there were notable discrepancies between the levels of each in any one individual. It is suggested that pregnancy resulted in increased synthesis of the variant form of von Willebrand factor resulting in progressively increasing platelet/variant form von Willebrand factor interaction and subsequent thrombocytopenia. Whether this reflects consumption or sequestration remains uncertain. Although spontaneous platelet aggregation was observed in some family members, the majority did not exhibit this phenomenon. Circulating platelet aggregates could not be detected. Both pregnancies were relatively uneventful and there is no history of unusual bleeding associated with pregnancy in the family. These observations suggest that Type IIb von Willebrand's disease should be considered in the differential diagnosis of thrombocytopenia developing during pregnancy, particularly in those individuals where evidence supporting the diagnosis of immune mediated thrombocytopenia is not forthcoming. Where the diagnosis of Type IIb von Willebrand's disease is established, active intervention other than confinement in a hospital with experience in haemostatic disorders is probably not required as the development of thrombocytopenia does not appear to exert an additive effect on the underlying defect relating to the variant form of von Willebrand's disease.
The platelet alloantigen Zwa or PlA1 is expressed by cultured endothelial cells
Authors: Leeksma O. C. , Giltay J. C. , Zandbergen‐Spaargaren J. , Modderman P. W. , Van Mourik J. A. , Kr. von dem Borne A. E. G. 
Published: July 2010

SummaryRecently, the synthesis by cultured human endothelial cells of a membrane protein complex immunologically related to platelet glycoprotein (GP) IIb/IIIa complex was demonstrated. Since platelet GP IIIa is known to carry the platelet alloantigen Zwa or PaA1, studies were performed to establish whether this antigen is also expressed on endothelial cells. The present report describes the results of these studies, which provide evidence for the presence of the Zwa or PlA1 antigen on the surface of cultured human endothelial cells. This evidence is based on the following observations: (1) cultured endothelial cells react with anti‐Zwa (PlA1) antibodies as shown by indirect immunofluorescence: (2) two proteins are precipitated by anti‐Zwa (PlA1) antibodies from lysates of 125I‐labelled endothelial cells with an electrophore‐tic mobility corresponding with that of GP IIb and IIIa; (3) anti‐Zwa (PlA1) reacts specifically, as shown by immunoblotting of sodium‐dodecylsulphate polyacrylamide gels of solubilized endothelial cells, with a protein with a mobility similar to that of platelet GP IIIa.
Serum levels of soluble CD30 molecule (Ki‐1 antigen) in Hodgkin's disease: relationship with disease activity and clinical stage
Authors: Pizzolo G. , Vinante F. , Chilosi M. , Dallenbach F. , Josimovic‐Alasevic O. , Diamantstein T. , Stein† H. 
Published: July 2010

SummaryIn all cases of Hodgkin's disease (HD) Reed‐Sternberg (RS) cells express the CD30 antigen. It has been recently demonstrated that this molecule can be released from the cell membrane of CD30+ neoplastic cells in a soluble form (sCD30), detectable in culture supernatants and body fluids. In this paper we investigated by an immunoassay the serum levels of sCD30 in 58 patients with HD, in order to define the possible relationship of this molecule to the clinical and pathological findings. sCD30 molecule was found at detectable levels in 24 out of 50 patients (48%) with active disease, whereas it was always absent in control sera and in cases in complete remission. Among the patients with active HD, the incidence and mean values of detectable levels (±SEM) of sCD30 were higher in cases with progressive or relapsing disease (61.5%, mean 458±190 U/ml) as compared to those at presentation (43.2%, mean 116 ± 3 3 U/ml). Among the cases at presentation, detectable levels were observed more often in patients with advanced stages (III+IV: 61%) and constitutional symptoms (‘B’: 61‐5%) than in early stages (I+11: 26%) and without symptoms (‘A’: 33.3%). In addition, higher mean values were found in stages III+IV (182±60 U/ml) and in ‘B’cases (208±73 U/ml) than in stages I+II (65 ± 30 U/ml) or ‘A’patients (64 ± 26 U/ ml).The above findings suggest a possible role for the sCD30 as a tumour marker in HD.
Interleukin 10‐induced thrombocytopenia in normal healthy adult volunteers: evidence for decreased platelet production
Authors: Sosman Jeffrey A. , Verma Amit , Moss Steven , Sorokin Patricia , Blend Michael , Bradlow Basil , Chachlani Nasir , Cutler David , Sabo Ronald , Nelson Mary , Bruno Edward , Gustin David , Viana Marlos , Hoffman Ronald 
Published: July 2010

Recombinant human interleukin 10 (rhuIL‐10) inhibits the production of proinflammatory cytokines and has shown promise in the treatment of inflammatory bowel disease. Clinical trials have been accompanied by a reversible decline in platelet counts. We conducted a randomized, double‐blinded, placebo‐controlled, parallel group trial in 12 healthy volunteers to investigate the aetiology of rhuIL‐10‐induced thrombocytopenia. Eight volunteers received 8 μg/kg/d of rhuIL‐10 subcutaneously, while four subjects received a placebo alone for 10 d. A reversible decline in the platelet counts from a mean of 275 × 109/l to 164 × 109/l was observed in the IL‐10‐treated cohort (P = 0·012). A fall in the haemoglobin mean levels was also observed in the IL‐10‐treated cohort from 13·7 to 11·7 g/dl (P = 0·011). No significant change was observed in the bone marrow cellularity or myeloid/erythroid ratio or in the number of megakaryocytes per high‐powered field (HPF). A fall was observed in the number of megakaryocyte colony‐forming units (CFU‐MKs) after the administration of IL‐10 compared with those receiving the placebo (P = 0·068). No difference in the change in granulocyte–macrophage CFUs (CFU‐GMs), mixed lineage CFUs (CFU‐GEMMs) or erythroid burst‐forming units (BFU‐Es) was observed when comparing the IL‐10‐ vs. placebo‐treated groups (P > 0·465). Serum cytokine levels of thrombopoietin (TPO), IL‐6 and granulocyte–macrophage colony stimulating factor (GM‐CSF) were not decreased following IL‐10 administration. In fact, both TPO and GM‐CSF appeared to be slightly increased in the serum. All subjects underwent In111‐labelled platelet survival studies with liver/spleen scans to assess splenic sequestration prior to and then on day 7 of treatment. A significant reduction in splenic sequestration of platelets (P = 0·012) was observed in the IL‐10‐treated group, but not in the placebo‐treated subjects.
Platelet and leucocyte activation in childhood sickle cell disease: association with nocturnal hypoxaemia
Authors: Inwald David P. , Kirkham Fenella J. , Peters Mark J. , Lane Rod , Wade Angie , Evans Jane P. , Klein Nigel J. 
Published: July 2010

We hypothesized that vaso‐occlusive events in childhood sickle cell disease (SCD) may relate to inflammatory cell activation as well as interactions between sickle erythrocytes and vascular endothelium. Peripheral blood was examined from 24 children with SCD, of whom 12 had neurological sequelae and seven had frequent painful crises, and 10 control subjects. Platelet (CD62P and CD40L expression) and granulocyte (CD11b expression) activation and levels of platelet–erythrocyte and platelet–granulocyte complexes were determined by flow cytometry. Platelets (P = 0·019), neutrophils (P = 0·02) and monocytes (P = 0·001) were more activated and there were increased platelet–erythrocyte complexes (P = 0·026) in SCD patients compared with controls. Platelet–granulocyte complexes were not raised. There were no differences between the different groups of SCD. As hypoxia activates monocytes, platelets and endothelial cells and causes sickling of SCD erythrocytes, we also investigated 20 SCD patients with overnight pulse oximetry. Minimum overnight saturation correlated with the level of platelet–erythrocyte complexes (Spearman's ρ−0·668, P < 0·02), neutrophil CD11b (Spearman's ρ−0·466, P = 0·038) and monocyte CD11b (Spearman's ρ−0·652, P = 0·002). These findings provide important clues about the mechanism by which SCD patients may become predisposed to vaso‐occlusive events.
OKT‐3‐based reconditioning regimen for early graft failure in HLA‐non‐identical stem cell transplants
Authors: Schlegel P. G. , Eyrich M. , Bader P. , Handgretinger R. , Lang P. , Niethammer D. , Klingebiel T. 
Published: July 2010

Primary non‐engraftment or early rejection after transplantation of haematopoietic stem cells represent life‐threatening complications of allogeneic stem cell transplantation. Management of early graft failure has been problematic, as the risk of fatal infectious complications increases with the time of pancytopenia and as a second transplant preceded by a conventional myeloablative conditioning regimen has been associated with high rates of cumulative organ toxicity. For paediatric patients with early graft failure following the transplantation of highly purified major histocompatibility complex (MHC)‐disparate haematopoietic stem cells, we have evaluated an immunosuppressive OKT‐3/methylprednisolone‐based reconditioning regimen with low toxicity in preparation for a secondary transplant of purified haematopoietic stem cells from the same donor. This report presents the results from a 4‐year pilot study including six patients with early graft failure. The results demonstrate that this antibody‐based regimen can be used effectively to prepare patients for secondary transplantation. Successful engraftment after a second transplant procedure was achieved in five of these six high‐risk patients. The median interval between first and second transplant was 27 d (range 22–51 d), and the median time for engraftment was 10 d (range 9–13 d). Chimaerism analysis of microsatellite regions by polymerase chain reaction (PCR) demonstrated complete donor chimaerism in four of these patients within the first month after secondary transplant and revealed mixed chimaerism in one patient who converted to complete chimaerism after T‐cell add‐back.
Insulin‐like growth factor induces the survival and proliferation of myeloma cells through an interleukin‐6‐independent transduction pathway
Authors: Ferlin Martine , Noraz Nelly , Hertogh Catherine , Brochier Jean , Taylor Naomi , Klein Bernard 
Published: July 2010

Multiple myeloma (MM) is a B‐cell neoplasia that is associated with an increased level of bone resorption. One important mediator of bone remodelling, insulin‐like growth factor (IGF‐I), has been shown to stimulate the proliferation of human myeloma cells. However, the mechanisms of action of IGF‐I in these cells have not been determined. Using interleukin (IL)‐6‐dependent myeloma cell lines, we show IGF‐I to be as potent a survival and proliferation factor as IL‐6. We demonstrated that IGF‐I functions independently of the IL‐6 transducer gp130 and that these two cytokines have additive effects. Moreover, inhibition of the IGF‐I pathway did not modulate the proliferative effect of IL‐6. Accordingly, we found that IL‐6 and IGF‐I activated distinct downstream signalling molecules: IL‐6 activated STAT3 phosphorylation, whereas IGF‐I treatment resulted in the phosphorylation of IRS‐1. Interestingly, these signalling pathways appear to converge as both cytokines activated the ras/MAPK pathway. Thus, IGF‐I acts as a potent survival and proliferation factor for myeloma cells by stimulating an IL‐6‐independent signalling cascade. These data, together with the finding that, in vivo, IGF‐I is normally expressed in close proximity to myeloma cells within the bone matrix, strongly suggest a role for this cytokine in the pathophysiology of multiple myeloma.
Molecular remission without blood product support using all‐trans retinoic acid (ATRA) induction and combined arsenic trioxide/ATRA consolidation in a Jehovah's Witness with de novo acute promyelocytic leukaemia
Authors: Kennedy Glen A , Marlton Paula , Cobcroft Ralph , Gill Devinder 
Published: July 2010

Arsenic trioxide has recently been used in the treatment of both relapsed and de novo acute promyelocytic leukaemia (APML). Molecular remissions have been attained using arsenic trioxide with minimal associated haematological toxicity, making protocols utilizing this drug an attractive option for Jehovah's Witnesses with APML. A 62‐year‐old female Jehovah's Witness with de novo APML was treated with all‐trans retinoic acid induction followed by combined arsenic trioxide/ATRA consolidation, and achieved molecular remission with minimal haematological toxicity and no blood product support.