bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of various factors on steady‐state plasma concentrations of risperidone and 9‐hydroxyrisperidone: lack of impact of MDR‐1 genotypes
Authors: Yasui‐Furukori Norio , Mihara Kazuo , Takahata Takenori , Suzuki Akihito , Nakagami Taku , De Vries Ronald , Tateishi Tomonori , Kondo Tsuyoshi , Kaneko Sunao 
Published: December 2004

AimsAn in vitro study has suggested that risperidone is a substrate of P‐glycoprotein, which is coded by MDR‐1 gene. Thus, we studied the effects of major polymorphisms of the MDR‐1 gene on plasma drug concentrations.MethodsSubjects were 85 schizophrenic patients receiving 3 mg twice daily of risperidone. Sample collections were conducted 12 h after the bedtime dosing. Plasma concentrations of risperidone and 9‐hydroxyrisperidone were quantified using LC/MS/MS. MDR‐1 genotypes (C3435T and G2677T/A) and CYP2D6 genotypes were identified using PCR‐RFLP methods.ResultsThere was no difference in geometric mean (95% CI) of steady‐state plasma concentration of risperidone between C3435T genotypes [C/C, C/T, T/T; 2.06 (1.63, 6.47), 2.96 (3.10, 7.91), 2.28 (1.81, 8.04) ng ml−1, P = 0.759] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 1.62 (0.08, 6.07), 2.64 (3.25, 7.10), 2.71 (2.77, 8.72) ng ml−1, P = 0.625] or 9‐hydroxyrisperidone between C3435T genotypes [38.3 (33.7, 50.1), 34.9 (32.9, 42.0), 35.7 (31.7, 42.3) ng ml−1, P = 0.715] or G2677T/A genotypes [40.6 (33.0, 51.8), 35.0 (33.3, 42.4), 36.1 (32.8, 47.2) ng ml−1, P = 0.601]. Multiple regression analyses including CYP2D6 genotypes, sex, and age revealed that steady‐state plasma concentration of risperidone correlated with the number of mutated alleles for CYP2D6 (standardized partial correlation coefficients (beta) = 0.540, P < 0.001) and those of 9‐hydroxyrisperidone (standardized beta = 0.244, P = 0.038) and active moiety (standardized beta = 0.257, P = 0.027) correlated with age.ConclusionsThese findings suggest that the MDR‐1 variants are not associated with steady‐state plasma concentration of risperidone or 9‐hydroxyrisperidone, but CYP2D6 genotypes and age are determinants of these concentrations.
Modelling the cardiovascular effects of ephedrine
Authors: Persky Adam M. , Berry N. Seth , Pollack Gary M. , Brouwer Kim L. R. 
Published: December 2004

Aims  Recent reports have called into question the safety of ephedra supplements especially with regards to their cardiovascular effects. The purpose of this analysis was to characterize, via pharmacokinetic/pharmacodynamic modelling, the cardiovascular effects of ephedrine, the main active ingredient of ephedra, in apparently healthy, overweight volunteers.Methods  In a randomized, double‐blind, crossover, placebo‐controlled study, eight subjects received either placebo, 0.25, 0.5 or 1.0 mg kg−1 ephedrine sulphate by mouth with a 7‐day washout between treatments. Plasma ephedrine concentrations, heart rate and blood pressure were determined for 8 h postdose.Results  The pharmacokinetics of ephedrine were best described by a one‐compartment model with first‐order absorption and elimination. The percentage change in heart rate was described by a linear model with a resulting slope of 0.14%·l µg−1 (CV = 59%). The percentage change in systolic blood pressure demonstrated clockwise hysteresis, and a sigmoidal tolerance model was used to describe the data. The mean maximum predicted effect (Emax) was 53.7% (CV = 41%) with an EC50 of 107 µg·l−1 (CV = 65%) and an inhibitory maximum (Imax) of 39.8% (CV = 60%). Tolerance developed with a mean half‐life of 15 min (range 6–140 min).Conclusions  This is the first study to apply a comprehensive pharmacokinetic/pharmacodynamic model to the cardiovascular effects of orally administered ephedrine. Although systolic blood pressure increases quickly after administration, the increase is nearly abolished by compensatory mechanisms.
Population pharmacokinetic modelling of Emfilermin (recombinant human leukaemia inhibitory factor, r‐hLIF) in healthy postmenopausal women and in infertile patients undergoing in vitro fertilization and embryo transfer
Authors: Goggin Timothy , Nguyen Quyen T. X. , Munafo Alain 
Published: December 2004

Aims  The aim of this analysis was to develop a population pharmacokinetic model for Emfilermin (recombinant human leukaemia inhibitory factor, r‐hLIF) following subcutaneous administration to healthy postmenopausal women and to infertile patients undergoing in vitro fertilization and embryo transfer (IVF‐ET).Methods  Data from three studies, a single and a repeat dose Phase I study in postmenopausal women as well as a proof of concept study in patients undergoing in vitro fertilization and embryo transfer were combined and analyzed. The structural pharmacokinetic model was developed using the rich data from the Phase I studies and the full pharmacostatistical model was then derived using all the data.Results  The pharmacokinetics of r‐hLIF after repeated subcutaneous administration were described by a one‐compartment disposition model with a zero order input. The duration of the absorption phase was short (0.8 h) and invariant. The apparent clearance in postmenopausal women was 57 l h−1 (CV = 17%). In in vitro fertilization and embryo transfer patients, the apparent clearance was decreased by 35% compared with postmenopausal women. The apparent volume of distribution was 235 l (interindividual CV = 28%) and exhibited an interoccasion variability of 23%. It increased (for weight above 62 kg) or decreased (for weight below 62 kg) by 29% for every 10 kg body weight. The median posthoc estimates of apparent clearance and volume of distribution and their variability were consistent with the population estimates. In postmenopausal women, the results were consistent with those obtained by noncompartmental analysis. The residual variability on r‐hLIF serum concentrations was 20%.Conclusions  The pharmacokinetics of r‐hLIF after repeated SC administration were described by a one compartment disposition model, with zero order input, in postmenopausal women and those undergoing IVF or intracytoplasmic sperm injection and embryo transfer. Absorption of r‐hLIF was rapid as was its subsequent clearance. The apparent volume of distribution of r‐hLIF was moderate to high, depended on body weight and showed interoccasion variability.
Single‐dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects
Authors: Kovarik John M. , Schmouder Robert , Barilla Denise , Wang Yibin , Kraus Gerolf 
Published: December 2004

AimsFTY720 is a sphingosine‐1‐phosphate receptor agonist that redirects lymphocytes from the circulation to lymph nodes without impairing lymphocyte function. It is being developed as an immunomodulator for the prevention of acute rejection after organ transplantation. This study was performed to provide guidance on administration with respect to meals and to measure pharmacologic responses in healthy subjects.MethodsIn this randomized, two‐period, crossover study, 14 healthy subjects received placebo on day −1 of each period with baseline circadian measurements of lymphocyte count and heart rate. Subjects subsequently received a single 1 mg oral dose of FTY720 on day 1 under fasting conditions and after a high fat meal. Blood FTY720 concentrations, lymphocyte count, and supine heart rate were assessed over an 8 day period after each FTY720 dose. The effect of food on FTY720 pharmacokinetics was assessed by standard bioequivalence testing.ResultsBoth the peak concentration (0.65 ± 0.17 vs 0.64 ± 0.18 ng ml−1) and total exposure (AUC 149 ± 65 vs 139 ± 43 ng ml−1 h) did not differ significantly between fasting and fed states, respectively. The corresponding fed/fasting ratios and 90% confidence intervals were 1.00 (0.86, 1.17) for Cmax and 0.98 (0.86, 1.11) for AUC. Under both treatment conditions peripheral blood lymphocyte count decreased from baseline by 38 ± 9% over the first 2 days postdose and then increased towards predose values over the subsequent week. Whereas a circadian rhythm in supine heart rate was preserved in the presence of FTY720, the heart rate vs time curve was shifted downwards by 10% over the first day postdose and then recovered to prestudy values by days 3–5 postdose. These changes were asymptomatic.ConclusionsSingle 1 mg doses of FTY720 were well tolerated in healthy subjects and elicited a moderate decrease in peripheral blood lymphocyte count and a transient decrease in heart rate consistent with its pharmacological mode of action. FTY720 may be administered without regard to the timing of meals or their fat content.
Tissue pharmacokinetics of levofloxacin in human soft tissue infections
Authors: Bellmann Romuald , Kuchling Gerald , Dehghanyar Pejman , Zeitlinger Markus , Minar Erich , Mayer Bernhard X. , Müller Markus , Joukhadar Christian 
Published: December 2004

AimsThe present study addressed the ability of levofloxacin to penetrate into subcutaneous adipose tissues in patients with soft tissue infection.MethodsTissue concentrations of levofloxacin in inflamed and healthy subcutaneous adipose tissue were measured in six patients by microdialysis after administration of a single intravenous dose of 500 mg. Levofloxacin was assayed by high‐performance liquid chromatography.ResultsThe mean concentrationvstime profile of free levofloxacin in plasma was identical to that in inflamed and healthy tissues. The ratios of the mean area under the free levofloxacin concentrationvstime curve from 0 to 10 h (AUC(0,10 h)) in tissue to that in plasma were 1.2 ± 1.0 for inflamed and 1.1 ± 0.6 for healthy subcutaneous adipose tissue (mean ± SD). The mean difference in the ratio of the AUCtissue : AUCplasmafor inflamed and healthy tissue was 0.09 (95% confidence interval −0.58, 0.759,P > 0.05). Interindividual variability in tissue penetration was high, as indicated by a coefficient of variation of approximately 82% for AUCtissue : AUCplasmaratios.ConclusionsThe penetration of levofloxacin into tissue appears to be unaffected by local inflammation. Our plasma and tissue data suggest that an intravenous dose of 500 mg levofloxacin provides effective antibacterial concentrations at the target site. However, in treatment resistant patients, tissue concentrations may be sub‐therapeutic.
Cardiac monitoring of patients receiving arsenic trioxide therapy
Authors: Unnikrishnan Dilip , Dutcher Janice P. , Garl Susan , Varshneya Nikita , Lucariello Richard , Wiernik Peter H. 
Published: December 2004

SummaryArsenic trioxide (ATO) is approved for the treatment of acute promyelocytic leukaemia and is under investigation for other malignancies. We report the cardiac findings in 18 patients with haematologic malignancies treated with ATO and assess the role of cardiac factors in fluid retention syndrome observed during ATO therapy. Based on initial observations in 10 patients treated with ATO, cardiac functions in the subsequent eight patients were evaluated prospectively. Evaluation included pre‐ and during‐treatment electrocardiograms, Holter monitoring, echocardiograms, multigated acquisition scan and cardiac stress tests if indicated. All eight patients developed fluid retention during ATO, evidenced by pulmonary congestion, oedema and pleural/pericardial effusions. No cardiac factors were identified that contributed to fluid retention. Six patients had prolonged corrected QT (QTc) compared with baseline, three developed ventricular tachycardia. Sinus tachycardia, ventricular premature contractions, and non‐sustained ventricular/supraventricular tachycardia were seen during ATO treatment. Fluid retention and cardiac events did not correlate with the dose or total amount of ATO or prior anthracycline therapy. In summary, fluid overload during ATO therapy does not appear to be cardiac in origin but appears to be drug‐related, and may reflect cytokine‐induced capillary leak. QTc prolongation, transient arrhythmias and clinically significant arrhythmias were seen with therapeutic doses of ATO.
Production of interferon‐γ by lymphocytes from paroxysmal nocturnal haemoglobinuria patients: relationship with clinical status
Authors: Coluzzi Serelina , Biffoni Mauro , Pasqualetti Daniela , Perrone Maria Paola , Vaglio Stefania , Rahimi Hassan , Arista Maria Cristina , Laurenti Luca , Cerretti Raffaella , Girelli Gabriella 
Published: December 2004

SummaryParoxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of phosphatidylinositol glycan class A (PIG‐A) defective haematopoietic cells, probably due to the immune‐mediated alterations of the bone marrow environment selecting PIG‐A− stem cells. The present study investigated the presence of alterations of the immune system in a population of 11 PNH patients. The production of interferon‐γ (IFN‐γ) and interleukin‐2 (IL‐2), evaluated by intracellular cytokine analysis, and the frequencies of class I and II human leucocyte antigen (HLA) alleles were studied in comparison with healthy human subjects. Similar percentages of lymphocytes produced cytokines in PNH patients and controls after costimulation‐independent activation; however, a negative correlation was found between the percentage of IFN‐γ producing cells and white cell or platelets counts. PNH patients showed an higher percentage, compared with controls, of IFN‐γ producing cells after costimulation‐dependent activation. The frequency of HLA‐A31 was higher in patients than in controls (27·2% vs. 4%), similarly to that of HLA‐B7 (27·2% vs. 6%). With regard to class II alleles, 18% of PNH patients expressed DQB1*04 compared with none of 50 control cases. This study supports the hypothesis that immune alteration are present in PNH and that the immunogenetic background could influence the development of the disease.
Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy‐proven primary refractory Hodgkin's disease
Authors: Moskowitz Craig H. , Kewalramani Tarun , Nimer Stephen D. , Gonzalez Maria , Zelenetz Andrew D. , Yahalom Joachim 
Published: December 2004

SummaryProspective randomized studies have determined that high dose therapy and autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed Hodgkin's disease (HD); however, the role of this approach in patients with primary refractory disease has been controversial. This report is an integrated analysis of 75 consecutive patients with biopsy‐confirmed primary refractory HD, who were treated with high dose chemoradiotherapy (HDT) and ASCT at the Memorial Sloan Kettering Cancer Center. The patients underwent conventional dose cytoreductive chemotherapy followed by HDT and ASCT. At a median follow‐up of 10 years for surviving patients, the event‐free survival (EFS), progression‐free survival (PFS) and overall survival (OS) rates were 45%, 49% and 48% respectively. Only chemosensitivity to standard‐dose second‐line chemotherapy (SDSC) predicted for a better survival, thus responding patients had an EFS, PFS and OS of 60%, 62% and 66%, respectively,versus19%, 23% and 17% for patients who had a poor response to SDSC (P < 0·001). While patients with chemosensitive disease have an excellent outcome with HDT and ASCT, novel approaches are needed to cure HD patients who fail front‐line and second‐line chemotherapy.
Intracellular signalling molecules as immunohistochemical markers of normal and neoplastic human leucocytes in routine biopsy samples
Authors: Pozzobon Michela , Marafioti Teresa , Hansmann Martin‐Leo , Natkunam Yasodha , Mason David Y. 
Published: December 2004

SummaryWe have investigated whether intracellular signal transduction molecules can be used as immunohistological markers of normal and neoplastic human leucocytes in routine tissue sections. We obtained selective labelling of white cells for eight such molecules (the ‘linker’ molecules SLP‐76 and BLNK, the Src family kinases Lyn, Fyn, Syk and Hck, and the phospholipases PLC‐γ1 and PLC‐γ2). Antibodies to SLP‐76 and PLC‐γ1 selectively labelled T cells, and antibodies to BLNK, Lyn, Fyn, Syk and PLC‐γ2 labelled B cells (although Fyn immunostaining was restricted to mantle zone B cells). Antibodies to the Syk and Hck kinases labelled probable thymocyte precursors at the periphery of the thymic cortex. In addition to lymphoid cells, several other leucocyte types were immunostained (e.g. SLP‐76, Lyn, Syk and Hck were found in megakaryocytes, myeloid cells and/or macrophages, and PLC‐γ2 was detected in arterial endothelium). SLP‐76 and PLC‐γ1 were found in most T‐cell lymphomas studied, and some B‐cell lymphomas were also positive for PLC‐γ1 (e.g. diffuse large cell and Burkitt's lymphoma). The five B cell‐associated markers were found in most B‐cell non‐Hodgkin's lymphomas, although some diffuse large B‐cell lymphomas were negative (e.g. for Lyn) and anti‐Fyn tended not to stain small B‐cell neoplasms. The observation that a range of leucocyte signalling molecules can be detected in routine biopsies offers new possibilities for studying normal and neoplastic human white cells in diagnostic tissue samples.
Intravenous (IV) anti‐D and IV immunoglobulin achieve acute platelet increases by different mechanisms: modulation of cytokine and platelet responses to IV anti‐D by FcγRIIa and FcγRIIIa polymorphisms
Authors: Cooper Nichola , Heddle Nancy M. , de Haas Masja , Reid Marion E. , Lesser Martin L. , Fleit Howard B. , Woloski B. M. R. , Bussel James B. 
Published: December 2004

SummaryIntravenous (IV) anti‐D and IV immunoglobulin (IVIG) slow the Fcγ receptor (FcγR)‐mediated destruction of antibody‐coated platelets in patients with immune thrombocytopenic purpura (ITP). This pilot study explored the mechanism of these immunoglobulin preparations by measuring interleukin‐10 (IL‐10), monocyte chemoattractant protein‐1 (MCP‐1), IL‐6 and tumour necrosis factor α (TNFα), before and after infusion and by assessing the effect of FcγRIIa and FcγRIIIa polymorphisms on both cytokine and haematologic responses to anti‐D. Following IVIG, only IL‐10 was increased at 2 h and MCP‐1 on day 7 (P < 0·05). In contrast, 2 h after anti‐D infusion, plasma levels of all four cytokines were increased (P < 0·01); five of six patients with the highest MCP‐1, IL‐6 and TNFα levels had chills. Higher IL‐10 levels correlated with platelet increases at 24 h and haemoglobin decreases at day 7 (P < 0·025). Patients with the FcγRIIa‐131HH genotype had significantly higher MCP‐1, IL‐6 and TNFα levels. Patients with the FcγRIIIa‐158VF genotype had higher platelet increments at day 7 (P < 0·05). Soluble CD16 (sCD16) was increased 2 h after IV anti‐D; day 7 levels correlated with day 7 haemoglobin decreases (P < 0·01). In conclusion, the relationship of FcγRIIa and FcγRIIIa polymorphisms with both cytokine levels and platelet increments implicated these receptors in responses to anti‐D and supported different mechanisms of FcγR interaction to those seen with IVIG.
Granulocyte‐macrophage colony‐stimulating factor to increase efficacy of mitoxantrone, etoposide and cytarabine in previously untreated elderly patients with acute myeloid leukaemia: a Swedish multicentre randomized trial
Authors: Löfgren C. , Paul C. , Åström M. , Hast R. , Hedenius M. , Lerner R. , Liliemark J. , Nilsson I. , Rödjer S. , Simonsson B. , Stockelberg D. , Tidefelt U. , Björkholm M. 
Published: December 2004

SummaryA total of 110 patients, aged 64 years or over, with de novo acute myeloid leukaemia (AML) and white blood cell counts <50 × 109/l were treated with 3 d of cytarabine 1 g/m2 twice daily, mitoxantrone 12 mg/m2 and etoposide 200 mg/m2, randomized with or without the addition of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) 200 μg/m2. The primary aim was to evaluate the effect of GM‐CSF on the remission rate. Secondary aims included comparison of duration of remission, survival and infectious complications and the impact of maintenance therapy with thioguanine. Complete remission (CR) was achieved by 64% of patients without GM‐CSF, and by 65% of patients who received GM‐CSF, the median remission duration was 13 vs. 6 months, the median overall survival (OS) was 14 vs. 9 months, the mean time to neutrophil recovery was 25 vs. 17 d (P = 0·03) and the number of positive blood cultures was 46 vs. 39 (P = 0·05) respectively. The impact of thioguanine remains unanswered since only 30 patients remained in CR after consolidation therapy. We conclude that induction therapy is feasible with acceptable toxicity in elderly patients with AML, albeit with a high relapse rate and short OS. GM‐CSF prior to, and in combination with, induction treatment reduced the time to neutrophil recovery and the number of neutropenic septicaemia cases but did not improve the OS of AML in the elderly.
Increased soluble guanylate cyclase activity in the red blood cells of sickle cell patients
Authors: Conran Nicola , Oresco‐Santos Camila , Acosta Heloisa C. , Fattori André , Saad Sara T. O. , Costa Fernando F. 
Published: December 2004

SummaryActivation of soluble guanylate cyclase (sGC) has been reported to up‐regulate γ‐globin gene transcription in erythroid cell lines and primary erythroblasts. sGC is activated by nitric oxide (NO), subsequently catalysing the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which mediates various physiological responses. To study the importance of this mechanism in the erythroid cells of sickle cell patients, cGMP levels were measured in the red blood cells (RBC) of normal individuals, steady‐state sickle cell patients (SS) and SS patients on hydroxyurea (HU) therapy (SS + HU). cGMP levels were found to be significantly higher in RBC of SS patients (SS RBC) than in RBC of normal individuals, and were further increased in RBC of SS + HU patients. cGMP levels correlated with fetal haemoglobin (HbF) levels in SS/SS + HU patients, but not with reticulocyte count. Furthermore, NO‐stimulated sGC activity, following incubation of cells with a NO donor, was significantly greater in SS RBC than in normal RBC. These results demonstrate, for the first time, an increased metabolism of NO mediated by sGC in the SS RBC, which is further increased by hydroxyurea. Augmentation of cGMP levels by NO in erythroid cells may constitute a mechanism for induction of HbF and other erythrocyte functions and represent a possible therapeutic target for treatment of sickle cell disease.
Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma
Authors: Paterson Joshua L. , Li Zhihua , Wen Xiao‐Yan , Masih‐Khan Esther , Chang Hong , Pollett Jonathan B. , Trudel Suzanne , Stewart A. Keith 
Published: December 2004

SummaryDysregulation of fibroblast growth factor receptor 3 (FGFR3) by the translocation t(4;14)(p16;q32) occurs in 15% of multiple myeloma (MM) patients and confers a growth and survival advantage to malignant plasma cells. As FGFR3 is a molecular target, we assessed the therapeutic potential of the FGFR‐specific tyrosine kinase inhibitors SU5402 and SU10991 in MM. SU5402 inhibited FGFR3 phosphorylation in vitro and in murine MM tumour models. B cells dependent on FGFR3 for survival were specifically sensitive to SU5402. A panel of 11 human myeloma cell lines was studied, five bearing the t(4;14) translocation. The KMS11 human myeloma cell line, which expresses constitutively active mutant FGFR3, displayed an 85% decrease in S‐phase cells, a 95% increase in G0/G1 cells, and 4·5‐fold increase in apoptotic cells after 72 h treatment with 10 μmol/l SU5402. Activated extracellular signal‐regulated kinases 1 and 2 and signal transducer and activator of transcription 3 were rapidly down‐regulated after SU5402 treatment. In human myeloma cell lines expressing wild‐type FGFR3 the stimulating effect of aFGF ligand was abrogated by SU5402 treatment. Myeloma cells lacking the t(4;14) or with the t(4;14) and a secondary RAS mutation did not respond to therapy. These findings support the development of clinical trials of early intervention with FGFR3 inhibitors in t(4;14) myeloma.