bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics and pharmacokinetic‐pharmacodynamic relationships of the novel anticancer agent E7070 in four phase I studies
Authors: Van Kesteren CH. , Mathôt R. A. A. , Raymond E. , Armand J. P. , Dittrich CH. , Dumez H. , Roché H. , Droz J. P. , Punt C. , Ravic M. , Wanders J. , Beijnen J. H. , Fumoleau P. , Schellens J. H. M. 
Published: March 2003

E7070 is a novel chloroindolyl sulphonamide being developed as an anti‐cancer agent for the treatment of solid tumours. E7070 arrests cell cycle progression in the G1 phase and induces apoptosis. In various in vitro and in vivo models, E7070 appeared to be highly active. Four phase I dose‐escalation studies have been conducted to identify the dose‐limiting toxicities (DLTs) and the maximum tolerated dose. Adult patients with advanced solid tumours resistant or not amenable to conventional therapy received E7070 at four different treatment schedules: 1) 1 h i.v. infusion (doses 50–1000 mg m−2), 2) daily times five 1 h i.v. infusion (d×5) (10–200 mg m−2 day−1), 3) weekly times four 1 h infusion (40–500 mg m−2 week−1), 4) 120 h continuous i.v. infusion (civ) (6–200 mg m−2 day−1). DLTs were haematological in all studies. Pharmacokinetic (PK) sampling was performed in 143 patients (corresponding numbers of patients were 40, 35, 43 and 25) during the first cycle. In this study we investigated the PK and its relationship with the pharmacodynamics for all studies. A population PK model was developed to describe the combined data of the four studies. E7070 showed non‐linear PK at higher dose levels. Therefore, a basic 3‐compartmental model was extended with saturable transport to one of the peripheral compartments and parallel linear and a non‐linear pathways of elimination from the central compartment. The model adequately described the data. A validation using a bootstrap procedure indicated that the model was robust. Total clearance (CL) of E7070 was highly dependent on the plasma concentration; shortly after infusion, at the higher concentrations (i.e. 10–200 mg l−1), CL was 0.5 l h−1 and gradually increased to 5.5 l h−1 at the lower concentrations (0.1–0.01 mg l−1). For each individual, Bayesian estimates of AUC (area under the plasma concentration time curve) were obtained using the PK model. The percentage decreases in neutrophils (ANC) and thrombocytes (THR) were plotted against dose, dose level and AUC for each study. In general, AUC was a better predictor for haematological toxicity than dose and dose level, as variability was reduced when related to AUC. The relationship between % decrease in ANC and THR and AUC could be described using a maximum effect (Emax) model. A maximum % decrease in ANC and THR of approximately 95% was reached with all four schedules.In conclusion, the non‐linear PK of E7070 in all treatment schedules was adequately described using the population PK model. The dose‐limiting, haematological toxicity of E7070 is related to the total exposure, expressed as AUC.
Rectal ropivacaine is absorbed proportionally to the dose, with low intraindividual variability
Authors: Arlander Eva , Sjövall Jan , Sörstad Jörgen , Norsten‐Höög Carina , Gustafsson Lars L. 
Published: March 2003

Aims  This study investigated the absorption characteristics and the tolerability of rectally administered ropivacaine, a local anaesthetic, intended as a new local therapy for ulcerative colitis.Methods  Thirty‐two healthy volunteers participated in a randomized, placebo‐controlled study. In study phase 1 (n = 16, double‐blind, crossover) single rectal doses of ropivacaine corresponding to 50, 100 and 200 mg base were given as 20‐ml gel enemas. Eight of these subjects also received an i.v. infusion corresponding to 20 mg (2H3)ropivacaine base given with the last rectal dose. In study phase 2 (n = 16, single‐blind, crossover) the same rectal doses were given but formulated in 20, 40 and 80 ml gel, respectively. Peripheral venous plasma samples and urine were collected over 12 h after dosing and analysed for ropivacaine base by gas chromatography and (2H3)ropivacaine by gas chromatography‐mass spectrometry. Ropivacaine and metabolites were analysed in urine by reversed phase liquid chromatography.Results  AUC was proportional to the dose with a point estimate [95% confidence interval (CI)] for the increase, after doubling the dose, of 1.91 (1.66–2.20) and 1.95 (1.78–2.13) in study phases 1 and 2, respectively. The increase in Cmax was also proportional to the dose with corresponding results of 1.76 (1.52–2.04) and 1.84 (1.70–1.99). The volume of the rectal formulation had no influence on either the extent or the time course of absorption. The mean (s.d.) absolute bioavailability (%F) was 56 (18)%. AUC and Cmax showed a two‐ to three‐fold lower intra‐ than interindividual variability. Zero‐order kinetics dominated the first 4 h of the absorption phase. Thereafter first‐order kinetics were observed. The terminal half‐lives were similar between the rectal doses and were longer than that after the i.v. administration, indicating an absorption‐dependent half‐life. The main urinary metabolite was 3‐hydroxyropivacaine corresponding to about 23% of the dose. The subjects had no difficulties in retaining the doses and rectal administration of ropivacaine was well tolerated, both locally and systemically.Conclusions  Plasma drug concentrations were proportional to the dose after rectally administered doses corresponding to 50–200 mg ropivacaine base in a gel formulation. The drug was well‐tolerated. Mean bioavailability was about 60% and not influenced by variations in the enema volume. Initial absorption seemed to follow zero‐order kinetics and then first‐order kinetics after about 4 h. Cmax and AUC showed considerably less intra‐ compared with inter‐individual variability, resulting in more consistent plasma concentrations within subjects.
Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients
Authors: Bauer Steffen , Störmer Elke , Johne Andreas , Krüger Hagen , Budde Klemens , Neumayer Hans‐Hellmut , Roots Ivar , Mai Ingrid 
Published: March 2003

Aim This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA).Methods In an open‐label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC.Results After 2 weeks of SJW coadministration, dose‐corrected AUC0−12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63–2.05)], 42%[1.72 (1.42–2.08)], and 41%[1.70 (1.17–2.47)], respectively. CSA doses were increased from a median of 2.7 mg day−1 kg−1 at baseline to 4.2 mg day−1 kg−1 at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose‐corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20–51% and 43–90%, respectively.Conclusion Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug.
Systemic lupus erythematosus with C1q deficiency
Authors: Stone N.M. , Williams A. , Wilkinson J.D. , Bird G. 
Published: March 2003

Abstract
We report a case of systemic lupus erythematosus associated with C1q deficiency. Our patient presented at the age of 6 years with cutaneous lupus. She later developed Raynaud’s phenomenon, non-scarring alopecia, oral ulceration and grand mal seizures due to cerebral vasculitis. Complement C3 and C4 levels were consistently normal during flares of her lupus and haemolytic activity of her complement was absent, suggesting a deficiency of an early component of the complement cascade. No C1q could be detected.
Pseudoscleroderma associated with lung cancer: correlation of collagen type I and connective tissue growth factor gene expression
Authors: Querfeld C. , Sollberg S. , Huerkamp C. , Eckes B. , Krieg T. 
Published: March 2003

Abstract
Pseudoscleroderma as a paraneoplastic syndrome is a rare disease. We report here a patient with lung cancer (undifferentiated squamous cell carcinoma), who developed acrosclerosis. Using in situ hybridization, marked expression of α1(I)-collagen and connective tissue growth factor (CTGF) mRNA was found in fibroblasts scattered throughout the dermis. However, transforming growth factor (TGF)-β1 expression was not detected. The pattern of CTGF gene expression and collagen synthesis was similar to that in systemic scleroderma. The absence of TGF-β1 mRNA could indicate that tumour-derived factors induce the expression of CTGF.
Functional granulocyte/macrophage colony stimulating factor receptor is constitutively expressed on neoplastic plasma cells and mediates tumour cell longevity
Authors: Villunger Andreas , Egle Alexander , Kos Marion , Egle Daniel , Tinhofer Inge , Henn Traudl , Überall Florian , Maly Karl , Greil Richard 
Published: March 2003

It has been shown that granulocyte/macrophage colony stimulating factor (GM‐CSF) is able to support myeloma cell propagation in cooperation with interleukin (IL)‐6, the major growth factor for malignant plasma cells, although the biological mechanisms involved remain unknown. Therefore we investigated (i) the expression levels of the GM‐CSF receptor (GM‐CSFR) constituents in three malignant plasma cell lines and in native malignant plasma cells, (ii) the ability of the receptor to mediate common signalling pathways regulating proliferation and cell survival in malignant plasma cell lines, and (iii) the effects of GM‐CSF on tumour cell biology.The GM‐CSFRα subunit was detected in the malignant plasma cell lines RPMI‐8226, MC/CAR, IM‐9 as well as 6/6 native myeloma cell samples derived from the bone marrow of patients with overt disease. Furthermore, GM‐CSFR expression was also detected in the CD19+ fraction from 2/3 bone marrow samples and 5/8 peripheral blood samples derived from patients with malignant plasma cell disorders, but not in the CD19+ fraction of peripheral blood from healthy donors. The expressed cytokine receptor α‐subunit was able to constitute a functional signalling complex with the ubiquitously expressed GM‐CSFRβ subunit, as demonstrated by the fact that GM‐CSF induced the p21‐ras/mitogen‐activated protein kinase (MAPK) signalling cascade in malignant plasma cell lines. Since this signalling cascade plays an essential role in the mediation of both proliferation and cell survival, we investigated the impact of GM‐CSF on these two events. Application of GM‐CSF led to an increase of DNA‐synthesis in MC/CAR, IM‐9 and RPMI‐8226 cells. Furthermore, it increased longevity of these malignant plasma cell lines by reducing the rates of spontaneous apoptosis. We conclude that (i) the functional GM‐CSFR is commonly expressed on malignant plasma cells and that (ii) GM‐CSF promotes the clonal expansion of myeloma cells by inhibiting spontaneous apoptosis and promoting DNA synthesis.
Low‐dose aspirin does not lower in vivo platelet activation in healthy smokers
Authors: Pernerstorfer  , Stohlawetz  , Stummvoll  , Kapiotis  , Szekeres  , Eichler  , Jilma  
Published: March 2003

Smoking causes atherosclerosis, and smokers have increased thromboxane (TXA2) formation. As aspirin inhibits TXA2 production we speculated that smokers would preferentially profit from inhibition of the TXA2 pathway by aspirin. Increased expression of P‐selectin, a constituent of the alpha‐granules of platelets, and increased levels of circulating (c)P‐selectin in plasma are markers for platelet activation.The aim of this study was to compare P‐selectin expression on platelets between smokers and nonsmokers, and to compare with placebo the effect of 2 weeks administration of 100 mg/d aspirin on platelet activation in smokers. Smokers exhibited higher P‐selectin expression on platelets than non‐smokers (2.7 ± 1.8% v 1.6 ± 0.6%, P = 0.018), thus confirming increased platelet activation. Aspirin did not reduce platelet activation as demonstrated by unchanged P‐selectin expression on platelets and cP‐selectin plasma levels.
Protein Z in healthy human individuals and in patients with a bleeding tendency
Authors: Ravi Subramaniasivam , Mauron Thomas , LÄmmle Bernhard , Wuillemin Walter A. 
Published: March 2003

Protein Z is a vitamin‐K‐dependent plasma glycoprotein; its physiological function is not clear. Low protein Z levels were found in patients with otherwise unexplained bleeding disorders. It was therefore suggested that low protein Z levels might be associated with a bleeding diathesis.In the present study we measured protein Z levels in plasma samples of 48 patients with a suspected bleeding disorder and in plasma samples of 200 healthy adult individuals. We found protein Z to have a wide normal range in healthy men and women. Significantly lower protein Z levels were observed in women compared to men, whereas no correlation was found with age or other vitamin‐K‐dependent coagulation proteins. None of the 48 patients with a bleeding disorder had a protein Z level below the normal range. However, protein Z was significantly lower in the group of male patients with a bleeding history as compared to healthy men.In conclusion, our data indicate that low‐normal protein Z levels are not associated with a bleeding tendency. However, it remains to be determined whether a low protein Z level is a weak cofactor associated with an increased bleeding tendency and whether decreased or absent protein Z (conditions not detected in our patients) might constitute a haemorrhagic diathesis.
Serological evidence of an association between chlamydial infections and malignant lymphomas
Authors: Anttila  , Lehtinen  , Leinonen  , Bloigu  , Koskela  , Lehtinen  , Saikku  
Published: March 2003

Chronic infections may predispose to malignant growth. Recently, serological markers of chronic Chlamydia pneumoniae infection have been associated with lung cancer. Our aim was to study the possible association between chronic chlamydial infections and malignant lymphomas.The present case–control study involved 72 patients with lymphoma (31 females and 41 males) and matched controls. 53 patients had non‐Hodgkin's lymphoma (NHL) and 19 had Hodgkin's disease. The sera, collected at the time of diagnosis, were tested for IgG antibodies and immune complexes to C. pneumoniae and C. trachomatis by a micro‐immunofluorescence method and ELISA and for IgG antibodies and immune complexes to Helicobacter pylori by ELISA.The serological markers suggesting chronic chlamydial infection were associated with malignant lymphoma. The association was most evident for the presence of C. pneumoniae‐specific immune complexes in NHL (OR = 7.3, 95% CI 2.2–25) and appeared to be limited to men. No association between H. pylori antibodies or immune complexes and malignant lymphomas could be demonstrated.Our study provides seroepidemiological evidence of an association between chronic chlamydial infections and lymphomas.
VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide–prednisone therapy (protocol MY 85)
Authors: Mineur  , MÉnard  , LE LOËT  , Bernard  , Grosbois  , Pollet  , Azais  , Laporte  , Doyen  , DE Gramont  , Wetterwald  , Euller‐Ziegler  , Peny  , Monconduit  , Michaux  
Published: March 2003

263 patients (median age 65±10 years) with multiple myeloma were treated with cyclophosphamide– prednisone. Out of this cohort, 103 patients had progressive disease and were randomly assigned to either VAD (vincristine, doxorubicin, dexamethasone; 50 cases) or VMBCP (vincristine, BCNU, cyclophosphamide, melphalan and prednisone; 53 cases). There were no statistical differences between the two groups with the respect to clinical, biological and radiological parameters.There was no difference in survival between the VAD and VMBCP groups. The 4 months response rate was similar in the two groups (50% VAD, 56% VMBCP). With multivariate analysis for survival (Cox model), two factors had a statistically significant impact: Karnofsky index (>60) and albuminaemia (<34 g/l). With both Karnofsky index > 60 and albuminaemia  34 g/l, the median survival was 29 months v 2 months with a Karnofsky index   60 and albuminaemia < 34 g/l (P < 0.05).In conclusion, VAD or VMBCP had similar activity for salvage treatment in MM refractory or relapsing to first‐line treatment with cyclophosphamide–prednisone.
Relationships between severe neonatal thrombocytopenia and maternal characteristics in pregnancies associated with autoimmune thrombocytopenia
Authors: VAlat Anne SYlvie , CAUlier Marie THÉRÈse , Devos Patrick , Rugeri Lucia , Wibaut BÉNÉdicte , Vaast PASCAl , Puech Francis , Bauters Francis , Jude Brigitte 
Published: March 2003

In pregnant women with antecedents of autoimmune thrombocytopenia (AITP), no predictive factor for severe fetal thrombocytopenia has been identified. We evaluated the relationships between the course of the maternal disease before and during pregnancy and the risk of severe fetal thrombocytopenia, in 64 pregnant women with known chronic AITP antecedents, over a 12‐year period. 28 pregnant women had undergone splenectomy before pregnancy and 17 experienced severe thrombocytopenia (< 50 × 109/l) during pregnancy (monthly determination). Eight infants presented with severe thrombocytopenia at birth (12.5%), and four in the following days (6.25%). No severe haemorrhage was observed. Severe thrombocytopenia at birth was present in 57% (CI 95% 18–90%) of the infants born to mothers with severe pregnancy‐associated thrombocytopenia and splenectomy antecedents, and in 0% (CI 95% 0–15%) of the infants born to mothers who presented none of these antecedents (P = 0.001). In thrombocytopenic mothers the infant platelet counts at birth were positively correlated to the nadir maternal platelet count during the index pregnancy (r = 0.42, P = 0.0075).These results suggest that severe autoimmune disease is a risk factor for severe fetal thrombocytopenia, and that pregnant women with no antecedent of splenectomy nor severe thrombocytopenia during pregnancy have a very low risk of severe fetal thrombocytopenia.
Iron status in pregnant women: which measurements are valid?
Authors: Van Den Broek  , Letsky  , White  , Shenkin  
Published: March 2003

Anaemia in pregnancy in developing countries continues to be a public health problem of significant proportion. At least 50% of the anaemia has been blamed on iron deficiency. In populations where chronic inflammation and iron deficiency anaemia coexist, the criteria to accurately define iron status are not always clear. Similarly, in pregnancy, with marked physiological changes, cut‐off points for biochemical parameters need to be re‐examined. In this study we examined the diagnostic accuracy of iron parameters including mean cellular volume (MCV), serum iron, transferrin, total iron binding capacity (TIBC) and its saturation, zinc protoporphyrin (ZPP), ferritin and serum transferrin receptor (TfR) for the assessment of iron status in a population of anaemic pregnant women in Malawi. Stained bone marrow aspirates were used as the standard for comparison.Results show that for the purpose of screening, serum ferritin is the best single indicator of storage iron provided a cut‐off point of 30 μg/l is used. A number of other commonly used parameters of iron status were shown to have limited diagnostic accuracy. Logistic regression was used to obtain mathematical models for the prediction of bone marrow iron status using a combination of available parameters.
The Fyx phenotype is associated with a missense mutation in the Fyb allele predicting Arg89Cys in the Duffy glycoprotein
Authors: Olsson Martin L. , Smythe Jonathan S. , Hansson Carola , Poole Joyce , Mallinson Gary , Jones Jeff , Avent Neil D. , Daniels Geoff 
Published: March 2003

The molecular basis of the three major alleles (Fya/Fyb/Fy) of the Duffy (FY) blood group system has recently been established but the Fyx phenotype associated with weak expression of the Fyb and other FY antigens is poorly understood.In the Fyx genes of five unrelated British and Swedish donors with the Fy(a+b+weak) phenotype we found two missense mutations predicting amino acid changes Arg89Cys and Ala100Thr in the FY glycoprotein.The same mutations were found in two Fy(a−b+weak) samples from individuals of Swedish and Algerian origin. Their red blood cells showed a marked decrease in Fyb, Fy3 and Fy6 expression measured by routine serology and flow cytometry. The rare FY genotypes FyxFyx and FyxFy were confirmed by family studies and DNA sequencing.Screening by allele‐specific primer PCR (ASP‐PCR) for these mutations among 100 Caucasian and 100 Black random blood donors indicated allele frequencies of 2.5% and 0%, respectively. Ala100Thr alone was present in 33% of the Caucasians (but none of the Blacks) with no weakening of FY expression.A novel allele at the FY locus associated with the Fyx phenotype was studied. Mistyping of this weak Fyb antigen in clinical transfusion medicine may lead to delayed haemolytic transfusion reactions in immunized patients. A potential role for genomic typing is proposed.
A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV
Authors: Noris Patrizia , Arbustini Eloisa , Spedini Pierangelo , Belletti Simona , Balduini Carlo Luigi 
Published: March 2003

We describe a new variant of Bernard‐Soulier syndrome characterized by almost normal amounts of GPIb and severely reduced GPIX and GPV. Despite surface expression, GPIbα failed to support ristocetin‐induced platelet agglutination and to bind two conformation‐dependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for GPIX revealed a T‐to‐C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIbα gene. Allele‐specific restriction enzyme analysis showed that the propositus and one of his sisters, both with severe bleeding diathesis, were homozygous for the GPIX mutation; the members of the family with mild bleeding diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele.Infusion of 1‐desamino‐8‐ d‐arginine vasopressin normalized bleeding time in the two severely affected patients, although it did not modify ristocetin‐induced platelet agglutination or membrane expression of GPIbα, GPIX, GPIIb–IIIa and GMP‐140. Moreover, in one patient, normalization of bleeding time and rise of von Willebrand factor plasma concentration did not seem to be directly related.