bluuebunny/crossref_metadata_2025_split huggingface dataset:
A placebo‐controlled study of retinal blood flow changes by pentoxifylline and metabolites in humans
Authors: Magnusson Marie , Bergstrand Ingar C. , Björkman Sven , Heijl Anders , Roth Bodil , Höglund Peter 
Published: December 2005

AimTo investigate the possible effects of pentoxifylline metabolites on retinal blood flow in humans.MethodsA randomized, placebo‐controlled, four‐period cross‐over study that was observer blinded and partly blinded for the eight participants. On one occasion a placebo was given as an intravenous (i.v.) infusion over 100 min. On the other three occasions pentoxifylline was administered as i.v. infusions over 100 min at a rate of 3 mg min−1. Before two of the pentoxifylline infusions the subjects were pretreated with either ciprofloxacin or rifampicin. Retinal blood flow was measured by scanning laser doppler flowmetry (SLDF) in a selected area of the central temporal retina before, during and until 5 h after the end of infusion. Blood samples for concentration analyses of pentoxifyllin, R‐M1, S‐M1, M4 and M5 were taken serially and areas under the curves (AUCs) were calculated. Linear mixed models were used for the statistical analyses.ResultsMean AUCs (ng h ml−1) were significantly increased for pentoxifylline (1964 vs. 1453) and S‐M1 (5804 vs. 4227), but not R‐M1 when pentoxifylline was co‐administered with ciprofloxacin. The mean AUC for M5 was significantly reduced when subjects were pretreated with rifampicin (2041 vs. 3080). Pentoxifylline with and without pretreatment with rifampicin significantly increased retinal blood flow assessed as mean flow, pulsation (i.e. 1‐systole/diastole), and diastolic flow (but not during systole), compared with placebo. The increases over placebo were more pronounced on diastolic flow, 9.7% (95% confidence interval 4.2, 15.5) than on mean flow, 4.6% (1.1, 8.3) after pentoxifylline administration. With pentoxifylline after rifampicin pretreatment the corresponding differences were 11.7% (5.8, 17.9) and 5.1% (1.4, 7.8) over placebo, respectively. After co‐administration of pentoxifylline and ciprofloxacin we saw only a nonsignificant trend towards increased flow during diastole, but a significant decrease in pulsation. When AUCs for pentoxifylline and its metabolites were used as regressor variables to retinal mean flow we found that pentoxifylline, R‐M1 and M5 had coefficients with a positive sign indicating that they enhanced the retinal blood flow. In contrast, S‐M1 and M4 had coefficients with negative sign and thus appeared to decrease the blood flow in subjects treated with pentoxifylline.ConclusionThe R‐M1 and M5 metabolites of pentoxifylline contributed significantly to the effects of pentoxifylline on retinal blood flow.
Tadalafil pharmacokinetics in healthy subjects
Authors: Forgue S. Thomas , Patterson Beverley E. , Bedding Alun W. , Payne Christopher D. , Phillips Diane L. , Wrishko Rebecca E. , Mitchell Malcolm I. 
Published: December 2005

AimsTo characterize tadalafil plasma pharmacokinetics in healthy subjects following single and multiple doses.MethodsNoncompartmental parameters were calculated for healthy subjects receiving a single 2.5–20‐mg tadalafil dose in 13 clinical pharmacology studies. An integrated statistical analysis of results in 237 subjects provided global averages and an assessment of effects of body mass index (BMI), age, gender and smoking status. Diurnal variation, food effects and proportionality of exposure to dose were analysed in three studies. Multiple‐dose pharmacokinetics were evaluated in a separate study in which parallel groups of 15 subjects received 10 or 20 mg tadalafil once daily for 10 days.ResultsTadalafil was absorbed rapidly with mean Cmax (378 µg l−1 for 20 mg) observed at 2 h; thereafter, concentrations declined nearly monoexponentially with a mean (5th, 95th percentiles) t1/2 of 17.5 (11.5, 29.6) hours. Mean oral clearance (CL/F) was 2.48 (1.35, 4.35) l h−1 and apparent volume of distribution (Vz/F) was 62.6 (39.5, 92.1) l. No clinically meaningful effect of BMI, age, gender or smoking was identified. Exposure was not substantially affected by time of dosing. Food had negligible effects on bioavailability as assessed by 90% confidence intervals for Cmax and AUC mean ratios. Parameters were proportional to dose, indicating that doubling the dose doubled exposure. Steady state was attained by day 5 following once‐daily administration, and accumulation (1.6‐fold) was consistent with the t1/2.ConclusionsTadalafil pharmacokinetics are linear with respect to dose and time, and are not affected by food. Systemic clearance is low relative to other phosphodiesterase 5 inhibitors.
Reduction of oxidative stress and modulation of autoantibodies against modified low‐density lipoprotein after rosuvastatin therapy
Authors: Resch Ulrike , Tatzber Franz , Budinsky Alexandra , Sinzinger Helmut 
Published: December 2005

AimsTo examine the effect of 24 weeks’ rosuvastatin treatment on oxidative stress and changes in immune response to oxidized low‐density lipoprotein (LDL).MethodsThis was an open‐label study of patients in Austria receiving 10 or 40 mg rosuvastatin daily alternately during 12 and 24 weeks. Circulating concentrations of antibodies to malondialdehyde‐oxidized LDL (MDA‐LDL), both IgG and IgM type, to copper‐oxidized LDL (Cu‐OxLDL‐IgG), concentrations of oxidized LDL complexed to IgG (OxLDL‐IC) and markers of oxidative stress and systemic inflammation in subjects with plasma LDL cholesterol concentrations between 130 mg dl−1 and 250 mg dl−1 and triglycerides ≤ 400 mg dl−1 were determined.ResultsDuring statin therapy, plasma endogenous peroxides (POX‐ACT) concentrations and peroxidase activity were significantly decreased, associated with a modest increase in total antioxidant capacity (TAC). Antibody titres to MDA‐LDL‐IgM, Cu‐OxLDL‐IgG and OxLDL‐IC decreased, whereas MDA‐LDL‐IgG concentrations were increased after therapy. These changes were dose‐ and LDL‐independent. POX‐ACT concentrations were significantly positively correlated with inflammation markers before and after therapy and inversely with high‐density lipoprotein‐cholesterol concentrations after therapy.ConclusionThis study provides in vivo evidence that rosuvastatin significantly reduces oxidative stress and has immunomodulatory properties in a dose‐ and LDL‐independent manner.
Initial phase of chronic medication use; patients’ reasons for discontinuation
Authors: Hugtenburg J. G. , Blom A. Th. G. , Kisoensingh S. U. 
Published: December 2005

Aim The aim of this study was to gain more insight into patients’ reasons for discontinuing chronic medication.Methods Electronic medication overviews recorded by a pharmacy were analysed with respect to patients’ return behaviour during 3 months following their first prescription. Patients who did not return in time were interviewed by telephone to find out their reasons for either returning too late or not returning at all to the pharmacy to collect their repeat medication.Results Of 232 first‐time chronic medication prescriptions, 132 were not collected at all (46.1%) or too late (11%). These prescriptions involved 121 patients, 113 (93.4%) of whom participated in the telephone interview. Twenty patients returned too late to collect their repeat prescriptions, largely because they had forgotten to take their medication according to schedule (n = 13). Ninety‐three patients did not return to the pharmacy at all because of side‐effects (24.5%), inefficacy (16.4%), medication not intended for chronic use (15.3%) and absence of need for continued use (14.3%).Conclusions About 50% of patients who have been prescribed chronic medication for the first time stop using their drugs within a matter of months. Perceived drug side‐effects, drug ineffectiveness and personal considerations related to use and a lack of need of treatment were the main reasons for discontinuing chronic drug therapy. This kind of noncompliance may result in an increased health risk as well as constituting a waste of a large amount of money. Adequate patient counselling and shared decision‐making between doctors and patients are needed to prevent the unnecessary cessation of chronic drug therapy.
The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia
Authors: Davies Benjamin J. , Coller Janet K. , James Heather M. , Somogyi Andrew A. , Horowitz John D. , Sallustio Benedetta C. 
Published: December 2005

AimsCYP2D6 protein expression is determined by the number of functional CYP2D6 alleles. It is also higher in individuals with at least one CYP2D6*2 allele. This study has investigated the effect of the number of functional CYP2D6 alleles and the influence of CYP2D6*2 alleles on plasma perhexiline concentrations in patients administered a standard loading regimen over 3 days.MethodsEighteen patients with myocardial ischaemia who were not taking any drugs known to inhibit CYP2D6 metabolism in vivo commenced treatment with 200 mg of perhexiline twice per day. On the fourth day, blood was drawn for genotyping and the measurement of trough plasma concentrations of perhexiline and its major metabolite, cis‐OH‐perhexiline.ResultsThe only genotypic CYP2D6 poor metabolizer had a trough plasma perhexiline concentration of 2.70 mg l−1 and no detectable cis‐OH‐perhexiline. The mean ± SD trough plasma perhexiline concentration in patients with one functional allele was significantly higher (0.63 ± 0.31 mg l−1, n = 8, P = 0.05) than in patients with two functional alleles (0.37 ± 0.17 mg l−1, n = 9). Conversely, the mean metabolic ratio was significantly lower in patients with one functional allele (2.90 ± 1.76, P < 0.01) compared with patients with two functional alleles (6.52 ± 3.26). Patients with at least one CYP2D6*2 allele had a lower plasma perhexiline concentration (0.20 ± 0.09 mg l−1, n = 5, P < 0.001) and a higher metabolic ratio (7.86 ± 2.51, P < 0.01) than the non‐poor metabolizer patients with no CYP2D6*2 alleles (0.62 ± 0.23 mg l−1 and 3.55 ± 2.54, respectively, n = 12).ConclusionPatients with only one functional allele and not CYP2D6*2 have diminished CYP2D6 metabolic capacity for perhexiline.
Curriculum development in pharmacotherapy: testing the ability of preclinical medical students to learn therapeutic problem solving in a randomized controlled trial
Authors: Vollebregt J. A. , Metz J. C. M. , De Haan M. , Richir M. C. , Hugtenburg J. G. , De Vries T. P. G. M. 
Published: December 2005

AimsTo determine whether preclinical medical students are able to learn therapeutic problem solving simultaneously with gaining knowledge of pharmacology.MethodsA randomized controlled pre/post‐test study among 85 3rd year preclinical medical students from two medical faculties in Amsterdam. In addition to the normal curriculum, the study group followed a course, which was a copy of the obligatory training in cognitive therapeutic skills for 5th year students who had gained knowledge first, followed by applying the knowledge. Before, immediately after and 9 months after the training both the study group and a control group took a test (T0, T1, T2). The level of knowledge and cognitive therapeutic skills were assessed. As a reference, 38 5th year students also took the tests.ResultsOn T0 the levels of cognitive therapeutic skills of the study and control groups were similar (26.7% and 27.4% of the required level for graduation, respectively). On T1 and T2, the study group scored significantly higher compared with the control group: 46.0/36.7% and 41.3/36.3%, respectively (P < 0.05). In comparison with T0, the scores of the study group on T1 increased significantly and showed no significant decline on T2. There were no differences between the groups with respect to the level of knowledge in any of the three tests. The level of cognitive therapeutic skills in the 5th year reference group increased slightly but not significantly from 40.3% to 44.5% after the training; the level of knowledge increased significantly from 48.8% to 68.0%.ConclusionsPreclinical medical students are able to learn cognitive therapeutic skills simultaneously with gaining knowledge of pharmacology.
Low incidence of hypertensive disorders of pregnancy in women treated with spiramycin for toxoplasma infection
Authors: Todros T. , Verdiglione P. , Oggè G. , Paladini D. , Vergani P. , Cardaropoli S. 
Published: December 2005

AimsToxoplasma infection in pregnancy is usually treated with long‐term administration of the macrolide spiramycin to prevent fetal malformations. We had empirically observed that treated patients seldom developed pregnancy‐induced hypertension (PIH), a common and severe disorder of pregnancy whose aetiology and pathogenesis are still debated. Some clinical and experimental data suggest that infection could play a role in its development.MethodsTo test this hypothesis, we studied a cohort of 417 pregnant women treated with spiramycin because of seroconversion for Toxoplasma gondii and 353 low‐risk women who did not take any antibiotic during pregnancy. PIH was defined as blood pressure >140/90 mmHg on two or more occasions, occurring after 20 weeks of gestational age.ResultsSeventeen (5.2%) women in the control group developed PIH compared with two (0.5%) in the case group. The odds of developing the disease were significantly lower in the treated subjects (odds ratio = 0.092, 95% confidence interval 0.021, 0.399; P < 0.001).ConclusionsOur results suggest that antibiotic treatment during pregnancy can reduce the incidence of PIH, thus opening new perspectives in its prevention and therapy.
Differentialin vitroinhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids
Authors: Morrish Glynn A. , Foster David J. R. , Somogyi Andrew A. 
Published: December 2005

AimsTo determine thein vitrokinetics of morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids.MethodsM3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µm) and the mechanism of inhibition determined for (R)‐ and (S)‐methadone (70–500 µm) using three microsomal samples.ResultsGlucuronide formation displayed single enzyme kinetics. The M3GVmax(mean ± SD) was 4.8‐fold greater than M6GVmax(555 ± 110vs.115 ± 19 nmol mg−1protein h−1;P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg−1protein h−1).Kmvalues for M3G and M6G formation were not significantly different (1.12 ± 0.37vs.1.11 ± 0.31 mm;P = 0.89, 0.02; − 0.29, 0.32 mm). M3G and M6G formation was inhibited (P < 0.01) with a significant increase in the M3G/M6G ratio (P < 0.01) for all compounds tested. Detailed analysis with (R)‐ and (S)‐methadone revealed noncompetitive inhibition with (R)‐methadoneKiof 320 ± 42 µmand 192 ± 12 µmfor M3G and M6G, respectively, and (S)‐methadoneKiof 226 ± 30 µmand 152 ± 20 µmfor M3G and M6G, respectively.Kivalues for M3G inhibition were significantly greater than for M6G for (R)‐methadone (P = 0.017, 128; 55, 202 µm) and (S)‐methadone (P = 0.026, 75; 22, 128 µm).ConclusionsBoth methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadone‐maintained patients and reduced relative formation of the opioid active M6G compared with M3G.
A randomised control trial of patient self‐management of oral anticoagulation compared with patient self‐testing
Authors: Gardiner Chris , Williams Karen , Longair Ian , Mackie Ian J. , Machin Samuel J. , Cohen Hannah 
Published: December 2005

SummarySeveral studies suggest that patient self‐management (PSM) may improve the quality of oral anticoagulation therapy as measured by time spent within the international normalised ratio (INR) target range. We performed a prospective randomised control trial to determine whether the improvement in quality of treatment afforded by PSM is greater than that achieved by patient self‐testing (PST) alone. A total of 104 of 800 eligible patients aged 22–88 years (median = 59·8), attending our hospital anticoagulant clinic and receiving long‐term warfarin for >8 months agreed to participate. Patients were randomised to PSM (n = 55) or PST (n = 49). Both groups measured their INR using the CoaguChek S every 2 weeks or more frequently if required, for a period of 6 months. Seventy‐seven of 104 (74%) patients completed the study (PSM = 41 and PST = 36). The ‘drop out’ rates for both groups were similar. There was no significant difference between the percentage time in target therapeutic range for PSM (69·9%) and PST (71·8%). Both groups combined showed a significant improvement over the previous 6 months (71·0% vs. 62·5%; P = 0·04). Changes in time within the therapeutic range in individual patients (+5·86) also showed a significant difference. The quality of warfarin control in both PST and PSM may be superior to that achieved by conventional management in a specialised hospital anticoagulation clinic.
Increased levels of soluble flt‐3 ligand in serum and long‐term bone marrow culture supernatants in patients with chronic idiopathic neutropenia
Authors: Papadaki Helen A. , Damianaki Athina , Pontikoglou Charalampos , Pyrovolaki Katerina , Eliopoulos Dimitris G. , Stavroulaki Emily , Eliopoulos George D. 
Published: December 2005

AbstractThe levels of serum and long‐term bone marrow culture supernatant soluble flt‐3 ligand (sFL) were determined in 54 patients with chronic idiopathic neutropenia (CIN) and 16 normal controls. Both serum and supernatant sFL levels were significantly increased in the patients compared with controls. Individual sFL values inversely correlated with the number of circulating neutrophils and the proportion of bone marrow CD34+ cells. Supernatant sFL values positively correlated with the levels of supernatant G‐CSF. These findings suggest that the impaired myelopoiesis in CIN patients is accompanied by a compensatory mechanism attempting to increase the neutrophil production at the myeloid progenitor cell level.
Analysis of immunoglobulin VH genes suggests cutaneous marginal zone B‐cell lymphomas recognise similar antigens
Authors: Bahler David W. , Kim Bong K. , Gao Aili , Swerdlow Steven H. 
Published: December 2005

SummaryExtranodal marginal zone B‐cell lymphomas (EMZL) are thought to develop from reactive infiltrates that represent immune responses to external or auto‐antigens. Except for gastric EMZL, the antigenic triggers of EMZL development are mostly unknown, although a subset of cutaneous EMZL have been associated with Borrelia burgdorferi infections. To further evaluate whether a common antigen may be promoting the development of cutaneous EMZL, the immunoglobulin heavy chain variable (VH) genes from eight USA cases were sequenced and analysed. All used VH3 family gene segments, with 2/8 using the same V3–30 segment, 2/8 using the closely related V3–30·3 or V3–33 segments, 6/8 containing mutations and 2/7 showing evidence of ongoing mutation. Many of the complimentarity‐determining region 3s (CDR3s) also showed similarities in length and displayed conserved amino acid motifs in the non‐templated areas between the diversity and joining segments. The use of similar VH gene segments and conserved CDR3 amino acid motifs suggests that some of these cutaneous EMZL may bind the same or similar antigen via their surface immunoglobulin receptor. Analysis of the somatic mutations present in many of the VH genes was also consistent with antigen directly stimulating the growth of cutaneous EMZL.
Correction of severe anaemia using immuno‐regulated gene therapy is achieved by restoring the early erythroblast compartment
Authors: Du  Roure Camille , Takács Katalin , Maxwell Patrick H. , Roberts Irene , Dazzi Francesco , Cannella Laura , Merkenschlager Matthias , Fisher Amanda G. 
Published: December 2005

SummaryPatients with chronic renal failure usually require exogenous erythropoietin (epo) to alleviate anaemia resulting from inadequate epo production by the kidneys. We have recently shown that severe anaemia in genetically manipulated epo‐deficient mice (EpoTAg) can be corrected by adoptively transferred epo‐producing lymphocytes. The aim of this study was to investigate the precise effects of human epo administration by this route on erythropoietic development in epo‐deficient mice. The erythroblast compartments of untreated and treated EpoTAg mice were analysed in comparison with wild‐type mice. The early erythroblast population was reduced in the bone marrow of epo‐deficient mice, whilst the number of erythroid colony‐forming units (CFU‐E) was not significantly compromised. This paucity in marrow early erythroblasts was restored to normal values in treated mutant mice. In addition, the early erythroblast population was expanded in the spleens of treated animals. These findings show that the early erythroblasts are important targets of epo and that epo corrects anaemia of epo‐deficient mice by restoring marrow function and splenic erythropoiesis.
Treatment for myeloid leukaemia of Down syndrome: population‐based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials
Authors: Rao Anupama , Hills Robert K. , Stiller Charles , Gibson Brenda E. , de Graaf Siebold S.N. , Hann Ian M. , O'Marcaigh Aengus , Wheatley Keith , Webb David K.H. 
Published: December 2005

SummaryDown syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population‐based data on 81 children with myeloid leukaemia of Down syndrome (ML‐DS) from the UK National Registry of Childhood Tumours and experience in the Medical Research Council (MRC) AML 10 and AML 12 trials, which enrolled 46 children with ML‐DS from 1988 to 2002. Eight per cent of UK children with AML had DS, but DS children comprised only 5% of children registered in MRC trials. The unique clinical characteristics of ML‐DS were confirmed. Overall survival (OS) of ML‐DS at 5 years increased from 47% in UK children diagnosed from 1988 to 1995 to 75% in children diagnosed from 1996 to 2002. OS for DS children registered in AML 10 and AML 12 was 74% in 5 years and improved from AML 10 to AML 12 (56% vs. 83%) There was no significant difference in OS between DS and non‐DS children (OS: 74% vs. 62%, P = 0·4) in the trials, but this result masked a significant increase in early death amongst DS children, with a significant reduction in mortality later on. Relapse was significantly reduced (3% vs. 39%, P = 0·0003), leading to the improved disease‐free survival (83% vs. 56%, P = 0·02). Given the increased number of earl treatment‐related deaths, future treatment protocols should aim to reduce chemotherapy dosage or intensity whilst maintaining low rates of resistant and recurrent disease.