bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of the relative bioavailability of salbutamol to the lungs and systemic circulation following nebulization
Authors: Silkstone V. L. , Corlett S. A. , Chrystyn H. 
Published: March 2003

Aims  Clinical studies comparing nebulized drug delivery systems could be flawed because of the high doses used. We have compared lung and total systemic delivery of salbutamol from a nebuliser with that from a metered dose inhaler by measuring urinary recovery of drug and its sulphate metabolite.Methods  Twelve healthy volunteers provided urine samples at 0, 0.5, 1, 2, 4, 8, 12 and 24 h after the start of dosing. Formulations and doses were 5×100 µg oral solution (ORAL), 5×100 µg from a metered dose inhaler (MDI), 2.5 mg using a nebuliser (NEB) and NEB with 25 g oral charcoal (NEBC). Each study phase was separated by 7 days and the order of dosing was randomized.Results  Mean (s.d.) 30 min urinary salbutamol excretion after ORAL, MDI, NEB and NEBC was 0.4 (0.7), 12.1 (3.7), 15.0 (3.9) and 18.2 (5.7) µg, respectively (all P<0.001 compared with ORAL). When normalized for the dose available for inhalation from MDI, NEB and NEBC, the mean (s.d.) 30 min urinary excretion of salbutamol was 2.4 (0.7), 2.9 (0.6) and 2.7 (0.6)%, respectively, with a mean ratio (90% confidence interval) between NEB and NEBC, of 95.3 (91.1, 99.5)%. The mean (s.d.) excretion of salbutamol plus its metabolite over 24 h post ORAL, MDI, NEB and NEBC dosing was 297.9 (38.3), 290.3 (41.4), 266.5 (44.6) and 151.7 (40.9) µg, respectively. The mean ratio (90% confidence interval) between MDI and ORAL, and NEB and ORAL were 97.5 (94.1, 101.0) and 90.7 (81.2, 100.2)%, respectively. The NEBC data indicate that 6.07 (1.04)% of the nominal nebulized dose was delivered to the lungs.Conclusions  The 30 min urinary recovery of salbutamol, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the lung deposition of nebulized systems. Similarly, the urinary 24 h recovery of salbutamol plus its metabolite, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the delivery of nebulized drug to the systemic circulation.
Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human
Authors: Zhang Mei , Fawcett J. Paul , Shaw John P. 
Published: March 2003

Aims
Formoterol is an inhaled β2‐adrenoceptor agonist used as a racemic mixture of the active (R; R)‐ and inactive (S; S)‐enantiomers (rac‐formoterol). Glucuronidation is an important route of metabolism in humans which occurs faster for (S; S)‐formoterol in human liver microsomes. The aim of this study was to investigate the stereoselectivity of urinary excretion of formoterol and its glucuronide conjugate after oral dosing with rac‐formoterol.
Methods
Seven nonsmoking volunteers (six males, one female) were included in the study. After an overnight fast, a single 60 µg oral dose of rac‐formoterol fumarate dihydrate was ingested. Urine samples were collected at 1 h intervals for the first 4 h, and at 6, 8, 12 and 24 h after dosing. Formoterol enantiomers were analysed by chiral h.p.l.c. assay and formoterol glucuronides were determined as formoterol enantiomers after enzymatic cleavage with β‐glucuronidase.
Results
The female subject displayed a different pattern of metabolism and statistical analysis was therefore limited to data for the six males. The median (range) of the total urinary excretion of formoterol was 37.8% (20.9–51.2%) of the dose. The medians (ranges) of the amounts of (R; R)‐ and (S; S)‐formoterol and of (R; R)‐ and (S; S)‐formoterol glucuronide excreted were 2.1 (1.0–2.9), 3.5 (2.6–3.8), 21.0 (13.1–31.0) and 10.3 (4.2–14.6)%, respectively, of the dose. Unchanged (S; S)‐formoterol excretion was significantly greater than that of unchanged (R; R)‐formoterol and (R; R)‐formoterol glucuronide excretion was significantly greater than that of (S; S)‐formoterol glucuronide. The total RR‐formoterol (unchanged drug plus glucuronide) excreted was significantly greater than the total (S; S)‐formoterol.
Conclusions
Our study demonstrates that the urinary excretion of formoterol in male humans after oral administration of rac‐formoterol is stereoselective with preferential excretion of the active (R; R)‐formoterol as unchanged drug and glucuronide. The different pattern of metabolism in the female subject provides impetus for further studies of the effect of gender on the stereoselective metabolism and pharmacokinetics of formoterol.
Repeatability of local forearm vasoconstriction to endothelin‐1 measured by venous occlusion plethysmography
Authors: Strachan Fiona E. , Newby David E. , Sciberras David G. , McCrea Jacqueline B. , Goldberg Michael R. , Webb David J. 
Published: March 2003

Aims
We  investigated  the  repeatability  of  the  forearm  blood  flow  response  to intra‐arterial infusion of endothelin‐1 (ET‐1), assessed by venous occlusion ­plethysmography.
Methods
In eight healthy men (aged 18–50 years), on four separate occasions, ET‐1 (2.5 or 10 pmol min−1) was infused for 120 min via a 27 SWG cannula sited in the brachial artery of the nondominant arm. Each dose level was administered twice on consecutive visits. The dose order was randomized. Results are expressed as percentage change from baseline at 120 min (mean ± s.e. mean).
Results
ET‐1 caused significant vasoconstriction (P < 0.0001 anova) at both doses (38 ± 3%, 2.5 pmol min−1 and 62 ± 3%, 10 pmol min−1; mean visit 1 and 2). There was no difference in the response to either dose on repeated challenge. Responses appeared to be less variable when expressed as percentage change in the ratio of blood flow (infused:noninfused) in both arms than as percentage change in blood flow in the infused arm alone, as indicated by repeatability coefficients (15% vs 21%, 2.5 pmol min−1 and 11% vs 13%, 10 pmol min−1; ratio vs infused arm alone).
Conclusions
We have shown dose‐dependent vasoconstriction in the forearm vascular bed to intra‐arterial infusion of ET‐1 and that this response is less variable when expressed as percentage change in the ratio of forearm blood flow than percentage change in the infused arm. These data should also provide useful information to determine the power of early clinical pharmacology studies investigating the activity of endothelin receptor antagonists.
Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administration
Authors: Corey Alfred E. , Agnew Jeffrey R. , Valentine Suzanne N. , Parekh Nikhil J. , Powell James H. , Thompson Gary A. 
Published: March 2003

Aims To assess the influence of severe renal impairment on azimilide pharmacokinetics.Methods A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22–28 and 10 days, respectively.Results Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h−1 kg−1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h−1 kg−1, 95% confidence interval on the ratio 0.67, 1.36) was observed.Conclusions Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.
Comparative study of analgesic efficacy and morphine‐sparing effect of intramuscular dexketoprofen trometamol with ketoprofen or placebo after major orthopaedic surgery
Authors: Hanna M. H. , Elliott K. M. , Stuart‐Taylor M. E. , Roberts D. R. , Buggy D. , Arthurs G. J. 
Published: March 2003

Aims Multimodal analgesia is thought to produce balanced and effective postoperative pain control. A combined therapy with nonsteroidal anti‐inflammatory drugs (NSAIDs) and opiates could result in synergistic analgesia by acting through different mechanisms. Currently there are very few parenterally administered NSAIDs suitable for the immediate postoperative period. Therefore, this study was undertaken to assess the analgesic efficacy, relative potency, and safety of parenteral dexketoprofen trometamol following major orthopaedic surgery.Methods One hundred and seventy‐two patients elected for prosthetic surgery, were randomized to receive two intramuscular injections (12 hourly) of either dexketoprofen 50 mg, ketoprofen 100 mg or placebo in a double‐blind fashion. Postoperatively, the patient's pain was stabilized, then they were connected to a patient‐ controlled analgesia system (PCA) of morphine for 24 h (1 mg with 5 min lockout).Results The mean cumulative amount of morphine (CAM) used was of 39 mg in the dexketoprofen group and 45 mg in the ketoprofen group vs 64 mg in the placebo group. (Reduction in morphine use was approximately one‐third between the active compounds compared with placebo (adjusted mean difference of −25 mg between dexketoprofen and placebo and −23 mg between ketoprofen and placebo. These differences were statistically significant: P ≤ 0.0003; 95% CI −35, −14. Pain‐intensity scores were consistently lower with the active compounds, the lowest corresponded to the dexketoprofen‐treated patients. Regarding sedation, there were statistically significant differences between the two active compounds and placebo only at the 2nd and 13th hours. Wound bleeding was specifically measured with no statistically significant differences found between all the groups.Conclusions Intramuscular administration of dexketoprofen trometamol 50 mg has good analgesic efficacy both in terms of opioid‐sparing effect and control of pain after major orthopaedic surgery.
A population‐based study of maternal use of amoxicillin and pregnancy outcome in Denmark
Authors: Jepsen Peter , Skriver Mette V. , Floyd Andrea , Lipworth Loren , Schønheyder Henrik C. , Sørensen Henrik T. 
Published: March 2003

Aims Amoxicillin is a widely used penicillin, but data on its safety in pregnancy are limited. We examined the association between amoxicillin exposure during pregnancy and birth weight, preterm delivery, congenital malformations, perinatal death, and spontaneous abortion.Methods We identified all primiparous women with a live birth, or a stillbirth after the 28th gestational week, from 1 January 1991–31 December 2000 in the County of North Jutland, Denmark. Data on prescriptions for amoxicillin and outcome were obtained from population‐based registries. Using a follow‐up and a case–control design, we compared pregnancy outcomes between women who had been prescribed amoxicillin during pregnancy and those who had not, adjusting for available potentially confounding factors.Results We identified 401 primiparous women who redeemed a prescription for amoxicillin during their pregnancy. The control group consisted of 10 237 primiparous women who did not redeem any prescriptions from 3 months before pregnancy until the end of pregnancy. The adjusted mean birth weight of children born to amoxicillin‐exposed mothers was 57 g [95% confidence interval (CI) 9, 105] higher than that of children born to controls. Odds ratios among amoxicillin‐exposed relative to controls were: low birth weight 0.63 (95% CI 0.26, 1.53), preterm delivery 0.77 (95% CI 0.49, 1.21), congenital malformation 1.16 (95% CI 0.54, 2.50), and spontaneous abortion 0.89 (95% CI 0.66, 1.18). We did not observe any cases of perinatal death in the amoxicillin‐exposed women.Conclusions We did not find any increased risk of adverse pregnancy outcome associated with amoxicillin exposure during pregnancy, but additional studies are warranted.
Differential effects of carvedilol and atenolol on plasma noradrenaline during exercise in humans
Authors: Herman Rahmatina B. , Jesudason Peter J. , Mustafa Ali M. , Husain Ruby , Choy Anna Maria J. , Lang Chim C. 
Published: March 2003

Aims Evidence of long‐term beneficial effects of β‐blockers on mortality and morbidity in patients with heart failure has been demonstrated in recent randomized trials. However, not all β‐blockers are identical. Carvedilol, a nonselective β‐ and α‐adrenergic blocker, can potentially blunt the release of noradrenaline by blocking presynaptic β2‐adrenergic receptors. To test this hypothesis, we have compared the effects of carvedilol and atenolol on plasma noradrenaline during exercise in healthy young volunteers.Methods This study investigated the differential effects of 2 weeks pretreatment with carvedilol 25 mg day−1 and atenolol 50 mg day−1 on plasma noradrenaline at rest and during exercise on a treadmill in a double‐blind randomized crossover study, involving 12 healthy male volunteers (mean age 21.6 ± 0.3 years).Results Haemodynamic parameters at rest and during exercise were not significantly different in either carvedilol or atenolol pretreatment groups. However, carvedilol pretreatment significantly blunted the increase in plasma noradrenaline during exercise [393.8 ± 51.7 pg ml−1 (pretreatment) to 259.7 ± 21.2 pg ml−1 (post‐treatment)], when compared with atenolol [340.4 ± 54.6 pg ml−1 (pretreatment) to 396.2 ± 32.0 pg ml−1 (post‐treatment)]. The difference between carvedilol and atenolol (95% confidence interval) was −145.2, −351.0, P < 0.05.Conclusions We have demonstrated that carvedilol but not atenolol significantly blunted the increase in plasma noradrenaline during exercise. These findings may suggest a sympathoinhibitory effect of carvedilol that may enhance its ability to attenuate the cardiotoxicity associated with adrenergic stimulation in patients with heart failure.
Regressing Merkel cell carcinoma—a case showing replacement of tumour cells by foamy cells
Authors: Maruo K. , Kayashima K-I. , Ono T. 
Published: March 2003

Abstract
Merkel cell carcinoma (MCC) is a malignant neuroendocrine tumour with a high rate of recurrence and metastasis. However, some cases of spontaneous regression have recently been reported. We describe the clinical course of an 80-year-old Japanese woman with regressing MCC. We also report histological findings of the regressing tumour for the first time. After the patient’s first visit to our hospital, the lesion was a rapidly progressive tumour, but suddenly began decreasing in size, and rapidly regressed. The surface of the tumour flattened, the colour changed from red to dark red, and finally the lesion appeared as a small yellowish plaque. Histopathological analysis of the completely regressed tumour revealed that the tumour cells were completely replaced by numerous foamy cells. This is the first report demonstrating the histopathological features of regressing MCC.
Thrombopoietin serum levels in patients with aplastic anaemia: correlation with platelet count and persistent elevation in remission
Authors: Schrezenmeier Hubert , Griesshammer Martin , Hornkohl Alex , Nichol Janet L. , Hecht Thomas , Heimpel Herrmann , Kubanek Bernhard , Raghavachar Aruna 
Published: March 2003

In an attempt to evaluate the role of thrombopoietin (TPO) in the pathobiology of aplastic anaemia (AA), we have examined TPO levels in sera from 54 AA patients and 119 healthy controls. A total of 92 samples were collected from AA patients: 43 samples were harvested at diagnosis, 23 samples in the cytopenic period after treatment, and 26 samples when patients were in partial (n = 10) or complete remission (n = 16) following immunosuppressive treatment. TPO serum levels were assessed by a sandwich‐antibody ELISA that utilized a polyclonal rabbit antiserum for both capture and signal. Serum samples from normal donors revealed a mean TPO level of 95.3 ± 54.0 pg/ml (standard deviation). Mean TPO levels in AA sera collected at diagnosis and before onset of treatment were 2728 ± 1074 pg/ml (P < 0.001 compared to normal controls; mean platelet count at that time: 27 × 109/l). TPO serum levels of AA patients in partial or complete remission after immunosuppressive treatment were significantly lower than TPO levels at diagnosis (P < 0.001). However, despite normal platelet counts (mean 167 × 109/l), TPO levels remained significantly elevated in complete remission (mean TPO 1009 ± 590 pg/ml, P < 0.001 compared to normal controls). There was a significant inverse correlation between serum TPO levels and platelet counts in AA patients who were not transfused for at least 2 weeks prior to sample collection (coefficient of correlation (r) = −0.70, P < 0.0001).In summary, TPO levels were highly elevated in sera of patients with AA. Thus there is no evidence to suggest an impaired TPO response contributing to thrombocytopenia in AA. Thrombopoietin did not return to normal levels in remission, indicating a persisting haemopoietic defect in remission of AA. We hypothesize that elevated levels of TPO may be required to maintain normal or near normal platelet counts in remission of AA.
Secondary haematological neoplasm after treatment of adult acute lymphoblastic leukaemia: analysis of 1170 adult ALL patients enrolled in the GIMEMA trials
Authors: Pagano Livio , Annino Luciana , Ferrari Antonella , Camera Andrea , Martino Bruno , Montillo Marco , Tosti Maria Elena , Mele Alfonso , Pulsoni Alessandro , Vegna Maria Luce , Leone Giuseppe , Mandelli Franco ,   for the GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto) Group
Published: March 2003

Between 1983 and 1994 the incidence of secondary haematological neoplasms (SHM) was evaluated in 1170 new cases of ALL enrolled in the GIMEMA trials. Of the 942 patients who achieved complete remission (CR); seven developed a SHM: four AMLs and three NHLs.The median latency from onset of ALL and of secondary haematological neoplasm was 69 months for AML and 61 months for NHL. Three out of four patients with secondary AML were unresponsive to the new chemotherapy and died, whereas the fourth patient achieved a new CR. Among the three NHL cases, two patients are presently alive in CR, whereas the third patient was refractory to chemotherapy and died.The relative risk of haematological malignancy among the GIMEMA trials population, as compared to that of the Italian Cancer Registries, was 15.25‐fold higher, and the actuarial estimated cumulative proportion of ALL patients with a secondary haematological neoplasm at 5 and 10 years were 0.59% and 3.63% respectively.The incidence of adult ALL who developed a SHM, although apparently lower than in the paediatric ALL series, was higher when compared to the normal population. The difference between paediatric and adult ALL is probably due to the lack of craniospinal radiotherapy and to the lower doses of epipodoxiphyllotoxins used in adult trials. The higher percentage of childhood ALL with a prolonged event‐free survival could result in an increase of secondary neoplasms in these cases, which suggests that secondary haematological neoplasms in adult ALL patients are real, although rare, events.
Trisomy 12 is seen within a specific subtype of B‐cell chronic lymphoproliferative disease affecting the peripheral blood/bone marrow and co‐segregates with elevated expression of CD11a
Authors: Su'ut  , O'Connor  , Richards  , Jones  , Roberts  , Davies  , Fegan  , Jack  , Morgan  
Published: March 2003

In order to delineate the specific morphological and immunophenotypic features of B‐cell lymphoproliferative disorders associated with trisomy 12, 172 sequential unselected cases of CD19+CD5+ B‐cell disorders, primarily affecting the peripheral blood and bone marrow, were studied. Trisomy 12 was found in 24 cases (13.9%), with all cases morphologically classified as either CLL‐PL or CLL‐mixed by FAB criteria. Trisomy 12 was not found in any cases of typical CLL. Trisomy 12 cases demonstrated a significant higher expression of CD11a (P<0.0001) and CD20 (P<0.0006) when compared to cases with the equivalent morphology and immunophenotype, but without the chromosomal abnormality. Trisomy 12 cases also demonstrated a higher frequency of FMC7, CD38 expression and moderate to strong surface immunoglobulin staining. However, no correlation was detected between the percentages of trisomy 12 cells and cells expressing CD11a, CD38, FMC7 or sIg mean fluorescent intensity. Cells from trisomy 12 positive cases were sorted according to their CD11a expression using fluorescent activated cell sorting. There was a significant increase in the percentage of trisomy 12 cells within the CD11a+ sorted fraction compared to the unsorted population (P<0.05), implying that trisomy 12 is associated with increased expression of CD11a.With the highly specific morphological and immunophenotypic features demonstrated by trisomy 12 cases in this study, it is highly likely that these cases constitute a specific group of B‐cell lymphoproliferative disorders.
Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience
Authors: Wheeler Kate , Richards Sue , Bailey Clifford , Chessells Judith ,   for the Medical Research Council Working Party on Childhood Leukaemia
Published: March 2003

We examined the outcome of the 489 children with acute lymphoblastic leukaemia (ALL) who relapsed in the UKALL X trial, and produced graphical displays of adjusted comparisons of event‐free survival (EFS) for chemotherapy versus bone marrow transplantation (BMT) from a sibling or volunteer unrelated donor, and autologous BMT (ABMT).EFS at 5 years was only 3% (95% CI 0–6%) for children who relapsed in the bone marrow (BM) within 2 years of diagnosis, irrespective of type of post‐relapse treatment, whereas for those with late extramedullary relapse it was 66% (95% CI 48–85%). Comparison of the types of treatment did not show benefit for ABMT. For allogeneic BMT the overall reduction in the odds of an event was 26% (95% CI 1–51%) (2P = 0.05), resulting in an absolute increase in 5‐year event‐free survival of 14% (from 26.4% to 40.7%).New approaches are needed for children with early BM relapses whose prognosis is virtually hopeless with current therapy; however, a conventional chemotherapy approach may be justifiable for late extramedullary relapses. For the remaining patients (71%), with later BM or early extramedullary relapses, the optimal treatment is still not clear. This uncertainty warrants a formal randomized comparison of BMT and chemotherapy, to avoid the biases due to unmeasurable selection factors.
Association between hyperflexibility of the thumb and an unexplained bleeding tendency: is it a rule of thumb?
Authors: Kaplinsky Chaim , Kenet Gili , Seligsohn Uri , Rechavi Gideon 
Published: March 2003

A bleeding tendency manifested by petechiae and ecchymoses is one of the most common causes for referral of patients to haematology clinics. Vessel wall pathology is not usually considered to be a cause for deranged haemostasis, although coexistence of increased capillary fragility and joint hypermobility have been reported.We determined the frequency of thumb hyperextensibility and scored the findings in a series of 44 patients referred because of ecchymoses and petechiae, as well as 261 control children and their mothers. All 44 patients had normal coagulation studies. Thumb flexibility score was +4 in 30 patients, +3 in eight patients, +2 in five patients and +1 in one of the index patients. In the control group, only one of 261 had a +4, and three had a +3 score, and two of 260 mothers had a +4 score. Ecchymoses were not observed in any of these subjects, nor in the +1 patients.Based on clinical presentation and normal coagulation studies, we suggest that our patients had an underlying subtype of Ehlers‐Danlos syndrome. In view of the dramatically high occurrence of thumb hyperextensibility in patients with unexplained mild bleeding tendency, costly haemostatic and coagulation studies on such patients may not be necessary.