bluuebunny/crossref_metadata_2025_split huggingface dataset:
Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man
Authors: Kupferschmidt Hugo H. T. , Fattinger Karin E. , Ha Huy Riem , Follath Ferenc , Krähenbühl Stephan 
Published: November 2003

Aims
Saquinavir is a potent HIV protease inhibitor whose effectiveness is limited in vivo by its low bioavailability. Since saquinavir is metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of CYP3A4, was investigated on its bioavailability.
Methods
After an overnight fast, eight healthy volunteers were treated with either 400 ml grapefruit juice or water before intravenous (12 mg) or oral saquinavir (600 mg) was administered. Serial blood samples were obtained over the following 24 h and standardized meals were served 5 and 10 h after the administration of saquinavir. The plasma concentrations of saquinavir were determined by high‐performance liquid chromatography and pharmacokinetic parameters were calculated by routine methods.
Results
The AUC was not affected by grapefruit juice after intravenous administration, but it increased significantly from 76±96 (water, mean (s.d.) to 114±70 (μg l−1 h (grapefruit juice) after oral saquinavir. Similarly, the oral bioavailability of saquinavir increased by a factor of 2 with grapefruit juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution and elimination half‐life of saquinavir were not affected by grapefruit juice. After oral, but not after intravenous administration, the plasma concentration‐time curve showed a second peak after lunch irrespective of pretreatment, suggesting enhancement of absorption by food.
Conclusions
The studies demonstrate that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute. Since the antiretroviral effect of saquinavir is dose‐dependent, inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.
Integrating clinical pharmacology teaching with general practice
Authors: Shenfield Gillian M. 
Published: November 2003

Aims
To make Clinical Pharmacology teaching relevant and introduce students to therapeutic problems relevant to general practice.
Methods
Six topics in the ‘core curriculum’ for Clinical Pharmacology were taught jointly by a Clinical Pharmacologist and General Practitioners (GPs). Formal teaching was reduced by issuing handouts containing copies of the overheads used. At least half the time was spent on interactive discussion of case histories.
Results
Students rated the sessions more highly than other Clinical Pharmacology teaching and were not disadvantaged in examinations. All participants enjoyed and learnt from the experience and the GPs gained confidence in their ability to teach.
Conclusions
This simple method is ideal for teaching Clinical Pharmacology and Therapeutics.
Are altered pharmacokinetics of non‐steroidal anti‐inflammatory drugs (NSAIDs) a risk factor for gastrointestinal bleeding?
Authors: Wynne H. A. , Long A. , Nicholson E. , Ward A. , Keir D. 
Published: November 2003

Aims
We hypothesised that pharmacokinetic factors might go some way to explaining the risk of major gastrointestinal haemorrhage with non‐steroidal anti‐inflammatory drugs (NSAIDs), with bleeders exhibiting a reduced clearance of NSAIDs compared with non‐bleeders and set out to investigate this.
Methods
Fifty patients presenting to hospital with acute gastrointestinal bleeding while taking piroxicam, indomethacin, diclofenac or naproxen and age, sex, musculoskeletal disease and drug matched community dwelling controls, up to two for each index case, who had not bled were recruited. Clinical details including duration of therapy were recorded. Bleeders discontinued the implicated NSAID at presentation, controls at least five half‐lives before the study. Bleeders were contacted by letter 1 month after discharge and invited to take part and were studied after a median delay of 5 months. Subjects received an oral dose of their respective NSAID and venous blood was sampled, over a period determined by the half‐life of the NSAID. Plasma concentrations were determined by high performance liquid chromatography.
Results
The median length of treatment for the index patients was 1 year (range 2 weeks—28 years) and for the control patients 2 years (1 month—25 years), P<0.0005. There were no significant differences in peak plasma concentration, time to peak plasma concentration or area under the plasma concentration‐time curve between bleeders or controls for any of the NSAIDs studied, apart from piroxicam Cmax being lower in bleeders at 2.07 mg l−1 than in controls at 3.21 mg l−1, mean difference (95% CI) −1.14 (−1.83–−0.48), P<0.005.
Conclusions
The data failed to support the hypothesis that reduced clearance of NSAIDs, which results in higher plasma concentrations, is a risk factor for acute gastrointestinal haemorrhage.
Indicators for Drug and Therapeutics Committees
Authors: Weekes Lynn M. , Brooks Colleen , Day Richard O. 
Published: November 2003

Aims
This study describes development and field testing of a set of indicators for drug and therapeutics committees (DTCs) in hospitals. It was intended that these indicators should be accessible, useful and relevant in the Australian setting.
Methods
Candidate indicators were written following consultation and data collection. A framework of outcome, impact and process indicators was based on DTC goals, objectives and strategies. The candidate indicators were field tested over a 2 month period in teaching, city non‐teaching, rural and private hospitals. The field tests provided response data for each indicator and evaluation of the indicators against criteria for accessibility, relevance, usefulness, clarity and resource utilisation. Consensus on which indicators to accept, modify or reject was reached at a workshop of stakeholders and experts, taking account of the field test results.
Results
Thirty‐five candidate indicators were tested in 16 hospitals. Twenty‐two had a response from >80% of sites, 23 had a mean relevance rating >3.5, 19 had a mean usefulness rating >3.5, 27 were correctly interpreted by >90% of sites and 25 could be collected in an acceptable time. The most acceptable indicators required least data collection or provided data deemed useful for purposes other than the field test. At the consensus workshop 13 indicators were accepted with no or minor change, nine were accepted after major modification and eight were discarded. It was recommended that a further five indicators should be merged or subsumed into one indicator.
Conclusions
This study has developed and field tested a set of indicators for DTCs in Australia. The indicators have been taken up enthusiastically as a first attempt to monitor DTC performance but require ongoing validation and development to ensure continuing relevance and usefulness.
Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole
Authors: Andersson Tommy , Holmberg Johan , Kerstin Röhss  , Walan Anders 
Published: November 2003

Aims
To study the pharmacokinetics of three proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole, as well as any potential influence on CYP1A2 activity (measured by means of rate of caffeine metabolism) of these compounds at single dose and repeated dose administration.
Methods
Fourteen healthy males, classified as 12 extensive metabolizers (EMs) and two poor metabolizers (PMs) according to the urinary S/R mephenytoin ratio, completed this open, randomized, three‐way cross‐over study. In each of the three 7‐day treatment periods either omeprazole (20 mg), lansoprazole (30 mg) or pantoprazole (40 mg) in therapeutically recommended doses was administered once daily, and the pharmacokinetics of the proton pump inhibitors as well as the rate of caffeine metabolism was measured on days 1 and 7.
Results
In the EMs there was an increase in AUC from day 1 to day 7 for omeprazole. In the PMs the AUC of both omeprazole and lansoprazole was unchanged during repeated dosing, while for pantoprazole there was a tendency to a slight decrease. The AUC at steady state was for all three proton pump inhibitors 5 fold higher in PMs compared with EMs, indicating that the same proportion of the dose, irrespective of compound, is metabolized by CYP2C19. No induction of CYP1A2 was evident for any of the compounds in either EMs or PMs.
Conclusions
The ∼5 fold difference in AUC between EMs and PMs indicates that approximately 80% of the dose for all three proton pump inhibitors is metabolized by the polymorphically expressed CYP2C19. None of the three proton pump inhibitors, administered in therapeutically recommended doses, is an inducer of CYP1A2—neither in PMs nor in EMs.
Effect of food on the pharmacokinetics of ropinirole in parkinsonian patients
Authors: Brefel C. , Thalamas C. , Rayet S. , Lopez‐Gil A. , Fitzpatrick K. , Bullman S. , Citerone D. R. , Taylor A. C. , Montastruc J. L. , Rascol O. 
Published: November 2003

Aims
Ropinirole is a specific non‐ergoline dopamine D2‐receptor agonist with antiparkinsonian properties.The pharmacokinetic parameters of ropinirole taken in the fasted condition were compared with those when it was co‐administered with food.
Methods
This was an open, randomized, two sessions cross over study in 12 patients with Parkinson’s disease, comparing the steady‐state pharmacokinetic profiles of ropinirole on two different study days: ‘fasted’ and ‘fed’.
Results
The mean Cmax was lower in the ‘fed’ regimen than in the ‘fasted’ one (−25%, P=0.002). The median tmax was observed 2.6 h later in the ‘fed’ regimen than in the ‘fasted’ regimen (P<0.05). There was a slight but significant decrease in AUC(0,8 h) in the ‘fed’ regimen (P=0.03).
Conclusions
Food decreases the rate of absorption of ropinirole, but has little effect on the extent of absorption.
Expression of nm23‐H1 is associated with poor prognosis in peripheral T‐cell lymphoma
Authors: Niitsu Nozomi , Nakamine Hirokazu , Okamoto Masataka , Akamatsu Hiroko , Honma Yoshio , Higashihara Masaaki , Okabe‐Kado Junko , Hirano Masami 
Published: November 2003

Summary. We have reported previously that the serum nm23‐H1 level is a prognostic factor for non‐Hodgkin's lymphoma. In this study, we examined nm23‐H1 expression in T‐ and natural killer (NK)‐cell lymphoma in order to evaluate whether lymphoma cells produce the protein. The clinical significance of the cytotoxic molecules, T‐cell intracellular antigen‐1 (TIA‐1) and granzyme B and nm23‐H1 expression were also examined. Expression of nm23‐H1, TIA‐1, or granzyme B was examined by immunohistochemistry in 137 previously untreated lymphoma patients. The relationship between the results and clinical outcome was examined in 81 patients with angioimmunoblastic T‐cell lymphoma, anaplastic large cell lymphoma, or peripheral T‐cell lymphoma, unspecified. The neoplastic cells of some lymphomas produced nm23‐H1 and the expression rates of nm‐23‐H1, TIA‐1 and granzyme B were 36·5%, 78·8% and 32·8% respectively. The nm23‐H1‐positive or TIA‐1‐positive groups had significantly shorter overall and disease‐free survivals. Multivariate analysis confirmed nm23‐H1 expression to be an independent prognostic factor. The nm23‐H1 protein can be an important prognostic factor in the lymphomas studied here. New treatments that target nm23 overexpression could be developed as a result of nm23‐HI production by lymphoma cells.
Early and late G2 arrest of cells undergoing radiation‐induced apoptosis or micronucleation
Authors: Abend M. , Gilbertz K‐P. , Rhein A. , Beuningen D. van 
Published: November 2003

AbstractConventional flow cytometric DNA measurements combined with the microscopic detection of cells in the late G2 phase of the cell cycle (characterized by the occurrence of paired kinetochores) enabled us to differentiate and to quantify early and late G2 cells 0–40 h after irradiation using a radioresistant (L929) and a radiosensitive (HL‐60) cell line. This approach provided us with (1) a new kind of G2 arrest characteristic revealing changes in the G2 phase which can not be detected by flow cytometric DNA measurements, (2) cell line dependent differences in the radiation‐induced transition through G2, accompanied by the occurrence of micronucleation and apoptosis, and (3) the characterization of apoptotic cells occurring probably during early G2 and bearing a rapidly reduced number of kinetochores in contrast to mitotic cells, suggesting processes different from those that operate in mitosis.
Direct comparison of bromodeoxyuridine and Ki‐67 labelling indices in human tumours
Authors: Wilson G. D. , Saunders M. I. , Dische S. , Daley F. M. , Robinson B. M. , Martindale C. A. , Joiner B. , Richman P. I. 
Published: November 2003

AbstractDirect comparison of bromodeoxyuridine (BrdUrd) and Ki‐67 labelling indices was achieved by selecting similar areas from serial sections of human tumours. Fifteen patients were selected who had been administered BrdUrd in vivo and both proliferation markers were assessed by immunohistochemistry. The data show a good correlation between both BrdUrd LI and MIB‐1 LI and Tpot (calculated using the flow cytometry derived duration of S phase) and MIB‐1 LI. The contribution of BrdUrd LI to growth fraction varied as a function of proliferation characteristics. In tumours with a high LI, the number of DNA synthesizing cells represented half the growth fraction, whilst in tumours with lower LI's (<10%) the ratio of DNA precursor labelled cells as a function of growth fraction fell to between 10% and 20%. Tpot showed a linear correlation with MIB‐1/BrdUrd ratio with a slope approaching unity. It was apparent that both intra‐ and interpatient variation in proliferation index was greater for BrdUrd labelling than for MIB‐1 expression.
Optimal control problems arising in cell‐cycle‐specific cancer chemotherapy
Authors: Swierniak A. , Polanski A. , Kimmel M. 
Published: November 2003

AbstractWe explore mathematical properties of models of cancer chemotherapy including cell‐cycle dependence. Using the mathematical methods of control theory, we demonstrate two assertions of interest for the biomedical community: 1 Periodic chemotherapy protocols are close to the optimum for a wide class of models and have additional favourable properties. 2 Two possible approaches, (a) to minimize the final count of malignant cells and the cumulative effect of the drug on normal cells, or (b) to maximize the final count of normal cells and the cumulative effect of the drug on malignant cells, lead to similar principles of optimization.From the mathematical viewpoint, the paper provides a catalogue of simplest mathematical models of cell‐cycle dependent chemotherapy. They can be classified based on the number of compartments and types of drug action modelled. In all these models the optimal controls are complicated by the singular and periodic trajectories and multiple solutions. However, efficient numerical methods have been developed. In simpler cases, it is also possible to provide an exhaustive classification of solutions.We also discuss developments in estimation of cell cycle parameters and cell‐cycle dependent drug action.
Tolerance to a rice hydrolysate formula in children allergic to cow's milk and soy
Authors: Fiocchi A. , Travaini M. , D'Auria E. , Banderali G. , Bernardo L. , Riva E. 
Published: November 2003

AbstractBackground
Even hydrolysed cow's milk formulae may retain residual allergens and there are few nutritional options for children with cow's milk allergy (CMA) who also react to soy.Objective  To assess clinical tolerance to a rice‐based hydrolysate in children with such a clinical presentation.Patients and methods
Eighteen children (six girls and 12 boys; median age 5 years; range 1–9 years) with CMA, who developed clinical reactions to a soy‐based formula after 2–18 months' treatment, were recruited between January 1998 and June 1999. Clinical evaluation was by skin prick test (SPT) with cow's milk, casein, lactalbumin, soy and rice allergen extracts, fresh cow's milk, soy and hydrolysated rice formula (HRF). Serology was investigated by CAP system technology and immunoblotting. Assessment of the rice formula was carried out by double‐blind, placebo‐controlled food challenge with rice hydrolysate.Results
Thirteen children had positive SPT to casein, 10 to lactalbumin, eight to rice and two to rice hydrolysate. Positive serology was found in all patients' sera tested with cow's milk, with soy in 13 sera and with rice in seven. Double‐blinded, placebo‐controlled challenge with an HRF was negative in all cases.Conclusions
Children allergic to cow's milk and soy tolerate an HRF clinically. This suggests that rice hydrolysate may be used as a protein source for children with multiple food‐induced reactions.
Oral administration of an edible‐mushroom‐derived protein inhibits the development of food‐allergic reactions in mice
Authors: Hsieh K.‐Y. , Hsu C.‐I. , Lin J.‐Y. , Tsai C.‐C. , Lin R.‐H. 
Published: November 2003

SummaryBackground
Food allergy is a common disease without effective treatment. Since strict elimination of food allergens may be difficult, strategies for effective intervention are urgently needed.Objective  The aim was to investigate the prophylactic use of orally administrated FIP‐fve, an immunomodulatory protein isolated from the edible mushroom Flammulina velutipes, in a murine model of food allergy.Methods
BALB/c mice were immunized twice intraperitoneally with ovalbumin (OVA), at an interval of 2 weeks. Before and during each period of immunization, FIP‐fve (200 μg per mouse) or phosphate‐buffered saline was given orally every other day with a total of five doses. Then OVA‐specific antibodies and cytokine profiles were determined. Subsequently, the mice were orally challenged with OVA. Symptoms of anaphylaxis, levels of plasma histamine, and histology of intestines were examined.Results
Mice receiving oral FIP‐fve treatment during sensitization to OVA had an impaired OVA‐specific IgE response with a Th1‐predominant cytokine profile. These mice were protected from systemic anaphylaxis‐like symptoms induced by subsequent oral challenge with OVA.Conclusion
Oral administration of FIP‐fve has a Th1‐skewing effect on the development of the allergen‐specific immune response, and may serve the purpose of immunoprophylaxis for food allergy and other allergic diseases.
In vitro expansion of human basophils by interleukin‐3 from granulocyte colony‐stimulating factor‐mobilized peripheral blood stem cells
Authors: Takao K. , Tanimoto Y. , Fujii M. , Hamada N. , Yoshida I. , Ikeda K. , Imajo K. , Takahashi K. , Harada M. , Tanimoto M. 
Published: November 2003

SummaryBackground
A number of studies support the belief that human basophils play an important role in allergic inflammation. The exact mechanism of basophil activation at the site of allergic inflammation, however, has not been well understood, mainly due to their low number in blood and difficulty in obtaining a sufficient number of highly purified basophils for investigation.Objective
The purpose of this study is to expand human basophils in vitro with high yield and purity by culturing peripheral blood stem cells (PBSCs).Methods
We collected PBSC‐rich mononuclear cells containing CD34+ cells (0.15–4.9%) by leukapheresis from patients with malignant lymphoma and lung cancer during haematopoietic recovery after chemotherapy plus granulocyte colony‐stimulating factor‐induced mobilization. PBSC‐rich mononuclear cells were cultured in the presence of IL‐3.Results
When PBSC‐rich mononuclear cells containing more than 1% of CD34+ cells were cultured, 20.0–83.3% of the cells, mostly with a yield of >10%, were metachromatic cells after 3 weeks of culture. These cells resembled mature peripheral blood basophils morphologically when examined by light and electron microscopy. Flow cytometric analysis showed that they expressed both FcɛRI and FcγRII. FcɛRI cross‐linking resulted in intracellular calcium mobilization, histamine release and synthesis of cysteinyl leukotrienes. The intracellular histamine content and the release of these chemical mediators triggered by anti‐IgE antibodies were comparable to those of peripheral blood basophils.Conclusion
These findings suggest that PBSC‐derived basophils expanded in vitro are morphologically and functionally mature and will be a useful tool for the analysis of basophil functions.
Levels of soluble CD30 in cord blood and peripheral blood during childhood are not correlated with the development of atopic disease or a family history of atopy
Authors: Holmlund U. , Bengtsson Å. , Nilsson C. , Kusoffsky E. , Lilja G. , Scheynius A. , Sverremark‐Ekström E. 
Published: November 2003

SummaryBackground
The CD30 molecule has been linked to Th2 responses. Furthermore, elevated levels of the soluble form of CD30 (sCD30) in blood as well as of the expression of CD30 on the plasma membrane of T cells are associated with atopic disease.Objective
To assess the potential usefulness of sCD30 levels as a prognostic indicator of and/or diagnostic marker for the development of atopic disease in children.Methods
sCD30 levels in cord blood and peripheral blood from 36 2‐year‐old (10 atopic and 26 non‐atopic) and 74 7‐year‐old (35 atopic and 39 non‐atopic) children were determined employing an ELISA procedure. Atopy was diagnosed on the basis of clinical evaluation in combination with a positive skin prick test.Results
No significant correlation between sCD30 levels in cord blood and the development of atopic disease at 2 or 7 years of age was observed. At 7 years of age, the circulating sCD30 levels in children with atopic disease (median 41 U/mL, range 6–503 U/mL) did not differ from the corresponding values for non‐atopic subjects (median 41 U/mL, range 8–402 U/mL). The same was true for children at 2 years of age. Furthermore, the sCD30 levels of children who had developed atopic eczema/dermatitis syndrome by the age of 7 years (median 49 U/mL, range 14–503 U/mL) were not significantly elevated in comparison with those of the non‐atopic children. Finally, neither sCD30 levels in cord blood nor peripheral blood at 2 or 7 years of age could be linked to a family history of atopy.Conclusion
These findings indicate that the sCD30 concentration in cord blood is not a reliable prognostic indicator of, nor a useful diagnostic marker for, atopic disease in children up to 7 years of age. If such correlations do exist, they might be masked by age‐dependent variations in the circulating levels of sCD30, which may reflect individual differences in the maturation of children's immunological responses.