bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of triptorelin after intravenous bolus administration in healthy males and in males with renal or hepatic insufficiency
Authors: Müller F. O. , Terblanchè J. , Schall R. , Van Zyl Smit R. , Tucker T. , Marais K. , Groenewoud G. , Porchet H. C. , Weiner M. , Hawarden D. 
Published: October 2003

Aims Triptorelin is a gonadotropin‐releasing hormone (GnRH) analogue with enhanced affinity for GnRH receptors and a prolonged half‐life due to its resistance to enzymatic degradation. The sustained‐release formulation of this molecule is advantageous in conditions requiring chronic hormone suppression. Methods This was an open study to determine the pharmacokinetics of a single i.v. bolus dose of 0.5 mg triptorelin acetate in four groups of six male subjects; namely in healthy subjects (Group I), in patients with varying degrees of renal insufficiency (Groups II and III), and in patients with hepatic insufficiency (Group IV). Results The maximum concentrations of triptorelin were found to be similar for all four study groups (geometric mean Cmax between 41.6 mg ml−1 and 53.9 mg ml−1 ). The total clearance of triptorelin decreased with increasing renal impairment, and was even lower in patients with hepatic insufficiency (geometric mean CLtot: 210 ml min−1, 113 ml min−1, 86.8 ml min−1 and 57.3 ml min−1 for Groups I, II, III and IV, respectively). Serum triptorelin concentrations in all four groups were adequately described by a three‐compartment model. The elimination half‐life for patients with hepatic impairment was similar to that of patients with renal impairment (geometric mean t1/2, z: 6.6 h, 7.7 h and 7.6 h for Groups II, III and IV, respectively), but significantly longer than in healthy volunteers (2.8 h for Group I). The first and second distribution half‐lives were similar for the four groups studied, with geometric mean distribution half‐lives of about 0.1 h (6 min) and 0.75 h (45 min), respectively. Conclusions Although both renal and hepatic function are important for the clearance of triptorelin, the liver plays the predominant role in subjects suffering from some degree of renal impairment.
Tolerance to the repolarization effects of ‘oorac‘ox‐sotalol during long‐term treatment
Authors: Padrini Roberto , Gusella Milena , Al Bunni Muhammed , Piovan Donatella , Zordan Rossella , Magnolfi Gianna , Maiolino Pietro , Ferrari Mariano 
Published: October 2003

Aims To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac‐sotalol. Methods The effect of rac‐sotalol on QT interval duration was studied in 10 patients after single oral administration (160 mg) and after 6‐day multiple oral dosing (80 mg two or three times daily). In order to separate the pure Class III effect from the bradycardia‐related QT prolongation, heart rate/QT relationship was preliminarly assessed in each patient after the administration of a pure &bgr;‐adrenoceptor blocker (propranolol, 80 mg orally). Repolarization changes were quantified as percent difference between the measured QT and the expected QT on the basis of the individual heart rate/QT relationship. Results In all patients QT interval prolongation was linearly correlated with rac‐sotalol log plasma concentration. The maximal QT prolongation and peak plasma concentration were not significantly different following acute and chronic administrations (QT effect: +18.1±6.3%vs +14.2±3.3%; peak concentration: 1.64±0.49 mg l−1vs 1.83±0.66 mg l−1 ). Line slopes were also unchanged following chronic treatment (21.8±8.9 vs 21.1±9.2). In four cases a significant rightward shift of the line occurred during repeated administrations, consistent with the appearance of pharmacodynamic tolerance. The inconstancy of this change in responsiveness may either be ascribed to a genetically determined individual susceptibility or to a variable interplay between Class III effect, gradual QT prolongation due to long‐term &bgr;‐adrenoceptor blockade and tolerance development. Conclusions During maintenance treatment with rac‐solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.
The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine
Authors: Eiermann Birgit , Engel Georg , Johansson Inger , Zanger Ulrich M. , Bertilsson Leif 
Published: October 2003

Aims Clozapine (CLZ), an atypical neuroleptic with a high risk of causing agranulocytosis, is metabolized in the liver to desmethylclozapine (DCLZ) and clozapine N‐oxide (CLZ‐NO). This study investigated the involvement of different CYP isoforms in the formation of these two metabolites. Methods Human liver microsomal incubations, chemical inhibitors, specific antibodies, and different cytochrome P450 expression systems were used. Results Km and Vmax values determined in human liver microsomes were lower for the demethylation (61±21 &mgr;m, 159±42 pmol min−1 mg protein−1 mean±s.d.; n=4), than for the N‐oxidation of CLZ (308±1.5 &mgr;m, 456±167pmol min−1 mg protein−1; n=3). Formation of DCLZ was inhibited by fluvoxamine (53±28% at 10 &mgr;m ), triacetyloleandomycin (33±15% at 10 &mgr;m ), and ketoconazole (51±28% at 2 &mgr;m ) and by antibodies against CYP1A2 and CYP3A4. CLZ‐NO formation was inhibited by triacetyloleandomycin (34±16% at 10 &mgr;m ) and ketoconazole (51±13% at 2 &mgr;m ), and by antibodies against CYP3A4. There was a significant correlation between CYP3A content and DCLZ formation in microsomes from 15 human livers (r=0.67; P=0.04). A high but not significant correlation coefficient was found for CYP3A content and CLZ‐NO formation (r=0.59; P=0.09). Using expression systems it was shown that CYP1A2 and CYP3A4 formed DCLZ and CLZ‐NO. Km and Vmax values were lower in the CYP1A2 expression system compared to CYP3A4 for both metabolic reactions. Conclusions It is concluded that CYP1A2 and CYP3A4 are involved in the demethylation of CLZ and CYP3A4 in the N‐oxidation of CLZ. Close monitoring of CLZ plasma levels is recommended in patients treated at the same time with other drugs affecting these two enzymes.
Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method
Authors: Jerling Markus , Merlé Yann , Mentré France , Mallet Alain 
Published: October 2003

Aims To evaluate the distribution of population kinetic parameters for clozapine and their relationship to age and gender in patients on continuous treatment with the drug. Methods Retrospective therapeutic drug monitoring data (391 samples from 241 patients) were evaluated using the nonparametric maximum likelihood method. Patients treated concomitantly with drugs known to interact with clozapine were not included. The distribution of clozapine clearance was compared with the distribution of the activity of the drug metabolic enzyme CYP1A2 found in other populations, as recent studies indicate that CYP1A2 is a major determinant for clozapine elimination. The kinetic linearity for clozapine was studied in 41 patients who each provided data from more than one dose level. Results Clozapine clearance was highly variable in the population and skewed towards high values. Men had higher clearances CL/F (median with 25% and 75% quartiles 38.2 (22.0, 60.0) vs 28.3 (15.2, 48.6) l h−1 ) and a larger volume of distribution V /F (694 (224, 970) vs 401 (189, 932) l) than women. Clearance did not decrease with age in any gender. Clozapine clearance was similarly distributed as the indices of CYP1A2‐activity found in other populations by other authors. Evidence of nonlinear kinetics was not found. Conclusion The large kinetic variability for clozapine found in this study implies that the dose of clozapine needs to be individualised over a wide dose range. The similarity of the distribution of clozapine clearance in this study and the CYP1A2‐activity in other populations support the assumption that CYP1A2 is a major determinant for clozapine elimination.
Transplacental distribution of salbutamol enantiomers at Caesarian section
Authors: Boulton* David W. , Paul Fawcett J. , Fiddes Thomas M. 
Published: October 2003

Aims To investigate the transplacental distribution of salbutamol enantiomers after administration of racemate to women prior to Caesarian section. Methods Five women about to undergo elective Caesarian section were administered a single 0.25 mg bolus intravenous dose of (R,S)‐salbutamol. The time from drug administration to delivery was different for each woman (27–105 min). Maternal and foetal umbilical cord venous blood samples were collected immediately after delivery and the plasma fraction analysed for salbutamol enantiomer concentrations by enantioselective high pressure liquid chromatography. Results The concentrations (mean± s.d.) of the active (R) enantiomer of salbutamol in cord and maternal plasma were 0.46±0.35 and 0.89±0.50 ng ml−1, respectively, and the difference was statistically significant (95% confidence interval (CI) of the difference: 0.12–0.74 ng ml−1 ). The corresponding concentrations of the (S) enantiomer of 0.92±0.45 and 1.11±0.67 ng ml−1, respectively, were not significantly different (95% CI of the difference −0.08–0.48 ng ml−1 ). The ratio of (R):(S) in cord plasma was significantly less than that in maternal plasma (P=0.016). Conclusions Transplacental distribution of salbutamol enantiomers at Caesarian section after prior administration of racemate to mothers leads to concentrations in cord plasma that are significantly less for the active (R) enantiomer and not significantly different for the (S) enantiomer than in maternal plasma presumably due to enantioselective placental‐foetal metabolism.
Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes
Authors: Zhao Xue‐Jun , Ishizaki Takashi 
Published: October 2003

Aims Nine antimalarial (plus two metabolites of proguanil) and twelve non‐antimalarial drugs were tested for their possible interaction with CYP3A4‐catalysed 3‐hydroxylation of quinine by human liver microsomes in vitro. Methods 3‐Hydroxyquinine was assayed in the incubation mixture by an h.p.l.c. method using fluorometric detection. The respective IC50 values were estimated for the twenty‐one drugs and two metabolites of proguanil tested herein. Results Thirteen drugs exhibited an inhibitory effect on the 3‐hydroxylation of quinine. According to the respective mean IC50 values, the inhibitory rank order of the drugs was: ketoconazole>troleandomycin (TAO, with preincubation)> doxycycline>omeprazole>primaquine>tetracycline=TAO (without preincubation)>nifedipine>erythromycin>verapamil>cimetidine>diltiazem>oleandomycin>hydralazine. Other drugs or metabolites showed little or no inhibition of quinine metabolism (mean IC50>200 or 500 &mgr;m ). Among the antimalarial drugs, doxycycline showed relatively potent inhibition of quinine 3‐hydroxylation with a mean IC50 value of 17 &mgr;m, followed by primaquine and tetracycline, with mean IC50 values of 20 and 29 &mgr;m, respectively. Conclusions When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, TAO and erythromycin are likely to be inhibitors of quinine metabolism in patients when the drugs are co‐administrated with quinine.
A prescription survey in a hospital hypertension outpatient clinic
Authors: Lee Pat K. F. , Li Robin K. L. , Chan Juliana C. N. , Chang Sophie , Lee S. C. , Tomlinson Brian , Critchley Julian A. J. H. 
Published: October 2003

Aims The objective of this study was to investigate drug utilization in the management of hypertension in Hong Kong. Methods We conducted a prescription survey to examine the use of antihypertensive drugs in a hypertension clinic in a regional hospital and the resulting expenditure incurred. The use of concurrent medications such as antidiabetic drugs and lipid‐lowering agents was also examined. Results During a 7‐week study period, 530 prescriptions were collected. All except 14 patients received antihypertensive drugs with 262 (50.8%) on monotherapy and 254 (49.2%) on combination therapy. Calcium channel blocking agents and β‐adrenoceptor blocking agents were the two most popular antihypertensive drugs used in both monotherapy (38% and 31%, respectively) and combination therapy (27% and 33%, respectively). Forty‐nine patients (19%) received three antihypertensive drugs or more. The number of antihypertensive drugs showed a significant positive correlation with the duration of attendance at the clinic (r=0.88, P<0.001). Of the total 530 prescriptions, 5.6% and 10% contained antidiabetic drugs and lipid‐lowering agents, respectively. Calcium channel blocking agents, angiotensin converting enzyme (ACE) inhibitors and lipid lowering agents, accounted for 82% (HK$211 654; £1HK$12) of the total drug expenditure (HK$258 115). Seventy‐nine percent of the lipid lowering agents prescribed were hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors. Amlodipine accounted for 26% of usage but contributed to 41% of the overall costs of calcium channel blocking agents. α1‐adrenoceptor blocking agents were only used infrequently and were the most expensive class of drugs, due to the preferred use of doxazosin rather than prazosin which is far cheaper than the former. Conclusions In view of the use of these often costly drugs for long‐term therapy, monitoring of their use and its correlation with clinical outcomes and quality of life is essential to ensure the optimal use of health care resources.
Characterization of the cytochrome P450 isoenzymes involved in the in vitroN‐dealkylation of haloperidol
Authors: Pan L. P. , Wijnant P. , De Vriendt C. , Rosseel M. T. , Belpaire F. M. 
Published: October 2003

Aims The present study was carried out to identify the cytochrome P450 isoenzyme(s) involved in the N‐dealkylation of haloperidol (HAL). Methods In vitro studies were performed using human liver microsomes and c‐DNA‐expressed human P450 isoforms. N‐dealkylation of HAL was assessed by measuring the formation of 4‐(4‐chlorophenyl)‐4‐hydroxypiperidine (CPHP). Results There was a tenfold variation in the extent of CPHP formation amongst the nine human liver microsomal preparations. The CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. Km and Vmax values ranged respectively from 50 to 78 μm and from 180 to 412 pmol mg−1 min−1. CPHP formation rates in the nine liver preparations were significantly correlated with dextromethorphan N‐demethylase activity (a marker of CYP3A4 activity), but not with the activity of dextromethorphan O‐demethylase (CYP2D6), phenacetin O‐deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). Ketoconazole, an inhibitor of CYP3A4, inhibited competitively CPHP formation (Ki=0.1 μm ), whereas sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine (CYP2D6) gave only little inhibition (IC50>100 μm ). CPHP formation was, moreover, enhanced by α‐naphtoflavone, an effect common to CYP3A4 mediated reactions. Anti‐CYP3A4 antibodies strongly inhibited CPHP formation, whereas no inhibition was observed in the presence of CYP2D6 antibodies. Among the recombinant human CYP isoforms tested, CYP3A4 exhibited the highest activity with respect to CPHP formation rate, with no detectable effect of other CYP isoforms (CYP1A2, CYP2D6 and CYP2C9). HAL inhibited dextromethorphan O‐demethylase (CYP2D6) with IC50 values between 2.7 and 8.5 μm, but not (IC50>100 μm ) dextromethorphan N‐demethylase (CYP3A4), phenacetin O‐deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). Conclusions These results strongly suggest that the N‐dealkylation of HAL in human liver microsomal preparations is mediated by CYP3A4.
Effect of platelet phospholipid exposure on activated protein C resistance: implications for thrombophilia screening
Authors: Luddington Roger , Brown Karen , Baglin Trevor 
Published: October 2003

The effect of platelet contamination and freeze‐thawing on the activated protein C sensitivity ratio (APCsr) was determined. With increasing platelet count there was a progressive reduction in the ratio. Filtration of samples through a 0.2 μm filter before or after freeze‐thawing abolished the development of resistance to the addition of activated protein C indicating that the phenomenon is due to the presence of a particulate factor. Contamination of normal plasma with platelets from a patient with homozygous factor V (FV) deficiency was also associated with the same development of resistance to activated protein C, indicating that the phenomenon was not due to exposure of platelet‐derived factor V that might be inaccessible to APC.82% (96/117) of FVQ506 and 32% (138/430) of FV R506 individuals had APC resistance on analysis of unfiltered plasma. However, 85% (42/50) of FVQ506 individuals had APC resistance on analysis of filtered plasma, whilst only 1/50 FV R506 individuals had APC resistance after filtration. For the purpose of identifying individuals at increased risk of venous thromboembolism due to the presence of the FVQ506 and associated APC resistance a PCR‐based genotypic analysis is recommended.
The influence of STAT5 antisense oligonucleotides on the proliferation and apoptosis of selected human leukaemic cell lines
Authors: Baśkiewicz‐Masiuk M. , Masiuk M. , Machaliński B. 
Published: October 2003

Abstract.  The signal transducers and activators of transcription – STAT5A and STAT5B – take part in the regulation of many essential physiopathological processes. They influence the cell cycle, apoptosis and the proliferation of different types of cell lines. The STAT5 proteins are induced in response to multiple haematopoietic cytokines. Because they are constitutively active in certain haemato‐oncologic diseases, it is also suggested that they play an important role in leukaemogenesis. However, function of these proteins in haematopoietic cell transformation and proliferation is not clear. The aim of this study was to evaluate the impact of perturbation of STAT5 expression [using oligodeoxynucleotide (ODN) against STAT5 mRNA], on the clonogenicity and survival of selected human leukaemic cell lines, HEL, HL‐60, K562, TF‐1. We analysed the effect of ODN pre‐treatment on the cell clonogenicity in methylcellulose cultures according to the time and the temperature of exposure. Moreover, we attempted to estimate apoptosis induced in examined cells, by flow cytometry using combined Annexin V‐PI staining and the TUNEL method. We also applied the RT‐PCR method to analyse Bax and Bcl‐xL gene expression. We found that the perturbation of STAT5 expression with antisense oligonucleotides caused a decrease in the proliferative potential of human K562 and TF‐1 cell lines. Also, we observed higher induction of apoptotic cell death in the K562 and TF‐1 cells incubated with the antisense STAT5A ODNs. We did not notice any impact of ODNs on the HL‐60 and HEL cells. Our studies using STAT5 antisense oligonucleotides showed that these proteins may be critical in the regulation of growth and apoptosis of some types of leukaemic blasts.
Epithelial progenitor cell lines as models of normal breast morphogenesis and neoplasia
Authors: Petersen Ole William , Gudjonsson Thorarinn , Villadsen René , Bissell Mina J. , Rønnov‐Jessen Lone 
Published: October 2003

Abstract.  The majority of human breast carcinomas exhibit luminal characteristics and as such, are most probably derived from progenitor cells within the luminal epithelial compartment. This has been subdivided recently into at least three luminal subtypes based on gene expression patterns. The value of knowing the cellular origin of individual tumours is clear and should aid in designing effective therapies. To do this, however, we need strategies aimed at defining the nature of stem and progenitor cell populations in the normal breast. In this review, we will discuss our technical approach for delineating the origin of the epithelial cell types. A major step forward was the purification of each cell type by the application of immunomagnetic cell sorting based on expression of lineage‐specific surface antigens. We then developed chemically defined media that could support either the luminal epithelial or the myoepithelial cell phenotype in primary cultures. Having succeeded in continuous propagation presumably without loss of markers, we could show that a subset of the luminal epithelial cells could convert to myoepithelial cells, signifying the possible existence of a progenitor cell population. By combining the information on marker expression and in situ localization with immunomagnetic sorting and subsequent immortalization, we have identifed and isolated a cytokeratin 19‐positive suprabasal putative precursor cell in the luminal epithelial compartment and established representative cell lines. This suprabasal‐derived epithelial cell line is able to generate both itself and differentiated luminal epithelial and myoepithelial cells, and in addition, is able to form elaborate terminal duct lobular unit (TDLU)‐like structures within a reconstituted basement membrane. As more than 90% of breast cancers arise in TDLUs and more than 90% are also cytokeratin 19‐positive, we suggest that this cell population contains a breast‐cancer progenitor.
Identification of novel expressed sequences, up‐regulated in the leucocytes of chronic fatigue syndrome patients
Authors: Powell R. , Ren J. , Lewith G. , Barclay W. , Holgate S. , Almond J. 
Published: October 2003

SummaryBackground
Chronic fatigue syndrome (CFS) is an increasing medical phenomenon of unknown aetiology leading to high levels of chronic morbidity. Of the many hypotheses that purport to explain this disease, immune system activation, as a central feature, has remained prominent but unsubstantiated. Supporting this, a number of important cytokines have previously been shown to be over‐expressed in disease subjects. The diagnosis of CFS is highly problematic since no biological markers specific to this disease have been identified. The discovery of genes relating to this condition is an important goal in seeking to correctly categorize and understand this complex syndrome.Objective
The aim of this study was to screen for changes in gene expression in the lymphocytes of CFS patients.Methods
‘Differential Display’ is a method for comparing mRNA populations for the induction or suppression of genes. In this technique, mRNA populations from control and test subjects can be ‘displayed’ by gel electrophoresis and screened for differing banding patterns. These differences are indicative of altered gene expression between samples, and the genes that correspond to these bands can be cloned and identified. Differential display has been used to compare expression levels between four control subjects and seven CFS patients.Results
Twelve short expressed sequence tags have been identified that were over‐expressed in lymphocytes from CFS patients. Two of these correspond to cathepsin C and MAIL1 – genes known to be upregulated in activated lymphocytes. The expression level of seven of the differentially displayed sequences have been verified by quantifying relative level of these transcripts using TAQman quantitative PCR.Conclusion
Taken as a whole, the identification of novel gene tags up‐regulated in CFS patients adds weight to the idea that CFS is a disease characterized by subtle changes in the immune system.