bluuebunny/crossref_metadata_2025_split huggingface dataset:
Solid‐phase microextraction: a powerful sample preparation tool prior to mass spectrometric analysis
Authors: Vas György , Vékey Károly 
Published: March 2004

AbstractSample preparation is an essential step in analysis, greatly influencing the reliability and accuracy of resulted the time and cost of analysis. Solid‐Phase Microextraction (SPME) is a very simple and efficient, solventless sample preparation method, invented by Pawliszyn in 1989. SPME has been widely used in different fields of analytical chemistry since its first applications to environmental and food analysis and is ideally suited for coupling with mass spectrometry (MS). All steps of the conventional liquid–liquid extraction (LLE) such as extraction, concentration, (derivatization) and transfer to the chromatograph are integrated into one step and one device, considerably simplifying the sample preparation procedure. It uses a fused‐silica fibre that is coated on the outside with an appropriate stationary phase. The analytes in the sample are directly extracted to the fibre coating. The SPME technique can be routinely used in combination with gas chromatography, high‐performance liquid chromatography and capillary electrophoresis and places no restriction on MS. SPME reduces the time necessary for sample preparation, decreases purchase and disposal costs of solvents and can improve detection limits. The SPME technique is ideally suited for MS applications, combining a simple and efficient sample preparation with versatile and sensitive detection. This review summarizes analytical characteristics and variants of the SPME technique and its applications in combination with MS. Copyright © 2004 John Wiley & Sons, Ltd.
Identification of MRI and 1H MRSI parameters that may predict survival for patients with malignant gliomas
Authors: Li Xiaojuan , Jin Hua , Lu Ying , Oh Joonmi , Chang Susan , Nelson Sarah J. 
Published: March 2004

AbstractAlthough MR imaging (MRI) and MR spectroscopic imaging (MRSI) have been applied in the diagnosis and treatment planning for brain tumors, their prognostic significance has not yet been determined. The goal of this study was to identify pre‐treatment MRI and MRSI parameters for patients with malignant glioma that may be useful in predicting survival. Two populations of patients with newly‐diagnosed malignant glioma were examined with MRI and three‐dimensional proton (1H) MRSI. Thirty‐nine patients (22 grade 3 and 17 glioblastoma multiforme, GBM) were studied prior to surgery, and 33 GBM patients were studied after surgery but prior to treatment with radiation and chemotherapy. Signal intensities of choline (Cho), creatine (Cr), N‐acetyl aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Recursive partitioning methods were applied to parameters that included age, histological grade, MRI and MRSI variables to generate survival trees. Patients were grouped into high and low risk categories and the corresponding Kaplan–Meier curves were plotted for comparison between groups. The parameters that were selected by recursive partitioning as being predictive of poor outcome were older age, larger contrast enhancement, higher Cho‐to‐Cr, higher Cho‐to‐NAA, higher LL and lower Cr‐to‐NAA abnormalities. The survival functions were significantly different between the sub‐groups of patients obtained from the survival tree for both pre‐surgery and post‐surgery data. The results of this study suggest that pre‐treatment MRI and three‐dimensional 1H‐MRSI provide information that predicts outcome for patients with malignant gliomas and have drawn attention to variables that should be examined prospectively in future studies using these techniques. Copyright © 2004 John Wiley & Sons, Ltd.
Magnetic resonance angiography of collateral vessels in a murine femoral artery ligation model
Authors: Wagner Shawn , Helisch Armin , Ziegelhoeffer Tibor , Bachmann Georg , Schaper Wolfgang 
Published: March 2004

AbstractThe in vivo detection of growing collateral vessels following arterial occlusion is difficult in small animals. We have addressed the feasibility of performing high resolution time‐of‐flight angiograms to monitor the growth of collateral vessels after femoral artery occlusion in mice. We will also present a low‐pass quadrature birdcage coil construction with a sufficient signal‐to‐noise ratio to produce high resolution. After a 4‐month recovery period a C57BL/6 mouse with a surgical occlusion of the right femoral artery was used to assess the image quality and time requirements to produce magnetic resonance angiograms sufficient to assess collateral artery development using a two‐dimensional gradient echo sequence. At a resolution of 100 × 100 × 100 μm and a matrix size of 256 × 128 × 256 for a 2.56 cm isometric volume, three scans were performed with one, two and four repetitions resulting in signal‐to‐noise ratios for the femoral artery proximal to the ligation site of 58, 126 and 194, respectively. Five C57BL/6 mice were additionally measured 4 weeks after occlusion using two repetitions and the visual collateral vessels were assessed for number and location: 2.0 ± 1.2 in quadriceps muscle, 0.6 ± 0.5 in adductor (deep adductor vessel), 0.0 ± 0.0 in adductor (surface adductor vessels). The results showed a significant difference, two‐sided t‐test, p < 0.05, in number of vessels in all the locations. We have shown that this method can be utilized to elucidate the contribution of collateral vessels to arterial flow. Copyright © 2004 John Wiley & Sons, Ltd.
Effects of temperature on intracellular sodium, pH and cellular energy status in RIF‐1 tumor cells
Authors: Babsky Andriy , Hekmatyar S. K. , Wehrli Suzanne , Nelson David , Bansal Navin 
Published: March 2004

AbstractMost perfused tumor cell experiments are performed at 37°C, the normal healthy body temperature. However, the temperature of subcutaneously implanted tumors in small animals is generally 29–33°C when the rectal temperature of the animal is maintained at 37°C. We have investigated the acute effects of increasing the temperature of perfused radiation‐induced‐fibrosarcoma (RIF‐1) tumor cells from 33 to 37°C (30 min) on intracellular sodium $({\rm Na}_{\rm i}^+)$, intracellular pH (pHi), and bioenergetic status. Heating the cells by 4°C produced a reversible increase in ${\rm Na}_{\rm i}^+$, slight acidification and no change in nucleotide triphosphate to inorganic phosphate ratio (NTP/Pi) as measured by shift‐reagent‐aided 23Na and 31P NMR spectroscopy. In the presence of 3 μM 5‐(N‐ethyl‐N‐isopropyl) amiloride (EIPA), a potent and specific inhibitor of Na+/H+ antiporter, the increase in ${\rm Na}_{\rm i}^+$ during the heating was completely abolished suggesting that the heat induced increase in ${\rm Na}_{\rm i}^+$ was caused by an increase in Na+/H+ antiporter activity. However, the changes in pHi with the heating were identical with or without EIPA, indicating that pHi is controlled by other ion exchange mechanisms in addition to Na+/H+ antiporter. NTP/Pi was significantly higher in presence of EIPA for some time points during the heating suggesting that both NTP production and consumption rates may be altered during the heating. These results indicate that a slight increase in temperature from 33 to 37°C induces significant changes in Na+ physiology largely because of activation of Na+/H+ antiporter but other ion exchange mechanisms are also involved in maintaining pHi in the RIF‐1 tumor cells. Thus, care must be taken in choosing the temperature for perfused cell studies. Copyright © 2004 John Wiley & Sons, Ltd.
St John's wort induces both cytochrome P450 3A4–catalyzed sulfoxidation and 2C19–dependent hydroxylation of omeprazole
Authors: Wang Lian‐Sheng , Zhou Gan , Zhu Bing , Wu Jun , Wang Jian‐Gang , El‐Aty A. M. Abd , Li Tong , Liu Jie , Yang Tian‐Lun , Wang Dan , Zhong Xiang‐Yang , Zhou Hong‐Hao 
Published: March 2004

ObjectiveSt John's wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St John's wort to induce cytochrome P450 (CYP) 3A4–mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St John's wort on the pharmacokinetic profiles of omeprazole and its metabolites.MethodsTwelve healthy adult men (6 CYP2C19*1/CYP2C19*1, 4 CYP2C19*2/CYP2C19*2 and 2 CYP2C19*2/CYP2C19*3) were enrolled in a 2‐phase randomized crossover design. In each phase the volunteers received placebo or a 300‐mg St John's wort tablet 3 times daily for 14 days. Then all subjects took a 20‐mg omeprazole capsule orally. Blood samples were collected up to 12 hours after omeprazole administration. Omeprazole and its metabolites were quantified by use of HPLC with ultraviolet detection.ResultsOmeprazole and its metabolites all exhibit CYP2C19 genotype–dependent pharmacokinetic profiles. After a 14‐day treatment with St John's wort, substantial decreases in plasma concentrations of omeprazole were observed. The peak plasma concentration (Cmax) significantly decreased by 37.5% ± 13.3% (P = .001) in CYP2C19*2/CYP2C19*2 or *3 and by 49.6% ± 20.7% (P = .017) in CYP2C19*1/CYP2C19*1; the area under the concentration‐time curve extrapolated to infinity [AUC(0‐∞)] decreased by 37.9% ± 21.3% (P = .014) and 43.9% ± 23.7% (P = .011) in CYP2C19 mutant and wild genotypes, respectively. Moreover, the Cmax and AUC(0‐∞) of omeprazole sulfone increased by 160.3% ± 45.5% (P = .001) and by 136.6% ± 84.6% (P = .014), 155.5% ± 58.8% (P = .001), and 158.7% ± 101.4% (P = .017) in mutant and wild genotypes, respectively. St John's wort increased the Cmax of 5‐hydroxyomeprazole by 38.1% ± 30.5% (P = .028) and the AUC(0‐∞) by 37.2% ± 26% (P = .005) in CYP2C19 wild‐type subjects, whereas it did not produce any significant alterations to the corresponding pharmacokinetic parameters in subjects with variant genotypes.ConclusionSt John's wort induces both CYP3A4‐catalyzed sulfoxidation and CYP2C19‐dependent hydroxylation of omeprazole and enormously decreases the plasma concentrations of omeprazole. Clinically relevant interactions with other drugs may occur and must be taken into account when St John's wort is being taken.Clinical Pharmacology & Therapeutics (2004) 75, 191–197; doi: 10.1016/j.clpt.2003.09.014
CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy
Authors: Peyvandi Flora , Spreafico Marta , Siboni Simona Maria , Moia Marco , Mannucci Pier Mannuccio 
Published: March 2004

ObjectiveVariant alleles of the CYP2C9 gene encoding the cytochrome P450 (CYP) enzyme (2C9*2 [Arg144Cys] and 2C9*3 [Ile359Leu]) are known to increase the anticoagulant effect of warfarin and decrease the mean daily dose required to maintain the international normalized ratio (INR) of the prothrombin time within the target therapeutic range. However, little information is available on the effect of CYP2C9 polymorphisms on dose requirements during the most critical step of anticoagulant therapy, the induction phase.MethodsThis retrospective study evaluated the dosages given to 125 patients who started therapy with warfarin in a clinical center where physicians used the same approach for dosing and frequency of monitoring. CYP2C9 allelic variants were evaluated by polymerase chain reaction followed by restriction enzyme analysis.ResultsFrom the time of the first INR estimate (day 4) until the end of the induction phase (arbitrarily established at day 24), patients with 2C9*2 or 2C9*3 variant alleles required lower mean daily doses than patients carrying only wild‐type alleles 2C9*1 (−17% and −40%, P < .0001). They also more frequently had INR values above the upper limit of the target range (3.0) (65% for 2C9*2/− and 66% for 2C9*3/− versus 33% for 2C9*1/*1; P = .006 and .012, respectively).ConclusionsThe requirement of smaller doses of warfarin in relation to CYP2C9 polymorphisms is already manifest on the fourth day of treatment, at the time of the first INR estimate. CYP2C9 genotyping is as yet not warranted, but frequent INR monitoring with appropriate dose adjustments is recommended during the first 3 weeks of treatment to avoid overanticoagulation and the inherent risk of bleeding in carriers of variant alleles.Clinical Pharmacology & Therapeutics (2004) 75, 198–203; doi: 10.1016/j.clpt.2003.09.015
Glyburide Inhibits Dipyridamole‐induced Forearm Vasodilation but not Adenosine‐induced Forearm Vasodilation
Authors: Bijlstra Peter , van Ginneken Egidia E. M. , Huls Marc , van Dijk Rob , Smits Paul , Rongen Gerard A. 
Published: March 2004

BackgroundThe mechanism of the vasodilator response to adenosine has not been elucidated in humans. Stimulation of adenosine receptors on endothelial and vascular smooth muscle cells with subsequent endothelial release of nitric oxide and opening of adenosine triphosphate (ATP)–sensitive potassium (KATP) channels has been suggested.AimThe aim of this study was to investigate the involvement of KATP channels in the vasodilator response to adenosine and the nucleoside transport inhibitor dipyridamole.Methods and resultsIn healthy male volunteers, adenosine (0.6, 1.9, 5.6, 19, 57, and 190 nmol · min−1 · dL−1) was infused into the brachial artery, and forearm blood flow (FBF) was measured by use of strain‐gauge plethysmography. Adenosine increased the FBF ratio (FBF in experimental arm/FBF in control arm) from 1.3 ± 0.2 to 1.2 ± 0.2, 1.5 ± 0.2, 2.8 ± 0.4, 7.3 ± 2.3, 11.1 ± 4.1, and 12.9 ± 3.7 for the six increasing adenosine doses, respectively. Simultaneous infusion of glyburide (INN, glibenclamide), a blocker of KATP channels, did not affect this response (from 1.7 ± 0.4 to 1.5 ± 0.2, 2.2 ± 0.3, 4.0 ± 1.0, 9.3 ± 4.0, 13.5 ± 6.4, and 15.9 ± 5.3 for the 6 increasing doses of adenosine, respectively; P = .439, n = 6). The increase in FBF ratio during infusion of the nucleoside transport inhibitor dipyridamole (20, 60, and 200 nmol · min−1 · dL−1) was significantly reduced by glyburide, as follows: from 1.2 ± 0.1 to 1.7 ± 0.2, 2.4 ± 0.5, and 2.9 ± 0.4, respectively, during saline solution and from 1.6 ± 0.2 to 1.8 ± 0.2, 2.1 ± 0.3, and 2.2 ± 0.4, respectively, during glyburide (P = .010 for effect of glyburide on response from baseline, ANOVA for repeated measures; n = 8). The vasodilator response to dipyridamole was significantly inhibited by the adenosine receptor antagonist theophylline.ConclusionOpening of vascular KATP channels is involved in the forearm vasodilator response to dipyridamole but not to adenosine. Differences in stimulated cell type (endothelium for adenosine versus smooth muscle cells for dipyridamole) may underlie this divergent pharmacologic profile.Clinical Pharmacology & Therapeutics (2004) 75, 147–156; doi: 10.1016/j.clpt.2003.09.016
Cyclic antidepressants and the risk of sudden cardiac death
Authors: Ray Wayne A. , Meredith Sarah , Thapa Purushottam B. , Hall Kathi , Murray Katherine T. 
Published: March 2004

BackgroundTricyclic and other related cyclic antidepressants (TCAs), used frequently for the treatment of depression and several other indications, have cardiovascular effects that may increase the risk of sudden cardiac death. We thus sought to quantify the risk of sudden cardiac death among TCA users, according to dose, as well as among users of selective serotonin reuptake inhibitors (SSRIs).MethodsWe conducted a retrospective cohort study in Tennessee Medicaid, from Jan 1, 1988, through Dec 31, 1993, which included large numbers of antidepressant users and computer files describing medication use and comorbidity. The cohort included 1,282,091 person‐years of follow‐up for persons aged 15 to 84 years who were not in a nursing home and were free of life‐threatening noncardiac illness. This included 58,956 person‐years for current use of TCAs alone, 6291 person‐years for SSRIs only, and 96,220 person‐years for former use.ResultsThe cohort included 1487 confirmed sudden cardiac deaths occurring in the community. When compared with nonusers of antidepressants, current users of TCAs had a dose‐related increase in the risk of sudden cardiac death. Rate ratios increased from 0.97 (95% confidence interval [CI], 0.72–1.29) for doses lower than 100 mg (amitriptyline or its equivalent) to 2.53 (95% CI, 1.04–6.12) for doses of 300 mg or more (P = .03, test for dose‐response). The rate ratio for SSRIs was 0.95 (95% CI, 0.42–2.15). There was no evidence that TCA doses lower than 100 mg increased the risk of sudden cardiac death in subgroups defined by pre‐existing cardiovascular disease, female sex, age 65 years or older, or use of amitriptyline.ConclusionsOur data suggest that SSRI antidepressants and TCAs in doses of less than 100 mg (amitriptyline equivalents) did not increase the risk of sudden cardiac death. However, higher doses of TCAs were associated with increased relative risk, which suggests that such doses should be used cautiously, particularly in patients with an elevated baseline risk of sudden death.Clinical Pharmacology & Therapeutics (2004) 75, 234–241; doi: 10.1016/j.clpt.2003.09.019
Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin
Authors: Kamali Farhad , Khan Tayyaba Irfan , King Barry P. , Frearson Richard , Kesteven Patrick , Wood Peter , Daly Ann K. , Wynne Hilary 
Published: March 2004

ObjectiveOur objective was to assess the contribution of CYP2C9 genotype, age, body size, and vitamin K and lipid status to warfarin dose requirements.MethodsPatients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range of 2.0 to 3.0 were recruited to the study. On arrival at the clinic in the morning, after an overnight fast, a blood sample was taken from each patient for CYP2C9 genotyping and for determination of venous INR and plasma vitamin K, R‐ and S‐warfarin, and triglyceride concentrations.ResultsA total of 121 patients were recruited to the study. CYP2C9 genotyping showed that 74 patients were homozygous wild‐type (*1/*1), 30 were heterozygous *1/*2, and 15 were heterozygous *1/*3 genotype. One patient was found to have the genotype *2/*3, and another was found to have the genotype *3/*3. The mean warfarin daily dose requirement in milligrams fell from 4.06 ± 1.72 mg in homozygous wild‐type patients to 3.63 ± 1.78 mg for *1/*2‐positive patients and 2.70 ± 1.36 mg for *1/*3‐positive patients. The multiple linear regression model for warfarin dose indicated significant contributions from age (r = 0.41, P < .001), genotype (r = 0.24, P < .005), and age and genotype together (r = 0.45, P < .005). Although there were significant linear correlations between warfarin dose and body surface area (r = 0.21, P = .02), body weight (r = 0.25, P = .005), and plasma vitamin K concentration (r = 0.18, P < .05), none of these variables made a significant contribution to the regression model for warfarin dose. CYP2C9 genotype had a significant effect on S‐warfarin clearance (r = 0.34, P < .0001) but none on R‐warfarin clearance.ConclusionThis study showed that age and CYP2C9 polymorphism affect warfarin dose requirements in patients receiving long‐term therapy and having stable control of anticoagulation. It is anticipated that using dosing regimens modified to take into account the contribution of age and CYP2C9 genotype has the potential to improve the safety of warfarin therapy.Clinical Pharmacology & Therapeutics (2004) 75, 204–212; doi: 10.1016/j.clpt.2003.10.001
CYP2D6genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects
Authors: Giessmann Thomas , Modess Christiane , Hecker Ute , Zschiesche Michael , Dazert Peter , Kunert‐Keil Christiane , Warzok Rolf , Engel Georg , Weitschies Werner , Cascorbi Ingolf , Kroemer Heyo K. , Siegmund Werner 
Published: March 2004

BackgroundClinical trials have indicated that the combined β‐ and α‐adrenergic receptor blocker carvedilol improves the survival rate in patients with advanced chronic heart failure. The objective of our study was the identification and quantification of factors that modulate steady‐state serum concentrations of carvedilol and its enantiomers and that may influence therapeutic efficacy and safety.MethodsThe influence of genetic variants of cytochrome P450 (CYP) 2D6 and CYP2C9 and of transporter proteins (P‐glycoprotein, multidrug resistance protein 2 [MRP2]) on the disposition of carvedilol and its enantiomers after intravenous (5 mg) and long‐term oral administration (25 mg for 7 days) was assessed in 12 healthy subjects. The intestinal expression of P‐glycoprotein and MRP2 was analyzed by quantitative real‐time polymerase chain reaction and immunohistochemical techniques.ResultsThe area under the serum concentration–time curve (AUC) values of carvedilol were significantly (P< .05) increased in 6 subjects with CYP2D6 deficiency, with effects being more pronounced forR(+)‐carvedilol (230 ± 72.6 ng · h/mL versus 93.9 ± 64.6 ng · h/mL in extensive metabolizers) than forS(−)‐carvedilol (62.9 ± 21.1 ng · h/mL versus 32.7 ± 14.5 ng · h/mL). The AUC and fecal excretion of intravenous carvedilol were correlated with the intestinal expression ofMDR1messenger ribonucleic acid (mRNA) (r= −0.67,P= .001;r= 0.83,P= .002) andMRP2mRNA (r= −0.74,P< .001;r= 0.70,P= .025). Furthermore, we measured the disposition of long‐term oral carvedilol after comedication of the pregnane X receptor ligand rifampin (INN, rifampicin) (600 mg, 9 days), which up‐regulates both P‐glycoprotein and MRP2 but not CYP2D6. Rifampin decreased the AUC of carvedilol to an extent independent of the CYP2D6 genotype (poor metabolizers, 341 ± 147 ng · h/mL versus 126 ± 41.7 ng · h/mL; extensive metabolizers, 173 ± 102 ng · h/mL versus 74 ± 41.4 ng · h/mL; bothP< .05). The AUC was significantly correlated with intestinal expression ofMDR1mRNA (r= −0.671,P= .001) andMRP2mRNA (r= −0.595,P< .006).ConclusionsVariable plasma concentrations of carvedilol during long‐term administration are predicted by CYP2D6 genotype and intestinal expression of P‐glycoprotein and MRP2.Clinical Pharmacology & Therapeutics(2004)75, 213–222; doi:10.1016/j.clpt.2003.10.004
Activities of Cytochrome P450 1A2, N‐acetyltransferase 2, Xanthine oxidase, and Cytochrome P450 2D6 are Unaltered in Children with Cystic Fibrosis
Authors: Kennedy Mary Jayne , Scripture Charity D. , Kashuba Angela D. M. , Scott Christy S. , Gaedigk Andrea , Kearns Gregory L. 
Published: March 2004

The activities of hepatic cytochrome P450 (CYP) 1A2, N‐acetyltransferase 2 (NAT‐2), xanthine oxidase (XO), and CYP2D6 were evaluated in 12 young children (aged 3–8 years) with mild cystic fibrosis (CF) and 12 age‐matched healthy control subjects by use of standard caffeine and dextromethorphan phenotyping methods. Subjects were given 4 oz of Coca‐Cola (approximately 35 mg caffeine) (The Coca‐Cola Company, Atlanta, Ga) and a single 0.5‐mg/kg dose of dextromethorphan. Urine was collected for 8 hours after biomarker administration, and enzyme activity was assessed by use of previously validated caffeine and dextromethorphan molar ratios. CYP2D6 genotyping was also performed in 10 of 12 subjects with CF and 11 of 12 control subjects. There were no significant differences in the urinary molar ratios for any of the enzyme systems evaluated. These data suggest that CF does not alter the activities of CYP1A2, NAT‐2, XO, and CYP2D6. Altered biotransformation of drugs in this patient population is likely enzyme‐ and isoform‐specific and thus is apparent for only selected compounds that are substrates for enzymes other than CYP1A2, NAT‐2, XO, and CYP2D6.Clinical Pharmacology & Therapeutics (2004) 75, 163–171; doi: 10.1016/j.clpt.2003.10.005