The racemic selective serotonin reuptake inhibitor citalopram (CIT) is increasingly used for depressive disorders. As both enantiomers of CIT differ in pharmacologic activity and demethylated metabolites might contribute to the antidepressent action of CIT, a stereoselective assay for all active compounds is needed, but will require that pharmacokinetic/pharmacodynamic relationships be investigated. A stereoselective high-performance liquid chromatography (HPLC)-assay (Chirobiotic V column) with UV-detection (lambda = 240 nm) for R- and S-CIT as well as both enantiomers of desmethyl(DM)-CIT and didesmethyl(DDM)-CIT was developed. The calibration range was linear from 5 to 200 ng/mL and the lower limit of detection averaged 2 ng/mL. Based on three quality controls (10, 75, and 150 ng/mL) the intraday and interday coefficients of variation ranged from 1.3% to 9.0% for CIT and from 2.2% to 10.3% for DM-CIT and DDM-CIT. The assay was used to analyze the trough steady state plasma levels of all 6 agents in 16 elderly patients treated daily with 20 to 40 mg CIT. For the dose of 20 mg (n = 14) mean values +/- SD of R- (and S-CIT) averaged 36.2+/-15.0 (27.4+/-13.1) ng/mL, respectively (mean R/S-ratio: 1.4+/-0.4), for R- (and S-DM-CIT) 7.2+/-3.1 (7.7+/-3.8) ng/mL, respectively (R/S-ratio: 1.0+/-0.3) whereas DDM-CIT was only detectable as R-enantiomer in 8 cases (13.2+/-12.1 ng/mL; range: 2.2-36.2 ng/mL). Significant (p < 0.01) linear correlations could be found between both enantiomers of CIT and DM-CIT as well as between parent drug and primary metabolite for the R-enantiomers. Apparently R/S- and metabolic ratios increased with dose; this might indicate that stereoselective disposition of CIT and DM-CIT is concentration-dependent. The present assay allows a rapid, sensitive, and reliable stereoselective determination of CIT and its (active) metabolites which can be applied for assessing pharmacokinetic parameters and evaluating putative relationships to clinical (side) effects.

Aims Theophylline is a model substrate of cytochrome P4501A2. The ability of the proton pump inhibitors (PPI) omeprazole, lansoprazole and pantoprazole to induce cytochrome P4501A2 has not yet been unequivocally resolved. The aim of this comprehensive study was to compare directly the effect of the three PPI on the absorption and disposition of theophylline. Methods Twenty healthy, nonsmoking, male and female volunteers (extensive metabolisers of cytochrome P4502C19 and Helicobacter pylori negative) participated in a randomized, double-blind, four-period, placebo-controlled crossover study. In each of the four periods they received either omeprazole (40 mg), lansoprazole (60 mg), pantoprazole (80 mg) or placebo once daily for 10 days. Sustained release theophylline (350 mg twice daily) was coadministered from day 8-10. Pharmacokinetics of theophylline as well as of all three PPI were determined at steady-state (day 10). Results In all periods, point estimates and 90% confidence intervals of the area under the concentration-time curves (AUC), maximum steady-state concentrations and peak-trough fluctuations of theophylline were not altered by PPI pretreatment and met the required limits for bioequivalence. Point estimates (90% confidence intervals) of the AUC ratios of theophylline plus PPI to theophylline alone were 0.92 (0.87-0.97), 0.90 (0.85-0.95) and 1.00 (0.95-1.06) for omeprazole, lansoprazole and pantoprazole, respectively. Conclusions Concomitant intake of omeprazole, lansoprazole or pantoprazole at high therapeutic doses does not affect the absorption and disposition of theophylline.Keywords: cytochrome P4501A2, drug interaction, proton pump inhibitors, theophylline isoenzymes of cytochrome P450 [6][7][8][9][10][11]. For example, Introduction omeprazole and lansoprazole were shown to be inducers of cytochrome P4501 A2 (CYP1A2) in human liver and The H + , K + -ATPase ( proton pump) inhibitors (PPI) omeprazole, lansoprazole and pantoprazole have been alimentary tract in vitro and in vivo [12][13][14]. The extent of CYP1A2 induction by omeprazole was dependent proved effective as monotherapy for gastric or duodenal ulcers and gastro-oesophageal reflux, and in combination both on the dose and the CYP2C19 phenotype resulting in a significant effect at lower doses of omeprazole in regimens for the eradication of Helicobacter pylori [1][2][3]. These drugs are structurally very similar and they are the subset of poor metabolisers of CYP2C19 [15]. Pantoprazole has been claimed to have less potential than mainly metabolized by the polymorphically expressed cytochrome P4502C19 (CYP2C19), which means that omeprazole and lansoprazole to interact with other drugs metabolized by cytochrome P450 enzymes [16, 17]. In about 3% of Caucasians ( poor metabolisers of CYP2C19) eliminate the compounds more slowly than the majority general, putative induction of CYP1A2 by PPI in vivo is highly controversial as clinical studies have shown that (extensive metabolisers of CYP2C19) of the Caucasian population [4,5]. As a class, be...

Stromal cell-derived factor-1 (SDF-1) is expressed in a wide variety of organs, such as heart, and plays a pivotal role in the mobilization of hematopoietic stem and progenitor cells in bone marrow. SDF-1α, a common subtype of SDF-1, may control hematopoiesis and angiogenesis, but its role in the pathogenesis of hyperlipidemia is unknown. The aim of this study was to determine the role of SDF-1α in the pathogenesis of hyperlipidemia. First, log-transformed SDF-1α serum levels (logSDF-1α) were significantly higher in male patients with borderline high lipid profile (BHLP; n = 28; 2.15 ± 0.08 ng/ml) compared to control subjects (n = 37; 1.94 ± 0.06 ng/ml; P < 0.01). The logSDF-1α in male patients with high lipid profile (HLP; n = 33; 1.95 ± 0.08 ng/ml) were lower than BHLP patients (P < 0.01). The logSDF-1α was positively associated with HDL-C only in female patients (n = 125; r = 0.379, P = 0.016). These results suggest the different pathophysiology in male and female patients with hyperlipidemia. Moreover, flow cytometry analysis showed that expression of the SDF-1α receptor, CXC-chemokine receptor 4, was lower in peripheral blood mononuclear cells of patients with BHLP (n = 10) and HLP (n = 10), compared to control subjects (n = 10; P < 0.001). Lastly, peripheral blood leukocyte, neutrophil and lymphocyte counts were higher in BHLP patients (n = 62; P < 0.05). Taken together, we suggest SDF-1α as a biomarker of hyperlipidemia that may be helpful to uncover the pathogenesis of hyperlipidemia.

Background: The study aimed to use machine learning algorithms to predict the need for revascularization in patients presenting with chest pain to the emergency department.Methods: We obtained data from 581 patients with chest pain, 264 who underwent revascularization, and the other 317 were treated with medication alone at 3 months. Using standard algorithms, linear discriminant analysis, and standard algorithms, we analyzed 41 features relevant to coronary artery disease (CAD). Results: We identified seven robust predictive features. The combination of these predictors gave an area under the curve (AUC) of 0.830 to predict the need for revascularization. By contrast, the GRACE score gave an AUC of 0.68.Conclusions: This machine learning-based approach predicts the need for revascularization in patients with CAD.