Platelet aggregation and risk of stent thrombosis or bleeding in interventionally treated diabetic patients with acute coronary syndrome.

BACKGROUND: Platelet aggregation monitoring in diabetic patients treated with coronary interventions (PCI) for an acute coronary syndrome (ACS) is a promising way of optimizing treatment and outcomes in this high risk group. The aim of the study was to verify whether clopidogrel response measured by Multiplate analyzer (ADPtest) in diabetic ACS patients treated with PCI predicts the risk of stent thrombosis or cardiovascular mortality and bleeding. METHODS: Into this prospective, observational study 206 elective PCI patients were enrolled. Two cutoff points of ADPtest were used in analysis to divide patients into groups. One (345 AU x min) was calculated based on ROC curve analysis; this cutoff provided the best ROC curve fit, although it did not reach statistical significance. The other (468 AU x min) was accepted based on the consensus of the Working Group on On-Treatment Platelet Reactivity. The risk of stent thrombosis and mortality was assessed using Cox regression analysis and Kaplan-Meier curves. RESULTS: The risk of stent thrombosis was higher in the group of patients with impaired clopidogrel response for either cutoff value (for >354 AU x min - HR 12.33; 95% CI 2.49-61.1; P = 0.002). Cardiovascular mortality was also higher in the impaired clopidogrel response group (for >354 AU x min - HR 10.58; 95% CI 2.05-54.58; P = 0.005). We did not find a clear relation of increased clopidogrel response to the risk of bleeding. CONCLUSIONS: The results of this study show that in diabetic ACS patient group treated with PCI an impaired platelet response to clopidogrel measured by the Multiplate analyzer results in increased risk of stent thrombosis and cardiac death.

A limited sampling strategy for estimating mycophenolic acid area under the curve in adult heart transplant patients treated with concomitant cyclosporine.

OBJECTIVE: Heart transplantation studies have shown a relationship between the mycophenolic acid area under the curve (AUC) 0-12 h (MPA AUC(0-12h)) values and risk of acute rejection episodes and fewer side-effects in patient receiving cyclosporine during the first year post-transplant. However, measurement of full AUC is costly and time consuming and in this case it is an impractical approach to drug monitoring. Therefore, the authors describe a limited sampling strategy to estimate the MPA AUC(0-12h) value in adult heart transplant recipients. METHODS: Ninety MPA pharmacokinetic (PK) profiles were studied. The samples were collected immediately before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12 h after the morning dose of mycophenolate mofetil (MMF) following an overnight fast. PK profiles were determined at 6-8 weeks, 6, 12 months and more than 1 year after transplantation. Using stepwise multiple linear regression analysis a sampling strategy from 60 of PK profiles was obtained and next the bias and precision of the model were evaluated in another 30 PK profiles. RESULTS: The three-point model using C(0.5h), C(1h), C(2h) was found to be superior to all other models tested (r(2) = 0.841). The regression equation for AUC estimation which gave the best fit to this model is: 9.69 + 0.63C(0.5) + 0.61C(1) + 2.20C(2). Using that model 63 of the 90 (70%) full AUC values were estimated within 15% of their actual value. For the best-fit model, the mean prediction error was 3.2%, with 95% confidence intervals for prediction error to range from -42.2% to 40.3%. All other models which use one, two or three time-points over the first 2 h are poorer predictors of the full AUC than the model above. CONCLUSION: The proposed three time-point equation to estimate AUC will be helpful in optimizing immunosuppressive therapy in heart transplantation.

Determination of loratadine in human plasma by high-performance liquid chromatographic method with ultraviolet detection.

A HPLC-UV determination of loratadine in human plasma is presented. After simple liquid-liquid extraction with 2-methylbutane-hexane (2:1) and evaporation of organic phase the compounds were re-dissolved in 0.01 M HCl, evaporated again and finally separated on a Supelcosil LC-18-DB column. The analyses were done at ambient temperature under isocratic conditions using the mobile phase: CH3CN-water-0.5 M KH2PO4-H3PO4 (440:480:80:1, v/v). UV detection was performed at 200 nm with a limit of quantification of 0.5 ng/ml. The precision was found to be satisfactory over the whole range tested (0.5-50 ng/ml) with relative standard deviations of 2.3-6.3 and 5.2-14.1% for intra- and inter-assays, respectively.

Simple and sensitive high-performance liquid chromatographic method for the determination of 1,5-benzodiazepine clobazam and its active metabolite N-desmethylclobazam in human serum and urine with application to 1,4-benzodiazepines analysis.

A HPLC-UV determination of clobazam and N-desmethylclobazam in human serum and urine is presented. After simple liquid-liquid extraction with dichloromethane the compounds and an internal standard diazepam were separated on a Supelcosil LC-8-DB column at ambient temperature under isocratic conditions using the mobile phase: CH3CN-water-0.5 M KH2PO4-H3PO4 (440:540:20:0.4, v/v and 360:580:60:0.4, v/v for serum and urine, respectively). The detection was performed at 228 nm with limits of quantification of 2 ng/ml for serum and 1 ng/ml for urine. Relative standard deviations for intra- and inter-assay precision were found below 8% for both compounds for all the tested concentrations. The described procedure may be easily adapted for several 1,4-benzodiazepines.

Therapeutic drug monitoring in depression.

The difference between Therapeutic Drug Monitoring (TDM) and uncontrolled therapy consists in the fact that in TDM we can predict a certain scheme of treatment according to clinical and laboratory results. It is a method which serves to increase the efficacy and safety of pharmacotherapy in an individual patient. This paper presents the results of the treatment with tricyclic antidepressants based on the monitoring of serum drug level in 32 patients with indications for using pharmacogenetic as well as pharmacoelectroencephalographic tests. Clinical status of the patients was evaluated according to: Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), Clinical Global Impression Scale (CGIS), and TCA concentration in serum was determined using Fluorescence Polarization Immunoassay (FPIA). Hydroxylation phenotype was determined using debrisoquine as a model drug. EEG was recorded in four leads: F3-C3, F4-C4, P3-O1, P4-O2. In the present study, we did not found any significant correlation between clinical status and serum TCAs concentrations measured by FPIA method. Efficacy of antidepressant treatment and stabilization of serum TCA concentrations depended largely upon the time course of the treatment. Debrisoquine phenotyping revealed the presence of one poor metabolizer (MR = 15) in the examined group of patients. A significant improvement in the clinical status of the patients, the stabilization of therapeutic drug concentrations, the appearance of antidepressive profiles in the pharmaco-EEG profile after 14 days of therapy, as well as the starting value determined by SERS were shown to be prognostic factors for the further antidepressant therapy.

[Evaluation of the rate for reaching steady state during oral propafenone therapy in patients with ventricular arrhythmias]. / Ocena szybkosci uzyskiwania stanu stacjonarnego w trakcie doustnego leczenia propafenonem chorych z komorowymi zaburzeniami rytmu.

UNLABELLED: We prospectively evaluated reaching of steady state and clinical efficacy of propafenone (PPF), class Ic antiarrhythmic agent, in 16 patients (pts) (age 46-69, mean 57 years) with symptomatic ventricular arrhythmias (Low class II and IV). The majority (13 pts) had coronary artery disease. Drug was administered for 7 days (daily dose: 3 x 150 mg). Efficacy was defined as > 80% reduction of ventricular premature complexes (VPC) and class IV elimination in 24-hours Holter recording. Responders were continued on PPF for 3 weeks, in non-responders dose was titrated to 900 mg a day for the next 7 days. After second Holter evaluation the treatment was continued for 2 weeks in responders group. The non-responders were switched to other drug. After 4 weeks final Holter monitoring was performed. Serum concentration of PPF and its 2 metabolites: 5-hydroxy PPF and N-depropyl PPF were determined in 2, 3, 4, 5, 6, 7th day, just before the morning dose (3 x 150 mg/day) in 9 pts. RESULTS: Trough serum concentrations of PPF differed in high degree: 0-226 ng/ml (2nd day), 22-438 ng/ml (4th day), 42-614 ng/ml (6-7 day). An increasing tendency of serum concentrations of PPF was observed, so steady-state was not reached. This great dispersion of concentration values is because of non-linear metabolism and individual differences. Defined efficacy critetion was achieved in 62% pts, 56% for lower dose. Mean frequency of VPC was reduced by 86% in 24-hour Holter recording and per hour (p = 0.0011). Reduction of couplets/24 h was 87% (p = 0.0175). Significant prolongation of PQ (14%, p = 0.009) and QRS (13%, p = 0.0052) were observed. Changes of QT interval were not significant. One case of proarrhythmia was the cause of stopping the treatment. CONCLUSIONS: Serum concentrations' values undermine common opinion, that steady state can be reached after 1-2 days of treatment. High dispersion of serum levels is the result of nonlinear metabolism of PPF and individual differences. In spite of this the study showed defined antiarrhythmic efficacy in 62.5% pts. In this group 90% success rate was achieved after lower dose 3 x 150 mg.

Debrisoquine hydroxylation in a Polish population.

The genetic polymorphism of drug oxidation mediated by cytochrome P450IID6 (CYP2D6) was determined in 154 Polish volunteers using debrisoquine as the test substance. The results showed a bimodal distribution of the debrisoquine metabolic ratio (MR). Nine persons (5.8%) with MR > 12.6 were classified as poor metabolisers (gene frequency 0.242), which is in substantial agreement with the data reported for other Caucasian populations.

High-performance liquid chromatographic method for the simultaneous determination of propafenone and 5-hydroxypropafenone in human serum.

A simple, rapid and sensitive high-performance liquid chromatographic method for the simultaneous determination of propafenone and 5-hydroxypropafenone in human serum is described. Method involves a single-step extraction of the drug and its metabolite with dichloromethane:2-propanol (4:1 v/v) mixture from 0.2 ml of serum. Separation of the investigated compounds on deactivated Supelcosil LC18-DB column is accomplished by ultraviolet detection at 210 nm. The limit of detection is 10 ng/ml for propafenone and 4 ng/ml for 5-hydroxypropafenone. The method is useful for the routine monitoring of propafenone and its main metabolite in serum as well as for the pharmacokinetic studies.