Milena Pokrajac

Prevalence of menstrually related migraine and nonmigraine primary headache in female students of Belgrade University.

Objectives.—To determine prevalence and characteristics of menstrually related migraine and nonmigraine headache in female students of Belgrade University.

Impact of age, weight and concomitant treatment on lamotrigine pharmacokinetics

What is known and Objective:  Lamotrigine metabolism may be substantially altered with concomitant administration of valproic acid and/or carbamazepine. Such alterations may require the adjustment of lamotrigine dose to ensure optimal treatment efficacy and safety.

Evaluation of Single‐Point Sampling Strategies for the Estimation of Moclobemide Exposure in Depressive Patients

Because moclobemide pharmacokinetics vary considerably among individuals, monitoring of plasma concentrations lends insight into its pharmacokinetic behavior and enhances its rational use in clinical practice. The aim of this study was to evaluate whether single concentration—time points could adequately predict moclobemide systemic exposure. Pharmacokinetic data (full 7‐point pharmacokinetic profiles), obtained from 21 depressive inpatients receiving moclobemide (150 mg 3 times daily), were randomly split into development (n = 18) and validation (n = 16) sets. Correlations between the single concentration—time points and the area under the concentration—time curve within a 6‐hour dosing interval at steady‐state (AUC0–6) were assessed by linear regression analyses. The predictive performance of single‐point sampling strategies was evaluated in the validation set by mean prediction error, mean absolute error, and root mean square error. Plasma concentrations in the absorption phase yielded unsatisfactory predictions of moclobemide AUC0–6. The best estimation of AUC0–6 was achieved from concentrations at 4 and 6 hours following dosing. As the most reliable surrogate for moclobemide systemic exposure, concentrations at 4 and 6 hours should be used instead of predose trough concentrations as an indicator of between‐patient variability and a guide for dose adjustments in specific clinical situations.

Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. Valproic acid (VPA) and carbamazepine (CBZ) have been found to interact with psychotropic medications of all classes and many other drugs; VPA acts as a broad-spectrum inhibitor, and CBZ as a potent inducer of a variety of drug-metabolizing enzymes. There have been no previous studies designed to investigate a potential pharmacokinetic (PK) interaction between MCB and VPA or CBZ; however, these agents are likely to be used concomitantly for the treatment of depressive disorders. WHAT THIS STUDY ADDS VPA does not significantly affect PK or metabolism of MCB at steady state. CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration. AIM To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. METHODS Twenty-one inpatients with recurrent endogenous depression received MCB (150 mg t.i.d.), either as monotherapy or in combination with VPA (500 mg b.i.d.) or CBZ (200 mg b.i.d.) in a nonrandomized manner. Steady-state plasma PK parameters of MCB and its two metabolites, Ro 12-8095 and Ro 12-5637, were derived. Clinical assessments of treatment efficacy were performed weekly using standard depression rating scales. RESULTS CBZ, but not VPA, was associated with decreases in the MCB AUC by 35% [from 7.794 to 5.038 mg h l(-1); 95% confidence interval (CI) -4.84863, -0.66194; P = 0.01] and C(max) by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P < 0.05), and an increase in its oral clearance by 41% (from 0.323 to 0.454 l h(-1) kg(-1); 95% CI 0.00086, 0.26171; P < 0.05) after 4 weeks of co-administration. MCB through concentrations were also decreased, on average by 41% (from 0.950 to 0.559 mg l(-1); 95% CI -0.77479, -0.03301; P < 0.05). However, the efficacy in this group of patients was not inferior to the controls, for several possible reasons. Overall tolerability of all study medications was good. CONCLUSIONS VPA does not significantly affect PK or metabolism of MCB, whereas CBZ time-dependently decreases MCB exposure, probably by inducing metabolism of MCB and its major plasma metabolite. The actual clinical relevance of the observed MCB-CBZ PK interaction needs to be further evaluated in a more comprehensive study.

Clinical response and plasma concentrations of amitriptyline and its metabolite-nortriptyline in depressive patients

SummaryAlthough many attempts have been made, to date no convincing evidence exists of a relationship between plasma concentrations of amitriptyline (AT), its active metabolite nortriptyline (NT) and clinical response. Fifteen patients with primary depression (according to DSM-IV) were divided in two groups according to given doses: (I) 6 patients received 3×50 mg of AT daily; and (II) 9 patients received 3×25 mg of AT daily, for 6 weeks. The clinical status was determined with Hamilton Depression Rating Scale. Both investigated doses were therapeutically effective. AT and NT plasma concentrations were assayed by high performance liquid chromatography. Following administration of 3×50 mg of AT daily, the correlation of concentrations of AT, NT, total AT+NT and clinical response were rAT=−0.702 (P<0.1), rNT=−0.761 (P<0.1), rAT+NT=−0.741 (P<0.1). The linear and very high correlation were also present with concentrations of AT, NT, total AT+NT and clinical response in depressive patients on 3×25 mg AT daily: rAT=−0.785 (P<0.02), rNT=−0.811 (P<0.01), rAT+NT=−0.848 (P<0.01). Our results support a high correlation between AT/NT plasma concentrations and clinical response indicating that therapeutic monitoring of AT and its metabolite, NT, can provide eventual clinical response.

Quantitative analysis of nimesulide in plasma by thin-layer chromatography: Application to pharmacokinetic studies in man

A thin-layer chromatographic (TLC) method for quantitative analysis of nimesulide in human plasma has been developed, validated, and applied to a pharmacokinetic study of healthy volunteers. Apreviously published method has been modified and simplified (instead of two-step sample preparation a single step extraction procedure was employed) which makes the new method time-saving. Nimesulide plasma concentrations were analyzed after singlestep extraction with dichloromethane. The sample preparation procedure described enables efficient extraction—recoveries were 99 ± 8% (mean ± SD). Chromatography was performed on silica gel 60 F254 TLC plates, developed with toluene—acetone, 100 + 10 ((v/v)) and evaluated densitometrically at λ = 310 nm in reflectance—absorbance mode. The RF was 0.5025. The method presented is characterized by high sensitivity (0.1 mg L−1) and within-run and day-to-day coefficients of variation of 2.8–4.5% and 4.8–8.5%, respectively. The method was used to determine the pharmacokinetic profile of nimesulide in healthy volunteers after oral administration.

Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease

SummaryThe pharmacokinetics of theophylline was investigated in five hyperthyroid, five hypothyroid, and five euthyroid patients, all with chronic obstructive pulmonary disease. Wide individual variability was found in theophylline kinetics, but the rate of elimination of theophylline was significantly higher in hyperthyroid, and lower in hypothyroid patients than in the euthyroid patients (kel=0.155, 0.060 and 0.107 h−1, respectively). The values for clearance and volume of distribution were not consistently changed compared with those in the euthyroid group, although all the parameters except AUC were significantly different in hyperthyroid and hypothyroid patients. There was a positive correlation between both thyroxine and triiodothyronine serum concentrations and total body clearance of theophylline (r=0.795 and r=0.791, respectively). It is concluded that in spite of the wide interindividual variability and the relatively small differences in the pharmacokinetics of theophylline in thyroid dysfunction compared with the euthyroid status, these differences have to be considered in certain clinical situations, as they may require changes in the therapeutic regimen for administration of theophylline in hyperthyroid or hypothyroid patients.

Solid-Phase Extraction and High Performance Liquid Chromatographic Determination of Amitriptyline and Nortriptyline in Human Plasma

Abstract A simple, rapid, cost-efficient solid-phase extraction and high performance liquid chromatographic method for the determination of amitriptyline and nortriptyline in human plasma is described. After conditioning of solid-phase sorbent diluted plasma samples were passed through the cartridge. Potentially interfering substances were washed, followed by elution of amitriptyline, nortriptyline and maprotiline (internal standard) from the sorbent. Eluates were collected, evaporated, reconstituted and injected directly and monitored at 215 nm. Samples were chromatographed on a 5 μm Supelcosil LC-PCN (150 × 4.6 mm) using 0.01 M dipotassium hydrogenphosphate (pH adjusted to 7 with 85% ortophosphoric acid)/ acetonitrile/methanol (15:60:25. v/v) as the mobile phase. Recoveries for amitriptyline and nortriptyline were 96% and 85%, respectively. The limit of detection and quantification for amitriptyline and nortriptyline were 1 ng/mL and 5 ng/mL, respectively. The calibration curves for amitriptyline and no...

Determination of Moclobemide and its Metabolites in Human Plasma by SPE-HPLC-UV: Evaluation of Critical Experimental Conditions and QSRR Study

Abstract A SPE-HPLC-UV method for determination of moclobemide and its major metabolites, Ro 12-5637 and Ro 12-8095, in human plasma had been developed previously and its selectivity was evaluated against the most frequently coadministered drugs. The objective of the present work was to develop a quantitative structure retention relationship (QSRR) model capable of providing good predictions of chromatographic behaviour of other related potentially interfering drugs, based on the previously generated data, in order to further improve the clinical applicability of the existing method. Moreover, the most critical factors affecting SPE and chromatographic separations of moclobemide and its metabolites were evaluated and discussed, taking into account molecular properties of the analyzed compounds.

Cerebrospinal Fluid and Plasma Pharmacokinetics of Phenobarbital after Intravenous Administration to Patients with Status Epilepticus

SummaryThe cerebrospinal fluid (CSF) and plasma pharmacokinetics of phenobarbital were studied after intravenous administration to 5 epileptic patients with convulsive status epilepticus and 6 seizure-free patients with newly diagnosed epilepsy. Phenobarbital (15 mg/kg) was infused at a rate of 100 mg/min. Plasma was collected prior to and throughout 24 hours after drug administration. The CSF samples were obtained by lumbar puncture 2 hours after the institution of phenobarbital infusion. Phenobarbital concentrations in plasma and the CSF were measured by reversed-phase liquid chromatography. The plasma values of pharmacokinetic variables of distribution and elimination did not differ between the groups. Slightly lower phenobarbital concentrations in the group of patients experiencing status epilepticus compared with seizure-free epileptic patients during the first hours after drug administration and the resultant elevated value of the rate constant of distribution (α) did not reach statistical significance, probably due to the small number of participants in the study. Phenobarbital concentrations were approximately 40% higher in the CSF of epileptic patients with status epilepticus compared with nonconvulsing subjects. The rate constant of phenobarbital distribution in the CSF (the ratio of the CSF concentration of the drug at time t1 and the area under the plasma concentration-time curve up to t1) in epileptic patients with status epilepticus exceeded that in seizure-free patients (0.29 ± 0.06h−1vs 0.19 ± 0.05h−1, p < 0.05). The study demonstrated statistically significantly higher phenobarbital concentrations and more rapid appearance of phenobarbital in the CSF of epileptic patients with status epilepticus compared with nonconvulsing patients with epilepsy. The alteration in the pharmacokinetics of phenobarbitone in patients experiencing status epilepticus reported here additionally supports the reported efficacy of intravenous phenobarbital in the treatment of this neurological disorder.