Clinical pharmacology in Russia-historical development and current state.

Clinical pharmacology in Russia has long history and is currently active, but rather unrecognized internationally. It is governmentally approved as a teaching/scientific specialty since 1983 and as a medical specialty since 1997. Courses of clinical pharmacology are included in the undergraduate curricula in the 5th and/or 6th year of education at all medical schools in the Russian Federation. Postgraduate education includes initial specialization in internal medicine with further residency in clinical pharmacology. Governmental legislation recommends that every healthcare institution has either a department or a single position of clinical pharmacologist. Major routine duties include information about and monitoring of medication use, consultations in difficult clinical situations, pharmacogenetic counseling, therapeutic drug monitoring, pharmacovigilance, and participation in drug and therapeutics (formulary) committees. There are official experts in clinical pharmacology in Russia responsible for coordinating relevant legislative issues. The chief expert clinical pharmacologist represents the discipline directly at the Ministry of Health. Research in clinical pharmacology in Russia is extensive and variable, but only some of it is published internationally. Russia is a participant of international societies of clinical pharmacology and therapeutics and collaboration is actively ongoing. There are still certain problems related to the development of the discipline in Russia-some healthcare institutions do not see the need for clinical pharmacology. However, the number of clinical pharmacologists in Russia is increasing as well as their role in physicians' education, national healthcare, and research.

CYP2D6 is a major determinant of metoprolol disposition and effects in hospitalized Russian patients treated for acute myocardial infarction.

PURPOSE: To investigate individual metabolism-related determinants of metoprolol disposition and effects in patients receiving the drug as standard treatment for acute myocardial infarction (AMI). METHODS: We recruited 187 AMI patients receiving metoprolol on clinical grounds and genotyped them for CYP2D6 *3, *4, *10, and gene duplication. Heart rates (HR) at admission and discharge were registered. Clinical details were derived from the case histories. Metoprolol and alpha-hydroxy-metoprolol were analyzed by HPLC in plasma before and after 2, 6 and 12 h post dose in the first 115 patients. HR at rest was registered after each sampling. Ventricular rhythm disturbance (VRD) association with CYP2D6 activity, found accidentally, was studied in a newly formed subgroup (n = 23). RESULTS: Metoprolol represented 85% of all beta-blocker prescriptions. CYP2D6 genotype distribution was comparable with other Caucasian populations. Genotypically poor metabolizers (PM, n = 2) exhibited the most pronounced bradycardia at discharge, while in the ultrarapid metabolizers (UM, n = 7) therapeutic effect was not achieved. Metoprolol and alpha-hydroxy-metoprolol plasma concentration AUCs differed significantly between the genotypes corresponding to predicted metabolic activity (P < 0.005). Correspondingly, the mean HRs were lower in PMs and increased with increasing number of active CYP2D6 genes (P < 0.05). Trough metoprolol concentrations were only quantifiable in patients with at least one mutated allele. Neither decreased cardiac ejection fraction nor age and gender influenced metoprolol disposition. Higher mean number of active CYP2D6 genes was found in patients with VRDs (2.2 vs. 1.7), which could not be clearly explained by metoprolol concentrations. CYP2D6 gene duplication was overrepresented in this group (22 vs. 2%, P = 0.0002). CONCLUSION: Metoprolol disposition and effects are mainly controlled by CYP2D6 genotype. Patients with gene duplication are at high risk of not benefiting from treatment due to lower metoprolol concentrations. Higher CYP2D6 activity seems to be associated with VRDs complicating AMI, being a negative prognostic factor for patients' survival.

Quality use of medicines: a new method of combining antibiotic consumption and sensitivity data--application in a Russian hospital.

PURPOSE: Antibiotic use and resistance is subject of great concern. There is a need for internationally comparable and locally useful data collection and reporting. We developed a new method to combine and present data on antibiotic use and resistance in a figure in a Russian 1300 bed-hospital. METHODS: We applied World Health Organization (WHO) Anatomic Therapeutic Chemical (ATC) classification/defined daily doses (DDD) analysis on antibacterials for systemic use (ATC: J01) delivered by the pharmacy for the years 2003-2005. Microbial resistance data were presented within the range of drugs accounting for 90% of the volume in DDD, i.e. drug utilisation 90% (DU90%). RESULTS: From the DU90% profile the following was seen: in 2003, 12 of 25 drugs accounted for 90% of the volume. For six of the most commonly used antibiotics, including the two cheapest (gentamicin, ampicillin), a significant number of the strains tested were resistant. For the remaining antibiotics no resistance data were available. These data were discussed in early 2004. A general decrease of antibiotic use and resistance was seen in 2005 (by 57% from 15.5 to 8.8 DDD/100 bed days) with a concomitant decrease in expenditures (by 64%) and a shift to more potent antibiotics. CONCLUSIONS: The created profile highlighted potential problems in a clear and easy form. Besides being an indicator of the quality of antibiotic use it was a powerful alert and driving force for change. It can be used for external comparisons and for local monitoring of antibiotic use and resistance and can be applied with routinely available data in any hospital.

Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI).

OBJECTIVE: To investigate the influence of paroxetine on metoprolol concentrations and its effect in patients treated for acute myocardial infarction (AMI) who are routinely given paroxetine as a co-treatment of depression. METHODS: We recruited 17 depressed AMI patients who received metoprolol as a routine part of their therapy (mean dose 75 +/- 39 mg/day). Patients were genotyped for CYP2D6 3, 4 and gene duplication. Metoprolol and alpha-hydroxy-metoprolol were analyzed in plasma 0, 2, 6 and 12 h post-dose. Heart rates (HR) at rest were registered after each sampling. Paroxetine 20 mg daily was then administered, and all measurements were repeated on day 8. RESULTS: All patients were genotypically extensive metabolizers (EMs) (nine with 1/1 and eight with 1/3 or 4). Following the administration of paroxetine, mean metoprolol areas under the concentration-time curve (AUC) increased (1064 +/- 1213 to 4476 +/- 2821 nM x h/mg per kg, P = 0.0001), while metabolite AUCs decreased (1492 +/- 872 to 348 +/- 279 n M x h/mg per kg, P < 0.0001), with an increase of metabolic ratios (MR) (0.9 +/- 1.3 to 26 +/- 29; P < 0.0001). Mean HRs were significantly lower after the study week at each time point. Mean area under the HR versus time curve (AUEC) decreased (835 +/- 88 to 728 +/- 84 beats x h/min; P = 0.0007). Metoprolol AUCs correlated with patients' AUECs at the baseline (Spearman r = -0.64, P < 0.01), but not on the eighth day of the study. A reduction of metoprolol dose was required in two patients due to excessive bradycardia and severe orthostatic hypotension. No other adverse effects of the drugs were identified. CONCLUSION: A pronounced inhibition of metoprolol metabolism by paroxetine was observed in AMI patients, but without serious adverse effects. We suggest, however, that the metoprolol dose is controlled upon initiation and withdrawal of paroxetine.