[Efficacy of Management for Rational Use of Antibiotics in Surgical Departments at a Multi-Disciplinary Hospital: Results of a 7-year Pharmacoepidemiological Research].

Background: Irrational medicine use including excessive use and abuse of antibiotics remains a crucial problem for the healthcare systems. In this regard, studies examining approaches to improving the clinical use of medicines are highly important. Aim: to assess the efficacy rate of management for the rational use of antibiotics in surgical departments of a multi-disciplinary hospital. Material and Methods: The intervention complex combined the research, educational, and methodological activities: local protocols for perioperative antibiotic prophylaxis (PABP) for various surgical departments were developed; local PABP protocols were discussed with the physicians of specialized surgical departments; official order on implementation of PABP was issued; the list of drug prescriptions for registration of the first pre-operative antibiotic dose was changed; audit and feedback processes were introduced as well as consultations of a clinical pharmacologist were implemented. We assessed the efficacy rate of the interventions basing on the changes in consumption of antibiotics (both quantitatively and qualitatively) at surgical departments of a hospital using ATC/DDD methodology. Comparison of the studied outcomes was performed before and after the intervention implementation and between the departments (vascular and abdominal surgery). The consumption of antibacterial agents (ATCJ01) was measured as a number of defined daily doses (DDD) per 100 bed-days (DDD/100 bed-days, indicator recommended by the World Health Organization, WHO) and DDD per 100 treated patients (DDD/100 treated patients). Results: From 2006 to 2012, a decrease in antibacterial consumption in surgical departments by 188 DDD/100 treated patients was observed. We obtained the opposite results when using an indicator of DDD/100 bed-days (increase by 2.5 DDD/100 bed-days) which could be explained by the dependence on indices of overall hospital work and its changes during the examined period. Observed changes in antibacterial consumption varied in different surgical departments. The most pronounced positive changes were noted in the department of vascular surgery: decrease in total antibacterial consumption by 298 DDD/100 treated patients, decrease in the use of cephalosporins of the III generation from 141 to 38 DDD/100 treated patients. These positive changes were accompanied by the same (low) level of consumption/use of reserve antibiotics. In the department of abdominal surgery, there was no decrease in total antibiotic consumption, as well as in consumption of broad-spectrum cephalosporins of the III generation and fluoroquinolones, and we observed an increase in the use of reserve antibiotics (carbapenems) during the study period. Positive changes in antibiotic consumption were associated with the positive attitude of the manager/head of the department towards interventions: we observed the most pronounced decrease in antibiotic consumption straight after the publication of the administrative order on perioperative antibacterial prophylaxis. Conclusion: The combination of scientific, educational, and methodological interventions is effective for improving antibiotic application. The study results provide the rationale for analyzing the drug consumption using the DDD/100 treated patients measure in addition to the WHO-recommended indicator of DDD/100 bed-days which depends on overall hospital performance.

POST-ANESTHETIC REHABILITATION PERIODS AND ANESTHESIA DOSAGE FOR LAPAROSCOPIC CHOLECYSTECTOMY: RELATIONSHIP TO THE TOTAL OXIDATIVE CAPACITY OF LIVER.

Analysis of the results of pharmacological phenotyping using antipyrine test prior to providing anesthesia for laparoscopic cholecystectomy showed that trimeperidine (promedol) dosing with allowance for the total oxidative capacity of liver and the patient mass allows the periods of post-anesthetic rehabilitation to be controlled. Clear algorithm of trimeperidine dosing based on established indices of the total oxidative capacity of liver and is yet nor developed because of restricted sampling set. The obtained results show expediency of using and studying antipyrine test as a simple, cheap, and informative method of individual anesthesia dosing for increasing the adequacy of general anesthesia.

[NEW APPROACH TO COMPARING NSAID EFFICACY BY LONG-TERM MONITORING OF EXPERIMENTAL INFLAMMATION MODELS.]

Experiments on inflammatory edema modeling by sub-plantar injection of carrageenan lambda (1 %) and formalin (2 %) showed substantial differences betwe- en the two models during long-term observation, including irreversible damage caused by formalin (at reversible carrageenan action) and high intensity of for- malin edema (in contrast to carrageenan edema) in mice. We propose a new approach to evaluation of the so-called total inflammatory burden (experimental analog of disease outcome) by calculating the area under the inflammation intensity versus time curve. With the use of this approach, we showed the absence of any effect of conventional NSAIDs (naproxen, diclofenac. indomethacin) on the total inflammatory burden induced by carrageenan or formalin injections in mice and rat paw edema models. These results show the need for using new approaches in the search for potential anti-inflammatory agents.

[ANTIOXIDANT ACTIVITY OF XYMEDONE IN RATS WITH CHRONIC AUTOIMMUNE INFLAMMATION].

Effects of drug xymedone (in comparison to ionol) in a group of 32 white rats with experimental model of chronic autoimmune inflammation of rat paws (induced by Freund's adjuvant) were studied by measuring the volume of paw edema and determining the levels of lipid peroxidation (LPO) products and the activity of antioxidant enzymes in various tissues. Chronic autoimmune inflammation induced by Freund's adjuvant was characterized by the LPO intensification and disturbances of the level of antioxidant enzymes. Intragastric administration of xymedone (2,2-dihydro-4,6-dimethyl,-N-(ß-oxy-ethyl)-2-pyrimidon) at a dose of 169 mg/kg and reference drug ionol (2,6-ditretbutyl-4-methylphenol) at a dose of 220 mg/kg increased the activity of serum antioxidant enzymes by 19% and 11%, respectively, decreased the serum level of nitrite ion by 62% and 50%, and reduced the levels of LPO products in rat blood and homogenates of liver, kidney, and spleen by up to 80% (p < 0.05).

[Experimental comparative study of the analgesic activity of the diurnal anxiolytic mebicar, amitriptyline, and diazepam].

It is established that mebicar, amitriptyline, and diazepam administered intraperitoneally at therapeutic doses increase the pain thresholds in mice as manifested in "hot plate" analgesia test. Mebicar was more effective than diazepam and not inferior to amitriptyline in increasing the pain thresholds at earlier time points.

[MODELING INFLAMMATORY EDEMA: ARE THE MODELS INTERCHANGEABLE].

Experimental modeling of inflammatory edema by sub-plantar injection of carrageenan and formalin in mice and rats is widely used to evaluate potential anti-inflammatory activity of new drugs. This systematic analysis of published data showed that carrageenan induced paw edema model is used for evaluating the anti-inflammatory activity mostly in rats rather than mice. Formalin induced paw edema in rats and mice is used primarily for evaluation of the analgesic activity of drugs. Taken together, the results of this systematic review of available literature on edema modeling substantiate recommendation to use carrageenan paw edema in rats and formalin paw edema in mice as complementary, but not interchangeable models of inflammation.

[Phenotyping by total oxidative hepatic capacity in patients undergoing laparoscopic cholecystectomy: two categories of patients and duration of post-anesthesia rehabilitation].

In patients, undergoing laparoscopy cholecystectomy, two phenotype categories were identified on the basis of the total oxidative hepatic capacity determined by antipyrine test, which differed by duration of post-anesthesia rehabilitation. The potential of antipyrine phenotyping for individualisation of anesthetics' dosing is discussed.

[Anti-inflammatory properties of antidepressants (a review of experimental results)].

The review presents comparative description of anti-inflammatory effects of antidepressants from various classes studied on carrageenan- and formalin-induced paw edema in rats. The role of the central and peripheral components in the mechanisms of anti-inflammatory activity and the drug effects on production of mediators and modulators of inflammation is discussed.

New specific marker of cytochrome P450 1A2 activity.

Various methods were proposed for phenotyping of patients by activity of cytochrome P450 1A2, each has some advantages and disadvantages. However, no reference parameters were developed for measuring CYP1A2 activity that could be used as a unified standard for phenotyping of patients. We propose a mathematic model of caffeine metabolism allowing calculation of rate constants for the formation of its primary metabolites. First-order rate constant of paraxanthine formation was tested as a new specific marker of isoenzyme 1A2 in healthy volunteers.

[Anti-inflammatory effects of amitriptyline, diazepam and mebicar using model of acute carrageenan-induced paw edema in rats].

The anti-inflammatory activity of amitriptyline, diazepam and a new, Russian tranquilizer mebicar was studied in a wide range of therapeutic doses on carrageenan-induced paw edema in rats. Mebicar at low doses showed greater and longer (up to 24 h) lasting anti-inflammatory activity as compared to that of amitriptyline and diazepam.

[Dimephosphone shows anti-inflammatory and anti-oxidative activity on chronic autoimmune inflammation model].

The anti-inflammatory activity of dimephosphone, xydiphone (ethidronate), and ionol (dibunol) and their effects on lipid peroxidation (LPO) indices and the activity of antioxidant enzymes in blood were studied on the model of Freund adjuvant induced arthritis in white laboratory rats. The Freund adjuvant induced chronic arthritis and increased the concentrations of PLO products and nitrite ions in the blood plasma. Only dimephosphone showed an anti-inflammatory action. Dimephosphone and ionol inhibited the LPO, whereas xydiphone did not influence the LPO indices in the blood.

Resource use during systematic review production varies widely: a scoping review.

OBJECTIVE: We aimed to map the resource use during systematic review (SR) production and reasons why steps of the SR production are resource intensive to discover where the largest gain in improving efficiency might be possible. STUDY DESIGN AND SETTING: We conducted a scoping review. An information specialist searched multiple databases (e.g., Ovid MEDLINE, Scopus) and implemented citation-based and grey literature searching. We employed dual and independent screenings of records at the title/abstract and full-text levels and data extraction. RESULTS: We included 34 studies. Thirty-two reported on the resource use-mostly time; four described reasons why steps of the review process are resource intensive. Study selection, data extraction, and critical appraisal seem to be very resource intensive, while protocol development, literature search, or study retrieval take less time. Project management and administration required a large proportion of SR production time. Lack of experience, domain knowledge, use of collaborative and SR-tailored software, and good communication and management can be reasons why SR steps are resource intensive. CONCLUSION: Resource use during SR production varies widely. Areas with the largest resource use are administration and project management, study selection, data extraction, and critical appraisal of studies.

[Comparative analysis of dimephosphon, ionol, and xydiphone effects on indomethacin-induced gastric lesions in rats].

Gastroprotective activity of dimephosphon, xydiphone, and ionol and their effects on the lipid peroxidation (LPO) indices and the activity of antioxidant enzymes in blood and organ tissues were studied on the model of indomethacin-induced gastric lesions in white rats. The indomethacin-induced gastropathy leads to increased concentration of LPO products in blood plasma and tissues. Dimephosphon and ionol reduced the number of gastric lesions and prevented LPO activation. In contrast, xydiphone administration had no effect on indometacin-induced gastric lesions and was accompanied by increased concentration of LPO products in the blood, liver, kidneys, spleen and stomachs of rats.

[On the possibility of patient phenotyping on the basis of cytochrome p-450 1A2 isoenzyme activity using caffeine as the test substrate].

Reactions of caffeine biotransformation and enzymes participating in the caffeine metabolism via the paraxanthine pathway are reviewed. Data on the drugs metabolized mainly in cytochrome P-450 1A2 isoenzyme (CYP 1A2) are analyzed. Information on the phenotypes of CYP 1A2 activity in smoking healthy volunteers, women using oral contraceptives, diabetes patients, those with liver disorders, etc. is summarized. Methodological approaches to patient phenotyping with respect to CYP 1A2 activity as proposed in the available literature are analyzed.

Fluoroquinolones for treating tuberculosis.

BACKGROUND: Fluoroquinolones are sometimes used to treat multiple-drug-resistant and drug-sensitive tuberculosis. The effects of fluoroquinolones in tuberculosis regimens need to be assessed. OBJECTIVES: To assess fluoroquinolones as additional or substitute components to antituberculous drug regimens for drug-sensitive and drug-resistant tuberculosis. SEARCH STRATEGY: In July 2007, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2007, Issue 3), MEDLINE, EMBASE, LILACS, Science Citation Index, Database of Russian Publications, and metaRegister of Controlled Trials. We also scanned reference lists of all identified studies and contacted researchers. SELECTION CRITERIA: Randomized controlled trials of antituberculous regimens containing fluoroquinolones in people diagnosed with bacteriologically positive (sputum smear or culture) pulmonary tuberculosis. DATA COLLECTION AND ANALYSIS: Two authors independently applied inclusion criteria, assessed methodological quality, and extracted data. We used relative risk (RR) for dichotomous data, weighted mean difference (WMD) for continuous data (both with 95% confidence intervals (CI)), and the random-effects model if we detected heterogeneity and it was appropriate to combine data. MAIN RESULTS: Eleven trials (1514 participants) met the inclusion criteria. No statistically significant difference was found in trials substituting ciprofloxacin, ofloxacin or moxifloxacin for first-line drugs in relation to cure (416 participants, 3 trials), treatment failure (388 participants, 3 trials), or clinical or radiological improvement (216 participants, 2 trials). Substituting ciprofloxacin into first-line regimens in drug-sensitive tuberculosis led to a higher incidence of relapse (RR 7.17, 95% CI 1.33 to 38.58; 384 participants, 3 trials) and longer time to sputum culture conversion (WMD 0.50 months, 95% CI 0.18 to 0.82; 168 participants, 1 trial), although this was confined to HIV-positive participants. Substituting for ethambutol in first-line regimens led to a higher incidence of total number of adverse events (RR 1.34, 95% CI 1.05 to 1.72; 492 participants, 2 trials). Adding or substituting levofloxacin to basic regimens in drug-resistant areas had no effect. A comparison of sparfloxacin versus ofloxacin added to regimens showed no statistically significant difference in cure (184 participants, 2 trials), treatment failure (149 participants, 2 trials), or the total number of adverse events (253 participants, 3 trials). AUTHORS' CONCLUSIONS: Only ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin and moxifloxacin have been tested in randomized controlled trials for treating tuberculosis. We cannot recommend ciprofloxacin in treating tuberculosis. Trials of newer fluoroquinolones for treating tuberculosis are needed and are on-going. No difference has been demonstrated between sparfloxacin and ofloxacin in drug-resistant tuberculosis.

[Pharmacoepidemiology of epilepsy].

The lecture presents the history of the pharmacotherapy of epilepsy and analyzes the current situation at the pharmaceutical market related to the appearance of new, high-cost antiepileptic drugs in recent decades. The lecture substantiates the need of pharmacoepidemiology studies for the objective assessment of efficacy, safety and economical impact of new antiepileptics, especially in children, taking into account limited randomized preclinical trials in this group of patients. The lecture describes the role of pharmacoepidemiology in supplementing the findings of randomized controlled trials with new real-life evidence, in quantitative evaluation of adverse reactions, and in discovery of new adverse effects, as well as in the development of cost-effective strategies for rational antiepileptic therapy of children and in the overall improvement of public health economics.

[Pharmacoepidemiology of antiepileptic drugs in children: comparative analysis of drug effectiveness and safety].

Pharmacoepidemiological analysis of the effectiveness and safety (tolerance) of antiepileptic drugs belonging to various classes has been carried out using data for a group of patients registered at municipal children epilepsy services, including 548 children in 2005 and 718 in 2007, aged between 2 months and 18 years. Remission lasting for at least 1 year or longer than 3 years was used as primary effectiveness criterion and the total number of adverse effects as the safety (tolerance) criterion. No advantages of new anticonvulsants over the older antiepileptic drugs in terms of efficacy and safety have been found.

[Hexestrol inhibits ATP-induced contractile response of isolated preparations of pregnant human uterus].

The results of in vitro experiments showed that hexestrol, a synthetic analog of estrogen hormones, at high concentrations inhibited the contractile response of isolated preparations of pregnant human uterus induced by ATP. It is suggested that estrogen hormones can interact with P2 receptors in human uterus during pregnancy.

[Clinical value of the local parameters of lipid peroxidation and antioxidative defense in patients after cataract extraction].

The postoperative period of cataract extraction and the parameters of lipid peroxidation (LPO) (dienic conjugates, TBA-active compounds) and the antioxidative activity (AOA) of tear were studied in 77 patients in relation to the type of a surgical intervention--extracapsular cataract extraction (ECCE) and phacoemulsification (PE). The incidence of severe postoperative uveitis was more than 3 times higher on days both 1 and 5 after surgery. Tear studies revealed a significant increase in the concentration of LPO products just on day 1, with its further slight increase by day 5 along with a further significant reduction in AOA, which indicates the significant consumption of antioxidative defense components and the expediency of using antioxidants. Comparison of tear biochemical parameters revealed no difference in patients after ECCE and PE. Thus, peroxidation processes reflect the severity of an inflammatory reaction in the early postoperative period, the study of the processes in tear is a noninvasive, high-informative method for recording the balance of LPO and antioxidative defense processes, which will assist in determining the direction of therapeutic measures to improve the outcome of a surgical intervention.

[Chromatographic determination of caffeine and its metabolites in saliva and plasma].

The authors made a comparative analysis of the well-known high performance liquid chromatographic (HPLC) techniques to detect caffeine and its primary metabolites in saliva and plasma when during their oral administration. The studies yielded a new specific and sensitive procedure for HPLC analysis of caffeine and its major metabolites, whose distinctive feature was to simultaneously separate six substances with a possibility of determining the activity of the cytochrome P-450 isozymes 1A2, 2E1, and 3A4.