PLASMA MICRORNA-133А LEVEL IN PATIENTS WITH ESSENTIAL ARTERIAL HYPERTENSION.

The aim of research was to investigate the plasma microRNA (miR-133а) level in patients with essential arterial hypertension (EAH). A total of 45 patients with EAH 2-3 degrees aged 52.14 ± 8.25 years and 21 healthy individuals (control group) with comparable age and sex distributions. The following frequency of risk factors was revealed among the examined patients: overweight (53%), dyslipidaemia (73%), pre-diabetes (13%), asymptomatic hyperuricemia (29%); hypertension-mediated organ damage: increased arterial stiffness (27%), left ventricular hypertrophy (55%), atherosclerotic plaque in the carotid artery (40%), microalbuminuria (15%), moderate stage of chronic kidney disease (22%) and cardiovascular diseases: stable ischemic heart disease (11%) and heart failure with preserved ejection fraction of NYHA functional class I (18%). The plasma miR-133a level was determined by polymerase chain reaction using "CFX96 Touch" detection system (BioRad) and "TaqMan microRNA Assay" and "TaqMan® Universal PCR Master Mix" reagents (Thermo Fisher Scientific, USA). It has been established that in patients with EAH the plasma level of miR-133a was significantly lower than in practically healthy individuals (0,182 [0,102; 0,301] ), vs (0,382 [0,198; 0,474]), p <0.05). It has also been revealed a significant decrease in the level of miR-133a in the blood plasma in patients with such organs damage as LVH (0,133 [0,099;0,184]) in comparison with patients without LVH (0,238 [0,155; 0,410]), p <0.05) and also significantly lower than in healthy subjects in the control group (0,382 [0,198; 0,474]), p<0.05). There were no statistically significant differences in the plasma levels of miR-133a in the group of patients with EAH, depending on the presence of risk factors, other organ damage and cardiovascular diseases. The findings suggest the significant role of reducing of plasma levels of miR-133a in the pathogenesis of hypertension itself and in pathological remodeling of the heart.

Fermi-Pasta-Ulam auto recurrence in the description of the electrical activity of the heart.

The authors proposed and mathematically described model of a new type of the Fermi-Pasta-Ulam recurrence (the FPU auto recurrence) and hypothesized an adequate description of the heart's electrical dynamics within the observed phenomenon. The dynamics of the FPU auto recurrence making appropriate electrical dynamics of the normal functioning of the heart in the form of an electrocardiogram (ECG) was obtained by a computer model study. The model solutions in the form of the FPU auto recurrence - ECG Fourier spectrum were evaluated for resistance to external disturbances in the form of random effects, as well as periodic perturbation at a frequency close to the heart beating rate of about 1Hz. In addition, in order to simulate the dynamics of myocardial infarction model, studied the effect of the surface area of the myocardium on the stability and shape of the auto recurrence - ECG spectrum. It has been found that the intense external disturbing periodic impacts at a frequency of about 1Hz lead to a sharp disturbance spectrum shape FPU auto recurrence - ECG structure. In addition, the decrease in the surface of the myocardium by 50% in the model led to the destruction of structures of the auto recurrence - ECG, which corresponds to the state of atrial myocardium. Research models have revealed a hypothetical basis of coronary heart disease in the form of increasing the energy of high-frequency harmonics spectrum of the auto recurrence by reducing the energy of low-frequency harmonic spectrum of the auto recurrence, which ultimately leads to a sharp decrease in myocardial contractility. In order to test the hypothesis has been studied more than 20,000 ECGs both healthy people and patients with cardiovascular disease. As a result of these studies, it was found that the dynamics of the electrical activity of normal functioning of the heart can be interpreted by the display of the detected by authors the FPU auto recurrence, and coronary heart disease is a violation of the energy ratio between the low and high frequency harmonics of the FPU auto recurrence Fourier spectrum equal to the ECG spectrum. Thus, the hypothesis has been confirmed.

[Content of circulating endothelial progenitor cells in patients with chronic ischemic heart failure with preserved left ventricular ejection fraction].

PURPOSE: To assess content of various subpopulations of endothelial progenitor cells (EPC) with CD45-CD34+, CD14+CD309+ and CD14+CD309+Tie2+ phenotypes in patients with chronic heart failure (CHF) of ischemic origin with preserved left ventricular ejection fraction. MATERIAL AND METHODS: We included into the study 126 patients (54 men) aged 48-62 years with angiographically confirmed ischemic heart disease (IHD) and 25 healthy volunteers. Eighty two (65%) patients had NYHA class I-II CHF. Phenotyping of populations of mononuclear cells was performed by flow cytometry with the use of fluorochrome-labeled monoclonal antibodies. Circulating EPC were determined as CD45-CD34+. For identification of subpopulations of EPC coexpressing CD14 antigen we determined CD309(VEGFR2) and Tie2 antigens. RESULTS: In the group of patients with IHD level of circulating proatherogenic mononuclear cells of CD14+CD309+ and CD14+CD309+Tie2+ phenotype depended more on the presence of CHF and number of risk factors of cardiovascular complications (CVC) but not on severity and extent of coronary atherosclerosis. Most important independent predictors of lowering of circulating EPC with CD14+CD309+Tie2+ phenotype were CHF (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.12 to 1.88, p = 0.004), type 2 diabetes (OR 1.21, 95% Cl 1.10 to 1.40; p = 0.008), NT-proBNP > 154 rg/ml (OR 1.13, 95% Cl 1.04 to 1.18, p = 0.003), hyperlipidemia (OR 1.12, 95% CI 1.05 to 1.23, p = 0.005), and presence of ± 3 traditional cardiovascular risk factors (OR 1.31, 95% CL 1.12 to 1.49, p = 0.008). CONCLUSION: Negative impact of factors of risk of CVC relative to manifestation of ischemic CHF might by mediated by deficit of nonhemopoetic circulating EPC, mobilization of which from peripheral tissues if reduced at early stages of formation of myocardial dysfunction.

Impaired immune phenotype of circulating endothelial-derived microparticles in patients with metabolic syndrome and diabetes mellitus.

INTRODUCTION: Type two diabetes mellitus (T2DM) remains a leading contributor to cardiovascular mortality worldwide. This study was conducted to investigate the pattern of circulating EMPs in T2DM patients in comparison with MetS subjects. METHODS: The study retrospectively included 101 patients (54 subjects with T2DM and 47 patients with MetS) and 35 healthy volunteers. All the patients gave written informed consent for participation in the study. Biomarkers were measured at baseline of the study. RESULTS: There is a significant difference between healthy subjects and patients regarding CD31+/annexin V+ EMPs to CD62E+ EMPs ratio, which reflects impaired phenotype of EMPs. Therefore, CD31+/annexin V+ EMPs to CD62E+ EMPs ratio was found to be higher in the T2DM patients compared to MetS patients. Using multivariate linear regression analyses, independent impact of T2DM (r = 0.40, P = 0.003), OPG (r = 0.37, P = 0.001), hs-CRP (r = 0.347, P = 0.001), and adiponectin (r = 0.33, P = 0.001) on increased CD31+/annexin V+ to CD62E+ ratio of EMPs was determined. Using C-statistics, we found that inflammatory biomarkers (hs-C-reactive protein, osteoprotegerin and adiponectin) added to the base model (T2DM) improved the relative IDI by 12.6 % for increased CD31+/annexin V+ EMPs to CD62E+ EMPs ratio. CONCLUSION: We found that patients with T2DM and MetS may be distinguished by predominantly appearing phenotypes of circulating EMPs associated with pro-inflammatory cytokine overproduction. Elevated CD31+/annexin V+ EMPs to CD62E+ EMPs ratio is an indicator of impaired immune phenotype of EMPs, which allows determining the pattern of EMPs in dysmetabolic disorder patients.

Circulating osteopontin as a marker of early coronary vascular calcification in type two diabetes mellitus patients with known asymptomatic coronary artery disease.

OBJECTIVE: To evaluate the interrelation between circulating osteopontin (OPN) and coronary atherosclerosis and calcification in type 2 diabetes mellitus patients (T2DM). DESIGN AND METHODS: 126 subjects (46 patients with T2DM) with previously documented asymptomatic coronary artery disease (CAD) were enrolled in the study. CAD was determined by contrast multispiral CT-angiography. OPN plasma levels were measured by ELISA. RESULTS: Analysis of the results showed that in a patient cohort the mean value of circulating OPN was 43.55 ng/mL (95% CI = 31.5-57.0 ng/mL). OPN plasma levels were correlated with Agatston score index (r = 0.418, P = 0.009), T2DM (r = 0.411, P = 0.006), gender (r = 0.395, P < 0.001 for male), TC (r = 0.405, P = 0.006), hsC-RP (r = 0.368, P = 0.008), age (r = 0.256, P = 0.001), smoking (r = 0.255, P = 0.001) and inversely to LVEF (r = -0.579, P = 0.001). Cox-regression analyzes showed that in T2DM patients upper quartile OPN compared with the lowest quartile are associated with Agatston score index (adjusted OR = 3.23, 95% CI = 1.09-5.20; P = 0.044), numerous of damaged coronary arteries (adjusted OR = 2.60, 95% CI = 1.10-9.20, P = 0.005). The findings suggest that the predictive power of the model for asymptomatic CAD patients with T2DM, the estimated AUC (area under curve) was 0.788. In this case, the concentration of OPN that had the best predict potential on the risk of coronary atherosclerosis was 48.5 ng/mL. In conclusions, we believe that elevated OPN in plasma can be considered as an independent predictor of coronary calcification in T2DM patients with known CAD.

Serum uric Acid as a marker of coronary calcification in patients with asymptomatic coronary artery disease with preserved left ventricular pump function.

Objective. To evaluate the interrelation between serum uric acid and artery calcification in asymptomatic coronary artery disease subjects. Design and Methods. 126 subjects with previously documented asymptomatic coronary artery disease were enrolled in the study. Results. Mean value of serum uric acid level was 23.84 mmol/L (95% confidence interval (CI) = 15.75-31.25 mmol/L). In multivariate Cox regression analysis, the results showed that serum uric acid levels (odds ratio (OR) = 1.42, 95% CI = 1.20-1.82; P < 0.001), osteopontin (OR = 1.14, 95% CI = 1.12-1.25; P < 0.001), osteoprotegerin (OR = 1.45, 95% CI = 1.20-1.89; P < 0.001), type 2 diabetes mellitus (OR = 1.41, 95% CI = 1.20-1.72; P < 0.001), and total cholesterol (OR = 1.13, 95% CI = 1.10-1.22; P < 0.001) were factors that independently associated with coronary artery calcification. The Cox models suggested that high quartile of serum uric acid level is very significant in predicting Agatston score index. In conclusion, we suggested that high quartile of serum uric acid level (cutoff point equaled 35.9 mmol/L) was a very significant predictor of coronary calcification examined by Agatston score index in subjects with asymptomatic coronary artery disease.

[Efficacy of various epidural analgesia regimens after lung surgery].

A prospective study included 90 adult patients undergoing thoracic surgery. After placing an epidural catheter at the Th4-Th5 level, all the patients were randomized in 3 groups. Twenty-nine patients received controlled epidural analgesia (PCEA) with fentanyl, 2 microg/ml, in 0.2% bupivacaine solution (Group 1). In other groups, these analgesics were given either as bolus infections (Group 2; n = 30) or as a continuous epidural infusion of fentanyl, 2 microg/ml, in 0.2% bupivacane solution (Group 3; n = 27). Pain scores and the incidence of adverse effects were assessed within the first 24 hours after surgery. The data were compared using the Student's t-test and x2 test with Bonferroni correction; p < 0.017 was regarded as statistically significant. The VAS scores in coating were significantly lower in Group 1 than in Groups 2 and 3. The need for epidural opioids for adequate analgesia within the first 24 hours after surgery was significantly less in Group 1 than in Groups 2 and 3. There were no excessive sedation episodes in all the groups. In Group 2, the incidence of nausea was 20%. These adverse reactions were not found during PCEA and continuous infusion (p < 0.017). Opioid-induced pruritus was mostly (23%) observed in Group 2. Thoracic PCEA with fentanyl-bupivacaine solution provided adequate postoperative analgesia after thoracotomy and reduced the need for opioids. In addition, PCEA reduced the incidence of adverse reactions of opioids.

[About the improvement of communication system and information transmission in medical service control in airborne division].

Frequent changes in tactical, rear and medical situations cause the medical service officials of airborne division (ABD) to obtain and transmit the data characterizing the medical service forces and means for a lot of times. It decreases the effectiveness of the control process. Equipping of ABD medical service staff with programming-and-technical systems (PTS), development of algorithm of official interaction, creation of report forms and selection of materials necessary for PTS database input will contribute to the effectiveness of ABD medical service control.

Remote helicopter-borne detector for searching of methane leaks.

Measurements of the content of various molecular impurities in the ambient air using helicopter- and aircraft-borne systems represent an extremely urgent challenge. In this respect, of special interest are the devices that that provide leakage monitoring in gas lines in order to prevent emergencies. In the paper results of the tunable diode laser-based instrument development and testing are presented.

UF6 enrichment measurements using TDLS techniques.

The objective of this work was investigation of possibility of tunable diode laser spectroscopy (TDLS) technique application for gaseous uranium hexafluoride (UF6) isotope measurement. Spectra of uranium hexafluoride gas mixture were investigated using two different Fourier Transform Spectrometers Vector 22 and Bruker 66v. Observed spectral features were identified and model spectra of different gas mixture components were developed. Optimal spectral range for measurements was determined near maximum of UF6 combination band nu1+nu3. Laboratory prototype of multi-channel instrument under consideration based on tunable diode lasers was built and algorithms were developed to measure gaseous UF6 isotopic ratios. Diode laser used operated at the wavelengths near lambda=7.68 microm. It was placed in a liquid nitrogen cooled cryostat. Three instrument channels were used for laser frequency calibration and spectra recording. Instrument was tested in measurements of real UF6 gas mixtures. Measurement accuracy was analyzed and error sources were identified. The root-mean-square random error in the 235U isotopic content is characterized by a spread of about 0.27% for quick measurements (at times less than 1 min) and 1% for periods of more than an hour. It was estimated that the measurement accuracy could be improved by at least an order of magnitude by minimizing the error sources.

[Effect of fosinopril on the rate of neurohumoral and proinflammatory activation in patients with heart failure]. / Vliianie fosinoprila na intensivnost' neirogumoral'noi i provospalitel'noi aktivatsii u bol'nykh serdechnoi nedostatochnost'iu.

The purpose of the study was to examine the effect of fosinopril on the magnitude of neurohumoral and proinflammatory activation in patients with severe heart failure (HF). Twenty-eight patients aged 52-68 years who had Functional Class (FC) III-IV HF that had developed due to coronary heart disease were examined. All the patients were divided into 2 groups (with 14 patients in each group) and they received routine therapy including an angiotensin-converting enzyme inhibitor (ACEI) and a beta-adrenoblocker. Group 1 patients were given the ACEI fosinopril in a dose of 10-20 mg/day, Group 2 patients took captopril in a dose of 50-75 mg/day. The course of therapy was 12 weeks. All the patients underwent echocardiography by the routine procedure. The plasma levels of angiotensin-II, aldosterone, and brain natriuretic peptide (BNUP) were determined by radioimmunoassay. The plasma contents of tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (C-RP) were verified by enzyme immunoassay. An analysis of the findings indicated that during therapy the FC of HF decreased on the average by 10.9% in Group 1 and by 11. 7% in Group 2 (p = 0.14). With this, fosinopril was superior to captopril not only in its capacity of improving overall left ventricular contractile function, but it was characterized by a more pronounced effect on regression of the plasma pool of C-RP and TNF-alpha. The marked depressive action of the ACEI fosinopril on the plasma pool of products of the renin-angiotensin system, BNUP, and proinflammatory cytokines may be considered to be as a basis for preferably prescribing the agent to patients with severe HF.

[Molecular mechanisms of cephalosporin resistance in Gram-negative bacteria of the Enterobacteriaceae family]. / Molekuliarnye mekhanizmy ustoichivosti gramotritsatel'nykh bakterii semeistva Enterobacteriaceae k tsefalosporinovym antibiotikam.

Extended spectrum beta lactamase genes were detected by the PCR in 87.6% of 231 Enterobacteriaceae strains isolated in medical institutions of Moscow, St. Petersburg, Tomsk and Nazran that showed a decrease in their susceptibility to 3rd generation cephalosporins. Alone or in various combinations TEM type beta lactamases were detected in 43.3% of the isolates, 46.8 and 51.2% of the isolates produced SHV type and CTX type beta lactamases respectively. Combinations of 2 and 3 different determinants were detected in 40 and 14% of the isolates respectively. Production of class C beta lactamases was suspected in 28% of the isolates by their resistance to cefoxitin. The gene of ACT type beta lactamase was detected in 1 strain of Klebsiella pneumoniae and the gene of CMY type beta lactamase was detected in 1 strain of Proteus mirabilis. By the NCCLS 100% of the isolates was susceptible to meropenem, 14% was susceptible to cefotaxime, 64% was susceptible to cefepime, 81% was susceptible to cefoperazone/sulbactam, 47% was susceptible to gentamicin, 57% was susceptible to amikacin and 36% was susceptible to ciprofloxacin.

[Prognostic value of elevation of plasma concentration of atrial natriuretic peptide in patients with cardiac failure. Results of a cohort study]. / Prognosticheskoe znachenie élevatsii plazmennoi kontsentratsii predserdnogo natriiureticheskogo peptida u bol'nykh serdechnoi nedostatochnost'iu. Rezul'taty kogortnogo issledovaniia.

A total of 172 patients with cardiac failure (CF) of functional class II-IV aged 46-62 years were studied. Clinical condition of the patients was stabilized by the conventional therapy including ACE inhibitor--enalapril in a dose 10-20 mg/day. In 3 weeks this therapy was combined with losartan in a dose 25-50 mg/day. The course of treatment was 48 weeks. Cardiodynamics was assessed by duplex echocardiography and dopplerography. Plasmic concentrations of atrial sodiumuretic peptide (ASUP), renin, angiotensin-II, aldosteron, norepinephrine, epinephrine, serotonin, hydrocortisone, endothelin-1 were measured with radioimmunoassay. In the study group there were 31 deaths for 48 weeks. ASUP concentration in the deceased was significantly higher than in the survivors (n = 141). The stepwise regression analysis discovered correlation between plasmic ASUP and end-diastolic volume of the left ventricle (r = 0.62; p = 0.01), dopplerographic index (r = 0.52; p = 0.001), left ventricular ejection fraction (r = -0.66; p = 0.002), velocity of early diastolic filling (r = -0.84; p = 0.001), plasmic pool of norepinephrine (r = 0.66; p = 0.001), endotheline-1 (r = 0.70; p = 0.03) and angiotensin-II (r = 0.55; p = 0.02), daily dose of furosemide (r = 0.80; p = 0.001), heart rate (r = 0.64; p = 0.02). The strongest negative effect on CF patients' survival was linked with plasmic content of ASUP (relative risk = 4.55), angiotensin-II (RR = 3.2), ejection fraction < 25% (RR = 3.02). Thus, elevation of ASUP in blood plasm can be regarded a marker of a high cardiovascular risk of CF patients treated with AT-antagonist.

[Characteristics and clinical value of extended-spectrum beta-lactamases]. / Kharakteristika i klinicheskoe znachenie beta-laktamaz rasshirennogo spectra.

The literature data and the findings of the authors' studies on the role of extended-spectrum bata-lactamases (ESBL) in providing the clinical effect in the treatment of infections due to ESBL-producing organisms were analyzed. The analysis allowed to consider the NCCLS recommendations not sufficiently valid. According to these recommendations the ESBL-producing organisms (among E. coli and Klebsiella spp.) should be regarded as resistant to penicillins, cephalosporins and aztreonam. Susceptibility of 62 Enterobacteriaceae strains that were isolated in 4 therapeutic centres of Tomsk, Nazran and Moscow and proved to be ESBL-producing organisms was tested and it was shown that the 3rd and 4th generation cephalosporins could not be referred to a homogenous group. The same was confirmed by the prospective and retrospective investigations of a multiprofile hospital on the clinical and bacteriological efficacies of the 3rd generation cephalosporins and cefepime in the treatment of hospital-acquired infections due to Enterobacteriaceae strains producing ESBL.

[Effect of long-term treatment with enalapril, losartan and their combination on the quality of life of patients with congestive heart failure]. / Vliianie dlitel'nogo primeneniia énalaprila, lozartana i ikh kombinatsii na kachestvo zhizni bol'nykh s zastoinoi serdechnoi nedostatochnost'iu.

AIM: To study the effect a combination of enalapril and losartan on life quality in patients with congestive heart failure (HF). MATERIAL AND METHODS: One hundred and eighty six patients with NYHA functional classes II to IV HF were examined. The study inclusion criteria were as follows: a left ventricular (LV) end-diastolic volume of > 160 ml, a LV ejection fraction of < 35%, sinus rhythm, a cardiothoracic index of > 0.55, no history data on prior treatment with an angiotensin-converting enzyme inhibitor (ACEI) and/or an AT1-antagonist, a patient's written free-will consent to participate in the study. The exclusion criteria were as follows: pacemaker migration, an artificial pacemaker, high-degree block, atrial fibrillation, cerebral circulatory disorders. All the patients were divided into 4 groups and received basic therapy with cardicet, 60-120 mg/day, aspirin, 250 mg/day, furosemide, 80-440 mg/week, and digoxin, 0.25-0.5 mg/day. Group 1 comprised 60 patients who refused therapy with ACEI and/or AT1-antagonist despite that they had indications for their use and they had been convinced many times. In Group 2 (n = 82) enalapril, an ACEI, was added to the basic therapy. Its initial dose of 2.5 mg/day was given once and slowly incremented to the therapeutical one (10-20 mg/day). Group 3 patients (n = 56) on the basic therapy were additionally treated with the AT1-antagonist losartan in a daily dose of 25-50 mg. They were started on 12.5 mg a day. In group 4 the basic therapy was added by a combination of enalapril and losartan in the same doses. The follow-up was 48 weeks. The efficiency of the treatments was controlled by the personal questionnaires SF-36, Life with Heart Failure, by evaluating the magnitude of clinical HF manifestations and by estimating the total life quality inxed. The data were analyzed by assuming that all the patients received the treatments. RESULTS: As compared with the conventional therapy and the use of each drug alone, a combination of the ACEI enalapril and the AT1-antagonist losartan promotes a more significant increase in the satisfaction of the patients with their vital activity, in the critical rate of their self-assessment of the "internal picture" of disease, and leads to a greater improvement of the quality of their life as a whole. CONCLUSION: The ICAE-AT1-antagonist combination exerts a positive impact on life quality in patients with heart failure.

[Relationship between myocardial remodeling and neurohumoral activation in patients with cardiac failure]. / Vzaimosviaz' protsessov remodelirovaniia miokarda i neirogumoral'noi aktivatsii u bol'nykh s serdechnoi nedostatochnost'iu.

50 healthy subjects and 685 patients with heart failure (NYHA functional class I-IV) due to coronary heart disease (CHD) aged 34-74 years (mean age 48.1 +/- 8.22 years) were examined. Cardio-hemodynamics was assessed by M- and B-echocardiography from parasternal, subcostal and apical view on a short and long axis with transmitral Doppler. Plasma levels of epinephrine, norepinephrine, serotonin, aldosterone, STH, hydrocortisone were measured in the patients. Progression of cardiac failure is characterized by evolution of the left ventricular ellipse form into a ball shape primarily due to an increase in cross sectional cavity size. The changes of the left ventricular geometry in heart failure patients are combined with progressive reduction of the relative wall thickness index, intensification of the myocardial stress and impairment of diastolic function. The clearest intercoupling between myocardial remodeling and neurohumoral activation was registered in patients with asymptomatic heart failure. With growing severity of left ventricular dysfunction, plasm activity of serotonin, hydrocortisone and aldosterone increase more than levels of norepinephrine, epinephrine and STH.

[Electrostimulation in the therapy of bronchial asthma]. / Elektrostimuliatsiia v terapii bronkhial'noi astmy.

Programmed electrostimulators of the sinocarotid nerves were implanted to 78 patients with bacterial asthma (BA) with a severe hormone-dependent course (age 18-67 years). Radiofrequency electrostimulation was performed daily for 6 years (impulse current, 30-150 Hz, 0.1-0.4 ms, 0.1-0.5 W. The regime was selected individually by the bronchodilating effect measured at pneumotachometry. The electrostimulation effectively arrested and prevented the majority of asphyxia attacks, reduced their frequency (2.7-fold) and need in medicines (2.7-3.4-fold). Serious complications were absent. Electrostimulation of the sinocarotid nerves can be applied in patients with bronchial asthma resistant to drug therapy, in side effects of glucocorticosteroids and adrenomimetic drugs.