Assessment of Awareness and Experience of Using off-label Drugs by Doctors of Clinical Specialties.

Aim      To evaluate the frequency of off-label prescription of medicines in practice of clinical specialists and the awareness of respondents of the procedure of justified off-label prescription.Material and methods  The sample included 542 clinical specialists who worked in definite medical organizations in 26 entities of the Russian Federation. The respondents were proposed to fill in remotely an anonymous questionnaire to evaluate the experience of prescribing medicines off-label to adult patients.Results Prescribing medicines not in consistence with the officially approved instruction for medical use (off-label or "outside instruction") is a relevant issue of global medical care since convincing scientific evidence for safety of such use is scarce. Analysis of information about off-label prescription is one of current tasks of national medical research centers according to the Federal Project "Development of a network of national medical research centers and implementation of innovative medical technologies". According to the responses about the frequency of off-label prescriptions 67.5 % of respondents reported of no experience of off-label prescription, 27.7 % said "rarely" or "sometimes", and 4.8 % said "frequently" and "very frequently". Specialties of physicians who have more often used medicines off-label (50% and more) included obstetrics and gynecology, pediatrics, rheumatology, hematology, and pulmonology. Cardiologists, neurologists and clinical pharmacologists use medicines off-label relatively rarely (19.6%, 28.6 %, and 22.2 %, respectively). 40 % of medicines used off-label were those designed for the treatment of coronavirus infection SARS-CoV-2. The medicines most frequently used off-label included metformin, rituximab, and thioctic acid. 65 % of respondents assessed their knowledge of off-label prescription as insufficient. In addition, 75 % of respondents consider it useful to receive additional information about risks and benefits of off-label prescription in clinical practice.Conclusion      The survey revealed the need of physicians for information about risks of the off-label use of medicines in clinical practice.

Comparison of the outcomes of the prolonged antianginal therapy use in stable coronary artery disease patients according to the data of randomized and observational studies.

OBJECTIVE: To compare the results of treatment with antianginal drug nicorandil in patients with stable coronary artery disease according to the results of the observational study (OS) «NIKEA¼ and randomized controlled trial (RCT) «IONA¼. METHODS: «NIKEA ¼ observational program included 590 patients with stable angina pectoris. Subgroups in the OS were formed based on the adherence to nicorandil use. Adherence was assessed during follow-up direct questioning. «IONA ¼ RCT included 5126 patients with stable angina pectoris. RESULTS: Follow-up period and mean age of patients were equal in OS and RCT. In OS the group of adherent to nicorandil use patients had fewer males, life-saving drugs were administered significantly more often than in RCT, comorbidities (arterial hypertension, peripheral atherosclerosis and diabetes mellitus) were more pronounced. Angina pectoris class III was diagnosed in 32% of the OS patients vs 11% of the RCT patients, and class I - in 4.4% and 26%, respectively (р<0.001). Both in RCT and OS, there were significantly fewer cases of all cardiovascular events in the groups of nicorandil and adherent to nicorandil use patients in comparison with the groups of placebo and nonadherent patients. Both in RCT and OS the use of nicorandil led to significant decrease in the risk of all cardiovascular events. CONCLUSION: Results of the efficacy and effectiveness studies complement each other and give the opportunity to assess the realisation of the RCT results in real clinical practice.

[Comparative Assessment of Antianginal Efficacy and Safety of Nicorandil at the Background of Therapy With -Adrenoblockers in Ischemic Heart Disease Patients With Stable Angina].

AIM: to demonstrate impact of addition of nicorandil to standard treatment in patients with stable ischemic heart disease (IHD) on clinical manifestations of the disease and safety of conducted therapy. MATERIAL AND METHODS: We included in this double-blind placebo controlled study with parallel groups 120 patients with verified IHD and stable effort angina. During the entire study all patients received metoprolol (100 mg/day). Patients of main group were given nicorandil (10 mg twice a day for 2 weeks and 20 mg twice a day thereafter); patients of control group were given placebo. Study duration was 6 weeks. RESULTS: Addition of nicorandil was associated with significant reduction of number of anginal attacks both compared with control period and addition of placebo. Consumption of short acting nitrates significantly decreased on both nicorandil doses compared with control period. Adverse events were registered in 10 of 61 and 7 of 59 patients (16.4 and 11.9%) taking nicorandil and placebo, respectively (n.s.). Three patients withdrew from the study because of headache. CONCLUSION: Addition of nicorandil to standard therapy in patients with chronic IHD and stable effort angina promoted significant reduction of number of angina attacks. Good tolerability of nicorandil was also demonstrated.

[Ursodeoxycholic acid-enhanced efficiency and safety of statin therapy in patients with liver, gallbladder, and/or biliary tract diseases: the RACURS study].

AIM: To evaluate the efficiency and safety of using statins in combination with ursodeoxycholic acid (UDCA) in patients with this or another liver disease at high risk for cardiovascular events (CVE). SUBJECTS AND METHODS: A register of 262 patients at high risk for CCE who needed statin therapy and have concomitant chronic liver and biliary tract diseases was created in 5 cities of the Russian Federation. RESULTS: After addition of statins or adjustment of their doses, the patients were recommended to include UDCA into their therapy. Six months after stabilization of the dose of statins, the whole group showed a significant reduction in the levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. Assessment of the laboratory parameters responsible for the safety of statin intake revealed no deterioration in the trend in the activity of alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, lactate dehydrogenase, as well as an increase in the serum level of bilirubin. The data obtained using a special questionnaire indicated that 196 patients had taken UDCA and 56 had not. The UDCA and non-UDCA subgroups did not differ in age, weight, or baseline lipid metabolic disturbances. An additional analysis showed that by the end of 6 months, the goal levels of LDL cholesterol in the UDCA and non-UDCA groups were reached in 37 and 20%, respectively (p = 0.01). CONCLUSION: UDCA added to statin therapy in patients at high risk for CVE and concurrent liver diseases contributes to an additional reduction in total cholesterol and LDL cholesterol and prevents enhanced hepatic transaminase activities.

[Effects of long-acting calcium antagonists--amlodipine and diltiazem in patients with stable angina of effort: comparative randomized controlled trial]. / Izuchenie deistviia dvukh antagonistov kal'tsiia prolongirovannogo deistviia--amlodipina i diltiazema u bol'nykh stabil'noi stenokardiei napriazheniia: dannye sravnitel'nogo randomizirovannogo issledovaniia.

AIM: To compare effectiveness of two long-acting calcium antagonists--amlodipin and diltiazem--in patients with ischemic heart disease (IHD) and stable angina of effort (SAE). MATERIAL AND METHODS: 31 IHD patients with SAE entered the double blind randomized trial. The patients received either amlodipin (5-10 mg once a day) or diltiazem (120-180 mg twice a day) for 4 weeks. Selection of the effective single dose and control over the drug effectiveness in regular intake was carried out using treadmill tests made at the height of the drug activity (peak effect) and before taking the next dose (end effect). RESULTS: 1 patient quitted the trial because of frequent anginal attacks while amlodipin administration. Both drugs showed positive effect in relation to exercise tolerance, peak effect of diltiazem was significantly higher than that of amlodipin, the end effect was the same. Amlodipin increased the heart rate at rest while diltiazem insignificantly decreased it. Amlodipin induced side effects more often, all of them were typical for dihydropiridin calcium antagonists. CONCLUSION: Amlodipin and diltiazem of prolonged action have pronounced antianginal effect, diltiazem being more effective and less toxic.

[Comparison of carvedilol and atenolol efficacy in patients with stable effort angina]. / Sravnenie éffektivnosti karvedilola i atenolola u bol'nykh so stabil'noi stenokardiei napriazheniia.

AIM: To compare effectiveness of carvedilol--beta-adrenoblocker with vasodilating action--with atenolol which is beta-adrenoblocker having no vasodilating activity in coronary heart disease (CHD) patients with stable effort angina. MATERIAL AND METHODS: The trial entered 28 CHD patients with a history of myocardial infarction (MI). All the patients had no contraindications to beta-adrenoblockers, had positive exercise tolerance test. After the control period of 7-10 days the patients received either carvedilol (14 patients) or atenolol (14 patients) in a mean daily dose 20.5 mg (6.25 to 50 mg) and 25.9 mg (12.5 to 100 mg), respectively, twice a day. The course of the treatment took 4 weeks. The effect was evaluated at treadmill exercise test. RESULTS: Both drugs diminished heart rate, carvedilol was less effective in this respect. Both drugs significantly prolonged time of exercise to the anginal attack and ST depression by 1.0 mm. Side effects arose in 6 and 4 patients, respectively. CONCLUSION: Carvedilol and atenolol are equally effective in the treatment of stable effort angina.

[Spirapril - a new long-acting ACE inhibitor: efficacy and safety in patients with arterial hypertension in combination with diabetes mellitus and impaired kidney function]. / Spirapril - novyi ingibitor angiotenzinprevrashchaiushchego fermenta dlitel'nogo deistviia: éffektivnost' i bezopasnost' u bol'nykh arterial'noi gipertoniei v sochetanii s sakharnym diabetom i narushennoi funktsiei pochek.

AIM: To examine effectiveness and safety of quadropril. MATERIAL AND METHODS: Changes in blood pressure (BP), heart rate (HR), levels of glucose, potassium and creatinine, creatinine clearance were studied in 120 patients (48 males and 72 females, mean age 60.6 +/- 0.7 years) with mild to moderate arterial hypertension (AH) with average duration 13.8 +/- 0.7 years. The patients were divided into 3 groups: with AH (n = 40), AH + noninsulindependent diabetes mellitus (DM) (n = 43), AH and nephropathy (n = 37). 8-week treatment was performed with a standard dose of 6 mg/day (1 tablet of quadropril). Control examinations were made 2, 4 and 8 weeks after the treatment. RESULTS: After 8 weeks of treatment a decrease in systolic blood pressure in AH group was 24.0 +/- 3.0 mm Hg and in diastolic blood pressure 16.3 +/- 1.3 mm Hg (P < 0.001). In the group with DM this decrease was 22.4 +/- 2.8 mm Hg and 15.7 +/- 1.4 mm Hg (p < 0.001), respectively. In the group with nephropathy this decrease was 26.4 +/- 2.4 and 16.5 +/- 1.3 mm Hg (p < 0.001), respectively. Heart rate changed significantly only in diabetics: from 75.1 +/- 1.7 to 72.9 +/- 1.3 beats/min. Biochemical parameters in the hypertensive and diabetic patients did not change significantly. In the nephropathy group there was a significant decrease in creatinine and increase in creatinine clearance. Their level of glucose and potassium changed insignificantly. CONCLUSION: The treatment with quadropril results in a significant decrease in blood pressure, does not influence parameters of carbohydrate metabolism, improves nitrogen eliminating function of the kidneys.

[Comparative study of spirapril (quadropril) and amlodipine efficacy. Results of randomized trial in patients with mild to moderate arterial hypertension]. / Sravnitel'noe izuchenie éffektivnosti spiraprila (kvadropril) i amlodipina. Rezul'taty randomizirovannogo issledovaniia u bol'nykh miagkoi i umerennoi arterial'noi gipertoniei.

AIM: To compare in the non-blind randomised parallel study the efficiency of quadropril and amlodipine in the treatment of mild to moderate arterial hypertension. MATERIAL AND METHODS: A total of 80 patients (57.6 +/- 1.0 years) were included in this study. The patients were randomised in two groups, 40 patients each. Patients of group 1 received monotherapy with quadropril, while those of group 2 were treated with amlodipine. The treatment duration was 8 weeks in both groups. Quadropril was given in a fixed dose of 6 mg once daily. The initial dose of amlodipine was 5 mg/day. In case of insufficient effect the dose was elevated to 10 mg/day. The efficacy was evaluated by changes in blood pressure (BP) measured at rest. Moreover, in 50 randomly chosen patients 24-h monitoring of BP was performed at the start and end of the treatment. RESULTS: In the quadropril group baseline systolic BP reached 158.6 +/- 2.1 mm Hg, diastolic BP--101.8 +/- 0.8 mm Hg, heart rate was 74.3 +/- 1.6 beats/min. In the amlodipine group baseline systolic BP was 159.9 +/- 2.4 mm Hg, diastolic BP--101.8 +/- 1.0 mm Hg, heart rate was 71.3 +/- 1.0 beats/min. Systolic BP decreased at the end of quadropril therapy to 138.5 +/- 2.2 mm Hg, diastolic BP to 88.1 +/- 1.4 mm Hg. No significant change of the heart rate was observed. Under 5 mg of amlodipine systolic BP decreased to 137.9 +/- 2.5 mm Hg and diastolic BP to 87.1 +/- 1.6 mm Hg. Heart rate increased to 73.3 +/- 2.2 beats/min. Under therapy with 10 mg amlodipine systolic BP decreased to 145.9 +/- 3.8 mm Hg, diastolic BP to 89.7 +/- 3.4 mm Hg. Heart rate increased to 77.3 +/- 4.0 beats/min (p < 0.01). The hypotensive effect of quadropril remained stable while the effect of amlodipine decreased by the 8th week of therapy (p < 0.01). Side effects were observed significantly more often in the amlodipine group, then in the quadropril group. The main quadropril side effect was cough. Side effects observed in the amlodipine group were edemas, tachycardia, weakness. CONCLUSION: Both quadropril and amlodipine demonstrated a comparable antihypertensive effect although in 11 of 40 patients in the amlodipine group a dose increase was necessary and tolerability of quadropril was better.

[Symptomless myocardial ischemia: feasibility of diagnostic mistakes]. / Bessimptomnaia ishemiia miokarda: vozmozhnost' oshibochnoi diagnostiki.

AIM: To examine feasibility of ST segment depression on ECG in treadmill exercise test and 24-h ECG monitoring in subjects with coronarographically intact coronary arteries. MATERIALS AND METHODS: 9 males aged 41 to 52 years with chest pains unrelated to muscular load. They had neither stenosis of coronary arteries, nor arterial hypertension, valvular defects, disturbance of electrolyte metabolism. All of them have undergone treadmill exercise test and 24-h ECG monitoring. RESULTS: The exercise test provoked chest pain in none of the examinees. ST segment was depressed in one patient. 24-h monitoring registered depression of ST segment in one more patient. The rest 7 patients showed no changes in ST segment either in exercise test or 24-h ECG monitoring. CONCLUSION: It is confirmed that typical ischemic ECG changes (horizontal depression of ST segment) in healthy persons can occur and may be mistaken for silent myocardial ischemia.

[The possibility of the development of isosorbide dinitrate and nifedipine withdrawal syndromes in patients with stable stenocardia of effort]. / Vozmozhnost' razvitiia sindroma otmeny izosorbida dinitrata i nifedipina u bol'nykh stabil'noi stenokardiei napriazheniia.

Exercise tests were performed in 18 patients with stable angina of effort treated with isosorbide dinitrate (ID) or nifedipine (NF) to see whether sharp discontinuation of the above drugs may entail withdrawal syndrome. Exercise tolerance declined 21 and 24 hours after the last administration of NF, 13 and 18 hours after that of ID. Compared to NF, ID tolerance decreased in a less degree. Some of the patients experienced myocardial ischemia in the course of the exercise tolerance tests, there were more frequent anginal episodes, arterial pressure rose. For ID withdrawal syndrome manifested weaker than for NF.

[Molsidomine and isosorbide dinitrate: a comparative trial of tolerance in long-term intake by IHD patients with stable angina of effort]. / Molsidomin i izosorbida dinitrat: sravnitel'noe izuchenie razvitiia tolerantnosti pri dlitel'nom prieme u bol'nykh IBS so stabil'noi stenocardiei napriazheniia.

Potential tolerance to isosorbide dinitrate (ID) and molsidomine (M) was studied in 18 ischemic heart disease (IHD) patients with stable angina of effort entered in a double blind cross-over trial. Each drug was administered for 3 weeks 4 times a day in individual effective dose. Single doses of ID and M were similar by effectiveness, but after 3 weeks of regular intake their efficacy fell, ID becoming less potent than M. For ID, tolerance after long-term intake manifested in 7 out of 18 patients, for M--in 5 out of 18. Complete tolerance was registered in 3 of 18 and 1 of 18 patients, respectively. Thus, tolerance is possible for the two drugs, but for M it is less pronounced.

[The emergence of silent myocardial ischemia as the manifestation of the nitrate withdrawal syndrome in patients with ischemic heart disease]. / Vozniknovenie bessimptomnoi ishemii miokarda kak proiavlenie sindroma otmeny nitratov u bol'nykh ishemicheskoi bolezn'iu serdtsa.

The aim of the study was to evaluate feasibility of emergence of nitrate withdrawal syndrome consequently to discontinuation of short-term nitrate administration for coronary heart disease. 12 males with stable effort angina functional class III were subjected to 24-h Holter ECG monitoring. In a randomized cross-over trial each patient received for 3 days isosorbide dinitrate (10-30 mg 4 times a day) followed by 3-day course of placebo. The monitoring was performed on day 3 of the drug or placebo administration and on the first day of their withdrawal. Isosorbide dinitrate discontinuation had no negative effects on the patients' condition though significantly increased the number and duration of episodes of asymptomatic myocardial ischemia. 4 patients developed episodes of asymptomatic myocardial ischemia at rest which were not observed in placebo application. It is believed that much caution should be used in planning interrupted regimes of nitrates therapy in patients with severe angina pectoris.

[The relationship between the isosorbide-5-mononitrate concentration and its antianginal effect following the administration of regular and prolonged-action drug forms in patients with stenocardia of effort]. / Sviaz' mezhdu kontsentratsiei izosorbid-5-mononitrata i antianginal'nym éffektom posle priema obychnoi i prolongirovannoi lekarstvennykh form u bol'nykh stenokardiei napriazheniia.

Isosorbide-5-mononitrate (IMN) concentration-antianginal effect relationships were studied in 14 coronary heart diseases patients with stable exertion-induced angina after administration of Efox (Schwarz-Pharma) as two dosage forms: routinely acting tablets (20 mg) and long-acting capsules (50 mg). The antianginal effect index was an increase of treadmill exercise duration (sec) as compared with placebo, the concentration and effect were measured in points 0, 1, 3, and 7 hours after administration, in some patients, investigations were conducted 12 and 24 hours. The two formulations were found to be highly effective drugs whose action lasted 7 hours, by that time the effect of the tablets substantially decreased, which was associated with decreases in drug concentrations. The efficiency of the capsules at this point was significantly higher than that of the tablets. The use of the capsules resulted in tachyphylaxis--rapid decreasing responses to IMN. Following 7 hours of their administration there is a significant decrease in their effect with an increase in IMN concentrations.

[The clinical pharmacology of antianginal agents]. / Klinicheskaia farmakologiia antianginal'nykh sredstv.

This paper provides the basic advances made in studying the clinical pharmacology of antianginal agents (AAs), demonstrates the contribution of current tools for evaluating their antianginal effects, namely pharmacodynamic studies using pair bicycle ergometry and repeated treadmill exercises, 24-hour ECG monitoring, pharmacokinetic studies. It shows that AAs can be chosen on an individual basis. The authors present pharmacodynamic characteristics of a number of new AAs from nitrates (trinitrolong, dinitrosorbilong, etc.), calcium antagonists, beta-adrenoblockers (proxodolol, etc.). They have developed a method for assessing the biological equivalence of AAs. The paper discusses the tolerance that can be developed to nitrates and how it can be prevented. It first demonstrates that nifedipine tolerance can develop and that the withdrawal syndrome can occur if nitrates and calcium antagonists are discontinued. There are screening data on various combinations of AAs. A two-stage scheme for choosing an AA therapy is given.

[The nifedipine withdrawal syndrome in patients with stable stenocardia of effort]. / Sindrom otmeny nifedipina u bol'nykh stabil'noi stenokardiei napriazheniia.

The effect of abrupt discontinuation of nifedipine (N) on exercise tolerance and myocardial ischemia was studied in 7 patients with stable angina pectoris of effort (AP). N was administered in a dose of 20 mg 4 times a day for 34 days. Exercise treadmill tests were performed before N therapy in placebo treatment, on N treatment day 1, 28, on the first day after abrupt N discontinuation and 8 days after the latter. Upon acute and regular administration N produced a significant improvement in exercise tolerance before the onset of AP, development of moderate AP and up to 1 mm depression of ST-segment. Abrupt N discontinuation resulted in substantial deterioration in exercise performance pronounced more definitely on hour 21 and 24 after the last dose intake. A substantial increase in the sum of ST-segment depression at the onset of AP and at the development of AP of moderate severity occurred on the first day of N withdrawal. 8 days after N cessation all the exercise parameters returned to the baseline levels. We conclude that abrupt cessation of regular N therapy may cause a withdrawal syndrome which manifested with a decrease in the exercise tolerance and an increase in exercise-induced myocardial ischemia.