Imidazoline Receptor Agonist Research Articles

Theory and practice of selective imidazoline receptor agonist use in Russia

Theory and practice of selective imidazoline receptor agonist use in Russia

Not first-line antihypertensive agents, but still effective-The efficacy and safety of imidazoline receptor agonists: A network meta-analysis.

Cardiovascular disorders are the leading cause of death in the world. Many organ diseases (kidney, heart, and brain) are substantially more prone to develop in people with hypertension. In the treatment of hypertension, first-line medications are recommended, while imidazoline receptor agonists are not first-line antihypertensives. Our goal was to conduct a network meta-analysis to assess the efficacy and safety of imidazoline receptor agonists. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, considering the CONSORT recommendations. Studies were collected from four databases: PubMed, Cochrane Library, Web of Science, and Embase. A total of 5960 articles were found. After filtering, 27 studies remained eligible for network meta-analysis. Moxonidine reduced blood pressure in sitting position statistically significantly after 8 weeks of treatment (SBP MD: 23.80; 95% CI: 17.45-30.15; DBP MD: 10.90; 95% CI: 8.45-13.35) compared to placebo. Moreover, moxonidine reduced blood pressure more effectively than enalapril; however, this difference was not significant (SBP MD: 3.10; 95% CI: -2.60-8.80; DBP MD: 1.30; 95% CI: -1.25-3.85). Dry mouth was experienced as a side effect in the case of all imidazoline receptor agonists. After 8 weeks of treatment, the appearance of dry mouth was highest with clonidine (OR: 9.27 95% CI: 4.70-18.29) and lowest with rilmenidine (OR: 6.46 95% CI: 0.85-49.13) compared to placebo. Somnolence was less frequent with moxonidine compared to rilmenidine (OR: 0.63 95% CI: 0.17-2.31). Imidazoline receptor agonists were nearly as effective as the first-line drugs in the examined studies. However, their utility as antihypertensives is limited due to their side effects. As a result, they are not first-line antihypertensives and should not be used in monotherapy. However, in the case of resistant hypertension, they are a viable option. According to our findings, from the point of view of safety and efficacy, moxonidine appears to be the best choice among imidazoline receptor agonists.

Targeting the sympathetic nervous system with the selective imidazoline receptor agonist moxonidine for the management of hypertension: an international position statement.

Hypertension is often linked with metabolic risk factors that share common pathophysiological pathways. Despite wide-spread availability of multiple drug classes, optimal blood pressure (BP) control remains challenging. Increased central sympathetic outflow is frequently neglected as a critical regulator of both circulatory and metabolic pathways and often remains unopposed therapeutically. Selective imidazoline receptor agonists (SIRAs) effectively reduce BP with a favorable side effect profile compared with older centrally acting antihypertensive drugs. Hard outcome data in hypertension, such as prevention of stroke, heart and kidney diseases, are not available with SIRAs. However, in direct comparisons, SIRAs were as effective as angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers, and diuretics in lowering BP. Other beneficial effects on metabolic parameters in hypertensive patients with concomitant overweight and obesity have been documented with SIRAs. Here we review the existing evidence on the safety and efficacy of moxonidine, a widely available SIRA, compared with common antihypertensive agents and provide a consensus position statement based on inputs from 12 experts from Europe and Australia on SIRAs in hypertension management.

Agmatine alleviates ethanol withdrawal-associated cognitive impairment and neurochemical imbalance in rats

The present study aimed to investigate the role of agmatine in the neurobiology underlying memory impairment during ethanol withdrawal in rats. Sprague-Dawley rats were subjected to a 21-day chronic ethanol exposure regimen (2.4 % w/v ethanol for 3 days, 4.8 % w/v for the next 4 days, and 7.2 % w/v for the following 14 days), followed by a withdrawal period. Memory impairment was assessed using the passive avoidance test (PAT) at 24, 48, and 72 h post-withdrawal. The ethanol-withdrawn rats displayed a significant decrease in step-through latency in the PAT, indicative of memory impairment at 72 h post-withdrawal. However, administration of agmatine (40 µg/rat) and its modulators (L-arginine, arcaine, and amino-guanidine) significantly increases the latency time in the ethanol-withdrawn rats, demonstrating the attenuation of memory impairment. Further, pretreatment with imidazoline receptor agonists enhances agmatine's effects, while antagonists block them, implicating imidazoline receptors in agmatine's actions. Neurochemical analysis in ethanol-withdrawn rats reveals dysregulated glutamate and GABA levels, which was attenuated by agmatine and its modulators. By examining the effects of agmatine administration and modulators of endogenous agmatine, the study aimed to shed light on the potential therapeutic implications of agmatinergic signaling in alcohol addiction and related cognitive deficits. Thus, the present findings suggest that agmatine administration and modulation of endogenous agmatine levels hold potential as therapeutic strategies for managing alcohol addiction and associated cognitive deficits. Understanding the neurobiology underlying these effects paves the way for the development of novel interventions targeting agmatinergic signaling in addiction treatment.

Molecular Modeling, Synthesis, and Antihyperglycemic Activity of the New Benzimidazole Derivatives - Imidazoline Receptor Agonists.

The paper presents the results of a study on the first synthesized benzimidazole derivatives obtained from labile nature carboxylic acids. The synthesis conditions of these substances were studied, their structure was proved, and some components were found to have sugar-reducing activity on the model of alloxan diabetes in rats. The study used molecular modeling methods such as docking based on the evolutionary model (igemdock), RP_HPLC method to monitor the synthesis reaction, and 1H NMR and 13C NMR, and other methods of organic chemistry to confirm the structures of synthesized substances. The docking showed that the ursodeoxycholic acid benzimidazole derivatives have high tropics to all imidazoline receptor carriers (PDB ID: 2XCG, 2bk3, 3p0c, 1QH4). The ursodeoxycholic acid benzimidazole derivative and arginine and histidine benzimidazole derivatives showed the highest sugar-lowering activity in the experiment on alloxan-diabetic rats. For these derivatives, the difference in glucose levels of treated rats was significant against untreated control. Therefore, the new derivatives of benzimidazole and labile natural organic acids can be used to create new classes of imidazoline receptor inhibitors for the treatment of diabetes mellitus and hypertension.

Place of imidazoline receptor agonists in the treatment of arterial hypertension

The review is devoted to one of the most controversial issues of modern antihypertensive therapy — the role of new generation sympatholytics — selective I1-imidazoline receptor agonists (AIRs). In modern European recommendations, AIR (moxonidine rilmenidine), along with other centrally acting drugs (reserpine, alpha-methyldopa, clonidine), are mainly intended for additional therapy in rare cases of resistant hypertension, when other treatment options have been ineffective. Nevertheless, AIR invariably finds its place in Russian recommendations for the treatment of arterial hypertension (AH). This class of drugs is recommended for patients with AH in combination with metabolic syndrome and obesity. It is noted that an important property of AIR is its positive effect on carbohydrate and lipid metabolism. This information is based on an analysis of Russian and foreign studies, which convincingly indicate that this class of drugs not only provides adequate and long-term blood pressure control, but also has the above-mentioned positive metabolic effects. At the same time, AIRs are much less likely to cause side effects characteristic of older generation centrally acting drugs. Thus, AIRs have become firmly established in clinical practice in Russia for the treatment of patients with AH in certain clinical situations.

Characteristics of patients with non-specific aortoarteritis and arterial hypertension based on retrospective analysis

The aim was to study the medical history, laboratory and instrumental data, the trends of arterial hypertension (AH), risk factors for cardiovascular events, target organ damage (TOD), and the development of cardiovascular complications in patients with NSAA (Non-Specific Aortoarteritis).Materials and Methods. The study included 33 women with confirmed NSAA who had been treated at the 5th Cardiology Department of the E.I. Chazov National Medical Research Center of Cardiology since 2005. Complete blood count, biochemical blood analysis, urine analysis, the following instrumental examinations, such as, ECG, echocardiography, ultrasound of the brachial, femoral, aortic, and renal arteries, MRA or CT angiography with contrast, blood pressure measurement in the arms and legs were performed for all patients. Telephone interviews were conducted to assess some patient's condition over time.Results. The most common symptom (84% of patients) was AH, the average age of AH onset was 30 [19; 40] years and the AH average duration is 7,5 [2; 13] years. Nearly half of the patients (45%) had AH as the leading symptom that led them to perform the examination that helped to the diagnosis of NSAA. The average systolic and diastolic blood pressure values were 123±35 mmHg and 66±17 mmHg in the upper extremities, and 166±31 mmHg and 78±18 mmHg in the lower extremities, respectively. About half of patients (51%) had stage 3 AH, and almost all of them had type 3 according to E. Lupi-Herrera classification. The most common risk factors for cardiovascular events were dyslipidemia (82%), a family history of early cardiovascular events (51%), resting heart rate above 80 bpm (25%), and carbohydrate metabolism disorders (21%). When assessing cardiovascular risk, moderate risk of developing cardiovascular events was observed in 3 patients (10,7%), high risk in 16 patients (57,1%), and very high risk in 9 patients (32,1%). The most common TODs were nervous system damage (53%), including cerebrovascular ischemic events (14%) and left ventricular hypertrophy (42%). This group of patients was characterized by resistant hypertension, and combination with other risk factors for cardiovascular events, it leds to severe TOD and influenced survival rate. In terms of antihypertensive therapy, 61% of patients received combination therapy, with CCB, beta-blockers, and imidazoline receptor agonist being the most prescribed. Two fatal cases were identified in the long-term follow-up, and cardiovascular events, most frequently stroke, were the main complications observed. Additionally, AH progression and its uncontrolled course despite going through multiple drug therapy were characteristic.Conclusion: AH is often difficult to diagnostic in patients with NSAA, and it significantly contributes to the structure of complications and mortality in this patient cohort, progressively worsening over time. It is important to measure blood pressure in both arms and legs to detect elevated values early. The main goals of treatment are achieving NSAA remission and blood pressure control and preventing cardiovascular events.

The effect of the imidazoline receptor agonist rilmenidine on visceral and thermal nociceptive pain in mice

The effect of the imidazoline receptor agonist rilmenidine on visceral and thermal nociceptive pain in mice

Drug-Facilitated Sexual Assault With Tetrahydrozoline (Visine): A Case Report.

This is a case presentation of an 18-year-old male victim who experienced a drug-facilitated sexual assault (DFSA). The drug used to incapacitate him was tetrahydrozoline (Visine) given rectally. Tetrahydrozoline, intended for ophthalmic administration, is in the class of drugs known as imidazoline receptor agonists and has been used as an agent for DFSA since the 1940s. DFSA is increasing, particularly among young men. Care of victims of DFSA is discussed with particular attention to mental health sequelae in this patient population.

Over-Prescription of the Imidazoline Receptor Agonists: Evidence for Restriction of the Therapeutic Indication

Major antihypertensive drug classes (but not Imidazoline Receptor Agonists) have been demonstrated to reduce cardiovascular morbidity and mortality. In 2017, Latvia and Lithuania had the highest cardiovascular mortality among the Eastern, Central, Northern, and Western Member States of the European Union (EU). Cardiovascular mortality in Estonia is much lower than in Lithuania and Latvia. To evaluate the consumption of Imidazoline Receptor Agonists in the Baltic States and its potential implications. The study included data on the sales of Imidazoline Receptor Agonists in Lithuania, Latvia, and Estonia; the marketing authorization databases of the competent authorities; the guidelines on the treatment of hypertension, and the reimbursement conditions. The study showed a very high consumption of the Imidazoline Receptor Agonists in Lithuania and Latvia. From 2016 to 2019, the average consumption of Imidazoline Receptor Agonists in Lithuania was 15.5 times higher than in Estonia; in Latvia, it was 8.9 times higher than in Estonia. The guidelines recommend the use of the Imidazoline Receptors Agonists as one of the last options in hypertension therapy, but the marketing authorizations do not restrict their line of therapy. Consumption of IRAs in Lithuania and Latvia is very high. The authorized use of the IRAs in the EU Member States is not in line with the guidelines on the management of arterial hypertension and therefore patients might be deprived of therapies that reduce the cardiovascular risk. The drug regulatory authorities of the EU should review the data on the safety and efficacy of the IRAs and restrict their therapeutic indications if necessary.

Abstract 4101: ADRENALINE, an atlas for drug and breast cancer survival interaction: Comedications at diagnosis and impact on breast cancer mortality of the French breast cancer cohort (n=235,375)

Abstract Background: Breast cancer (BC) incidence increases with age, as well as the incidence of many other chronic diseases. Between 42 and 68% of BC patients suffer from other chronic conditions -comorbidities- at BC diagnosis. Comorbidities may be associated with the intake of chronic medications -comedications. The French health insurance system routinely collects health care reimbursements of almost 98% of the population: hospital abstracts, long-term diseases, outpatient care (medical consults, drug purchases under prescription⋯) and death status. The project ADRENALINE (Atlas for DRug and brEast caNcer survivAL INtEraction) analyzes the impact of comedications at diagnosis on BC survival on a French cohort using data from the French social security system. Methods: We identified all women diagnosed with an incident BC treated with surgery in France from 2011 to 2017 and affiliated to the general health insurance scheme. Women with concomitant cancer or metastases at diagnosis were discarded from the analyses. Comedication intake was defined as the delivery in pharmacy of at least 3 months of full treatment (e.g. 90 pills) the 6 months preceding BC diagnosis. The analysis was restricted to drugs taken by at least 300 women. A Cox proportional hazard model was used to estimate the hazard ratio (HR) for each molecule. The model was adjusted on more than 100 confounding variables: social factors, comorbidities and other comedications. Two adjustment methods were tested: Inverse Probability of Treatment Weighting (IPTW) and matching. We assumed that the adjustment was sufficient to control for confounding if the standardized mean difference of each confounder after adjustment did not exceed 0.1. Molecules which did not pass the adjustment quality test were discarded. Results: 235,375 patients were included in the study. Among 219 selected drugs, 91 and 171 passed the adjustment quality test for IPTW and for matching, respectively. The full set of results is available on a web application. Among main findings, several drugs or drug classes were associated with an improved survival: proton-pump inhibitors (IPTW; HR=0.93; p=0.002); statins (e.g. rosuvastatin, IPTW, HR=0.65, p<0.001); beta-blocking agents (atenolol, IPTW, HR=0.78, p=0.003); alverine (IPTW, HR=0.78, p<0.001). Conversely, imidazoline receptor agonists may be deleterious (moxonidine; matching; HR=2.12; p = 0.001). Conclusion: ADRENALINE reports the impact on BC survival of 219 widely prescribed drugs. It can be used to identify molecules with a potential protective or deleterious effect relative to BC. Some of them are currently under mechanistical investigation within a drug screening program. This atlas highlights candidates to drug-repurposing trials or pharmacovigilance warnings, and will be extended to cancers of other localizations in a near future. Citation Format: Elise Dumas, Beatriz Grandal, Lucie Laot, Eric Daoud, Lidia Delrieu, Marc Espié, Sophie Houzard, Christine Le Bihan-Benjamin, Philippe-Jean Bousquet, Elodie Anthony, Aurélien Latouche, Nadir Sella, Thierry Dubois, Annabelle Ballesta, Amyn Kassara, Elaine Del Nery, Benjamin Marande, Samar Alsafadi, Paul Gougis, Chloé-Agathe Azencott, Fabien Reyal, Anne-Sophie Hamy. ADRENALINE, an atlas for drug and breast cancer survival interaction: Comedications at diagnosis and impact on breast cancer mortality of the French breast cancer cohort (n=235,375) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4101.

EFFECT OF CORONAVIRUS INFECTION ON PATIENTS WITH CONTROLLED AND UNCONTROLLED ARTERIAL HYPERTENSION

Objective: To assess the severity of coronavirus infection in patients with hypertension, including resistantand refractory hypertension, and to assess the effect of taking ACE inhibitors and ARBs on the course of COVID-19. Design and method: We called 252 people with an established diagnosis of hypertension, included in the database from November 2018 to July 2021, in order to identify patients who have recently undergone COVID-19. Initially, the patients were divided into groups depending on the number of drugs taken and the achievement of target blood pressure levels. Results: 21 (8.3%) of 252 people had a coronavirus infection. 10 out of 21 patients (48%) noted blood pressure destabilization. 6 (60%) of these 10 initially belonged to the group of uncontrolled hypertension (4 of 6 had refractory hypertension, 2 of 6 had uncontrolled resistant hypertension), however, all of them noted worsening blood pressure control and increased frequency of hypertensive crises compared with the period before COVID-19. In 4 out of 9 patients with initially controlled hypertension, BP was destabilized with subsequent normalization of BP during the recovery period. COVID-19 lasted no more than 14 days in all patients and hypertensive crises was treated by taking short-acting drugs, including an ACE inhibitor (Captopril) and an imidazoline receptor agonist (Moxonidine). 7 (33.3%) and 12 (57.1%) of 21 patients continued to take ACE inhibitors and ARBs, respectively, during coronavirus infection. In 2 (9.6%) of 21 patients, the target BP values were achieved during monotherapy with calcium channel antagonists. All patients with Covid-19 had mild or moderate disease; hospitalization was not required in any of the cases. Conclusions: COVID-19 can destabilize blood pressure in patients with hypertension. Taking an ACE inhibitor / ARB does not worsen the course of coronavirus infection in patients with both controlled and uncontrolled hypertension.

Modulation of sympathetic nervous system activity through various therapeutic approaches in patients with resistant hypertension and heart failure with preserved ejection fraction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Agency for Research and Development Purpose The increased activity of the sympathetic nervous system is the pathophysiological key of several pathologies, such as hypertension, heart failure, diabetes, etc., the modulation of its activity can improve the management of these diseases and represents an increased scientific interest. Aim Comparatively evaluation of the effects of modulating SNS activity at different levels through various therapeutic approaches on the NYHA functional class of heart failure and physical capacity to exercise in patients with resistant hypertension. Material and method 75 patients with resistant hypertension and heart failure with the preserved ejection fraction were enrolled in the study. All patients for 21 days underwent standardized ambulatory treatment with Losartan 100 mg, Amlodipine 10 mg and Indapamide 1.5 mg, and were subsequently randomized into three equal groups of 25 patients according to treatment supplemented to the previous treatment: group I M - Moxonidine, group II B - Bisoprolol and group III D – renal denervation. Patients were evaluated clinically, echocardiographically and by the 6-minute walking test at baseline, 3 and 6 months. Results The clinical improvement of NYHA class was confirmed by the progressive increase of the distance traveled in the 6 minute walk test. Thus, the groups being comparable according to the distance traveled at the enrollment stage in the study, noted a statistically authentic dynamic starting with 3 months of continuous medication constituting 392.48 ± 14.88 m in the I M group (+ 20.45% from initial values ) versus 359.84 ± 15.15 m in group II B (+ 15.0% of initial values) and 386.08 ± 11.99 m in group III D (+ 24.33% of initial values), p> 0.05. The increase of the distance traveled continued until 6 months of evaluation in all three observation lots with the following values: 416.12 ± 13.50 m (+ 25.06% from the initial) versus 387.80 ± 12.85 m (+ 21.55% from the initial) and 424.28 ± 10.30 m (+ 31.06% from the initial) in lots I M, II B and III D, respectively. Comparative analysis of the dynamics between groups showed a comparable beneficial effect in improving the distance traveled in the 6 minute walk test in groups of patients treated with Moxonidine and Bisoprolol and the superiority of minimally invasive renal denervation treatment over drug treatment, an event notable starting with 3 months of evaluation and maintained until the end of the supervision period. Conclusions Blockade of the sympathetic nervous system at the central level with the selective imidazoline receptor agonist I1 Moxonidine, at the peripheral level by administration of the β1-cardioselective adrenoblocker Bisoprolol or by the minimally invasive method of renal artery denervation resulted in progresive amelioration of NYHA class and increasing physical capacity to exercise, the pharmacological treatment groups showing a comparable effect, but lower than the group of patients undergoing renal denervation.

Place of imidazoline receptor agonists in the treatment of hypertension

The review is devoted to selective I1-imidazoline-receptor agonists. An analysis of Russian and foreign studies is presented, the results of which indicate that this drug class not only provides adequate and long-term control of blood pressure, but also has a number of favorable metabolic effects. Therefore, it contributes to reducing insulin resistance (weight loss) and has organ protective properties (endothelial function improvement, left ventricular hypertrophy regression, microalbuminuria reduction). At the same time, selective I1-imidazoline-receptor agonists are much less likely to cause side effects characteristic of old-generation sympatholytic agents. This class of drugs is invariably included in Russian guidelines for the diagnosis and treatment of hypertension.

Pharmacoepidemiology of the administration of antihypertensive drugs by doctors in the Voronezh region in comparison with the results of the PYTHAGOR IV study

Background: To examine the pharmacoepidemiology of treatment for arterial hypertension (AH) in Russia, the PYTHAGOR study has been conducted since 2001, including PYTHAGOR III (20012002), PYTHAGOR III (2008), and PYTHAGOR IV (2013). Increasing the role of doctors of outpatient care in the pharmacotherapy of patients with AH creates prerequisites for conducting new pharmacoepidemiological studies.
 Aim: To investigate the structure of prescriptions of antihypertensive drugs (AHD) by outpatient doctors at the regional level in comparison with the results of PYTHAGOR IV pharmacoepidemiological study.
 Materials and methods: In 2018, a survey was conducted in the Voronezh region among 104 doctors, including 58 general practitioners (55.8%), 37 therapists (35.6%), and four cardiologists (3.8%). The average age of the doctors was 45.7 13.5 years, the accumulated period of work was 21.0 13.7 years, and the period of work in an outpatient clinic was 16.6 12.4 years.
 Results: In the structure of doctors pREFERENCES in selecting free combinations of AHD, doctors preferred angiotensin-converting enzyme inhibitors (iACE; 90.3%), but they were prescribed more rarely than that in PYTHAGOR IV study (93.8%). The remaining AHD groups were used by doctors of the VR more often than in the PYTHAGOR IV study: beta-adrenoblockers, 89.4% (PYTHAGOR IV, 73.1%); diuretics, 88.4% (73.2%); calcium antagonists (CА), 86.5% (67.3%); angiotensin II receptor blockers (ARB), 81.7% (62.1%); imidazoline receptor agonists, 57.6% (13.3%). In the selection of fixed combinations of AHD: iACE or ARB with a diuretic was used in 71.9% and 36.4%, respectively, and iACE with CA in 46.2%. In the PYTHAGOR IV study, these combinations were used more rarely, i.e., in 33.3%, 28.0%, and 24.1%, respectively.
 Conclusion: The data obtained indicate adherence of doctors to modern clinical guidelines for the pharmacotherapy of AH.

Assessment of drug-drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice.

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I1 -imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.

Dexmedetomidine Exerts a Negative Chronotropic Action on Sinoatrial Node Cells Through the Activation of Imidazoline Receptors.

Dexmedetomidine (DEX), an α2-adrenoreceptor (α2-AR) and imidazoline receptor agonist, is most often used for the sedation of patients in the intensive care unit. Its administration is associated with an increased incidence of bradycardia; however, the precise mechanism of DEX-induced bradycardia has yet to be fully elucidated. This study was undertaken to examine whether DEX modifies pacemaker activity and the underlying ionic channel function through α2-AR and imidazoline receptors. The whole-cell patch-clamp techniques were used to record action potentials and related ionic currents of sinoatrial node cells in guinea pigs. DEX (≥10 nM) reduced sinoatrial node automaticity and the diastolic depolarization rate. DEX reduced the amplitude of hyperpolarization-activated cation current (If or Ih) the pacemaker current, even within the physiological pacemaker potential range. DEX slowed the If current activation kinetics and caused a significant shift in the voltage dependence of channel activation to negative potentials. In addition, efaroxan, an α2-AR and imidazoline I1 receptor antagonist, attenuated the inhibitory effects of DEX on sinoatrial node automaticity and If current activity, whereas yohimbine, an α2-AR-selective antagonist, did not. DEX did not affect the current activities of other channels, including rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs), L-type Ca2+ current (ICa,L), Na+/Ca2+ exchange current (INCX), and muscarinic K+ current (IK,ACh). Our results indicate that DEX, at clinically relevant concentrations, induced a negative chronotropic effect on the sinoatrial node function through the downregulation of If current through an imidazoline I1 receptor other than the α2-AR in the clinical setting.

Features of antihypertensive pharmacotherapy in patients with metabolic syndrome and diabetes mellitus

The article describes the results of analyzing the available literature concerning specifics of pharmacotherapy for hypertension in elderly patients and patients with metabolic syndrome and diabetes mellitus. Authors present statistical data on the prevalence of hypertension among elderly patients and the incidence of obesity and diabetes in the Russian Federation. The paper highlights the characteristics of clinical course of hypertension in the older age group including the predominance of isolated systolic hypertension, vascular stiffness, and increased endothelial dysfunction. The need for administration of antihypertensive drugs to reduce the risk of complications and improve the quality of life even in older patients is confirmed. The analysis of data from numerous large studies allowed the authors to identify the main principles for selecting antihypertensive drugs in elderly patients. Slow calcium channel blockers, angiotensin converting enzyme inhibitors, and low-dose diuretics should be prescribed as first-line drugs. At the next stage of treatment, in case of unsatisfactory results of initial therapy, the addition of mineralocorticoid receptor antagonists, alpha-blockers, and selective imidazoline receptor agonists should be considered. The main approaches to antihypertensive therapy in patients with metabolic syndrome and diabetes mellitus are described. The authors note the fact of unfavorable impact of metabolic syndrome on cardiovascular system, which provides rationale for aggressive treatment of hypertension in such clinical cases where several drugs may be used to achieve a stable antihypertensive effect. Diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers are recommended as first-line antihypertensive pharmacotherapy in these patients. The authors argue in favour of the use of antihypertensive drug combinations in one dosage form as one of the effective ways to solve the problem of adherence to treatment in elderly patients and patients with concomitant metabolic disorders.

Features of antihypertensive therapy and real-world prescription of selective imidazoline receptor agonists in Russia vs other countries: STRAIGHT study data analysis

To compare the strategies for hypertension management and features of clinical use of I1-imidazoline receptor (I1-IR) agonists in the Russian Federation and other countries where the STRAIGHT (Selective imidazoline receptor agonists Treatment Recommendation and Action In Global management of HyperTension) study was conducted. It was a cross-sectional online study involving physicians of various specializations. The study was conducted from January 18 to July 1, 2019, in seven countries with a high rate of I1-IR agonist prescription, including Russia. A total of 125 (4.5%) responders filled out the survey in the Russian Federation, which was somewhat lower than in other countries (6.8%). The participants were mostly general practitioners (54.0%) and cardiologists (42.0%), while in other countries greater diversity was seen. Most Russian physicians (83.0%) seemed to rely on national clinical guidelines in their routine practice, while in other countries the US guidelines were more popular (66.0%). The majority of responders stated that they took into account the traditional risk factors of hypertension when initiating the therapy; every second responder noted if sleep apnea was present. Awareness of I1-IR agonists, their prescription rate and their preference were higher in Russia. The main reported benefits of I1-IR agonists were their efficacy, including in resistant hypertension, and their metabolic effects (in Russia). Most participants preferred I1-IR agonists as third-line therapy (65.0% in Russia vs 60.0% in other countries) and in combination with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARB) (55.0% in Russia vs 54.0% in other countries). Compared to responders from other countries, Russian physicians prescribe I1-IR agonists as first-line (15.0% vs 5.0%) and second-line (48.0% vs 21.0%) therapy more often. Russian physicians were the most aware of I1-IR agonists and tended to prescribe drugs of this class for hypertension management more often, and I1-IR agonist combination with ACEi was preferable compared to physician responders from other countries. Antihypertensive efficacy and metabolic effects were reported as the major benefits of I1-IR agonist therapy.

Medically induced bradycardia in the elderly and senile patients

Abstract Background Elderly and senile people are most likely to develop cardiovascular diseases, while they have a higher risk of adverse drug reactions. Systemic analysis of medically induced bradycardia (MIB) has not been performed. Aim To analyze the clinical features of MIB in patients ≥65 and ≥75 years according to the Hospital Register of Cardiac Drug Overdoses (storm) data. Materials and methods Analyzed 17,826 cases of hospitalization in the Regional Vascular Center from 01 Jan 2017 to 31 Dec 2019, of them with all types of cardiac drug overdoses – 363, of them with MIB – 52.6% (n=191). Results Average age of those hospitalized with MIB – 74.0 [65.0; 80.0] years: 76.0% were ≥65 years, 49.4% – ≥75 years. Among the cohort ≥65 years, there were more women – 74.3% (vs 52.3%, p=0.003), ≥75 years – 74.4% vs 65.5% (p=0.107). The ratio of absolute and relative overdoses did not depend on age and was 1:9. The frequency of pulse-reducing drug admission before hospitalization did not differ in age groups. In General, in the cohort with MIB: 68.4% – beta-blockers, 25.8% – digoxin, 38.9% – antiarrhythmic drugs with pulse-reducing action (PRA), 9.5% – imidazoline receptor agonists, 10.5% – calcium channel blockers with PRA, 7.4% – other drugs with PRA, while 54.5% of patients received a combination of ≥2 drugs with PRA, 15.7% – ≥3, and even 3.1% – ≥4. In older age groups, a Glomerular Filtration Rate (GFR) decrease in was more often: among ≥65 years GFR <60 ml/min × 1.73 m2 – 83.2% (vs 40.0% in younger patients, p<0.001), <45 ml/min × 1.73 m2 – 61.5% (vs 22.5%, p<0.001), <30 ml/min × 1.73 m2 – 34.5% (vs 15.0%, p<0.001), <15 ml/min × 1.73 m2 – 11.1% (vs 7.5%, p<0.264); among patients ≥75 years: GFR <60 ml/min × 1.73 m2 – 87.4% (vs 60.8%, p<0.001), <45 ml/min × 1.73 m2 – 66.0% (vs 40.2%, p<0.001), <30 ml/min × 1.73 m2 – 37.1% (vs 23.4%, p<0.018), <15 ml/min × 1.73 m2 – 12.0% (vs 8.4%, p<0.357). Patients ≥65 and ≥75 years were more likely to require: emergency hospitalization (97.0% vs 84.1% in younger patients, p<0.001 and 97.0% vs 91.1%, p=0.033), treatment in the intensive care unit (44.7% vs 20.5%, p=0.003 and 48.8% vs 29.2%, p=0.001), temporary pacemaker (58.3% vs 20.0%, p=0.107 and 57.1% vs 40.0%, p=0.284). Hospital mortality in persons ≥75 was 7.7% (vs 1.8% in younger patients, p=0.047), ≥65 – 3.8% (vs 4.6%, p=0.814). Conclusions Older age groups predominate among those hospitalized for MIB. They are characterized by a more pronounced lesion of glomerular filtration, a more severe condition, and a higher risk of death. Practical physicians underestimate the danger of prescribing drugs with PRA, especially in the form of combined therapy, in patients of older age groups, with impaired glomerular filtration, which requires drawing attention to this problem. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Ryazan State Medical University