Sympathomimetic Activity Research Articles

β-Blockers and Asthma: Surprising findings from the FAERS database

Introductionβ-Blockers are essential for cardiovascular disease management but can induce respiratory issues, particularly with non-selective β-blockers. Their safety in asthmatic patients is debated. ObjectiveThis study investigates the link between different classes of β-blockers and the risk of asthma and asthma-like adverse events (AEs) using data from the Food and Drug Administration's Adverse Event Reporting System (FAERS). Methodsβ-Blockers were first reviewed according to European Society of Cardiology classification and then using the Vashistha and Kumar classification. The risk associated with different β-blocker classes was evaluated through disproportionality analysis using the reporting odds ratio (ROR). ResultsAmong 251,145 AEs reported for β-blockers, 4104 were asthma-related. Selective β1-blockers had a higher asthma risk signal (ROR: 1.15) compared to non-selective β-blockers (ROR: 0.90). α- and β-Blockers showed the lowest risk (ROR: 0.51). The Vashistha and Kumar classification detailed risk profiles for various β-blockers, highlighting differences even within the same class. Dual α- and β-blockers, hydrophilic, and lipophilic β-blockers posed lower asthma risks, while selective β1-blockers had higher risks regardless of intrinsic sympathomimetic activity. ConclusionAlthough the signals detected by disproportionality analysis are only candidate risks, the risk stratification resulting from our analysis highlights the need for cautious β-blocker selection in asthmatic patients or those predisposed to asthma. Furthermore, despite the limitations associated with the FAERS data, the study reveals significant variability in risk among different β-blocker classes, crucial for clinical decisions and patient management. Drugs like esmolol, metoprolol, nebivolol, and nadolol may be safer for asthmatic patients, whereas betaxolol, bisoprolol, timolol, and propranolol should be avoided.

Are adolescents with premenstrual disorder at risk for cardiac arrhythmias?

One of the most commonly experienced symptoms of premenstrual disorder (PMD) is anxiety, and there is a notable rise in sympathomimetic activity in this patient group. Studies have linked fluctuations in systemic autonomic tone to electrocardiography (ECG) changes. This study aims to investigate the relationship between anxiety, a common symptom of PMD, and alterations in QT dispersion (QTd) and P-wave dispersion (Pd) in adolescent females. This cross-sectional study included female adolescents aged 12-18 with regular menstruation for at least 3 months. Participants completed the premenstrual syndrome scale (PMSS) and were divided into two groups, PMD and control, according to the PMSS score. A standard 12-lead body surface ECG was performed and QTd and Pd values were determined in each participant. Of the 43 participants, 27 were categorized into the PMD group, with a mean age of 15.15 ± 1.43 years. Age at menarche and menstrual cycle patterns were comparable between the PMD and control groups. Statistical analysis revealed significantly higher Pmin (p = 0.010) and Pd values (p < 0.001) in the PMD group compared to controls. A positive correlation between PMSS scores and Pd (p = 0.049) was also observed. Changes in atrial conduction and ventricular repolarization due to the pathophysiology of PMD may increase the risk of developing atrial and ventricular tachyarrhythmias over time. Screening patients with PMD using an ECG may be useful in identifying potentially at-risk adolescents.

Beta-blockers and their impact on metabolic processes

The aim of the study is to determine the effect of beta-blockers on lipid status, triglycerides and Body Mass Index (BMI) in patients using beta-blockers in the treatment of arterial hypertension. Our study included 120 patients at the Public Health Institution "Dom zdravlja" Živinice. The participants were monitored over a period of 3 years. Measurements were made after 12, 24 and 36 months of treatment. Patients were divided into two groups. The experimental group included 60 patients, who used beta-blockers in the treatment of arterial hypertension. The control group included 60 patients who used other antihypertensives as their first choice medication in the treatment of arterial hypertension. By monitoring cholesterol and triglyceride levels in patients using beta-blockers and other antihypertensive medications, and comparing these values within the group, no statistically significant difference in cholesterol and triglyceride levels was found in patients who used beta-blockers after 12, 24, and 36 months of treatment. There was also no statistically significant effect of therapy on the change in cholesterol and triglyceride values at observed time intervals, nor was there a statistically significant difference between these values. BMI monitoring showed a statistically significant difference between patients using beta-blockers and other antihypertensive drugs, with patients using beta-blockers having a higher BMI after 36 months of treatment. There was no statistically significant difference in BMI between patients using bisoprolol and carvedilol and patients using other beta-blockers, but patients using bisoprolol and carvedilol had lower BMI values. In studies conducted in recent years, it has been noted that many beta-blockers cause dose-dependent adverse metabolic effects on glucose and lipid metabolism, with the most adverse metabolic effects observed in patients treated with conventional non-selective beta-blockers. On the other hand, more favorable metabolic profile have drugs with β1 selective activity, such as atenolol and metoprolol, especially those with intrinsic sympathomimetic activity such as pindolol. In fact, with these beta-blockers, the adverse metabolic effects appear to be less prominent. In conclusion, beta-blockers do not lead to an increase in cholesterol and triglycerides, but they do lead to an increase in BMI in patients with arterial hypertension

Two‐Step Biocatalytic Synthesis of (1S)‐Nor(pseudo)ephedrine Catalyzed by Immobilized Enzymes

AbstractNor(pseudo)ephedrines [N(P)Es] are naturally occurring compounds showing sympathomimetic activity that have many applications especially in the chemical industry and in the pharmaceutical field. Recently a two‐step biocatalytic cascade for the preparation of (1S)‐N(P)E was designed, consisting of a benzoin‐type condensation catalyzed by the (S)‐selective acetoin:dichlorophenolindophenol oxidoreductase (Ao : DCPIP OR) followed by a transamination mediated by either a (S)‐ or (R)‐selective amine transaminase (ATA). In this study, we successfully immobilized both Ao : DCPIP OR and two ATAs of opposite enantioselectivity and used them in the biosynthetic cascade to N(P)Es. Immobilization yield, activity recovery, and stability of the immobilized enzymes, both after use (enzyme recycling) and storage (shelf‐life), were assessed. Ao : DCPIP OR immobilized on glyoxyl‐agarose exhibited remarkable stability under storage conditions throughout the 30‐days monitoring period. Moreover, it was successfully reused in the synthesis of (S)‐phenylacetylcarbinol [(S)‐PAC] yielding high conversion (&gt;94 %) and enantiomeric excess (&gt;99 %). The (R)‐selective At‐ATA from Aspergillus terreus, immobilized on Eupergit® C, demonstrated a slightly higher storage stability when compared to the (S)‐selective Sbv333‐ATA from Streptomyces sp. Bv333 immobilized on the same carrier. Remarkably, both enzymes were effectively reused for ten reaction cycles in the synthesis of N(P)Es, starting from the enzymatically synthesized (S)‐PAC, achieving complete conversions and excellent diastereoselectivity (&gt;99 %).

Medications for attention deficit hyperactivity disorder associated with increased risk of developing glaucoma.

Attention deficit hyperactivity disorder (ADHD) therapies including atomoxetine, methylphenidate, and amphetamines are some of the most prescribed medications in North America. Due to their sympathomimetic action, these drugs are contraindicated in patients with a history of angle closure glaucoma (ACG). This study aims to determine the risk of ACG and open angle glaucoma (OAG) among users of these treatments. This is a retrospective cohort study with a case control analysis using the PharMetrics Plus Database (IQVIA, USA). We created a cohort of new users of atomoxetine, methylphenidate, and amphetamines and they were followed to the first diagnosis of (1) ACG or OAG; or (2) end of follow up. For each case, four age-matched controls were selected. A conditional logistic regression model was used to adjust for confounders and to calculate adjusted incidence-rate-ratios (aIRRs). A total of 240,257 new users of the ADHD medications were identified. The mean age was 45.0 ± 19.4 years and 55% of the cohort was female. Regular users of atomoxetine and amphetamines had a higher aIRR for developing ACG compared with non-users (aIRR = 2.55 95% CI [1.20-5.43] and 2.27 95% CI [1.42-3.63], respectively); while users of methylphenidate had a higher aIRR for developing OAG (aIRR = 1.23 95% CI [1.05-1.59]). Use of amphetamines and atomoxetine had a higher risk for ACG, while use of methylphenidate was associated with a higher risk for OAG. Given the prevalence of ADHD medication use (medically and recreationally), our current data on their associated risk of glaucoma have profound public health implications.

Continuous peripheral electrical nerve stimulation improves cardiac function via autonomic nerve regulation in MI rats

BackgroundPeripheral electrical nerve stimulation (PENS) reportedly improves cardiac function after myocardial ischemia (MI) by rebalancing the cardiac autonomic nervous system. The dynamic and continuous influence of PENS on autonomic and cardiac function based on cardiac self-repair is not well understood. ObjectivesThis study aimed to explore the relationship between autonomic nervous balance and functional cardiac repair after MI and to clarify the optimal acupoint selection and time course for PENS. MethodsThe activities of the superior cervical cardiac sympathetic nerve and vagus nerve were recorded to evaluate the autonomic tone directly. The pressure-volume loop system was used for left ventricular diastolic and systolic function. Noninvasive continuous electrocardiography and echocardiography were performed to analyze heart rate, heart rate variability, and left ventricular function. The effect of continuous PENS (cPENS) or instant PENS (iPENS) on autonomic and cardiac indications was tested. ResultsSympathetic nerve activity and vagus nerve activity increased as compensatory self-regulation on days 7 and 14 post-MI, followed by an imbalance of autonomic tone and cardiac dysfunction on day 28. cPENS at acupoint PC6 maintained autonomic hyperexcitability, improved myocardial systolic and diastolic abilities, and reduced myocardial fibrosis on day 28 post-MI, whereas cPENS at acupoint ST36 had a limited effect. Both iPENS at PC6 and ST36 improved the autonomic and cardiac function of rats in the cPENS groups. ConclusionRats showed autonomic fluctuations and cardiac dysfunction 28 days post-MI. cPENS produced sympathomimetic action to sustain cardiac self-compensation, but with acupoint specificity. On the basis of cPENS, iPENS evoked autonomic regulation and cardiac benefits without acupoint differentiation.

Roles of β-adrenoceptor Subtypes and Therapeutics in Human Cardiovascular Disease: Heart Failure, Tachyarrhythmias and Other Cardiovascular Disorders.

β-Adrenoceptors (β-ARs) provide an important therapeutic target for the treatment of cardiovascular disease. Three β-ARs, β1-AR, β2-AR, β3-AR are localized to the human heart. Activation of β1-AR and β2-ARs increases heart rate, force of contraction (inotropy) and consequently cardiac output to meet physiological demand. However, in disease, chronic over-activation of β1-AR is responsible for the progression of disease (e.g. heart failure) mediated by pathological hypertrophy, adverse remodelling and premature cell death. Furthermore, activation of β1-AR is critical in the pathogenesis of cardiac arrhythmias while activation of β2-AR directly influences blood pressure haemostasis. There is an increasing awareness of the contribution of β2-AR in cardiovascular disease, particularly arrhythmia generation. All β-blockers used therapeutically to treat cardiovascular disease block β1-AR with variable blockade of β2-AR depending on relative affinity for β1-AR vs β2-AR. Since the introduction of β-blockers into clinical practice in 1965, β-blockers with different properties have been trialled, used and evaluated, leading to better understanding of their therapeutic effects and tolerability in various cardiovascular conditions. β-Blockers with the property of intrinsic sympathomimetic activity (ISA), i.e. β-blockers that also activate the receptor, were used in the past for post-treatment of myocardial infarction and had limited use in heart failure. The β-blocker carvedilol continues to intrigue due to numerous properties that differentiate it from other β-blockers and is used successfully in the treatment of heart failure. The discovery of β3-AR in human heart created interest in the role of β3-AR in heart failure but has not resulted in therapeutics at this stage.

Insight into the Stereoselective Synthesis of (1S)‐Nor(pseudo)ephedrine Analogues by a Two‐Steps Biocatalytic Process

AbstractNor(pseudo)ephedrines (N(P)Es), vicinal amino alcohols possessing sympathomimetic biological activity, constitute valuable intermediates and chiral building blocks for the organic synthesis of several active pharmaceutical ingredients (APIs). Due to the presence of two chiral centers, their conventional chemical asymmetric syntheses often involve long, multi‐step procedures, frequently with the aid of expensive and harmful metal catalysts, making it challenging to achieve high yields and optical purities overall. A two‐steps biocatalytic synthetic sequence for the preparation of (1S)‐N(P)E analogues was therefore designed and carried out, consisting of a benzoin‐type condensation catalysed by the (S)‐selective acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) and a transamination mediated by either an (S)‐ or (R)‐selective amine transaminase (ATA). A multistep chemical synthesis of racemic N(P)Es was also optimised in order to obtain reference material for evaluating the performance of the biocatalysed reactions. The novel bi‐enzymatic synthesis provided the desired products with acceptable yields and good diastereo‐ and enantiomeric excesses, thereby paving the way for greener production of these important building blocks.

Разработка и валидация методики количественного определения метопролола в плазме крови пациентов методом ВЭЖХ-МС/МС

INTRODUCTION: Metoprolol is a selective β1-adrenoblocker without intrinsic sympathomimetic activity. The effectiveness of metoprolol has been proven in numerous clinical studies in the treatment of arterial hypertension, stable angina, myocardial infarction, chronic heart failure. To improve the efficiency and safety of the therapy, it is advisable to carry out therapeutic drug monitoring of metoprolol, which requires a sensitive method for its quantitative determination. AIM: To develop, validate and test a method for the determination of metoprolol in human plasma using high performance liquid chromatography (HPLC) with tandem mass spectrometric detection (MS/MS). MATERIALS AND METHODS: The work was performed on Ultimate 3000 TSQ Fortis HPLC-MS/MS (Thermo Fisher, USA). For sample preparation, acetonitrile was used with fexofenadine hydrochloride at a concentration of 10 ng/ml as an internal standard, which was added to plasma samples in 3:1 ratio. The volume of the injected sample was 5 μl. Separation was performed on UCT Selectra C18 4.6 mm × 100 mm, 3 um, 100 A column with a similar pre-column at 35°C, in gradient elution mode in proportion of 0.1% formic acid solution/acetonitrile: 0 min — 80%/20%, 0.1 min — 45%/55%, 5 min — 10%/90%, 10 min — 80%/20%, at flow rate of 300 µl/min. Detection was performed in positive electrospray ionization mode, electrospray voltage 4000 V, sheath gas 50 arb, auxiliary gas 10 arb, purge gas 1 arb, evaporator temperature 350°C, ion transport tube temperature 300°C, using the multiple reaction monitoring mode (MRM) at argon flow rate 2 mTorr, 268 m/z → 115.5 m/z, Collision Energy 18 V, Tube lens 95 V, 268 m/z → 191 m/z, Collision Energy 17 V, Tube lens 95 V. The blood plasma of healthy volunteers served as matrix. RESULTS: The analytical range of the technique was 2–1000 ng/ml. The developed technique was tested on a patient with arterial hypertension. During the analysis, an equilibrium concentration of metoprolol of 12.0 ng/ml was detected in the patient's blood plasma (previously, the patient took metoprolol tartrate at a dose of 12.5 mg twice a day for a week), and in 2 hours after taking the drug — 31.0 ng/ml. CONCLUSION: A method for the quantitative determination of metoprolol in human blood plasma using HPLC-MS/MS has been developed, validated and tested.

A burst of fenoterol excretion during the recovery of a weight loss protocol

Fenoterol is a sympathomimetic β2 receptor agonist primarily used as a bronchodilator. Due to its sympathomimetic actions, the World Anti-Doping Agency (WADA) has banned it. Multiple acute weight loss protocols (WLP) are used by Olympic athletes for sports that segregate athletes by weight; these generally involve caloric and water deprivation combined with heat exposure. Athletes use WLP before weigh-in, then transition to different body acute weight regain protocols (WRP) before competitions. Here, we studied the pharmacokinetics of fenoterol under WLP conditions: energetic dietary restriction, decreased water intake, and exposure to a dry sauna (80 ± 2 °C), followed by a WRP. Five elite-level female judo athletes participated in the study. Four received fenoterol (200 μg; n = 2 or 400 μg; n = 2), while one was a control receiving placebo under identical conditions. We measured excretion of the fenoterol parent molecule and presented qualitative data of its sulfated metabolite using QqQ tandem quadrupole mass spectrometry for 118 h. The fenoterol parent appeared earlier in urine than did its conjugated metabolite; excretion profiles were similar among all subjects. The centers of mass for fenoterol parent curves were (time, fenoterol): athlete A (10.9, 7.3); athlete B (9.2, 27.3); athlete C (8.5, 6.9); athlete D (9.7, 5.0). After initiating WRP, we observed a burst in urinary fenoterol excretion once in complete decay. This trend was observed for all four athletes who received fenoterol. Our results suggest that during hypohydration, some of the unmetabolized fenoterol accumulates in tissues, then is released during rehydration. These findings can be important for detecting fenoterol use in athletes.

Clinically Relevant Drug Interactions with Monoamine Oxidase Inhibitors.

Monoamine oxidase inhibitors (MAOI) are a class of drugs that were originally developed for the treatment of depression but have since been expanded to be used in management of affective and neurological disorders, as well as stroke and aging-related neurocognitive changes. Ranging from irreversible to reversible and selective to non-selective, these drugs target the monoamine oxidase (MAO) enzyme and prevent the oxidative deamination of various monoamines and catecholamines such as serotonin and dopamine, respectively. Tyramine is a potent releaser of norepinephrine (NE) and is found in high concentrations in foods such as aged cheeses and meats. Under normal conditions, NE is unable to accumulate to toxic levels due to the presence of MAO-A, an enzyme that degrades neurotransmitters, including NE. When MAO-A is inhibited, the capacity to handle tyramine intake from the diet is significantly reduced causing the brain to be vulnerable to overstimulation of postsynaptic adrenergic receptors with as little as 8-10 mg of tyramine ingested and can result in life-threatening blood pressure elevations. In addition to adverse reactions with certain foods, both older and newer MAOIs can negatively interact with both sympathomimetic and serotonergic drugs. In general, patients on a MAOI want to avoid two types of medications: those that can elevate blood pressure via sympathomimetic actions (e.g., phenylephrine and oxymetazoline) and those that can increase serotonin levels via 5-HT reuptake inhibition (e.g., dextromethorphan, chlorpheniramine, and brompheniramine). Illicit drugs that stimulate the central nervous system such as ecstasy (MDMA, 3,4-methylenedioxymethamphetamine) act as serotonin releasers. Patient involvement is also crucial to ensure any interaction within the healthcare setting includes making other providers aware of a MAOI prescription as well as avoiding certain OTC medications that can interact adversely with MAOIs.

Beta-adrenergic receptor blockade in angiosarcoma: Which beta-blocker to choose?

Beta-blockers are currently studied to improve therapeutic options for patients with angiosarcoma. However, most of these patients have no cardiovascular co-morbidity and it is therefore crucial to discuss the most optimal pharmacological properties of beta-blockers for this population. To maximize the possible effectiveness in angiosarcoma, the use of a non-selective beta-blocker is preferred based on in vitro data. To minimize the risk of cardiovascular adverse events a beta-blocker should ideally have intrinsic sympathomimetic activity or vasodilator effects, e.g. labetalol, pindolol or carvedilol. However, except for one case of carvedilol, only efficacy data of propranolol is available. In potential follow-up studies labetalol, pindolol or carvedilol can be considered to reduce the risk of cardiovascular adverse events.

Anti-Hypertensive Activity of Some Selected Unani Formulations: An Evidence-Based Approach for Verification of Traditional Unani Claims Using LC-MS/MS for the Evaluation of Clinically Relevant Blood Parameters in Laboratory Rats.

Background: Systemic arterial hypertension, which is associated with an increased risk of cardiovascular disease(CVD), is the most significant modifiable risk factor for mortality and morbidity worldwide. WHO has recognized Unanipathy as an alternate system of medicine. The aim of the present study is to investigate the anti-hypertensive activity of some selected unani formulations using L-NAME model. Method: Group I or hypertensive control group: L-NAME administered for 7 days and left for the next 7 days; Group II or KASgroup: L-NAME administered (i.p) for 7 days and L-NAME + KAS (1000 mg/kg b.w) for the next 7 days; Group III or DMM group: L-NAME administered (i.p) for 7 days and L-NAME + DMM (2000 mg/kg b.w) for the next 7 days; Group IV or MSR group: L-NAME administered (i.p) for 7 days and L-NAME + MSR (300 mg/kg b.w) for the next 7 days; Group V or HJ group: L-NAME administered (i.p) for 7 days and L-NAME + HJ (113 mg/kg b.w) for the next 7 days; Group VI or KGS group: L-NAME administered (i.p) for 7 days and L-NAME +KGS (2000 mg/kg b.w) for the next 7 days. Non-invasive systolic blood pressure and RR-interval (ECG) was measured. Plasma was investigated forsodium, potassium, nitrite, ANP, adrenaline, noradrenaline and aldosterone on day 0, 7 and 14 using LC-MS/MS. Result: Treatment showed a non-significant lowreduction in SBP (systolic blood pressure) of KAS, MSR and HJ while that of DMM was quite significant (p < 0.05), but in the case of KGS, SBP increased. DMM on day 14 significantly (p < 0.05) reduced plasma nitrite while no significant plasma Na+ was noted. In the case of both DMM and KGS, potassium increased significantly (p < 0.05) on day 14. No significant changes in plasma ANP and aldosterone was observed against DMM and KGS while blood levels of adrenaline and noradrenaline significantly (p < 0.05) changed. No significant change in body weight was found. Conclusions: L-NAME KAS, MSR and HJ showed no change in SBP while DMM showed a significant reduction in SBP with decreased plasma nitrite. Probably, DMM may have anti-hypertensive activity mediated through NO inhibition while KGS may involve central sympathomimetic action.

Methamphetamine-Induced Alterations of Vaginal Blood Flow in Rats

ABSTRACT Introduction Those suffering with vaginal dryness, whether experienced once or chronically, frequently experience painful and unpleasurable sexual experiences and diminished self-esteem as a result. Although the physiology of vaginal transudate production is long established, no pharmacological treatment other than estrogen has shown promise in attenuating vaginal dryness. Previously, our lab has shown that methamphetamine (meth) induced vaginal lubrication in adult women and anesthetized rats. The production of these vaginal secretions was shown to be dose-, as well as nitric oxide-dependent. As the secretion of vaginal lubrication is immensely dependent on local hemodynamics and the resulting increased blood flow to the genital tissues, determining meth-induced alterations in blood flow to these tissues is paramount. Objective The purpose of the current study is to determine if increased vaginal blood flow correlates with increased vaginal lubrication in response to meth, and to determine if alterations in this blood flow are nitric oxide-dependent. Methods Adult female Wistar rats were implanted with chronic indwelling jugular catheters and allowed at least one week to recover from surgery. Rats anesthetized with isoflurane gas were intravenously infused with meth (0.06-0.96 mg/kg) or saline via the implanted catheter. Vaginal blood flow, measured using a Periflux System 5000 and a small laser probe inserted 5-10 mm into the vaginal canal, was continuously recorded before and for at least twenty minutes following drug administration. After establishing meth-induced alterations in vaginal blood flow, pre-treatment with L-NG-Nitro arginine methyl ester (L-NAME), a non-specific nitric oxide synthase inhibitor, followed by meth administration following the same procedure for measuring blood flow allowed us to determine the contribution of nitric oxide to the observed changes in blood flow. Results Preliminary findings show that an IV infusion of meth induces an immediate increase in vaginal blood flow, followed by decreased blood flow due to vasoconstriction via increased sympathetic tone. We anticipate inhibition of nitric oxide production will reduce the increase in blood flow immediately after meth administration since this decreased vaginal lubrication in response to the same treatment. Conclusions These findings provide insight into the meth-induced vaginal lubrication we have previously reported, and that meth, whose sympathomimetic action traditionally induces vasoconstriction, produces increased blood flow in vaginal tissues, which is likely the driving force for the increased transudate produced. This advancement is critical for uncovering a mechanism that may serve as the optimal pharmacological target to treat vaginal dryness. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Embera NeuroTherapeutics &amp; JanOne

Khat Chewing and Cardiovascular Disease.

Khat chewing is a deeply rooted habit in Yemen. It has social, economic, and medical problems. Chronic use of khat chewing increases the risk of many medical complications. Cathinone, the main khat leaf constituent, has an indirect sympathomimetic action. The effect of khat chewing and cathinone on the cardiovascular system have been identified, including increased risk of hypertension and acute cardiovascular events, as well as increased risk of cardiovascular complications among patients presenting with Acute Coronary Syndrome who are khat chewers.

Possibilities and limitations of the use of beta-blockers in patients with cardiovascular disease and chronic obstructive pulmonary disease

In medical literature, increasing attention is paid to comorbidities in patients with chronic obstructive pulmonary disease (COPD). In clinical practice, physicians often hesitate to prescribe beta-blockers (β1-adrenoblockers) to COPD patients. This article summarized new results of using beta-blockers in patients with COPD. According to reports, the selective β1-blocker treatment considerably increases the survival rate of patients with COPD and ischemic heart disease, particularly after myocardial infarction (MI), and with chronic heart failure (CHF). The benefit of administering selective β1-blockers to patients with CHF and/or a history of MI overweighs a potential risk related with the treatment even in patients with severe COPD. Convincing data in favor of the β1-blocker treatment in COPD patients without the above-mentioned comorbidities are not available. At present, the selective β1-blocker treatment is considered safe for patients with cardiovascular diseases and COPD. For this reason, selective β1-blockers, such as bisoprolol, metoprolol or nebivolol can be used in managing this patient cohort. Nonselective β1-blockers may induce bronchospasm and are not recommended for COPD patients. For the treatment with β-blockers with intrinsic sympathomimetic activity, the probability of bronchial obstruction in COPD patients is lower; however, drugs of this pharmaceutical group have not been compared with cardioselective beta-blockers. For safety reasons, the beta-blocker treatment should be started outside exacerbation of COPD and from a small dose. Careful monitoring is recommended for possible new symptoms, such as emergence/increase of shortness of breath, cough or changes in dosing of other drugs (for example, increased frequency of using short-acting bronchodilators).

Clinical Pharmacology of Propranolol in Infants and Children

Propranolol is α nonselective β adrenergic receptor antagonist with equal affinity for β1 and β2 adrenergic receptors, lacks intrinsic sympathomimetic activity, and does not block α receptors. Propranolol is absorbed following oral administration and consists in two enantiomers, the (-) enantiomer is the active form and is cleared from the body more slowly than the inactive (+) enantiomer. Much of propranolol is metabolized in the liver and the metabolites of propranolol are 4-hydroxypropranolol, 5-hydroxypropanolol, N-desisopropranol, and propranolol β-D-glucuronide. The oral dose of propranolol hydrochloride is 250 to 750 µg/kg thrice-daily in infants and in children it is 200 to 500 µg/kg thrice-daily or 4 times-daily. Propranolol has been found efficacy and safe in infants and children but may induce adverse-effects. The elimination half-life of propranolol is about 15 hours in term and preterm infants and the distribution volume of propranolol is larger than the water volume. Propranolol interacts with drugs. Halofenate, phenytoin, phenobarbitone, rifampicin, and ethanol which affect the clearance of propranolol, and chlorpromazine and cimetidine inhibit the metabolism of propranolol. The prophylaxis, treatment, and trials with propranolol have been extensively studied in infants and children. Propranolol crosses the human placenta but it does not equilibrate between the maternal and foetal compartment and migrates into the beast-milk. The aim of this study is to review the published of propranolol dosing, efficacy and safety, effects, adverse-effects, metabolism, pharmacokinetics, interaction with drugs, prophylaxis, treatment and trials in infants and children and propranolol transfer across the human placenta and migration into the beast-milk.

Comparative Characteristics of Beta-Blockers in Patients with Congenital Long QT Syndrome

Congenital long QT syndrome is a pathology that requires special attention and knowledge about the safety and effectiveness of various medications. Prolongation of the QT interval due to congenital or acquired causes is an important factor in the development of an unfavorable life forecast with the formation of an elongated QT syndrome. With an unfavorable course, patients suffer from loss of consciousness, episodes of tachycardia. Often, stable polymorphic ventricular tachycardia develops. The risk of sudden cardiac death in this pathology can vary from 0.33% to 5%. In people who have suffered an episode of cardiac arrest, and do not have a permanent prescribed antiarrhythmic therapy, the mortality rate reaches 50% within 15 years. Preventive administration of antiarrhythmic drugs is not always effective. A positive result of treatment depends on the severity of long QT syndrome and its genotype. Beta-blockers are often prescribed to patients of different ages with various cardiac pathologies, including for the prevention of arrhythmia in long QT syndrome. Beta-blockers differ in various pharmacokinetic and pharmacodynamic parameters (lipophilicity/hydrophilicity, selectivity, presence/absence of internal sympathomimetic activity), which, along with the variant of the disease genotype, can affect their effectiveness and safety in the considered pathology. This review article presents the results of major studies on the safety and effectiveness of different groups of beta blockers in various variants of long QT syndrome. The preferred beta-blockers for various genotypes of the syndrome were determined, and a comparative characteristic of beta-blockers for their safety and preventive effectiveness was given.

Methamphetamine and heightened risk for early-onset stroke and Parkinson's disease: A review

IntroductionMethamphetamine users are typically young adults, placing them at risk for significant drug-related harms. Neurological harms include stroke and Parkinson's disease, both of which may develop prematurely in the context of methamphetamine use. Material and methodsWe conducted a narrative review examining the evidence first, for stroke under 45 years and second, early onset of Parkinson's disease (PD) and parkinsonism related to methamphetamine use. We summarise epidemiological factors and common clinical features, before examining in detail the underlying pathology and causal mechanisms. Results and discussionMethamphetamine use among young people (<45 years) is associated with heightened risk for haemorrhagic stroke. Compared to age-matched all-cause fatal stroke, haemorrhage secondary to aneurysmal rupture is more common among young people with methamphetamine-related stroke and is associated with significantly poorer prognosis. Aetiology is related primarily to both acute and chronic hypertension associated with methamphetamine's sympathomimetic action. Evidence from a variety of sources supports a link between methamphetamine use and increased risk for the development of PD and parkinsonism, and with their early onset in a subset of individuals. Despite this, direct evidence of degeneration of dopaminergic neurons in methamphetamine users has not been demonstrated to date. ConclusionsStroke and Parkinson's Disease/parkinsonism are neurological harms observed prematurely in methamphetamine users.

β-Blockade for Patients with Hypertension, Ischemic Heart Disease or Heart Failure: Where are We Now?

β-blockers are a heterogeneous class of drugs, with varying selectivity/specificity for β1 vs β2 receptors, intrinsic sympathomimetic activity (ISA), and vasodilatory properties (through β2 stimulation, α receptor blockade or nitric oxide release). These drugs are indicated for the management of arterial hypertension, heart failure or ischemic heart disease (IHD; eg angina pectoris or prior myocardial infarction). Most of the benefit of β-blockade in these conditions arises from blockade of the β1 receptor, and, in practice, the addition of ISA appears to reduce the potential for improved clinical outcomes in people with heart failure or IHD. Aspects of the benefit/risk balance of β-blockers remain controversial, and recent meta-analyses have shed new light on this issue. We have reviewed the current place of cardioselective β-blockade in hypertension, IHD and heart failure, with special reference to the therapeutic profile of a highly selective β1-adrenoceptor blocker, bisoprolol.