Antiadrenergic Agents Research Articles

Treatment of hypertension during pregnancy: a cohort of pregnancy episodes from the SIDIAP database, Catalonia, Spain.

Hypertension during pregnancy is one of the most frequent causes of maternal and fetal morbimortality. Perinatal and maternal death and disability rates have decreased by 30%, but hypertension during pregnancy has increased by approximately 10% in the last 30years. This research aimed to describe the pharmacological treatment and pregnancy outcomes of pregnancies with hypertension. We carried out an observational cohort study from the Information System for the Development of Research in Primary Care (SIDIAP) database. Pregnancy episodes with hypertension (ICD-10 codes for hypertension, I10-I15 and O10-O16) were identified. Antihypertensives were classified according to the ATC WHO classification: β-blocking agents (BBs), calcium channel blockers (CCBs), agents acting on the renin-angiotensin system (RAS agents), diuretics, and antiadrenergic agents. Exposure was defined for hypertension in pregnancies with ≥2 prescriptions during the pregnancy episode. Descriptive statistics for diagnoses and treatments were calculated. In total, 4,839 pregnancies with hypertension diagnosis formed the study cohort. There were 1,944 (40.2%) pregnancies exposed to an antihypertensive medication. There were differences in mother's age, BMI, and alcohol intake between pregnancies exposed to antihypertensive medications and those not exposed. BBs were the most used (n = 1,160 pregnancy episodes; 59.7%), followed by RAS agents (n = 825, 42.4%), and CCBs were the least used (n = 347, 17.8%). Pregnancies involving hypertension were exposed to antihypertensive medications, mostly BBs. We conduct a study focused on RAS agent use during pregnancy and its outcomes in the offspring.

A retrospective cohort study of prescription drug use among youth with intellectual/developmental disabilities in British Columbia.

People with intellectual/developmental disabilities (IDD) are known to have high rates of prescription drug use, particularly for psychotropic medications. This is of concern due to the many side effects associated with these medications and because of the risks of polypharmacy. In this paper we compare the most commonly dispensed drugs and all psychotropic medications for youth with IDD compared with youth without IDD. Using population-level administrative health data over a 10-year period, this study examined medications dispensed to youth with an IDD aged 15-24years compared with youth without an IDD. The most common medications dispensed and the number of youth they were dispensed to were determined. As well a wide variety of psychotropic medications were examined. There were a total of 20591 youth with IDD and 1293791 youth without IDD identified. Youth with IDD had higher odds of being dispensed pain medications, amoxicillin, salbutamol, levothyroxine and all the psychotropic medications (antidepressants, antipsychotics, anxiolytics, anti-adrenergic agents, mood stabilisers and stimulants). For youth with IDD, 6558 (31.85%) were dispensed two or more different psychotropic medications within a year, compared with 75963 (5.87%) of youth without IDD. Compared to youth without IDD, youth with IDD had significantly higher odds of being dispensed most of the prescription medications studied, including all of the psychotropic medications. They were also twice as likely to be dispensed two or more medications from different classes of psychotropic drugs within the same year. These findings have important implications for the health of people with IDD and for their health care providers.

RETROSPECTIVE, OBSERVATIONAL, LONGITUDINAL STUDY OF DRUG UTILIZATION FOR THE TREATMENT OF UNCOMPLICATED ESSENTIAL HYPERTENSION IN BULGARIA

Objective: To evaluate drug utilization and assess rational drug use in the treatment of patients with uncomplicated essential hypertension in Bulgaria, using quantitative and qualitative measures at national level. Design and method: Retrospective, observational, longitudinal study of data from the public registers of the National Health Insurance Fund for the period 2017-2021 using the WHO ATS/DDD methodology and descriptive statistical methods. Results: The analyzed population included 129 312 patients with uncomplicated essential hypertension /I10/ - 11.09% of all hypertensive patients in Bulgaria. The average cost per year was 8 229 567.10 BGN (1 Euro=1.95583 BGN) - respectively the cost per patient per year was 63.64 BGN, the monthly cost was 5.30 BGN and the cost per day was 0.17 BGN. The amount of 8 229 567.10 BGN was divided into two groups - costs for mono-products (67.73%) and costs for combined products (32.27%). The analysis of the actual therapeutic practice in Bulgaria showed that the most prescribed products for this indication were beta-blockers Nebivolol and Bisoprolol, calcium channel blocker Lercanidipine and centrally acting anti-adrenergic agents Moxonidine and Rilmenidine. Sartans were represent predominantly by Telmisartan. In all cross-sectional analyses, the significant use of Lercanidipine was very prominent. Regarding the fixed-dose combinations, medicinal products, containing AT1-blocker and thiazide diuretic were preferred choice for treatment - the most prescribed combination was Valsartan with Hydrochlorothiazide (15.93% of the reimbursement costs for fixed-dose combinations). Conclusions: Despite of the clear recommendation in the guidelines, monotherapy was still preferred treatment for uncomplicated essential hypertension /I10/ in Bulgaria, during the studied period /2017-2021/. We must persist with the continuous education of the GPs, in order to improve the therapy and control of the arterial hypertension in Bulgaria.

Evaluation of antihypertensive medications use and survival in patients with ovarian cancer: a population-based retrospective cohort study

BackgroundDespite declining mortality in most countries and in Lithuania, ovarian cancer burden has remained high. Studies have indicated that antihypertensive medications use may help to improve ovarian cancer survival, however findings remain controversial. The aim of the study was to analyse the association between post-diagnosis antihypertensive medications intake and cancer-specific survival in ovarian cancer patients.MethodsThis retrospective cohort study included 588 ovarian cancer cases diagnosed between 2013 and 2015. Hazard ratios (HR) and corresponding 95% confidence intervals (95%CI) were estimated using multivariable Cox proportional hazards models to assess associations between antihypertensive medications and ovarian cancer-specific mortality.ResultsIn total, 279 (47%) patients died during the follow-up; 242 (87%) of them died due to ovarian cancer. The risk of ovarian cancer death was reduced in angiotensin-converting enzyme inhibitors (ACE inhibitors) users vs. non-users (HR 0.55, 95% CI: 0.36–0.83). Subgroup analysis showed better ovarian cancer survival in higher dose ACE inhibitors users (HR 0.46, 95% CI: 0.28–0.77, p for trend 0.002); the effect was also stronger in age 51–65 years, stage I–III, surgery or chemotherapy treatment, pre-diagnosis ACE inhibitor users’ and pre-diagnosis hypertension subgroups. The risk of cancer-specific death was slightly lower among calcium-channel blocker and angiotensin-receptor blocker users and higher among beta-blocker users as compared to non-users, however chance and confounding could not be ruled out. We found no association between the use of centrally and peripherally acting antiadrenergic agents and diuretics and risk of ovarian cancer-specific mortality.ConclusionsOur findings imply that post-diagnosis use of ACE inhibitors may be associated with reduced ovarian cancer-specific mortality; however, further research is needed for the comprehensive assessment.

Experimental pharmacological approaches to reverse impaired awareness of hypoglycemia-a review.

The colossal global burden of diabetes management is compounded by the serious complication of hypoglycemia. Protective physiologic hormonal and neurogenic counterregulatory responses to hypoglycemia are essential to preserve glucose homeostasis and avert serious morbidity. With recurrent exposure to hypoglycemic episodes over time, these counterregulatory responses to hypoglycemia can diminish, resulting in an impaired awareness of hypoglycemia (IAH). IAH is characterized by sudden neuroglycopenia rather than preceding cautionary autonomic symptoms. IAH increases the risk of subsequent sudden and severe hypoglycemic episodes in patients with diabetes. The postulated causative mechanisms behind IAH are complex and varied. It is therefore challenging to identify a single effective therapeutic strategy. In this review, we closely examine the efficacy and feasibility of a myriad of pharmaceutical interventions in preventing and treating IAH as described in clinical and preclinical studies. Pharmaceutical agents outlined include N-acetyl cysteine, GABA A receptor blockers, opioid receptor antagonists, AMP activated protein kinase agonists, potassium channel openers, dehydroepiandrosterone, metoclopramide, antiadrenergic agents, antidiabetic agents and glucagon.

The Use of Anti-Adrenergic Agents as a Predictor of AKI and Delayed Recovery of Kidney Function: The NARA-AKI Cohort Study

The Use of Anti-Adrenergic Agents as a Predictor of AKI and Delayed Recovery of Kidney Function: The NARA-AKI Cohort Study

Evaluating potentially inappropriate medications in elderly patients in a pharmacy setting in Bulgaria: A pilot study utilizing the EU (7)-PIM List

Objective: The primary aim of this study was to evaluate, for the first time, the use of the EU-7 PIM List in identifying potentially inappropriate medications among older patients. Researchers have firmly established the connection between drug-related problems, which include increased morbidity and mortality rates and the heightened utilization of healthcare services. While previous studies have focused on methodologies for identifying potentially inappropriate medications in Bulgaria, further research is warranted to explore the applicability of the widely recognized EU(7)- PIM List. Materials and methods: A prospective review was conducted on patient prescriptions aligned with the National Health and Insurance Fund, explicitly focusing on patients aged over 65 years from a single pharmacy in Veliko Turnovo City, Bulgaria. The review spanned from November 2022 to April 2023. The prescriptions analyzed in this study exclusively comprised medications covered by the insurance fund. The pharmacy manager provided patient prescription data in a coded form, which included information on the patients’ age, corresponding medications, and accompanying ICD codes. Results: The study analyzed a sample of 255 patients. Healthcare providers prescribed 2,623 medications, and 61.96% of the patients had polypharmacy, taking more than five medications daily. Among the study population, 67% with polypharmacy had at least one PIM based on the EU (7)-PIM List criteria. In total, 173 potentially inappropriate medications (PIMs) were identified. The main PIMs were categorized into four groups: alimentary tract and metabolism, blood and blood-forming organs, cardiovascular system (CVS), and nervous system. Most PIMs (75.72%) were in the ATC cardiovascular system. Within the CVS category, 11 PIMs were associated with digoxin intake and 11 with antiarrhythmics such as propafenone, flecainide, and amiodarone. In addition, trimetazidine was linked to 9 PIMs, and centrally acting antiadrenergic agents had 22 PIMs, with moxonidine being the most prevalent (n=16). Peripherally acting agents were linked to 22 PIMs, primarily doxazosin. The study identified 24 PIMs related to diuretics, specifically spironolactone, and 18 PIMs related to selective calcium channel blockers such as verapamil. The antithrombotic agent category had the highest share, with 30 identified PIMs, including acenocoumarol, dabigatran, rivaroxaban, and apixaban. Furthermore, the examination of ICD codes confirmed that most PIMs occurred within CVS, with patients having ICD I11.0 and ICD I11.9 being associated with 40 and 47 PIMs, respectively. Conclusion: This study highlights many PIMs among patients with cardiovascular diseases. Using the EU (7)-PIM List as a pilot study demonstrates its effectiveness in managing adult patients’ conditions. Given the significant role of PIMs in deprescribing strategies for older patients with polypharmacy, there is a need for prescribers, educators, and drug regulatory institutions to show increased interest in regulatory measures and specific aspects related to PIM use. This is important because the demographic trend of population ageing continues, and organizations increasingly focus on the elderly population.

The use of anti-adrenergic agents as a predictor of acute kidney injury and delayed recovery of kidney function: the NARA-AKI cohort study.

Association of preoperative regular use of anti-adrenergic agents with postoperative acute kidney injury (AKI) and with trajectory of kidney function after AKI is still unknown. In a retrospective cohort study, adults undergoing non-cardiac surgery under general anesthesia were included. Obstetric or urological surgery, missing data, or preoperative dialysis was excluded. The exposure of interest was preoperative regular use of anti-adrenergic agents. The outcomes were AKI within 1 week postoperatively and trajectories of kidney function within 2 weeks postoperatively among patients with AKI. Multivariable logistic regression models were used to examine the association of anti-adrenergic agents with AKI. Linear mixed-effects models were used to compare the trajectories of postoperative kidney function after AKI between patients with and without anti-adrenergic agents. Among 5168 patients, 245 had used anti-adrenergic agents. A total of 309 (6.0%) developed AKI, and the use of anti-adrenergic agents was independently associated with postoperative AKI even after adjustment for preoperative and intraoperative potential confounders [odds ratio (95% confidence interval): 1.76 (1.14-2.71)]. The association was similar across preexisting hypertension or cardiovascular disease. Analyses restricted to patients with AKI suggested that the timing and stage of AKI were similar among those with and without anti-adrenergic agents; however, the recovery of kidney function was delayed among those with anti-adrenergic agents (P for interaction = 0.004). The use of anti-adrenergic agents was associated with postoperative AKI and delayed recovery of kidney function after AKI. Temporary withdrawal of anti-adrenergic agents during perioperative periods may contribute to prevent AKI and shorten the duration of AKI.

Retrospective analysis of drug utilization and rational drug use in treatment of essential arterial hypertension in Bulgaria: Generic perception

Aim: To analyze drug utilization and rational drug use in treatment of essential arterial hypertension in Bulgaria by using quantitative and qualitative parameters at national level. To assess generic penetration as a part of rational drug use. Materials and methods: Design: retrospective study of publicly accessible data from registries of National health insurance fund for the period January–December 2017. The analyses are in accordance with ATC/DDD methodology of WHO. The data was processed via descriptive statistical methods. Results: The analyzed population includes 185 671 patients with essential arterial hypertension—13.33% of all hypertensive patients. The expenses for 2017 are 9 796 940.12 BGN (Bulgarian leva; 1 Euro=1.95,585 BGN). The expense per patient per year is 52.76 BGN, monthly expense is 4.40 BGN and daily expense is 0.14 BGN. The sum of 9 796 940.12 BGN is divided into two groups—expenses for monoproducts 65.88% and expenses for combined products 34.12%. Blockbusters are INNs lercanidipine and nebivolol. The total expenses for uncomplicated essential arterial hypertension are 1.22% of the total expenses. With this resource, 1.6 DDD/Patient/Day is provided. Discussion: In Bulgarian therapeutic practice, the most prescribed products are beta-blockers nebivolol and bisoprolol, calcium antagonist lercanidipine, and centrally acting antiadrenergic agents rilmenidine and moxonidine. Sartanes are represented mainly by valsartan. In all section analyses, the considerable use of lercanidipine is evident. Reference (original) medicinal products are mainly prescribed, while the market share of generic products, both in terms of costs and DDD, is significantly lower. Obtained results are inconsistent with European recommendation, while lack of national pharmacotherapeutic guideline poses a serious challenge.

Effects of β-Blockers on the Sympathetic and Cytokines Storms in Covid-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a causative virus in the development of coronavirus disease 2019 (Covid-19) pandemic. Respiratory manifestations of SARS-CoV-2 infection such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) leads to hypoxia, oxidative stress, and sympatho-activation and in severe cases leads to sympathetic storm (SS). On the other hand, an exaggerated immune response to the SARS-CoV-2 invasion may lead to uncontrolled release of pro-inflammatory cytokine development of cytokine storm (CS). In Covid-19, there are interactive interactions between CS and SS in the development of multi-organ failure (MOF). Interestingly, cutting the bridge between CS and SS by anti-inflammatory and anti-adrenergic agents may mitigate complications that are induced by SARS-CoV-2 infection in severely affected Covid-19 patients. The potential mechanisms of SS in Covid-19 are through different pathways such as hypoxia, which activate the central sympathetic center through carotid bodies chemosensory input and induced pro-inflammatory cytokines, which cross the blood-brain barrier and activation of the sympathetic center. β2-receptors signaling pathway play a crucial role in the production of pro-inflammatory cytokines, macrophage activation, and B-cells for the production of antibodies with inflammation exacerbation. β-blockers have anti-inflammatory effects through reduction release of pro-inflammatory cytokines with inhibition of NF-κB. In conclusion, β-blockers interrupt this interaction through inhibition of several mediators of CS and SS with prevention development of neural-cytokine loop in SARS-CoV-2 infection. Evidence from this study triggers an idea for future prospective studies to confirm the potential role of β-blockers in the management of Covid-19.

Potentially inappropriate medication and associated factors such as depression and dementia: An analysis of middle-aged and elderly people

AIMS: To establish the frequency potentially inappropriate medications use and the associated factors, such as signs and symptoms of depression and cognitive deficit among middle-aged and elderly people.METHODS: A cross-sectional population study was performed with 2,350 people, aged between 55-103 years, registered in the primary health care. Potentially inappropriate medications were defined by updated 2019 Beers criteria. Studied variables were sociodemographic, lifestyle and health, and signs and symptoms of depression and cognitive deficit. Multinomial regression analysis was executed.RESULTS: The frequency of potentially inappropriate medications use was 65.4%. Former and current smokers, regular self-perception of health, polypharmacy, and individuals with signs and symptoms of depression and cognitive deficit were significantly associated with potentially inappropriate medications use. Antiarrhythmics, antihistamines and antiadrenergic agents were the highest potentially inappropriate medications classes used for individuals with signs and symptoms of depression and cognitive deficit.CONCLUSIONS: The frequency of use of potentially inappropriate medications is high among middle-aged people, a population that was previously under-researched, as well as among elderly people. Cognitive impairment alone or together with depression symptoms were associated factor for a potentially inappropriate medications use. Knowledge of the pharmacoepidemiology of potentially inappropriate medications is an important for the promotion of the rational use of drugs in public health.

5.73 USE OF PRAZOSIN FOR INTRUSIVE SYMPTOMS IN PEDIATRIC PTSD: A PROOF-OF-PRINCIPLE STUDY

Only few studies have investigated pharmacologic treatment for juvenile PTSD. Antiadrenergic agents are an interesting option, because of an autonomic nervous system hyperactivation in PTSD. Prazosin, an α-1 antagonist, has proven its efficacy in an adult population. In the pediatric population, few data support its use for nightmares and sleep disturbances in PTSD. We aim to assess the efficacy and safety of prazosin in a pediatric population.

Potentially inappropriate medications with risk of cardiovascular adverse events in the elderly: A systematic review of tools addressing inappropriate prescribing.

In the last decades, many lists have been developed to screen for inappropriate prescribing. However, information on which potentially inappropriate medications (PIMs) could increase the cardiovascular risk in the elderly is not objectively presented. This review aimed to identify and quantify those PIMs by extracting information from published PIM-lists. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA), a systematic review of PIM-lists was conducted. The search strategy was run in PubMed, MEDLINE and Google Scholar (1991-09/2017). All PIMs described in those lists were extracted and stratified by their potential cardiovascular risk (including major adverse cardiovascular events-MACE). The number of times each PIM was reported on those lists was also assessed. We identified 724 papers, and 24 were retained. From those, a total of 17 PIMs to be avoided by the elderly and 21 drug-disease interactions were retrieved. The reporting of PIMs with risk of cardiovascular adverse events was 15.3%, whereas the reporting of those with MACE risk was 7.2%. PIMs most frequently described were tricyclic antidepressants (TCAs; 12/24), centrally acting antiadrenergic agents (11/24), NSAIDs (7/24), antiarrhythmics (Class I and III; 6/24), peripherally acting antiadrenergic agents (6/24) and antithrombotic agents (5/24). Most frequently described PIMs with MACE risk were NSAIDs (7/24), antiarrhythmics (Class I and III) (7/24), selective calcium channel blockers with vascular effects (6/24) and antipsychotics (4/24). Data suggest that PIM-lists focus mainly on common adverse events and often poorly describe the potential consequence for MACE occurrence. This systematic review could help healthcare professionals in the identification and deprescribing of these medicines in older patients with high cardiovascular risk during medication review.

Comparative chemoreactome analysis of dexketoprofen, ketoprofen, and diclofenac

Cyclooxygenase-2 (COX-2) is the main targeted protein of non-steroidal anti-inflammatory drugs (NSAID); nevertheless, the latter substantially differ in pharmacological properties. Objective : to establish the spectrum of pharmacological actions of dexketoprofen, ketoprofen, and diclofenac, by using a chemoreactome analysis. Material and methods . A chemoinformation analysis was used to determine a list of the chemical structures closest to dexketoprofen. For each molecule, the investigators extracted the results of experimental measurements of the rheological properties of this molecule from databases and a chemoreactome analysis was carried out. The comparative chemoreactome analysis of the molecule of dexketoprofen and control molecules (ketoprofen, diclofenac) could assess the biological activity of the studied molecule. Results and discussion . Unlike the molecules of comparison, dexketoprofen was found to be able to accumulate mainly in muscles, adipose tissue, and adrenal glands. The anti-inflammatory and analgesic effect of dexketoprofen can be carried out via modulation not only of the metabolism of prostaglandins, but also that of leukotrienes and encephalins, as well as via inhibition of metalloproteinases and glutamate receptors. In addition, the analysis showed a considerable difference in the interaction profiles of dexketoprofen, ketoprofen, and diclofenac with cytochrome P450 enzymes. Dexketoprofen can enhance the efficacy of anti-arrhythmic and antiadrenergic agents, whereas ketoprofen and diclofenac are able to negatively affect the metabolism of omega-3 polyunsaturated fatty acids and vitamin D. Conclusion . The chemoreactome analysis could identify the promising vasodilatory, antiplatelet, antidiabetic, and antitumor effects of dexketoprofen in addition to its main action.

Antihypertensive drugs use and the risk of prostate cancer: a meta-analysis of 21 observational studies

BackgroundDue to the lack of strong evidence to identify the relationship between antihypertensive drugs use and the risk of prostate cancer, it was needed to do a systematic review to go into the subject.MethodsWe systematically searched PubMed, Web of Science and Embase to identify studies published, through May 2015. Two evaluators independently reviewed and selected articles involving the subject. We used the Newcastle-Ottawa Scale (NOS) to assess the quality of the studies. All extracted results to evaluate the relationship between antihypertensive drugs usage and prostate cancer risk were pool-analysed using Stata 12.0 software.ResultsA total of 12 cohort and 9 case-control studies were ultimately included in our review. Most of the studies were evaluated to be of high quality. There was no significant relationship between angiotensin converting enzyme inhibitors (ACEI) usage and the risk of prostate cancer (RR 1.07, 95% CI 0.96–1.20), according to the total pool-analysed. Use of angiotensin receptor blocker (ARB) was not associated with the risk of prostate cancer (RR 1.09, 95% CI 0.97–1.21), while use of CCB may well increase prostate cancer risk based on the total pool-analysed (RR 1.08, 95% CI 1–1.16). Moreover, subgroup analysis suggested that use of CCB clearly increased prostate cancer risk (RR 1.10, 95% CI 1.04–1.16) in terms of case-control studies. There was also no significant relationship between use of diuretic (RR 1.09, 95% CI 0.95–1.25) or antiadrenergic agents (RR 1.22, 95% CI 0.76–1.96) and prostate cancer risk.ConclusionsThere is no significant relationship between the use of antihypertensive drugs (ACEI, ARB, beta-blockers and diuretics) and prostate cancer risk, but CCB may well increase prostate cancer risk, according to existing observational studies.

P.3.013 - Hypermethylation of the monoamine oxidase A gene – a new epigenetic marker for posttraumatic stress disorder?

Posttraumatic Stress Disorder (PTSD) can develop after experiencing or witnessing any severe traumatic event such as combat. Point prevalence rates in war-affected regions, e.g. Bosnia-Herzegovina and Kosovo, range from 18% to 35%. Noradrenergic dysfunction as represented by e.g. elevated noradrenaline concentrations in the cerebrospinal fluid of PTSD patients is known to play a substantial role in the pathogenesis of PTSD symptoms [1]. Epigenetic regulation (i.e. DNA methylation) is strongly suggested to moderate the interaction between environmental influences and a genetic predisposition. Therefore, differential methylation of genes involved in the noradrenergic system such as the monoamine oxidase A (MAOA) gene might be part of the complex biological underpinnings of a dysregulated noradrenergic system and thereby contribute to PTSD risk. The present study aimed at investigating MAOA gene methylation as a possible epigenetic marker of PTSD status and severity in a sample comprising patients with PTSD and healthy controls recruited from war-affected regions in Bosnia-Herzegovina, Croatia and Kosovo. DNA methylation levels of MAOA (exonI/intronI region) were analyzed in PTSD patients [N=216; m=157, age (mean±s.d.): 50.08±6.74 years], remitted PTSD patients [N=151; m=98, age (mean±s.d.): 49.48±8.20 years] and healthy controls [N=349, m=232, age (mean±s.d.): 48.81±8.50 years] by direct sequencing of sodium bisulfite-treated DNA followed by semi-quantitative analysis of the sequencing results via the Epigenetic Sequencing Methylation software. Severity of PTSD symptoms was assessed by the Clinician-Administered PTSD Scale (CAPS). All participants were assessed for potential confounders of methylation (sex, age, or smoking status). Possible categorical differences were analyzed by (M)ANCOVAs with age and smoking status as covariates. Post-hoc tests (Bonferroni) were performed to test individual differences in methylation across groups. Associations between dimensional measures were analyzed performing partial correlation analyses controlled for age and smoking status. In the male subsample, analyses revealed significant methylation differences at three out of 13 CpG sites between patients with current PTSD, remitted PTSD patients, and healthy controls. Post-hoc tests showed trend-wise significant (padjusted In the female subsample, we failed to observe association of MAOA methylation with either current or remitted PTSD, while there was a positive correlation between MAOA methylation and symptom severity (r=0.294, p=0.033). The results of the present study for the first time suggest MAOA hypermethylation – possibly resulting in an increased noradrenergic tonus – as a disease status and severity marker of PTSD particularly in male patients. Given robust replication, MAOA hypermethylation might thus serve as an epigenetic marker within the complex risk factor constellation of PTSD. Furthermore, applying a personalized pharmaco-therapeutic approach, anti-adrenergic agents might prove to be beneficial in counterbalancing increased noradrenergic signalling specifically in male PTSD patients displaying MAOA hypermethylation.

Monoamine Oxidase A Gene Methylation and Its Role in Posttraumatic Stress Disorder: First Evidence from the South Eastern Europe (SEE)-PTSD Study.

BackgroundPosttraumatic stress disorder is characterized by an overactive noradrenergic system conferring core posttraumatic stress disorder symptoms such as hyperarousal and reexperiencing. Monoamine oxidase A is one of the key enzymes mediating the turnover of noradrenaline. Here, DNA methylation of the monoamine oxidase A gene exonI/intronI region was investigated for the first time regarding its role in posttraumatic stress disorder risk and severity.MethodsMonoamine oxidase A methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells in a total sample of N=652 (441 male) patients with current posttraumatic stress disorder, patients with remitted posttraumatic stress disorder, and healthy probands (comparison group) recruited at 5 centers in Bosnia-Herzegovina, Croatia, and the Republic of Kosovo. Posttraumatic stress disorder severity was measured by means of the Clinician-Administered Posttraumatic Stress Disorder Scale and its respective subscores representing distinct symptom clusters.ResultsIn the male, but not the female sample, patients with current posttraumatic stress disorder displayed hypermethylation of 3 CpGs (CpG3=43656362; CpG12=43656514; CpG13=43656553, GRCh38.p2 Assembly) as compared with remitted Posttraumatic Stress Disorder patients and healthy probands. Symptom severity (Clinician-Administered Posttraumatic Stress Disorder Scale scores) in male patients with current posttraumatic stress disorder significantly correlated with monoamine oxidase A methylation. This applied particularly to symptom clusters related to reexperiencing of trauma (cluster B) and hyperarousal (cluster D).ConclusionsThe present findings suggest monoamine oxidase A gene hypermethylation, potentially resulting in enhanced noradrenergic signalling, as a disease status and severity marker of current posttraumatic stress disorder in males. If replicated, monoamine oxidase A hypermethylation might serve as a surrogate marker of a hyperadrenergic subtype of posttraumatic stress disorder guiding personalized treatment decisions on the use of antiadrenergic agents.

Medications that affect CNS neurotransmitter levels may induce tactile hallucinations

Tactile hallucinations may be induced by some prescription medications, recreational drug use and underlying organic and psychiatric conditions, as well as being a manifestation of monosymptomatic hypochondriacal psychosis. This article reviews the evidence, albeit limited, indicating that tactile hallucinations may be induced by medications that affect CNS neurotransmitter levels (i.e. dopaminergic, serotonergic and anti-adrenergic agents). Medication-induced tactile hallucinations can generally be managed by modifying the dosage of the causative drug or discontinuing treatment.

ALPHA ANTIADRENERGIC EFFECT OF Achyrocline bogotensis EXTRACT (“Vira Vira”) IN ISOLATED RAT AORTIC RING

Background: The treatment of symptoms of prostatic hyperplasia is among the traditional uses of Achyrocline bogotensis (Kunth) [N.V. “Vira Vira”, Compositae] in Colombia. Pharmacological therapy for this disorder depends mainly on alpha-1 antiadrenergic agents, and the mechanism has not been studied previously using A. bogotensis. Objectives: To assess the alpha-1 antiadrenergic effect of the extract obtained from the aerial parts of A. bogotensis in isolated aortic rings from Wistar rats. Methods: The study compared the effects of the ethanol extract of A. bogotensis, prazosin (reference) and DMSO (control) in rings stimulated with phenylephrine (PE) or KCl. The capacity to reduce the PE pressor effect by the ethanol extract (pD2’ value) was determined. To quantify the A. bogotensis relaxant potency, increasing concentrations of the ethanol extract (0.1 µg/mL-0.1 mg/mL), were added cumulatively to isolated aortic rings pre-contracted with PE (0.1 µM) or KCl (80 mM). To explore the possible participation of nitric oxide (NO), L-NAME (100 µM) was administered to aortic rings exposed to cumulatively increasing concentrations of PE in isolated aortic rings in the presence of the extract (10 µg/mL). Aqueous, butanol and dichloromethane fractions (10 µg/mL) obtained from the ethanol extract were assayed. Phytochemical screening was also performed. Results: Prazosin and A. bogotensis extract notably reduced the contraction induced by PE whereas their inhibitory effect in rings contracted with KCl were lower. A. bogotensis ethanol extract showed a high capacity for reducing the PE pressor response (pD´2 : 5.51) as well as total efficacy for relaxing rings previously precontracted with PE. The relaxant efficacy and potency of A. bogotensis extract against rings previously contracted with KCl were notably lower. L-NAME partly reverted the inhibitory effect of A. bogotensis. Aqueous, butanol and dichloromethane fractions gave inhibitory responses lower than that obtained with the ethanol extract. Phytochemical screening of A. bogotensis extract revealed the significant presence of flavonoid and triterpene metabolites. Conclusions: These results suggest that A. bogotensis elicits a smooth muscle relaxant effect related to the alpha-1 antiadrenergic mechanism. This response is partially NO dependent and seems to be due to interactions among active metabolites likely to be of flavonoid and/or terpenoid nature.

Pharmacologic Considerations for Youth with Posttraumatic Stress Disorder

Children exposed to potentially traumatic events are at risk of developing posttraumatic stress disorder (PTSD). However, the subsequent developmental course of posttraumatic stress symptoms appears to vary considerably. In this regard, some PTSD symptoms resolve without significant interventions, while for many children and adolescents, they persist until the patient receives appropriate treatment specifically designed to address PTSD and other trauma related symptoms. Evidence-based psychotherapies represent the standard of care for children with PTSD and, while psychopharmacologic interventions are utilized for many youth with posttraumatic stress symptoms and PTSD, there is little data available to guide the use of these medications in this population. However, given the structural challenges involved in disseminating and delivering evidence-based psychotherapies in all settings, prescribing clinicians should be aware of the medications whose use in children with pediatric PTSD has been studied. Herein, we review the PTSD assessment modalities, as well as the use of pharmacologic interventions in PTSD, including antiadrenergic agents, selective serotonin reuptake inhibitors and other medications.