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Ocular allergies to brimonidine are frequent in patients treated for glaucoma. There is variability in reporting due to the lack of diagnostic criteria and the absence of cutaneous testing. Many false-negative patch tests (PT) have been described. Alternative methods, such as strip and scratch PT, have been used without a standardized method.The primary objective is to identify the best method of cutaneous testing and brimonidine concentration for patch testing. The secondary objective is to identify clinical signs and symptoms suggestive of ocular allergy.A retrospective review of patient files suspected of brimonidine ocular allergy was performed. Patch testing method, brimonidine concentration and clinical symptoms were reviewed.Of the 36 patients identified, half tested positive for brimonidine for at least one of the testing methods. The scratch PT demonstrated 17 positive reactions (94% detection rate). Three patients reacted with strip PT. No positive results were found with standard PT. The 5% brimonidine concentration demonstrated the highest sensitivity. The absence of eyelid pruritus was associated with negative testing.In the investigation of ocular allergy to brimonidine, scratch PT proved to be an essential tool. Brimonidine 5% pet. appeared as the most sensitive concentration for scratch PT.

Hair transplantation (HT) is a safe and rewarding procedure for a patient as well as the surgeon. Clonidine may be a good adjuvant in HT because of its analgesic, anxiolytic, and sedative effects.To study efficacy of Clonidine as a preoperative medication in HT.The study was a prospective trial of 46 consecutive patients who underwent HT between January and May 2017. Patients with normal vital parameters on arrival were given Tab clonidine (0.1 mg) 30 min before starting of the procedure [Clonidine group (n = 30)]; rest were included in the control group (n = 16). Vitals were monitored every 30 min during surgery until the end. Patients were assessed for pain, level of sedation during surgery and for postoperative analgesia.All patients who received clonidine, except one, were comfortable and experienced no pain throughout the duration of surgery; nine went into deep sleep. Of the 16 patients in the control group, no patients reported deep sleep, 3 felt restless, and 4 had mild pain. There were no untoward effects in both groups.Our study suggests that clonidine is useful as a pre-anesthetic medication in HT. However, this is a pilot study and further larger studies are needed.

Background There is no consensus on what dose of norepinephrine corresponds with futility. The purpose of this study was to investigate the maximum infusion and cumulative doses of norepinephrine associated with survival for patients in medical and surgical intensive care units (MICU and SICU). Materials and Methods A retrospective review was conducted of 661 critically ill patients admitted to a large academic medical center who received norepinephrine. Univariate, multivariate, and area under the curve analyses with optimal cut offs for maximum infusion rate and cumulative dosage were determined by Youden Index. Results The population was 54.9% male, 75.8% white, and 58.7 ± 16.1 y old with 384 (69.8%) admitted to the MICU and 166 (30.2%) admitted to the SICU, including 38 trauma patients. Inflection points in mortality were seen at 18 mcg/min and 17.6 mg. The inflection point was higher in MICU patients at 21 mcg/min and lower in SICU patients at 11 mcg/min. MICU patients also had a higher maximum cumulative dosage of 30.7 mg, compared to 2.7 mg in SICU patients. In trauma patients, norepinephrine infusions up to 5 mcg/min were associated with a 41.7% mortality rate. Conclusion A maximum rate of 18 mcg/min and cumulative dose of 17.6 mg were the inflection points for mortality risk in ICU patients, with SICU patients tolerating lower doses. In trauma patients, even low doses of norepinephrine were associated with higher mortality. These data suggest that MICU, SICU, and trauma patients differ in need for, response to, and outcome from escalating norepinephrine doses.

Pineal gland secretes the hormone melatonin at night with a circadian rhythm. The synthesis and secretion of melatonin are stimulated at night by norepinephrine released by sympathetic postganglionic neurons projecting from the superior cervical ganglia. Norepinephrine simultaneously activates α- and β-adrenoceptors, triggering melatonin synthesis.To study the regulation of melatonin production and secretion, it is very convenient to use an ex vivo preparation. Thus, it is possible to keep intact pineal glands in culture and to study the actions of agonists, antagonists, modulators, toxic agents, etc., in melatonin synthesis. Artificial melatonin synthesis stimulation in vitro is usually achieved by using a β-adrenergic agonist alone or in association with an α-adrenergic agonist. In this chapter, the methodology of cultured pineal glands will be described. Several papers were published by our group using this methodology, approaching the role played in melatonin synthesis control by angiotensin II and IV, insulin, glutamate, voltage-gated calcium channels, anhydroecgonine methyl ester (AEME, crack-cocaine product), monosodium glutamate (MSG), signaling pathways like NFkB, pathophysiological conditions like diabetes, etc.

The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α

Ocular redness, or conjunctival hyperemia, is a common ophthalmic sign associated with reduced quality of life. For redness without apparent underlying pathology, topical ophthalmic decongestants have been widely used.Brimonidine tartrate was approved in 2017 as a topical vasoconstrictor at a 0.025% concentration for relief of ocular redness. Since then, investigators have reported on efficacy and safety findings from studies evaluating low-dose brimonidine for reducing ocular redness.Brimonidine is highly selective for α

Introduction: Polymyxin B hemoperfusion (PMX) reduces endotoxin in septic shock patients’ blood and can improve hemodynamics and organ functions. However, its effects on the reduction of septic shock mortality are controversial. Methods: Using the Japanese diagnosis procedure combination database from April 2016 to March 2019, we identified adult septic shock patients treated with noradrenaline. This study used propensity score matching to compare the outcome between PMX-treated and non-treated patients. The primary endpoint was 28-day mortality, counting from the day of noradrenaline initiation. The secondary endpoints were noradrenaline-, ventilator-, and continuous hemodiafiltration (CHDF)-free days at day 28. Results: Of 30,731 eligible patients, 4,766 received PMX. Propensity score matching produced a matched cohort of 4,141 pairs with well-balanced patient backgrounds. The 28-day survival rate was 77.9% in the PMX group and 71.1% in the control group (p < 0.0001). Median days of noradrenalin-, CHDF-, and ventilator-free days were 2 days (p < 0.0001), 2 days (p < 0.0001), and 6 days (p < 0.0001) longer in the PMX group than in the control group, respectively. When stratified with the maximum daily dose of noradrenaline, the PMX group showed a statistically significant survival benefit in the groups with noradrenaline dose Conclusion: Analysis of large Japanese databases showed that septic shock patients who received noradrenaline might benefit from PMX treatment.

BACKGROUND Diastolic dysfunction is a risk factor for postoperative major cardiovascular events. During anesthesia, patients with diastolic dysfunction might experience impaired hemodynamic function and worsening of diastolic function, which in turn, might be associated with a higher incidence of postoperative complications.We aimed to investigate whether patients with diastolic dysfunction require higher doses of norepinephrine during general anesthesia. Furthermore, we aimed to examine the association between the grade of diastolic dysfunction and the E/e' ratio during anesthesia. A high E/e' ratio corresponds to elevated filling pressures and is an important measure of impaired diastolic function. METHODS We conducted a prospective observational cohort study at a German university hospital from February 2017 to September 2018. Patients aged ≥60 years and undergoing general anesthesia (ie, propofol and sevoflurane) for elective noncardiac surgery were enrolled. Exclusion: mitral valve disease, atrial fibrillation, and implanted mechanical device.The primary outcome parameter was the administered dose of norepinephrine within 30 minutes after anesthesia induction (μg·kg-1 30 min-1). The secondary outcome parameter was the change of Doppler echocardiographic E/e' from ECHO1 (baseline) to ECHO2 (anesthesia). Linear models and linear mixed models were used for statistical evaluation. RESULTS A total of 247 patients were enrolled, and 200 patients (75 female) were included in the final analysis. Diastolic dysfunction at baseline was not associated with a higher dose of norepinephrine during anesthesia (P = .6953). The grade of diastolic dysfunction at baseline was associated with a decrease of the E/e' ratio during anesthesia (P < .001). CONCLUSIONS We did not find evidence for an association between diastolic dysfunction and impaired hemodynamic function, as expressed by high vasopressor support during anesthesia. Additionally, our findings suggest that diastolic function, as expressed by the E/e' ratio, does not worsen during anesthesia.

Background: Recently, there have been some trials to use dexmedetomidine in the obstetric field but concerns regarding the drug include changes in uterine contractions after labor. We aimed to evaluate the effects of dexmedetomidine on the myometrial contractions of pregnant rats.Methods: In a pilot study, the contraction of the myometrial strips of pregnant Sprague-Dawley rats in an organ bath with oxytocin at 1 mU/ml was assessed by adding dexmedetomidine from 10-6 to 10-2 M accumulatively every 20 min, and active tension and the number of contractions were evaluated. Then, changes in myometrial contractions were evaluated from high doses of dexmedetomidine (1.0 × 10−4 to 1.2 × 10−3 M). The effective concentrations (EC) for changes in uterine contractions were calculated using a probit model.Results: Active tension and the number of contractions were significantly decreased at 10-3 M and 10-4 M dexmedetomidine, respectively (P < 0.05). A complete loss of contractions was seen at 10-2 M. Dexmedetomidine (1.0 × 10−4 to 1.2 × 10−3 M) decreased active tension and the number of contractions in a concentration-dependent manner. The EC95 of dexmedetomidine for inhibiting active tension and the number of contractions was 5.16 × 10-2 M and 2.55 × 10-5 M, respectively.Conclusions: Active tension of the myometrium showed a significant decrease at concentrations of dexmedetomidine higher than 10-3 M. Thus, clinical concentrations of dexmedetomidine may inhibit uterine contractions. Further research is needed for the safe use of dexmedetomidine in the obstetrics field.

Renal fibrosis is a common pathological hallmark of chronic kidney disease (CKD). Renal sympathetic nerve activity is elevated in patients and experimental animals with CKD and contributes to renal interstitial fibrosis in obstructive nephropathy. However, the mechanisms underlying sympathetic overactivation in renal fibrosis remain unknown. Norepinephrine (NE), the main sympathetic neurotransmitter, was found to promote TGF-β1-induced epithelial-mesenchymal transition (EMT) and fibrotic gene expression in the human renal proximal epithelial cell line HK-2. Using both genetic and pharmacological approaches, we identified that NE binds Gαq-coupled α1-adrenoceptor (α1-AR) to enhance EMT of HK-2 cells by activating p38/Smad3 signaling. Inhibition of p38 diminished the NE-exaggerated EMT process and increased the fibrotic gene expression in TGF-β1-treated HK-2 cells. Moreover, the pharmacological blockade of α1-AR reduced the kidney injury and renal fibrosis in a unilateral ureteral obstruction mouse model by suppressing EMT in the kidneys. Thus, sympathetic overactivation facilitates EMT of renal epithelial cells and fibrosis via the α1-AR/p38/Smad3 signaling pathway, and α1-AR inhibition may be a promising approach toward treating renal fibrosis.

Post-inflammatory erythema (PIE) is a common sequalae of acne inflammation, persistent post acne erythema (PAE) is cosmetically unacceptable and sometimes its complete clearance could not be achieved. Oxymetazoline (OXZ) is a synthetic, direct-acting, sympathomimetic agonist that is highly selective for the 1α-adrenoceptor. It is a potent vasoconstrictor and well known for its ability to clinically 'get the red out'.The aim of this study was to evaluate the efficacy and safety of topical oxymetazoline (OXZ) 1.5% in treatment of post acne erythema (PAE) in a left to right face comparative study.This study was conducted on 40 patients diagnosed with post acne erythema for at least 3 months, the left side of the face was treated with topical OXZ 1.5% in liposomal base and was compared to the right side to which topical lipogel was applied as a control.According to the investigator's global assessment of photographs and the analysis of erythema with image analysis software, topical OXZ was significantly effective in diminishing PAE when compared to topical placebo lipogel.Topical OXZ is a safe and effective treatment for post-acne erythema.

Locomotion and mobility have been studied extensively in Drosophila melanogaster but less is known about the locomotor capacity of other Drosophila species, while the response to chronic exercise in other species has yet to be examined. We have shown that adult male D. melanogaster adapt to exercise training with improved running endurance, climbing speed, and flight ability compared to unexercised flies. Here, we examine baseline mobility of D. sechellia, D. simulans, and D. virilis, and their response to chronic exercise training. We found significant interspecific differences in mobility and in the response to exercise. Although there is a significant sex difference in exercise adaptations in D. melanogaster, intraspecific analysis reveals few sex differences in other Drosophila species. As octopamine has been shown to be important for exercise adaptations in D. melanogaster, we also asked if any observed differences could be attributed to baseline octopamine levels. We find that octopamine and tyramine levels have the same rank order as baseline climbing speed and endurance in males, but do not predict the response to chronic exercise in males or females. Future research should focus on determining the mechanisms responsible for the inter- and intraspecific differences in mobility and the response to exercise.

Introduction: Though many unanswered questions about the pathophysiology of Tourette Syndrome remain, several pharmacotherapies for tics have been studied, with varying results in terms of efficacy and the strength of evidence.Areas covered: This literature review encompasses pharmacotherapies for tics. The pharmacotherapies discussed in this review include: alpha agonists, antipsychotics, topiramate, botulinum toxin, and dopamine depleters.Expert opinion: Once the presence of tics is confirmed and psychoeducation and support are provided to patients and caregivers, one must examine the degree of tic-related impairment and the presence of psychiatric comorbidities. These factors influence treatment decisions as the presence of comorbidity and related impairment may shift the treatment target. When selecting a medication for tics, the presence of ADHD (the most frequent comorbidity) strengthens the case for choosing an alpha agonist. The case for antipsychotic medications is strongest when tic-related impairment is severe and/or the tics are refractory to more conservative measures. All medications require drug safety monitoring procedures and reevaluation over time.

Objective To determine the impact of epidural phentolamine on the duration of anaesthesia following epidural injection of lidocaine–epinephrine. Study design Blinded randomized experimental study. Animals A group of 12 adult ewes weighing 25.7 ± 2.3 kg and aged 8–9 months. Methods All sheep were administered epidural lidocaine (approximately 4 mg kg–1) and epinephrine (5 μg mL–1). Of these, six sheep were randomized into three epidural treatments, separated by 1 week, administered 30 minutes after lidocaine–epinephrine: SAL: normal saline, PHE1: phentolamine (1 mg) and PHE2: phentolamine (2 mg). The other six sheep were administered only epidural lidocaine–epinephrine: treatment LIDEP. Each injection was corrected to 5 mL using 0.9% saline. Noxious stimuli were pinpricks with a hypodermic needle and skin pinch with haemostatic forceps to determine the onset and duration of sensory and motor block. Heart rate, noninvasive mean arterial pressure (MAP), respiratory rate and rectal temperature were recorded. Results The onset times were not different among treatments. Duration of sensory block was significantly shorter in SAL (57.5 ± 6.2 minutes), PHE1 (60.7 ± 9.0 minutes) and PHE2 (62.0 ± 6.7 minutes) than in LIDEP (81.7 ± 13.4 minutes) (p Conclusion and clinical relevance Epidural administration of 5 mL normal saline after epidural injection of lidocaine–epinephrine reduced the duration of sensory but not motor block in sheep. Epidural administration of phentolamine diluted to the final volume of 5 mL diminished both the duration of sensory and motor block in sheep administered epidural lidocaine–epinephrine.

Objective: To examine medication prescribing patterns for preschool-aged children with diagnoses of attention-deficit/hyperactivity disorder (ADHD) and/or disruptive behavior disorder (DBD). Second...

The paper describes 2 case reports of non-medical use of Naphazoline (Naphthyzin). Both demonstrate that the peripherally acting alpha-adrenergic agonist Naphazoline obtains some addictive potential. The drug produces a feeling of euphoria, which resembles the perceived effects of psychostimulants. Both patients and people who consume Naphazoline for intoxication report increased tolerance after repeated use which indicates the addictive potential of the substance. To the best of our knowledge, this is the first examination of non-medical Naphazoline use and the first attempt to describe its addictive potential. Clinical psychiatrists should be aware of this phenomenon when addressing polysubstance use behavior.

Severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) is associated with multisystem inflammatory syndrome in children (MIS-C) that ranges from mild symptoms to cardiopulmonary collapse. A 5-year-old girl presented with shock and a rapid decline in left ventricular function requiring intubation. SARS-CoV-2 was diagnosed by viral Polymerase Chain Reaction (PCR), and she received remdesivir and COVID-19 convalescent plasma. Initial echocardiogram (ECHO) demonstrated low normal left ventricular function and mild left anterior descending coronary artery dilation. She remained hypotensive, despite high-dose epinephrine and norepinephrine infusions as well as stress-dose hydrocortisone. Admission SARS-CoV-2 IgG assay was positive, meeting the criteria for MIS-C. An ECHO 9 hours after admission demonstrated a severe decline in left ventricular function. Due to severe cardiogenic shock, she was cannulated for venoarterial extracorporeal support (ECMO). During her ECMO course, she was treated with remdesivir, intravenous methylprednisolone, intravenous immunoglobulin, and anakinra. She was decannulated on ECMO day 7, extubated the following day, and discharged home 2 weeks later without respiratory or cardiac support. The use of ECMO for cardiopulmonary support for pediatric patients with MIS-C is feasible and should be considered early as part of the treatment algorithm for patients with severe cardiopulmonary dysfunction.

This study aims to assess the effect of topical 0.5% apraclonidine on Intraocular pressure (IOP) in horses and compare the effects of timolol maleate 0.5% with 0.5% apraclonidine in the equine eye. Twenty healthy female thoroughbred horses were used. Horses were divided into two groups. Ten horses received single dose of 0.2 mL of 0.5% apraclonidine in one randomly selected eye and the contralateral eye received single dose of 0.2 mL of artificial tears. In the second group, 10 horses received single dose of 0.2 mL of 0.5% timolol maleate in one eye and the opposite eye received single dose of placebo (0.2 mL of artificial tears). Intraocular pressure was measured using rebound tonometer at the baseline and 30, 60, 120, 240, 360 minutes, and 24 hours after topical ophthalmic drops instillation. Any ocular side effects were recorded at each time point. Mean (SD) baseline IOPs of the treated and placebo eyes were 26.2(3.1) and 23.5(3.4) in apraclonidine group, and 25.7(2.6) and 23.2(3.3) in timolol group. In the apraclonidine group, significant reduction in the mean IOP started after 60 minutes (P= .005) and was still present after 24 hours (P.001). In timolol group, IOP was reduced in the treated eyes, but this reduction was only significant in the treated eyes at T24h (P= .03). The highest reduction in IOP in timolol group was observed at T360 (21.0(2.2); 14.7%). Mean IOP was decreased prominently by apraclonidine compared to timolol in treated eyes. In conclusion, single dose of topical 0.5% apraclonidine reduced IOP significantly among normal horses in the present study. Further investigations are necessary for evaluating efficacy and safety of apraclonidine in horses.

PURPOSE: To summarize the pharmacological strategies that are being explored for presbyopia correction. METHODS: The review concentrates on pharmacologically induced pupillary miosis to increase depth-of-focus and lens softening or other measures to restore active accommodation. RESULTS: Several studies suggest that near vision improves and distance vision is unaffected for many hours after either monocular or binocular instillation of any one of several drug combinations that cause miosis. Unfortunately, in most studies, measurements were limited to photopic visual acuity for near and distance vision, whereas it is anticipated that pupil constriction may have adverse effects on mesopic and scotopic vision. It is not clear whether improved near vision was due entirely to increased depth-of-focus, or whether, for example, a drug-induced myopic shift in refraction was also involved. Currently, no study has provided direct evidence for drug-induced restoration/enhancement of true accommodation involving an ocular power change. CONCLUSIONS: Although it is possible that, in the future, pharmacological drops may offer a safe and reliable solution for presbyopia correction, more evidence of their effectiveness and limitations is required. [ J Refract Surg. 2019;35(12):803–814.]

Neryl butyrate is a constituent of volatile oils obtained from aromatic plants. Aliphatic organic compound analogues chemically close to neryl butyrate possess vasodilator properties in rat aorta. To evaluate whether neryl butyrate has relaxing properties, this study tested its effects on isolated rat aorta. Unlike the analogues, neryl butyrate did not show relaxant profile in aortic rings precontracted with phenylephrine, but induced a contraction when it stimulated aortic rings under resting tonus. The contractile effect augmented in endothelium-denuded aortic rings. Treatment of endothelium-intact preparations with the nitric oxide synthase inhibitor L-NAME or the guanylyl cyclase inhibitor ODQ also augmented the contractile effect of neryl butyrate. Such phenomenon was absent in the presence of the cyclooxygenase inhibitor indomethacin. Contractile responses decreased in the presence of verapamil, a L-type Ca2+ channel blocker, or when Ca2+ was removed from the extracellular solution. Antagonists of α-adrenergic receptors (prazosin and yohimbine), but not the thromboxane-prostanoid receptor seratrodast, reversed the contraction induced by neryl butyrate. The α1A selective antagonist RS-17053 antagonized the neryl butyrate-induced contraction. The contraction caused by neryl butyrate was decreased by inhibiting the phospholipase C or the rho-associated kinase with U-73122 or Y-27632, respectively. Injected intravenously to awake rats, neryl butyrate induced arterial hypotension and bradycardia. Decreased frequency was also present in isolated right atrium preparations. In conclusion, the contractile effects of neryl butyrate were inhibited by α-adrenergic antagonists, indicating the involvement of α-adrenoceptors in the mechanism of action. In vivo, neryl butyrate caused hypotension, suggesting that other systemic influence than vasoconstriction may occur.

Background The timing of initiation of Norepinephrine (NEP) in septic shock is controversial. Aim of the study We evaluated the impact of early NEP simultaneously with fluids in those patients. Methods We randomized 101 patients admitted to the emergency department with septic shock to early NEP simultaneously with IV fluids (early group) or after failed fluids trial (late group). The primary outcome was the in-hospital survival while the secondary outcomes were the time to target mean arterial pressure (MAP) of 65 mmHg, lactate clearance and resuscitation volumes. Results There was no significant difference between the two groups regarding the baseline characteristics. NEP infusion started after 25 (20–30) and 120 (120–180) min in the early and late groups (p = 0.000). MAP of 65 mmHg was achieved faster in the early group (2 [1–3.5] h vs. 3 [2–4.75] h, p = 0.003). Serum lactate was decreased by 37.8 (24–49%) and 22.2 (3.3–38%) in both groups respectively (p = 0.005). Patients with early NEP were resuscitated by significantly lower volume of fluids (25 [18.8–28.7] mL/kg vs. 32.5 [24.4–34.6] mL/kg) in the early and late groups (p = 0.000). The early group had survival rate of 71.9% compared to 45.5% in the late group (p = 0.007). NEP started after 30 (20–120 min) in survivors vs. 120 (30–165 min) in non-survivors (p = 0.013). Conclusions We concluded that early Norepinephrine in septic shock might cause earlier restoration of blood pressure, better lactate clearance and improve in-hospital survival.

Aim: to investigate the functional interaction of α2-adrenergic and imidazoline receptors recently identified on the sarcolemma of isolated cardiomyocytes for regulation of the intracellular calcium and the production of the signal molecule of nitric oxide (NO).Materials and methods:experiments were performed on isolated left ventricular cardiomyocytes of Wistar rats. Potential-dependent Ca2+-currents were measured from the whole-cell by the patch-clamp method in “perforated-patch” configuration. The intracellular calcium and the production of nitric oxide were estimated from the changes in fluorescence intensity of the Ca2+-specific and NO-sensitive dyes at fluorescent or confocal microscope.Results:It has been shown that α2‑adrenergic and imidazoline receptor agonists inhibit L-type Ca2+-currents by themselves, but their effects do not develop against each other’s background. The blockade of key effector molecules: protein kinase B (Akt kinase) for α2‑adrenergic receptors, and protein kinase C for imidazoline receptors causes the action of agonists to become additive. Both the selective α2‑agonist, guanabenz, and the specific agonist of the first type imidazoline receptors, rilmenidine, show an additional inhibition of Ca2+-currents against the basal background already reduced by the activation of one of the two receptor systems. Wherein rilmenidine increases the level of free Ca2+in the cytosol, and guanabenz, on the contrary, decreases it. The action of guanabenz does not develop against the background of rilmenidine, although it, in turn, effectively increases the intracellular level of calcium in guanabenz-pretreated cardiac cells. Activation of α2‑adrenergic receptors leads to significant stimulation of the endothelial isoform of NO-synthase, and as a result to an increase in the NO level. Activation of imidazoline receptors itself does not affect NO synthesis but it prevents the production of NO induced by α2‑agonists.Conclusion:obtained data make it possible to formulate a number of useful recommendations for clinical practice, and also to clarify the non-central peripheral effects arising from the activation of α2‑adrenergic or imidazoline systems under conditions of endogenous hyperactivation on of the two systems.

Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early-onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease-modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease-modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha-adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of "disease-specific" therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood-onset movement disorders. © 2019 International Parkinson and Movement Disorder Society.

Type I Diabetes (T1D) is associated with reduced leptin levels and increased stress axis activity marked by elevations in norepinephrine (NE) levels in the paraventricular nucleus (PVN) of the hypothalamus. We hypothesized that leptin suppresses stress axis activity in T1D through central and peripheral mechanisms. In the first experiment, adult male Sprague Dawley rats were implanted with a cannula in the PVN and randomly divided into a non-diabetic group treated with vehicle (n = 6) and a diabetic group treated with streptozotocin (n = 13). Food intake and water intake was measured for 14 days. On the last day, a subset of diabetic rats were treated with 500 µg of leptin i.p. Rats were subjected to push-pull perfusion of the PVN and hourly blood sampling for 5 h. In the next experiment, diabetic rats were treated either with an alpha-2 adrenergic agonist, clonidine (CLON), or a beta adrenergic agonist isoproterenol (ISO), to reverse the effects of leptin. Rats were subjected to push pull perfusion and hourly blood sampling. In experiment 1, T1D increased food intake, water intake, NE release in the PVN and circulating CS levels. Leptin treatment decreased NE release modestly but produced a robust reduction in corticosterone (CS) levels. In experiment 2, CLON but not ISO was able to reverse the effect of leptin on NE levels in the PVN, however, both agonists were capable of blocking leptin’s effects on circulating CS. These results suggest that in diabetic rats, the sensitivity of the hypothalamus to beta adrenergic agonists is altered, while the adrenals remain sensitive to both alpha and beta adrenergic agonists.

Objectives/hypothesis Oxymetazoline is an α-adrenergic agonist that is commonly used as a topical hemostatic agent in the operating room during ear, nose, and throat surgery. There are limited data on oxymetazoline pharmacokinetics in children who undergo general anesthesia. We assessed the hemodynamic effects and systemic absorption of topically applied oxymetazoline in children undergoing various nasal procedures. Study design Prospective trial. Methods Children ages 2 to 17 years undergoing functional endoscopic sinus surgery, turbinate resection, or adenoidectomy were enrolled. The surgeon placed oxymetazoline-soaked pledgets (1.5 mL of 0.05% solution) according to our usual clinical practice. Blood samples for oxymetazoline assay were drawn at 5, 10, 20, 45, 90, and 150 minutes, and hemodynamic data were recorded at 5-minute intervals. Data analysis included mixed-effects regression and population pharmacokinetic/pharmacodynamic modeling. Results The analysis included 27 patients, age 7 ± 4 years, who received between 2 and 12 pledgets (3-18 mL) of oxymetazoline. Relative bioavailability compared to the spray formulation was 2.3 (95% confidence interval [CI]: 1.6-3.2), with slow absorption from the mucosal surface (absorption half-life 64 minutes; 95% CI: 44-90). Mean arterial pressure did not increase with oxymetazoline instillation at the observed oxymetazoline serum concentrations (0.04-7.6 μg/L). Conclusions Despite concerns regarding oxymetazoline administration to mucosal membranes, we found that hemodynamic changes were clinically negligible with our usual clinical use of pledgets soaked in oxymetazoline. Compared to data on oxymetazoline in spray formulation, bioavailability was increased twofold with pledgets, but systemic absorption was very slow, contributing to low serum concentrations and limited hemodynamic effects. Level of evidence 1b. Laryngoscope, 129:2775-2781, 2019.

OBJECTIVES Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return. Incremental exogenous catecholamines doses may be required to counteract such effects, aggravating the deleterious effects of sympathetic overstimulation. α-2 adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock. The aim of the present study is to test the hypothesis that switching from sedation with propofol to the α-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock. DESIGN Prospective open-label crossover study. SETTINGS University hospital, ICU. PATIENTS Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between -3 and -4. INTERVENTIONS An initial set of measurements including hemodynamics, norepinephrine doses, and depth of sedation were obtained during sedation with propofol. Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion. Sedation was switched back to propofol, and a final set of measurements was obtained after 8 hours. A Richmond Agitation-Sedation Scale score between -3 and -4 was maintained during the study period. MEASUREMENTS AND MAIN RESULTS Norepinephrine requirements decreased from 0.69 ± 0.72 μg/kg/min before dexmedetomidine to 0.30 ± 0.25 μg/kg/min 4 hours after dexmedetomidine infusion, increasing again to 0.42 ± 0.36 μg/kg/min while on propofol 8 hours after stopping dexmedetomidine (p < 0.005). Dexmedetomidine dosage was 0.7 ± 0.2 μg/kg/hr. Before and after dexmedetomidine infusion, sedative doses remained unchanged (propofol 2.6 ± 1.2 vs 2.6 ± 1.2 mg/kg/hr; p = 0.23 and remifentanil 1.27 ± 0.17 vs 1.27 ± 0.16 μg/kg/hr; p = 0.52, respectively). Richmond Agitation-Sedation Scale was -4 (-4 to -3) before, -4 (-4 to -3) during, and -4 (-4 to -4) after dexmedetomidine (p = 0.07). CONCLUSIONS For a comparable level of sedation, switching from propofol to dexmedetomidine resulted in a reduction of catecholamine requirements in septic shock patients.

The article reviews historical aspects of direct and indirect (by reducing intraocular pressure (IOP)) neuroprotective effect of brimonidine in terms of modern views on glaucoma monitoring and treatment. Brimonidine, a selective alpha-adrenergic receptor agonist, is the first-line treatment choice for glaucoma. This agent reduces IOP by decreasing aqueous humor production and improving uveoscleral outflow. The result is the achievement of target IOP. Brimonidine prevents ganglionic cell death in glaucomatous optic neuropathy. Several in vitro and in vivo studies describe the mechanism of preventing mitochondrial dysfunction and excitotoxic retinal cell damage in ischemia. Brimonidine affects NMDA receptors, inhibits proapoptotic protein expression, activates neurotrophic processes, and normalizes oxidative phosphorylation thus preventing mitochondrial dysfunction. According to the modern concept, the aim of glaucoma treatment is to avoid vision loss by preventing ganglionic cell death. Therefore, lifelong visual field monitoring and neuroprotective therapy are required. Brimonidine provides target IOP and prevents retinal cell death thus preserving vision in glaucoma. Keywords: glaucoma, intraocular pressure, neuroprotection, visual field, monitoring, brimonidine, Luxfen. For citation: Erichev V.P., Petrov S.Yu., Volzhanin A.V. et al. Alpha-adrenergic receptor agonists in terms of modern views on glaucoma monitoring and treatment. Russian Journal of Clinical Ophthalmology. 2019;19(2):87–91. About the authors: 1Valery P. Erichev — MD, PhD, Professor, Head of Glaucoma Department, ORCID iD 0000-0001-6842-7164; 1Sergey Yu. Petrov — MD, PhD, Leading Research Associate of Glaucoma Department, ORCID iD 0000-0001-6922-0464; 1Andrey V. Volzhanin — postgraduate, ORCID iD 0000-0002-1421-8882; 1Darya M. Safonova — MD, PhD, Junior Research Associate of Modern Treatmen in Ophthalmology, ORCID iD 0000-0002-5082-1494; 2Tamara V. Yaremenko — postgraduate, ORCID iD 0000-0002-3094-1958; 3Serzh A. Kazaryan — resident, ORCID iD 0000-0003-2258-2964. 1Reseach Institute of Eye Diseases. 11A Rossolimo str., Moscow, 119021, Russian Federation. 2Sechenov University. 8 Trubeckaya Str., Moscow, 119146, Russian Federation. 3Mkhitar Heratsi Yerevan State Medical University. 2 Koryuna str., Erevan, 0025, Republic of Armenia. Contact information:Andrey V. Volzhanin, e-mail:avolzhanin@mail.ru.Financial Disclosure:no author has a financial or property interest in any material or method mentioned. There is noconflict of interests. Received11.04.2019.

Omecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. To assist translation to clinical practice we investigated OMs effect on explanted human failing hearts, specifically; contractile dynamics, interaction with the β1–adrenoceptor (AR) agonist (−)‐noradrenaline and spontaneous contractions. Left and right ventricular trabeculae from 13 explanted failing hearts, and trabeculae from 58 right atrial appendages of non‐failing hearts, were incubated with or without a single concentration of OM for 120 min. Time to peak force (TPF) and 50% relaxation (t 50%) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration‐effect curves were established to (−)‐noradrenaline at β1‐ARs in the absence or presence of OM. OM prolonged TPF and t 50% in ventricular trabeculae (600 nM, 2 µM, p, In human failing ventricular trabeculae, omecamtiv mecarbil preserved contractile force over time, but produced concentration dependent increases in time to peak force and time to 50% relaxation. In the presence of omecamtiv mecarbil, (−)‐noradrenaline reversed the negative diastolic effects, but its potency remain unchanged.

Background: Intranasal sprays (INSs) are commonly used medications for the treatment of many rhinologic conditions. Despite their popularity, an analysis of a nationwide reporting database and comparison to the available literature has never been performed. Methods: The Food and Drug Administration Adverse Event Reporting System (FAERS) database was accessed to obtain adverse event (AE) records from 2014 to 2019 for varying INSs, including: 10 corticosteroids, 1 alpha adrenergic, and 3 antihistamines. The Proportional Reporting Ratios (PRR) and Reporting Odds Ratios (ROR) were calculated for dyspnea, anosmia, ageusia/dysgeusia, epistaxis, and headache. A PRR ≥ 2 or ROR ≥ 1 was considered significant. Results: Corticosteroids had 98 864 total reported AEs to the database, followed by antihistamines (7011) and alpha adrenergics (2071). In total, dyspnea was reported 5843 times, followed by headache (4230), epistaxis (1205), ageusia/dysgeusia (920), and anosmia (312). Overall, PRR and ROR values for dyspnea ranged from 0.51 to 4.25 and 0.51 to 4.49; for dysgeusia/ageusia from 0.56 to 6.09 and 0.56 to 6.12; and for epistaxis from 1.03 to 27.24 and 1.03 to 30.76, respectively. All medications which listed anosmia within the top AEs had PRR and ROR values exceeding 2 and 1, respectively. The PRR for headache exceeded 2 for 1 medication and the ROR exceeded 1 in 7 medications. Conclusion: The AEs of dyspnea, anosmia, ageusia/dysgeusia, epistaxis, and headache are reported within the FAERS database for commonly prescribed INSs. When compared against the existing scientific literature, the clinical significance of this reporting tool from the FDA for these classes of medications remains unvalidated.