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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.

We present a 62-year-old female who collapsed with a subarachnoid haemorrhage. This was complicated by profound shock secondary to neurogenic stunned myocardium. As the patient demonstrated life-threatening catecholamine-resistant shock that was unresponsive to conventional treatment measures, hyperinsulinaemic euglycaemic therapy was utilised as a rescue therapy. To our knowledge this has not previously been described in the literature. The patient proceeded to stabilise and made a good recovery.

Objective: To review and summarize topical oxymetazoline’s pharmacology, pharmacokinetics, efficacy, safety, cost, and place in therapy for persistent redness associated with erythematotelangiectatic rosacea. Data Sources: Literature searches of MEDLINE (1975 to September 2017), International Pharmaceutical Abstracts (1975 to September 2017), and Cochrane Database (publications through September 2017) using the terms rosacea, persistent redness, α -agonist, and oxymetazoline. Study Selection and Data Extraction: Results were limited to studies of human subjects, English-language publications, and topical use of oxymetazoline. Relevant materials from government sources, industry, and reviews were also included. Data Synthesis: Data support the efficacy of oxymetazoline for persistent facial redness. Little study beyond clinical trials cited in the drug approval process has been conducted. Current data suggest that oxymetazoline is similar in safety and efficacy to brimonidine. Head-to-head comparisons of topical α-agonists for erythema caused by rosacea are needed. Conclusion: The topical α-agonist, oxymetazoline, is safe and effective for reducing persistent facial redness associated with erythematotelangiectatic subtype of rosacea. Health care practitioners selecting among treatments should consider not only the subtype of rosacea but also individual patient response, preference, and cost.

Anaphylactic shock is a rare, but potentially lethal complication, combining life-threatening circulatory failure and massive fluid shifts. Treatment guidelines rely on adrenaline and volume expansion by intravenous fluids, but there is no solid evidence for the choice of one specific type of fluid over another. Our purpose was to compare the time to achieve target mean arterial pressure upon resuscitation using adrenaline alone versus adrenaline with different resuscitation fluids in an animal model and to compare the tissue oxygen pressures (PtiO2) with the various strategies. Twenty-five ovalbumin-sensitised Brown Norway rats were allocated to five groups after anaphylactic shock induction: vehicle (CON), adrenaline alone (AD), or adrenaline with isotonic saline (AD+IS), hydroxyethyl starch (AD+HES) or hypertonic saline (AD+HS). Time to reach a target mean arterial pressure value of 75 mmHg, cardiac output, skeletal muscle PtiO2, lactate/pyruvate ratio and cumulative doses of adrenaline were recorded. Non-treated rats died within 15 minutes. The target mean arterial pressure value was reached faster with AD+HES (median: 10 minutes, range: 7.5 to 12.5 minutes) and AD+IS (median: 17.5 minutes, range: 5 to 25 minutes) versus adrenaline alone (median: 25 minutes, range: 20-30 minutes). There were also reduced adrenaline requirements in these groups. The skeletal muscle PtiO2 was restored only in the AD+HES group. Although direct extrapolation to humans should be made with caution, our results support the combined use of adrenaline and volume expansion for resuscitation from anaphylactic shock. When used with adrenaline the most effective fluid was hydroxyethyl starch, whereas hypertonic saline was the least effective.

Use of norepinephrine to increase blood pressure in septic animals has been associated with increased efficiency of hepatic mitochondrial respiration. The aim of this study was to evaluate whether the same effect could be reproduced in isolated hepatic mitochondria after prolonged in vivo exposure to faecal peritonitis. Eighteen pigs were randomized to 27 h of faecal peritonitis and to a control condition (n = 9 each group). At the end, hepatic mitochondria were isolated and incubated for one hour with either norepinephrine or placebo, with and without pretreatment with the specific receptor antagonists prazosin and yohimbine. Mitochondrial state 3 and state 4 respiration were measured for respiratory chain complexes I and II, and state 3 for complex IV using high-resolution respirometry, and respiratory control ratios were calculated. Additionally, skeletal muscle mitochondrial respiration was evaluated after incubation with norepinephrine and dobutamine with and without the respective antagonists (atenolol, propranolol and phentolamine for dobutamine). Faecal peritonitis was characterized by decreasing blood pressure and stroke volume, and maintained systemic oxygen consumption. Neither faecal peritonitis nor any of the drugs or drug combinations had measurable effects on hepatic or skeletal muscle mitochondrial respiration. Norepinephrine did not improve the efficiency of complex I- and complex II-dependent isolated hepatic mitochondrial respiration [respiratory control ratio (RCR) complex I: 5.6 ± 5.3 (placebo) vs. 5.4 ± 4.6 (norepinephrine) in controls and 2.7 ± 2.1 (placebo) vs. 2.9 ± 1.5 (norepinephrine) in septic animals; RCR complex II: 3.5 ± 2.0 (placebo) vs. 3.5 ± 1.8 (norepinephrine) in controls; 2.3 ± 1.6 (placebo) vs. 2.2 ± 1.1 (norepinephrine) in septic animals]. Prolonged faecal peritonitis did not affect either hepatic or skeletal muscle mitochondrial respiration. Subsequent incubation of isolated mitochondria with norepinephrine and dobutamine did not significantly influence their respiration.

Bu çalışma, 05-07 Mayıs 2006 tarihleri arasında İzmir[Türkiye]’da düzenlenen 6. National Congress of Thrombosis, Haemostasis and Angiology’da bildiri olarak sunulmuştur. Objectives: The lack of response of platelets against epinephrine has been discovered with a frequency of 14% to 40% in previous studies. There are studies that have demonstrated the effect of aspirin on platelets may resemble the lack of response to epinephrine. In this study, the extent of the effects of aspirin treatment on aggregation and secretion in healthy males with a lack of response to epinephrine and the frequency of aspirin resistance were investigated. Methods: Blood samples were collected at the beginning and at the end of a 10-day aspirin usage in 52 healthy males. Epinephrine, adenosine diphosphate (ADP), collagen, arachidonic acid (AA) and thrombin aggregations, and adenosine triphosphate (ATP) secretion were studied. Participants were assigned to nonresponder (< 20%), semiresponder (20%-60%), and responder (> 60%) groups, depending on their maximum aggregation responses to epinephrine. Participants who displayed an aggregation to AA at the end of the aspirin treatment were accepted to be aspirin resistant. Results: Of the 52 participants, 4 were found to be nonresponders and 3 of 52 of the participants were found to be semiresponders. Although the lack of response to epinephrine and aspirin treatment displayed similarities in aggregations using epinephrine, ADP, collagen, and thrombin, they differed in aggregations using AA and for ATP secretion. The ratio of aspirin resistance was determined to be 4:52. Conclusions: The observation of AA aggregation in the participants with a lack of response to epinephrine demonstrates that epinephrine nonresponse cannot substitute aspirin treatment. The fact that aspirin resistance is observed in healthy males supports the view that aspirin resistance exists even before the first usage.

SUNCT syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) is a primary headache characterised by a high frequency of attacks associated with marked autonomic periocular signs and symptoms. Activation of the hypothalamus via the superior salivary nucleus is probably responsible for some of the autonomic involvement observed during SUNCT attacks. We describe a case of SUNCT with unusual autonomic features (e.g., mydriasis) and early onset. Pupillometric studies were performed both in a basal condition (without anisocoria) and after instillation of phenylephrine (a drug with direct sympathomimetic activity) and pilocarpine (a parasympathetic agonist). The findings in this patient seem to indicate involvement of the ocular sympathetic supply in SUNCT, responsible for the mydriasis, and seem to strengthen the possibility that the autonomic phenomena in this syndrome vary with different levels of pain severity.

Objective: To review the pharmacology, toxicology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines for lofexidine, an α2-agonist, for opioid detoxification. Data Sources: Primary literature was identified through a MEDLINE search (1950–September 2009), EMBASE (1988–Juty 2009), International Pharmaceutical Abstracts (1970–September 2009), and the Cochrane Library (1996–September 2009) using the key words lofexidine and opioid withdrawal. Abstracts were included in the absence of published results of studies. Study Selection and Data Extraction: Studies published in English-language literature reporting on animal and human pharmacology, toxicology, and pharmacokinetics were included in addition to clinical trials using lofexidine for opioid detoxification in comparison to placebo or active controls. Data Synthesis: Lofexidine is an α2-agonist structurally related to clonidine. It is not an effective antihypertensive agent; however, it decreases the sympathetic outflow responsible for many opioid withdrawal symptoms. Nine clinical studies were reviewed representing 354 patients receiving lofexidine including a recent Phase 3 clinical trial. Eight studies involved comparisons of lofexidine to an opioid receptor agonist or clonidine for opioid detoxification. In these trials, lofexidine dosing was titrated to a maximum of 1.6–3.2 mg/day in divided doses for a total of 5–18 days. The data suggest that lofexidine has positive efficacy in reducing opioid withdrawal symptoms and is at least as effective as the opioid receptor agonists utilized for detoxification. Not all withdrawal symptoms are alleviated by α2-agonists, with many patients complaining of insomnia and aching. The most common adverse event with lofexidine in the Phase 3 trial was insomnia. Hypotension was also reported; however, the studies comparing clonidine with lofexidine suggest decreased incidence and severity of adverse events with lofexidine. Conclusions: Lofexidine appears to be a promising agent for opioid detoxification. If approved, it would be the first nonopioid agent approved for this indication. Further large-scale controlled studies are needed to identify the safest, most effective dosage regimen required to achieve opioid detoxification.

The aim of the present study was to review the dopamine theory of attention-deficit–hyperactivity disorder (ADHD), in light of recent use of noradrenergic therapies. A historical review of pharmacological theories of ADHD was conducted, including inverted-U, spatial working memory and neural circuit aspects. Pharmacological advances, including animal and human studies of dopaminergic and noradrenergic mechanisms at the prefrontal cortex (PFC), indicate that α-2A adrenoreceptor stimulation results in increased dendritic firing during delay periods for preferred directions, while moderate levels of D1 receptor stimulation result in reduction of delay-related firing to non-preferred directions, allowing representational control in the PFC. Recent studies of the COMT val/met gene and stimulant medication response may help explain variation in inverted-U responses in individuals. Further studies utilizing delay-related firing paradigms should be useful in the investigation of attentional syndromes, and responses to newer pharmacological treatments.

Dexmedetomidine is a centrally acting α2-adrenergic agonist which is currently Food and Drug Administration— approved for the short-term (less than 24 hours) sedation of adults during mechanical ventilation. Given its beneficial physiologic effects and limited adverse effect profile, there is growing interest regarding its potential applications in the Pediatric intensive care unit patient including sedation during mechanical ventilation, procedural sedation, the treatment of withdrawal, and prevention of emergence agitation. Although generally safe and effective, occasional hemodynamic effects including bradycardia and hypotension have been reported. Clinical experience has demonstrated that bradycardia may be more common when dexmedetomidine is administered with other medications that have negative chronotropic effects. We report 2 pediatric patients with traumatic brain injury who had good long-term neurologic outcomes, but developed clinically significant bradycardia when therapeutic hypothermia was added to a sedation regimen that included dexmedetomidine and remifentanil. The role of dexmedetomidine as a neuroprotective agent is explored as well as a review presented of previous reports of bradycardia related to dexmedetomidine.

Carotid artery interventions can be associated with adverse hemodynamic changes, including bradycardia and hypotension. These hemodynamic changes are believed to be caused by direct stimulation of the carotid sinus baroreceptors, mimicking normal physiological response to rises in blood pressure. During open carotid surgery, these hemodynamic changes can be controlled by direct injection of medications that block fast voltage gated sodium channels in the neuron cell membrane, thus preventing depolarization of the presynaptic neuron in the carotid sinus. This form of control is difficult or impossible during percutaneous carotid interventions because direct access to the carotid artery and carotid sinus is not available. This discussion focuses on the cause, effects, and possible treatments for the hemodynamic changes associated with carotid artery stenting procedures.

Background Xylometazoline is a nasal decongestant spray that constricts nasal blood vessels and increases nasal airflow, enabling patients with a blocked nose to breathe more easily. The purpose of this study was to characterize objectively and subjectively the decongestant and additional effects of xylometazoline in the common cold. Methods A double-blind, placebo-controlled, parallel group study was performed. Patients with a common cold (n = 61) were treated with xylometazoline 0.1% (n = 29) or placebo (saline solution; n = 32; 1 spray three times a day for up to 10 days). The primary objective was to determine the decongestant effect (nasal conductance); the secondary objectives were to determine the peak subjective effect (visual analog scale), duration of relief of nasal congestion, total and individual cold symptoms and general well-being (patients’ daily diary), and adverse events (AEs). Results The decongestant effect of xylometazoline was significantly greater than placebo, as shown by the nasal conductance at 1 hour (384.23 versus 226.42 cm3/s; p ≤ 0.0001) and peak subjective effect (VAS, 20.7 mm versus 31.5 mm; p = 0.0298). Nasal conductance was significantly superior for up to 10 hours (p = 0.0009) and there was a trend in favor of xylometazoline for up to 12 hours (not statistically significant). Xylometazoline significantly improved total and some individual common cold symptoms scores (p < 0.05), leading to significantly greater patient general evaluation and satisfaction with treatment (p < 0.05). Nineteen AEs were reported: 8 with xylometazoline (all mild-moderate) and 11 with placebo (1 severe). Conclusion Xylometazoline is an effective and well-tolerated decongestant nasal spray that significantly relieved nasal congestion compared with placebo in the common cold and provided long-lasting relief with just 1 spray, helping patients to breathe more easily for a longer period of time.

Obective: To report a case of reversible left posterior fascicular block (LPFB) associated with high-dose interleukin-2 (IL-2) therapy. Case Summary: A 50-year-old white, nonsmoking male with a history of hypertension, hyperlipidemia, paroxysmal atrial fibrillation, and hypothyroidism had been recently diagnosed with metastatic clear cell-type renal cell carcinoma. He was started on high-dose IL-2 therapy (600,000 IU/kg/dose by 15-min intravenous infusion every B h for up to 14 consecutive doses over 5 days, as tolerated). He developed new-onset LPFB after the second dose of IL-2, which was diagnosed electrocardiographically with right axis deviation; deep S waves in lead I; and qR waves in leads II, III, and aVF. He denied chest pain, palpitations, or syncope. The LPFB resolved 18 hours after discontinuation of IL-2 without any potential complications or delay of hospital discharge. The patient completed 9 of 14 doses of IL-2 therapy. Similar electrocardiogram changes were noticed during 2 subsequent cycles of high-dose IL-2 treatment, both of which resolved spontaneously. Discussion: High-dose IL-2 is a Food and Drug Administration-approved biological agent used as monotherapy for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Capillary leak syndrome has been associated with IL-2 therapy and many of its cardiac and noncardiac toxicities. In our patient, LPFB was observed as a reversible adverse reaction to high-dose IL-2 therapy. The Naranjo probability scale indicates a probable relationship between LPFB and high-dose IL-2 in this patient. LPFB has not previously been reported as an adverse reaction associated with high-dose IL-2 therapy. Conclusions: LPFB may be a reversible cardiac complication associated with high-dose IL-2 therapy. Healthcare professionals should be aware of this potential adverse effect.

Objectives We investigated the effects of oxymetazoline hydrochloride on the regulation of healthy human nasal ciliary beat frequency (CBF) and its influence on nasal mucociliary transport time (MTT). Methods Changes in (cultured) human nasal CBF in response to increasing concentrations of oxymetazoline within 20 minutes were quantified by use of high-speed digital microscopy. Moreover, the MTT before and after application of 0.05% oxymetazoline was determined by use of the saccharin test. Results Whereas no statistically significant difference was identified when compared to basal CBF at the concentration of 0.025% or 0.05%, both 0.10% and 0.20% oxymetazoline induced a significantly lower CBF at the end of the observation period. The decrement induced by 0.20% oxymetazoline appeared earlier. At concentrations ranging from 0.025% to 0.20%, the inhibitory effect was dependent on the concentration of oxymetazoline. In addition, the use of 0.05% oxymetazoline increased the mean (±SD) human nasal MTT from 474 ± 21 seconds to 572 ± 41 seconds (n = 29). Conclusions The clinical concentration of oxymetazoline, 0.05%, has no obvious inhibitory effect on human nasal CBF in vitro. The increased MTT caused by 0.05% oxymetazoline in vivo is within the normal range.

Background. Phenylephrine (PE) is a α-adrenergic agent commonly administered by perfusion and anesthesia. It is important to identify the effect of PE, especially on cardiac function. This study was intended to show the effects of PE on cardiac function in the murine model via pressure-volume loops. Methods. Six C57BL/6J twelve-week-old female mice were studied prior to and following PE administration at 50 μg/kg IV. In vivo pressure-volume loops were recorded at both time points. Results. There was an expected increase in maximum arterial pressure by 30% (p < 0.001) and end-systolic pressure by 34% (p < 0.001). However, there was a decrease in cardiac output by 30% (p = 0.0006), ejection fraction by 36% (p = 0.0003) and stroke volume by 25% (p < 0.004). Conclusions. This study demonstrates that PE has an effect on cardiac function beyond increasing vascular resistance. The data suggest the negative effects of PE on cardiac function may be related to stimulation of cardiac α-adrenergic receptors. Perfusion (2007) 22, 289—292.

Background Rhinorrhea and nasal congestion are simultaneous symptoms associated with the common cold. This study investigated the efficacy and safety of a combination nasal spray of ipratropium and xylometazoline for simultaneous treatment of these symptoms. Methods The trial was a multicenter double-blind, parallel-group, randomized design on patients with common cold symptoms. Patients scored symptoms of runny nose and nasal congestion and recorded adverse events in a diary for up to 7 days. Patients also recorded tissue use. The five test treatments consisted of ipratropium, 0.6 mg/mL, and xylometazoline, 1.0 mg/mL; ipratropium, 0.6 mg/mL, and xylometazoline, 0.5 mg/mL; ipratropium, 0.6 mg/mL; xylometazoline, 1.0 mg/mL; and placebo solution. Results Eight hundred sixty-four patients were screened and 786 patients received treatment. One day after treatment there was a clear separation between the scores for the placebo and ipratropium treatment groups for rhinorrhea and between the placebo and xylometazoline treatment groups for congestion. Both ipratropium/xylometazoline 1.0 and ipratropium/xylometazoline 0.5 treatments were superior to xylometazoline with respect to rhinorrhea (p < 0.0001) and superior to ipratropium with respect to nasal congestion scores (p < 0.001). Both the ipratropium combination treatments had significantly lower tissue use than the xylometazoline treatment group (p < 0.0001). Adverse events were distributed equally between the treatments, except mucus tinged with blood, epistaxis, nasal passage irritation, and nasal dryness, which had a higher incidence in the three groups that received medicines containing ipratropium. Conclusion The results indicate that a combination medicine of ipratropium and xylometazoline is safe and effective for treatment of rhinorrhea and nasal congestion associated with common cold.

Autotransplantation of the submandibular gland is a potential treatment for severe kerato-conjunctivitis sicca. However, one of the major barriers to this procedure is that secretions from the transplanted gland decrease shortly after the operation, which may lead to obstruction of Wharton’s duct, or even to transplantation failure. Using a rabbit model, we investigated whether phenylephrine could improve the secretion from the transplanted gland. We found that phenylephrine treatment significantly reversed the decrease in salivary secretion after transplantation, enhanced the expressions of α1A-, α1B-, and α1D-adrenoceptor mRNA, and ameliorated atrophy of acinar cells. Furthermore, phenylephrine also induced translocation of aquaporin-5 from the cytoplasm to the apical membrane, and increased the levels of phospho-ERK1/2, ERK1/2, phospho-PKCζ, and PKCζ in the transplanted gland. These results indicate that phenylephrine treatment moderates structural injury and improves secretory function in the transplanted submandibular gland through promoting α1-adrenoceptor expression and post-receptor signal transduction.

We prospectively evaluated the effect of Clonidine as an adjuvant to bupivacaine for continuous paravertebral intercostal nerve block, measuring pain and sedation scores and pulmonary function tests. Thirty patients scheduled to undergo thoracotomy were randomized to receive either a bolus of 0.125% bupivacaine 2 mg/kg (group BUP) or 0.125% bupivacaine 2 mg/kg with Clonidine 2 μg/kg (group BUP+CLO), followed by an infusion of 0.125% bupivacaine at 0.5 mg/kg/h, or 0.125% bupivacaine at 0.5 mg/kg/h with Clonidine at 2 μg/kg/h, in respective groups, through a paravertebral intercostal catheter. Haemodynamic parameters, pain and sedation scores and pulmonary function tests were recorded at 6, 12, 24 and 48 hours after arrival in postoperative care unit.There were significantly lower pain scores at rest and on coughing in group BUP+CLO compared with group BUP (PWe conclude that using Clonidine as an adjunct to bupivacaine for continuous paravertebral intercostal nerve block improves pain relief after thoracotomy, but hypotension and sedation are adverse effects interfering with its clinical application.

Clonidine has recently been used as a pre-operative medication and sedative/anxiolytic drug. Its extended duration of action makes it suitable for longer procedures. In this randomized, crossover, placebo-controlled clinical trial, we characterized the effects of oral clonidine pre-treatment on intravenous diazepam/meperidine sedation using the bi-spectral index (BIS) in 13 participants. Clonidine significantly increased the numbers of BIS-depressed readings and percent memory loss during sedation, while reducing total diazepam and post-operative analgesic dosages by 44% and 55%, respectively. Systolic, diastolic, and mean arterial blood pressures, as well as pulse rates, were reduced. Respiratory rate, oxygen saturation, end-tidal CO2, and recovery from sedation were unchanged. Participants, surgeons, and sedationists preferred clonidine over the placebo. Clonidine pre-treatment increased and prolonged sedation and amnesia and stabilized vital signs while significantly decreasing diazepam and post-operative analgesic usage. These results suggest that pre-operative clonidine administration could be a useful supplement to intravenous sedation for dental procedures of long duration.

Tics, patterned movements distinct from stereotypies, myoclonus, and other hyperkinetic movements, are quite common in children, particularly among those with developmental and psychiatric disorders. Thus, tics can indicate the presence of atypical neurodevelopment or broader difficulties with cognition or mood. Tics are also the cardinal feature of Tourette syndrome, a childhood-onset neurobehavioral disorder characterized by a chronic inability to suppress or an urge to perform patterned, repetitive movements. Patients with Tourette syndrome most commonly have, in addition to tics, symptoms of inattention, hyperactivity, obsessiveness, or anxiety. Achieving the most effective treatment of a child with tics is contingent on proper diagnosis of the movement disorder and thorough assessment for other problems, followed by consideration of both nonpharmacologic and pharmacologic interventions for any and all symptoms interfering with the child's function and quality of life. This review focuses primarily on the diagnosis and medical treatment of tics in children and adolescents with Tourette syndrome. (J Child Neurol 2006;21:690—700; DOI 10.2310/ 7010.2006.00161).

α1-Adrenoceptor has been discovered to exist in many human tissues and mediates important physiological functions. The purpose of this study was to detect the expression, distribution, and function of α1-adrenoceptor subtypes in human submandibular glands. α1A- and α1B-Adrenoceptor mRNAs were identified by reverse-transcription/polymerase chain-reaction (RT-PCR), and their proteins were detected by Western blotting. No expression of the α1D-adrenoceptor mRNA and protein was found. By in situ hybridization and immunohistochemistry, α1A- and α1B-adrenoceptor mRNAs and proteins were shown to be widespread in both ductal and acinar cells. By confocal microscopy, phenylephrine (stimulating both α1A- and α1B-adrenoceptors) or A61603 (α1A-selective agonist) induced an increase in intracellular calcium by 2.33 ± 0.18-fold and 1.81 ± 0.43-fold, respectively, while 5-methylurapidil (α1A-selective antagonist) partly blocked calcium mobility stimulated by phenylephrine. The results indicated that functional α1A- and α1B-adrenoceptors were expressed in human submandibular glands, and might contribute to the regulation of saliva synthesis and secretion.

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist in both the central and peripheral nervous systems. Its cardiorespiratory effects have been described; however, these effects have not been reported when it is used in combination with volatile anaesthetics in rats. The cardiovascular and respiratory actions of a continuous intravenous infusion of 0.25 μg/kg/min of DEX administered to rats anaesthetized at 1 minimum alveolar concentration (MAC) of either halothane (HAL) or isoflurane (ISO) were studied. Twenty-eight rats were grouped into four treatment groups: HAL alone, ISO alone, DEX + HAL and DEX + ISO. The MACHAL or MACISO was determined in each rat from alveolar gas samples at the time of tail clamping. Control MAC values, expressed as mean ± standard deviation, were 1.31 ± 0.1% for HAL and 1.46 ± 0.05% for ISO. DEX reduced HAL MAC from 1.31 ± 0.1% to 0.36 ± 0.22% (72 ± 17% MAC reduction) and ISO MAC from 1.46 ± 0.05% to 0.83 ± 0.2% (43 ± 14% MAC reduction). Heart rate (HR) was decreased in both DEX groups at 1 MAC, with no differences between HAL and ISO. The mean arterial pressure was significantly depressed in the DEX + ISO group compared with the ISO only group. This difference in mean arterial blood pressure (MABP) was not seen between the DEX + HAL and HAL only groups. Respiratory depression was minor at 1 MAC with both inhalant anaesthetics. DEX reduced the MAC of HAL to a degree greater than it decreased the MAC of ISO. The effects of DEX on HR and ventilation were similar in rats anaesthetized with HAL or ISO at 1 MAC; however, hypotension was more pronounced when DEX was combined with ISO at 1 MAC.

The current experiments were designed to study the antinociceptive effects of intrathecal (i.t.) administration of cannabinoid CB1 receptor and 2-adrenoceptor drugs in the nociceptive processing and also their receptor interactions. Different doses of a cannabinoid receptor agonist, CP 55,940, and an 2-adrenoceptor agonist, clonidine induced a dose-dependent antinociception in both phases of the formalin test. CP 55,940-induced antinociception was reduced by pretreatment of a selective cannabinoid CB1 receptor antagonist, SR 141716A, but not by pretreatment with an 2-adrenoceptor antagonist, yohimbine in both phases of the test. However, yohimbine and SR 141716A attenuated the antinociception induced by clonidine in the early phase but not in the late phase of the test. While SR 141716A by itself did not influence pain behaviour, the reversal effect of clonidine by SR 141716A indicate that clonidine stimulate the release of endocannabinoid(s). In conclusion, our findings may suggest that: (1) spinal cannabinoid and 2-adrenoceptor systems are able to induce antinociception in both phases of formalin test, and (2) the cannabinoid system may be involved in the antinociception induced by adrenoceptors in the early phase.

Objectives: This study was performed to explore the antimicrobial activity of two commercially available oxymetazoline hydrochloride preparations against the common pathogens of otitis media and to demonstrate the lack of ototoxicity of these agents and of United States Pharmacopeia (USP) oxymetazoline in a standard animal model. Methods: Disc diffusion assays and minimum inhibitory concentration studies against American Type Culture Collection reference strains of common middle ear pathogens were used to evaluate the antimicrobial activity of oxymetazoline solutions and fluoroquinolone drops, and outer hair cell counts were performed on scanning electron micrographs of guinea pig basal cochlear segments after chronic exposure to oxymetazoline solutions and positive and negative controls. Results: Oxymetazoline nasal spray and eyedrops had activity against all species tested except Haemophilus influenzae and Pseudomonas aeruginosa. The USP oxymetazoline had limited antimicrobial activity. Oxymetazoline nasal spray, oxymetazoline eyedrops, and USP oxymetazoline had ototoxicity profiles indistinguishable from that of the saline solution control. Conclusions: Commercially available oxymetazoline solutions are active against several of the common pathogens of otitis media. This antimicrobial activity is not due to oxymetazoline, and is more likely due to preservatives present in the solutions. The solutions tested are not ototoxic to guinea pig outer hair cells. Oxymetazoline solutions are potential substitutes for broad-spectrum antibiotic drops after tympanostomy tube placement.

Cortical spreading depression (CSD) is thought to be a neuronal mechanism that expands the penumbra zone after focal brain ischemia and that causes migraine aura. Both adrenergic agonists and antagonists significantly influence the size of the penumbra zone and decline the frequency of migraine. To study whether these compounds act by influencing CSD, we applied different drugs topically to an area of the exposed cortex of anesthetized adult rats and observed the migration of CSD-related DC potential deflections across the treated area. The adrenergic agonist norepinephrine (1 mmol/L) and the α2-agonist clonidine (0.56 mmol/L) blocked reversibly the migration of CSD. The β-blocker propranolol (250 μmol/L to 1 mmol/L) dose-dependently diminished migration velocity or even blocked migration of CSD. The CSD blockade by the α2-antagonist yohimbine (1.75 mmol/L) was because of its action on inhibitory 5-HT1Areceptors. None of the substances in the concentrations used had influence on regional cerebral blood flow or on systemic arterial blood pressure. The data suggest that the interference of these compounds with CSD may contribute to their beneficial therapeutic effect. The effect of β-receptor antagonists in human migraine needs further exploration, since these drugs also work in migraine without aura.

Taking into account the drawbacks associated with the use of triptans, attempts are being made to explore other avenues for the treatment of migraine. Recently, it has been shown that both α1- and α2-adrenoceptors mediate the constriction of porcine carotid arteriovenous anastomoses, which has effectively served as an experimental model predictive of anti-migraine activity. The present study investigated the effects of a novel α-adrenoceptor agonist S19014 {spiro[(1,3- diazacyclopent-1-ene)-5 : 2′-(4′,5′-dimethylindane)] fumarate} on carotid and systemic haemodynamics in anaesthetized pigs, and on human isolated coronary arteries. Increasing doses of S19014 (1-30 μg/kg, i.v.) produced a dosedependent initial short-lasting vasopressor response and a decrease of total carotid blood flow and conductance. The carotid blood flow and conductance changes were exclusively due to constriction of carotid arteriovenous anastomoses (capillary blood flow increased) and were accompanied by an increase in arterio-jugular venous oxygen saturation difference. Whereas prazosin (100 μg/kg, i.v.) was ineffective, rauwolscine (300 μg/kg, i.v.) attenuated the responses to S19014. The compound did not much affect the distribution of cardiac output to peripheral organs when compared with the vehicle group. Furthermore, S19014 only slightly contracted the human isolated coronary artery and its contractions, contrary to those of sumatriptan, were not increased in blood vessels precontracted with U46619. These results suggest that (i) the systemic and carotid vascular effects of S19014 are mainly mediated by α2-adrenoceptors, and (ii) S19014 could be effective in the treatment of migraine with an improved cardiovascular tolerance.

In exercising dogs, increased myocardial O2consumption (MVO2) of the left ventricle is met primarily by hyperemia, whereas increased O2extraction makes a greater contribution to right ventricular (RV) O2supply. We hypothesized that α-adrenergic vasoconstrictor tone limits right coronary (RC) blood flow during exercise, forcing increased O2extraction. This tone might also contribute to lesser RC vascular conductance at rest. Accordingly, RV O2balance was examined at rest and during graded treadmill exercise before and during α-adrenergic blockade with phentolamine (1 mg/kg, iv, n = 6). The transmural distribution of RC flow was measured with radiolabeled microspheres in 4 additional dogs. At rest, α-adrenergic receptor blockade did not significantly increase RC flow or conductance. During exercise, α-adrenergic blockade increased RC flow and conductance responses to increased RV MVO2by 25% and 60%, respectively. The transmural distribution of RC flow was not altered by exercise or by α-adrenergic blockade. Before α-adrenergic blockade, hyperemia provided 39%–66% of the additional O2consumed by the right ventricle during graded exercise; after α-adrenergic blockade, hyperemia contributed 74%–85%. After α-adrenergic blockade, the slope of the relationship between RC venous PO2and RV MVO2became less steep, reflecting less O2extraction due to enhanced hyperemia. Additional experiments were conducted on 5 anesthetized, open-chest dogs with constant RC perfusion pressure and β-adrenergic blockade. The RC flow response to intracoronary norepinephrine was shifted to the left compared with that measured in the left coronary circulation, consistent with observations in the conscious exercising dogs. In conclusion, α-adrenergic vasoconstrictor tone does not restrict resting RC blood flow, but during exercise, this tone transmurally blunts RC hyperemia and forces the right ventricle to mobilize its O2extraction reserve. This effect is more pronounced than has been reported for the left ventricle.

This study was designed to evaluate the effect of sufentanil, tramadol or clonidine added to lignocaine for intravenous regional anaesthesia. We investigated the onset and duration of sensory and motor block, the quality of the anaesthesia, intraoperative and postoperative haemodynamics, intraoperative and postoperative pain and sedation. Sixty patients undergoing ambulatory hand surgery received intravenous regional anaesthesia using 35 ml of 0.5% lignocaine and either 5 ml saline (Group L, n=15); sufentanil 25 μg (Group LS, n=15); tramadol 100 mg (Group LT, n=15) or clonidine 1 μg.kg –1 (Group LC, n=15). Before and after the tourniquet application, haemodynamic data, tourniquet pain, sedation scores and analgesic use were recorded. After tourniquet deflation, haemodynamic data, pain and sedation, time to first analgesic requirement and analgesic use were noted. There were no differences among groups in intraoperative haemodynamic data, the time to recovery of sensory block, the onset and the recovery of motor block, sedation scores or postoperative pain. Compared to the other groups, in Group L the onset of sensory block was longer, the time to initial tourniquet pain was shorter and the intraoperative tourniquet pain scores and use of the opioid were higher (P In conclusion, the addition of sulfentanil, tramadol or clonidine to lignocaine shortened the onset of the sensory block, delayed the onset time of the tourniquet pain and reduced the intraoperative consumption of opioid, but did not affect postoperative pain.

Objective α1-adrenoceptor activation confers myocardial protection from ischemic injury. We tested whether norepinephrine mediates delayed cardioprotection against stunning and whether this alters postischemic arrhythmias. Methods New Zealand White rabbits were assigned to three groups: Control-group ( n = 7): no drugs. Norepinephrine-group ( n = 7): 75 μg norepinephrine/kg bodyweight (bw). Norepinephrine/prazosin-group ( n = 7):75 μg norepinephrine and 15 μg prazosin/kg bw. After 24 h, hearts were excised, perfused with buffer and subjected to 20 min of ischemia followed by 120 min of reperfusion. Results (a) Developed pressures (dP) ( Psyst– Pdiast) at the end of reperfusion: C: 51.2 ± 5.0%, NE: 71.7 ± 5.1% ( p < 0.05 vs. C), NEP: 50.7 ± 5.0%. (b) Ventricular extra beats (vebs) were detected throughout the experiments. C: 0.41 ± 0.15 vebs/min, NE: 1.06 ± 0.18 vebs/min ( p < 0.05 vs. C), NEP: 1.17 ± 0.3 vebs/min. Conclusion Norepinephrine confers delayed preconditioning against myocardial stunning via an α1-adrenoceptor mediated pathway. Norepinephrine-mediated preconditioning involves a beneficial effect towards stunning, but at the expense of a higher rate of postischemic ventricular arrhythmia.

Previously, we have demonstrated that in contrast to male rats, female rats do not show an age-related reduction of depolarization-elicited norepinephrine (NE) release from cardiac synaptosomes (resealed nerve terminals). These results suggest that sex hormones such as estrogen may modulate NE release from cardiac synaptosomes prepared from female rats. The present study was designed to test the hypotheses that long-term estrogen depletion, resulting from ovariectomy, and estrogen replacement alters depolarization-elicited NE release from cardiac synaptosomes. Female F344 rats were divided into two groups, one of which underwent bilateral ovariectomy, whereas the other underwent a sham operation. Three ovariectomized subgroups received daily injections of conjugated equine estrogens, Δ8,9-dehydroestrone or 17α-dihydroequilenin. Another ovariectomized control subgroup and the sham-operated animals received daily injections of vehicle. After 90 or 270 days of treatment, the animals were sacrificed. Cardiac synaptosomes were prepared from each heart, incubated with [3H]-NE, and used to evaluate NE release capacity by exposure to 50 mM K+. The effectiveness of the ovariectomy and the estrogenic actions of the test compounds was confirmed by evaluating vaginal smears, determining uterine weights, and measuring serum luteinizing hormone (LH) concentrations. Ovariectomy (after both 90 and 270 days) significantly increased depolarization-induced NE release compared with sham-operated rats. Treatment with all three estrogenic preparations reduced NE release in ovariectomized rats to values similar to those observed in sham-operated animals. Interestingly, NE release rates from rats treated with conjugated estrogens for 270 but not 90 days were significantly below that observed in age-matched sham animals. These results demonstrate that estrogen modulates depolarization-elicited NE release from cardiac nerve terminals. Such modulation may represent a protective action by estrogen at the cardiac synapse.

The post-training administration of tricyclic antidepressant imipramine impairs memory consolidation in the passive avoidance task. The present study investigated the effects of intrahippocampal (i.h.) injection of adrenoceptor agents on imipramine-induced (2-8 microg/rat) amnesia. The administration of the alpha1-adrenoceptor agonist phenylephrine (0.05 microg/rat) and the alpha1-adrenceptor antagonist prazosin (0.5 microg/rat) did not alter the effect of imipramine. The lower doses of phenylephrine (0.005 and 0.015 microg/rat) impaired, while the higher dose of the drug (0.025 and 0.05 microg/rat) improved retention. The effect of phenylephrine was not altered by prazosin (0.5 and 1 microg/rat) pretreatment, although prazosin alone decreased retention latencies. The alpha2-adrenoceptor antagonist yohimbine (0.5 and 1 microg/rat) decreased the response induced by imipramine. However, the alpha2-adrenoceptor agonist clonidine (0.08 microg/rat) did not alter the effect of the drug. Clonidine (0.15 and 0.3 microg/rat) by itself decreased, while yohimbine (1 and 2 microg/rat) increased retention latencies. Yohimbine pretreatment attenuated the effect of clonidine. It is concluded that alpha2-adrenoceptor mechanism(s) may be involved in imipramine-induced impairment of memory.

Purpose: To examine retrospectively the magnitude of change in systolic blood pressure (SBP) during carotid artery stenting and its relationship to neurological events. Methods: In a 5-year period ending October 2000, 60 patients (36 men; mean age 67 ± 9 years) were enrolled in a study to evaluate stenting in symptomatic or asymptomatic high-risk patients with ≥70% carotid artery stenosis. The majority (48, 80%) of the patients were symptomatic. Five patients with bilateral lesions were treated in staged procedures. Sixteen (25%) of the 65 lesions were postsurgical stenoses and 12 (18%) were secondary to neck radiation therapy. Results: There were 2 (3%) minor and 2 (3%) major strokes (94% procedural success), of which 1 was fatal. Six (9%) transient neurological events were recorded during balloon inflation. The mean SBP change during or after stenting in 55 cases without neurological events was 34 ± 14 mmHg, while the patients with transient or permanent neurological events had significantly greater changes in SBP (107 ± 31 mmHg [pConclusions: Patients with severely elevated baseline SBP (>180 mmHg) may be at higher risk for hemodynamic instability and neurological events during carotid stenting. The greater the change in SBP, the more severe the neurological event seems to be, but further studies in a greater number of patients are needed to evaluate the potential causes of SBP fluctuations in an effort to avoid neurological events.

Purpose We evaluated the efficacy of topical brimonidine in visual field preser vation and/or improvement in eyes undergoing controlled glaucoma. Methods Seventy eyes of patients were trained with two different visual field test strategies: The Octopus Tendency Oriented Perimetry (TOP) G1 and the Frequency Doubling Technology (FDT) 30°. Following 2–4 months of brimonidine treatment, there were significant improvements in visual field, as assessed using the TOP G1 strategy (p = 0.003). The FDT 30° test revealed no statistically significant differences. Conclusions These data support the results of other studies, which indicate that brimonidine may increase mean sensitivity in visual field tests. Since it is known that the control of intraocular pressure does not fully protect glaucomatous eyes from visual field loss, it is possible that the neuroprotective qualities of brimonidine may contribute to visual field preservation in glaucomatous eyes.

The efficacy of continuous low-dose xylazine infusion following an initial loading dose in providing analgesia in sheep was examined using an algesimetry method based on a leg lifting response to an electrical stimulus. Sheep received a 5 mg intramuscular injection of xylazine followed by continuous infusion of intravenous xylazine (2 mg/h) for 90 min. This treatment resulted in significant increases in the level of current required to elicit a leg lifting response (287% of baseline) and steady state analgesia was maintained from 10 min after the start of the infusion until the end of the experimental period. This protocol appears to be a simple and effective regimen for providing steady state analgesia in sheep.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30–500 ms before the ‘startle-eliciting’ stimulus (prepulse inhibition). We examined the effects of two sedative/anxiolytic drugs, diazepam and clonidine, on prepulse inhibition of these two responses in healthy volunteers. Fifteen males (aged 18–35 years) participated in three sessions in which they received oral doses of placebo, diazepam 10 mg and clonidine 0.2 mg according to a balanced double-blind protocol. Thirty-minute simultaneous recordings of the electromyographic (EMG) responses of the orbicularis oculi muscle of the right eye and the vertex auditory evoked potentials took place 120 min after ingestion of clonidine and 60 min after ingestion of diazepam. Sound stimuli (1 kHz) were presented in 60 trials separated by variable intervals (mean 25 s): (i) 40-ms 115-dB (‘pulse alone’, 20 trials); (ii) 40-ms 85-dB (20 trials); (iii) 40-ms 85-dB, followed after 120 ms by 40-ms 115-dB (‘prepulse/pulse’, 20 trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. The amplitude of the EMG response was significantly reduced both by diazepam and by clonidine; neither drug significantly altered prepulse inhibition of the EMG response. Diazepam, but not clonidine, significantly reduced the amplitude of the N1/P2 potential; neither drug significantly affected prepulse inhibition of the N1/P2 potential. Both drugs reduced self-rated alertness and anxiety, and systolic blood pressure; clonidine, but not diazepam reduced diastolic blood pressure and salivation. The results confirm previous findings that sedative drugs can suppress the startle response without affecting prepulse inhibition of this response, and provide new information on the effects of these drugs on the N1/P2 potential and its inhibition by prepulses.

Rapid and dramatic changes occur in cardiorespiratory function during early human life. Catecholamines within select brain stem nuclei are implicated in the control of autonomic and respiratory function, including in the nucleus of the solitary tract and the dorsal motor nucleus of X. Animal and adult human studies have shown high binding to α2-adrenergic receptors in these regions. To determine the developmental profile of brainstem α2-adrenergic binding across early human life, we studied brain stems from five fetuses at mid-gestation, three newborns (37–38 postconceptional weeks), and six infants (44–61 postconceptional weeks). We used quantitative tissue receptor autoradiography with [3H]para-aminoclonidine as the radioligand and phentolamine as the displacer. In the fetal group, binding was high (63–93 fmol/mg tissue) in the nucleus of the solitary tract, dorsal motor nucleus of X, locus coeruleus, and reticular formation; it was low (

Nonselective adrenergic α-agonists such as phenylpropanolamine and d-pseudoephedrine are widely used as decongestants to treat nasal congestion associated with a variety of nasal diseases. Although the activity of these drugs is well established in clinical studies, a direct comparison of their nasal decongestant effect as determined by changes in nasal cavity dimensions and nasal architecture has not been studied. Using acoustic rhinometry, we evaluated the effects of these drugs on nasal cavity volume, minimum cross-sectional area (Amin), and the distance from the nosepiece to the Amin (Dmin) in a feline, pharmacological model of nasal congestion. Administration of topical compound 48/80 (1%), a mast cell histamine liberator, into the left nasal passageway decreased nasal volume by 66%, reduced Amin by 51%, and increased Dmin by 116%. The congestive responses to compound 48/80 (1%) were reproducible through six weeks. In a subset of cats, the nasal cavity volume effect of repetitive exposure to compound 48/80, given once every two weeks for six weeks, was not different from the nasal responses after the initial exposure to compound 48/80. Pretreatment with oral phenylpropanolamine (10 mg/kg) or oral d-pseudoephedrine (10 mg/kg) attenuated the nasal effects of compound 48/80, but were associated with a pronounced increase in systolic blood pressure of +51 and +82 mmHg, respectively. A similar decongestant profile was observed with phenylpropanolamine (1%) and d-pseudoephedrine (1%) when given topically. Topical phenylpropanolamine (1%) and d-pseudoephedrine (1%) 45 minutes after dosing increased blood pressure +44 and +17 mmHg, respectively, over control animals. We conclude that oral and topical phenylpropanolamine and d-pseudoephedrine display equieffective nasal decongestant activity and produce similar cardiovascular profiles characterized by significant increases in blood pressure.

Objective: To describe a case of tramadol withdrawal in a neonate and treatment with clonidine after exposure to long-term maternal use of high-dose tramadol. Case Summary: A 34-week gestational age neonate displayed symptoms of tramadol withdrawal within 48 hours of delivery. Due to a confusing initial clinical picture, including presumed congenital Chlamydia, questionable seizures, and an original report of maternal use of ketorolac (Toradol), diagnosis was delayed until day of life 5. Symptoms included jitteriness, myoclonic movements, and irritability. Upon further questioning of the mother, it was revealed that she was actually taking tramadol 600–800 mg daily. The infant was placed on maintenance therapy with oral clonidine (from 1 to 3 μg/kg orally every 3 hours) until discontinuation on day of life 11. After 3 days off treatment, he began to display symptoms of withdrawal again. Clonidine was restarted at 1 μg/kg orally every 8 hours and he was discharged home on maintenance clonidine therapy at 18 days postnatal age. A 7-day tapering regimen was initiated 2 weeks after discharge, and no further withdrawal symptoms occurred. Discussion: Few published articles are available to guide clinicians on the clinical course and treatment strategies for tramadol dependence and withdrawal. In neonates, the reports are particularly sparse. Traditional agents used in neonatal opioid withdrawal are narcotics (morphine, tincture of opium, methadone), benzodiazepines (diazepam, lorazepam), and phenobarbital. Clonidine use for neonatal abstinence syndrome from narcotics has been shown to be effective alone or in combination with agents such as other opiates and chloral hydrate. Potential benefits of clonidine therapy include shorter duration of therapy, reduced withdrawal symptoms, and decreased length of hospital stay. Conclusions: Withdrawal can be prolonged in infants exposed to maternal tramadol use. Clonidine may be a safe and effective option for managing symptoms of neonatal tramadol abstinence.

The alpha-adrenergic agonists have been demonstrated to have synergistic effects with opioids and local anesthetics in animal research. The present study was performed to determine whether the addition of adrenaline improves the analgesic effects of an epidural infusion of a combination of fentanyl and bupivacaine after abdominal surgery. We studied 90 ASA 1 or 2 patients scheduled for abdominal surgery under epidural anaesthesia, with or without general anaesthesia. Patients were randomly divided into two groups to receive a postoperative epidural infusion of fentanyl 5 μg/ml in bupivacaine 0.2%, with or without adrenaline 5 μg/ml, at a rate of 2 ml/h for more than 48 hours. Postoperative pain relief was assessed using visual analog scales (VAS), both at rest and during coughing, at 2, 24, and 48 hours after surgery. The number of rescue analgesics and side-effects such as nausea, vomiting, pruritus, respiratory depression, headache, muscle weakness, and hypotension were recorded. Patients who received adrenaline (n=40) reported significantly lower mean VAS scores than those who received no adrenaline (n=37), both at rest at 24 hours postoperatively and during coughing at 24 and 48 hours. The number of additional analgesics and incidence of side-effects did not differ between groups. In conclusion, the results of the present study demonstrate that the addition of adrenaline to a combination of fentanyl and bupivacaine improves the quality of epidural analgesia after abdominal surgery. Under the conditions of the study, we did not detect any disadvantage from the addition of adrenaline.

A patient with perforated appendicitis developed progressive vasodilatory shock which was complicated by perioperative acute myocardial infarction. Cardiovascular support included dopamine infusion, and later, intra-aortic balloon counterpulsation balloon pump and noradrenaline and dobutamine infusion. Vasopressin was introduced as a final attempt to reverse the refractory shock and was associated with recovery. The experience with this case suggests that vasopressin may be a valuable adjunct to the treatment of catecholamine-resistant vasodilatory shock.

OBJECTIVE: To describe a patient who experienced a hypertensive crisis and myocardial infarction following a massive dose of parenteral clonidine. CASE SUMMARY: A 62-year-old white woman with stage 3 breast cancer metastatic to the spine and a history of hypertension received a combined injection of hydromorphone 48.3 mg and clonidine 12.24 mg subcutaneously in an attempt to refill an implanted epidural infusion pump. She promptly developed mental deterioration, blurred vision, worsening respiration, tachycardia, and hypertension. She was immediately treated with naloxone, but subsequently experienced hypertensive urgency, a short-duration tonic–clonic seizure, and an anteroseptal myocardial infarction. Cardiac catheterization showed no arteriolar narrowing or blockage, but an anterior infarct was confirmed. DISCUSSION: Clonidine is a commonly used α-adrenergic agonist. At usual oral doses of 0.2–2 mg/d, it acts centrally to produce hypotensive effects; at doses >7 mg/d, it acts peripherally to stimulate α1- and α2-adrenergic receptors, leading to vasoconstriction and increased blood pressure. These effects are not easy to control by standard medical therapies and can cause significant morbidity. CONCLUSIONS: Clonidine, although a safe medication with usual dosages, must be used with caution when given in injectable form. An overdose of this α-adrenoreceptor agonist can produce significant vasospasm and hypertensive emergency. Drugs used to treat overdose, such as naloxone, can potentiate clonidine's adverse effects, leading to further morbidity.

Clonidine may have beneficial effects in patients undergoing major surgery. We enrolled 156 patients having elective CABG surgery in a double-blind, randomized trial. Patients were randomized to receive either two doses of placebo (Group PP) or clonidine 5 μg/kg (Group CC). Perioperative measurements included haemodynamics, anaesthetic and analgesic drug usage, creatinine clearance, cortisol excretion, recovery times and quality of life (SF-36) after surgery. Overall, there was no significant difference with time to tracheal extubation (median [10–90 centile]): CC 7.1(3.4–18)h vs PP 8.0(4.3–17) h, P=0.70; but there was a higher proportion of patients extubated within four hours: CC 20% vs. PP 8%, P=0.038. Clonidine resulted in a number of significant (P

In strial marginal cells, Na+/K+-ATPase activity is abundant, and contributes to maintain the characteristic electrolyte composition of the cochlear endolymph. In the present study, to clarify the relationship between epinephrine and strial Na+/K+-ATPase activity, the ouabain-sensitive, K+-dependent p-nitrophenylphosphatase (K+-NPPase) activity of strial marginal cells was investigated with a cerium-based method in normal guinea pigs and guinea pigs treated with reserpine, epinephrine, and reserpine plus epinephrine. In our previous study, K+-NPPase activity had almost completely decreased 3 to 20 days after reserpine administration. In the present study, at 10 days after reserpinization and following repeated epinephrine treatment, enzyme activity was detectable. These results suggest that exogenous epinephrine was able to restore strial K+-NPPase activity in the reserpine-treated animals, and that epinephrine might increase strial Na+/K+-ATPase activity.

Purpose The selective alpha-2 agonist brimonidine was used as a pharmacological probe to activate α2 receptor-mediated neuroprotective signaling pathways and quantitate the enhancement of retinal ganglion cell survival and function in animals with ischemic retinal and optic nerve injury. Methods Two animal models were used to achieve different methods of neuronal insult. The first model involved mechanical injury of the rat optic nerve after treatment with a single intraperitoneal (IP) dose of brimonidine or a control vehicle. The second model involving acute retinal ischemic/reperfusion injury was used in a variety of experiments in which rats were treated with either intraperitoneal brimonidine or single dose topical brimonidine at various strengths. In all cases retinal ischemia was induced and maintained followed by reperfusion. In some cases, TUNEL staining was performed on histologic sections of the retinas of rats that had been sacrificed after 24 hours. To examine the activation of neuronal survival pathways at the molecular level, rats were injected with IP brimonidine followed by the isolation of mRNAs from whole retinas 24 hours after ischemic injury. Results Intraperitoneal brimonidine enhanced rat RGC survival and function in the partial crush injury model, and neuroprotection was dose-dependent. Topical application of brimonidine 1 hour before injury was effective in decreasing ischemic retinal injury. Ischemic retinas treated with brimonidine resulted with a large decrease in TUNEL staining. Conclusions Treatment with the α2 adrenoreceptor agonist brimonidine was found to confer neuroprotection to retinal ganglion cells in two distinct models of neuronal injury resulting from acute retinal ischemia/reperfusion and calibrated optic nerve compression.

Purpose The efficacy and adverse effects of 0.25% apraclonidine on intraocular pressure (IOP) after Nd: YAG laser posterior capsulotomy were investigated, and the results were compared with placebo, 0.50% timolol maleate and 1% apraclonidine. Methods Eighty eyes were randomly assigned to four groups of 20 eyes. In a double-masked design, the groups were treated with placebo (group I), 0.50% timolol maleate (group 2), 1% apraclonidine (group 3), 0.25% apraclonidine (group 4) one hour before and five minutes after Nd:YAG laser posterior capsulotomy. IOP was measured by applanation tonometry 1 hour before (baseline IOP) and 1,3, 24 hours after capsulotomy. Results The average baseline IOP increased respectively 3.90 ± 5.35, 5.95 ± 5.32, 1.15 ± 3.20 mmHg in the first group 1, 3 and 24 hours post-treatment. There were significant differences between baseline IOP and 1 and 3 hours but not at 24 hours (p=0.004, p=0.001, p=0.13). IOP increased 0.40 ± 4.08, 0.75 ± 5.33, 0.80 ± 6.03 mmHg in the second group at the same times. The differences between the average baseline IOP and the 1, 3 and 24h measurement were not significant (p=0.83, p=0.65, p=0.93). In the third group, IOP decreased 3.70 ± 2.40, 3.30 ± 2.47, 2.65 ± 1.56 mmHg at the measurement times, with significant differences between the average baseline IOP and the 1, 3 and 24 hour measurements (p=0.001, p=0.0001, p=0.01). In the fourth group IOP increased 0.35 ± 3.32 mmHg at 1 hour, but decreased 1.25 ± 3.41, 0.90 ± 2.07 mmHg at 3 and 24 hours. The differences were not significant (p=0.94, p=0.16, p=0.08). When the 0.25% and 1% apraclonidine groups were compared, there were significant differences between the average IOP at 1 hour in both groups but not at 3 and 24 hours (p=0.01, p=0.17, p=0.21). Similarly, there were no significant differences between the average IOP at the same times when the 0.25% apraclonidine group was compared with the timolol group (p=0.30, p=0.08, p=0.16). Some systemic and local side effects were seen in the timolol and 1% apraclonidine groups, but none with 0.25% apraclonidine. Conclusions It was concluded that 0.25% apraclonidine is effective in preventing the early elevation of IOP after Nd:YAG laser posterior capsulotomy and may offer an alternative to 0.50% timolol maleate and 1% apraclonidine.

Few data exist in the literature to support the use of high dosages of oral baclofen and clonidine that are frequently required to treat children with spasticity. This study was a retrospective chart review of baclofen and clonidine dosages used in children diagnosed with cerebral palsy or traumatic brain injury. The primary objective was to calculate the mean dosages of baclofen and clonidine based on the duration of spasticity postinjury. Secondary objectives included determining correlations between dosage and age, injury type, location of spasticity, comorbid seizures, or concomitant antispasticity medications. Eighty-seven children receiving baclofen and/or clonidine were included in this study. Mean dosages of 40 mg/day ( n = 86) and 0.4 mg/day ( n = 31) were required for baclofen and clonidine, respectively. The maximum dosage was 240 mg/day for baclofen and 3.6 mg/day for clonidine. Duration postinjury, age, and concomitant antispasticity medications were the most predictive variables for baclofen dosage as a model ( r = .522; P = .000). Duration postinjury and location of spasticity were the most predictive variables for clonidine dosage as a model ( r = .523; P = .000). The average dosages of baclofen and clonidine used in this population of children with cerebral palsy or traumatic brain injury were similar to those reported in the literature, with higher maximum dosages found in this investigation.

Background The purpose of this study was to evaluate the effect of low temperature on basal tension in isolated hypertrophic human nasal mucosa with or without α1-agonist stimulation. Methods A tissue bath for isolated nasal mucosa was used. Tension in strips of human turbinate mucosa that were untreated and treated with an α1-adrenoreceptor agonist, methoxamine (10 μM), was recorded continuously in a stepwise manner in temperatures that varied from 37 to 10°C. Results The changes of tension in the human nasal mucosa were found to be temperature-dependent in both untreated and treated tissues, with tension decreasing to 48.6% at 10°C in comparison with 100% at 37°C in the untreated group, the presence of methoxamine (10 μM) had minimal effect. Conclusion Low temperature induced a rapid and reproducible relaxation in isolated hypertrophic human nasal mucosa that was not affected by the presence of the α1-agonist methoxamine (10 μM).

Increased shear, pressure, and oxygen tension in vein grafts may alter production of endothelium-derived vasoactive and anti-mitogenic factors such as nitric oxide which subsequently affect development of neointimal hyperplasia. This study was designed to determine whether or not nitric oxide mediates endothelium-dependent responses in femoral in situ vein grafts. Non-reversed, canine femoral vein grafts were placed bilaterally to bypass a ligated segment of the femoral artery in dogs. After 6 weeks, the grafts were removed, cut into rings, and suspended in organ chambers for measurement of isometric force. In some rings the endothelium was removed deliberately. In the presence of indomethacin, the synthetic analog of l -arginine, l -NG-monomethyl-arginine (10−4 M; l -NMMA) did not cause a significant change in baseline tension of rings with endothelium. l -NMMA reduced only contractions of rings with endothelium to the alpha-adrenergic agonist UK 14,304. The analog also reduced maximal relaxations to the calcium-ionophore, A23187 in rings with endothelium. In addition, l -NMMA reduced relaxations of rings without endothelium to adenosine diphosphate by 35%. Positive immunostaining for nitric oxide synthase was present in both the myointima and media of histological sections of grafts. In conclusion, these results suggest that in situ vein grafts exhibit two unique properties which are unlike unoperated arteries or veins: (i) alpha2-adrenergic receptors may be coupled to the release of contractile endothelium-derived factors associated with production of nitric oxide; and (ii) nitric oxide may be released by the smooth muscle in response to purinergic stimulation. The presence of nitric oxide synthase throughout the wall of the graft may result in production of nitric oxide in response to adenosine diphosphate released by platelets and to circulating catecholamines. © 1997 The International Society for Cardiovascular Surgery.

The present study investigated the role of α1 adrenergic receptors in the modulation of working memory and behavioural activity by assessing the effects of α1 adrenergic receptor stimulation or blockade on the performance of rats in a delayed non-matching to position task. St-587 (a putative agonist of α 1 adrenoceptors) at a dose of 100 μg/kg slightly increased choice accuracy (per cent correct responses) of rats, but the effect was delay-independent which is interpreted as an improvement in choice accuracy and non-mnemonic (non-working memory) in character. Neither St-587 (300 or 1000 μg/kg) nor prazosin (a prototype antagonist of α1 adrenoceptors) (100 or 300 μg/kg) significantly affected the choice accuracy of rats in this task. Prazosin 300 μg/kg lengthened the latency for correct responses in the working memory task but did not affect food collection latencies. This combination of effects may reflect decreased motor output. St-587 300 and 1000 μg/ kg, but not prazosin, increased food collection latencies in the working memory task. Thus, the present results suggest that α 1 adrenergic receptors do not play any important role in spatial working memory as assessed using the delayed non-matching to position task, but that modulation of α1 adrenoceptors may affect motor activity and motivation in rats.