Neuronal Norepinephrine Reuptake Research Articles

Computational modeling reveals multiple abnormalities of myocardial noradrenergic function in Lewy body diseases.

Lewy body diseases, a family of aging-related neurodegenerative disorders, entail loss of the catecholamine dopamine in the nigrostriatal system and equally severe deficiency of the closely related catecholamine norepinephrine in the heart. The myocardial noradrenergic lesion is associated with major non-motor symptoms and decreased survival. Numerous mechanisms determine norepinephrine stores, and which of these are altered in Lewy body diseases has not been examined in an integrated way. We used a computational modeling approach to assess comprehensively pathways of cardiac norepinephrine synthesis, storage, release, reuptake, and metabolism in Lewy body diseases. Application of a novel kinetic model identified a pattern of dysfunctional steps contributing to norepinephrine deficiency. We then tested predictions from the model in a new cohort of Parkinson disease patients. Rate constants were calculated for 17 reactions determining intra-neuronal norepinephrine stores. Model predictions were tested by measuring post-mortem apical ventricular concentrations and concentration ratios of catechols in controls and patients with Parkinson disease. The model identified low rate constants for three types of processes in the Lewy body group-catecholamine biosynthesis via tyrosine hydroxylase and L-aromatic-amino-acid decarboxylase, vesicular storage of dopamine and norepinephrine, and neuronal norepinephrine reuptake via the cell membrane norepinephrine transporter. Post-mortem catechols and catechol ratios confirmed this triad of model-predicted functional abnormalities. Denervation-independent impairments of neurotransmitter biosynthesis, vesicular sequestration, and norepinephrine recycling contribute to the myocardial norepinephrine deficiency attending Lewy body diseases. A proportion of cardiac sympathetic nerves are "sick but not dead," suggesting targeted disease-modification strategies might retard clinical progression. This study was not a clinical trial. The research reported here was supported by the Division of Intramural Research, NINDS.

'Sick But Not Dead': Multiple Denervation-Independent Abnormalities of Myocardial Noradrenergic Function in Lewy Body Diseases

Background: Lewy body diseases such as Parkinson disease (PD) are well known to be characterized by nigrostriatal dopamine deficiency. These disorders also entail drastic (95-99%) myocardial depletion of the sympathetic neurotransmitter norepinephrine. Catecholamine loss in both regions cannot be accounted for by denervation alone. We evaluated the possibility of decreased innervation combined with functional abnormalities in residual nerves, using previously published data and a novel, comprehensive kinetic model. We then tested predictions from the model in new subject cohorts. Methods: We calculated rate constants for 17 reactions related to myocardial intra-neuronal norepinephrine synthesis, storage, and disposition in control subjects and patients with Lewy body diseases. Post-mortem apical ventricular concentrations and concentration ratios of catechols were used to test predictions from the model in 11 controls and 11 patients with autopsy-proven PD. Results: Calculated rate constants for vesicular storage of dopamine and norepinephrine, catecholamine biosynthesis via tyrosine hydroxylase and L-aromatic-amino-acid decarboxylase, and neuronal norepinephrine reuptake via the cell membrane norepinephrine transporter were reduced in the Lewy body group. In PD myocardial norepinephrine content was decreased by 99% from controls (p<0.0001). Post-mortem catechols and catechol ratios in PD patients confirmed the pattern of model-predicted functional abnormalities. Conclusions: Denervation-independent impaired neurotransmitter biosynthesis, vesicular sequestration, and norepinephrine recycling via neuronal reuptake contribute importantly to the myocardial norepinephrine deficiency attending Lewy body diseases. The finding that a substantial proportion of catecholaminergic neurons are sick but not dead offers new hope for disease-modification strategies that might slow or prevent progression of this family of neurodegenerative disorders. Funding: The research reported here was supported by the Division of Intramural Research, NINDS. Declaration of Interest: The Authors have no conflicts of interest to disclose. Ethical Approval: For all the subjects, written informed consent was obtained prior to participation in protocols approved by the Institutional Review Board of the National Institute of Neurological Disorders and Stroke, or else the next of kin gave written informed consent for post-mortem tissue harvesting for research purposes.

The switch from buprenorphine to tapentadol: is it worth?

Opioid analgesia continues to be the primary pharmacologic intervention for managing acute pain and malignant pain in both hospitalized and ambulatory patients. The increasing use of opioids in chronic nonmalignant pain is more problematic. Opioid treatment is complicated with the risks raised by adverse effects, especially cognitive disturbance, respiratory depression but also the risk of tolerance, opioid abuse and drug-disease interactions. Despite the growing number of available opioids within the last years, adequate trials of opioid rotation are lacking and most of the information is anecdotal. This article reviews the clinical evidence surrounding the switch from transdermal buprenorphine to tapentadol in malignant and non-malignant pain. Tapentadol acts on both the μ-opioid receptors (MOR) and on the neuronal reuptake of noradrenaline with a limited usefulness in acute pain management while buprenorphine is a mixed agonist-antagonist, and both present some advantages over other opioids. Both drugs show particular pharmacodynamic and pharmacokinetic properties which reduce the risks of development of tolerance, opioid abuse, diversion and determine fewer hormone changes than the "classical opioids" making these opioids more attractive than other opioids in long term opioid treatment. However, in the absence of powered clinical trials, the evidence to support the method used for transdermal buprenorphine rotation to tapentadol is weak.

Pain in the Frail or Elderly Patient: Does Tapentadol Have a Role?

Persistent pain affects the elderly disproportionally, occurring in 50% of elderly community-dwelling patients and 80% of aged care residents. The management of pain in the elderly and frail patient is complicated because of the risks posed by changes in pharmacokinetics and pharmacodynamics, polypharmacy, and drug-disease interactions. Trials evaluating the efficacy of analgesics have often excluded elderly patients and universally excluded frail patients; therefore, the true efficacy and side-effect profiles in these population groups are largely unknown, especially for long-term use. A stepwise approach is recommended to managing pain, commencing with paracetamol and adding on opioids when needed to manage pain. However, because of the short duration of clinical trials, exclusion of frail patients, and minimal inclusion of elderly patients, the decision as to which opioid should be added on to paracetamol is a difficult one. This article reviews the evidence surrounding a newer opioid, tapentadol. Tapentadol acts on both the mu receptors and on neuronal reuptake of noradrenaline, and has no significant analgesically active metabolites, which theoretically presents some advantages, particularly in comparison with tramadol. However, the evidence to support tapentadol is weak and the trials were often methodologically poor and sponsored almost universally by the drug company. Currently, there is insufficient evidence to support the use of tapentadol over other opioids, which have been on the market longer, are less expensive, and have better established safety profiles. As a first-line agent after the failure of paracetamol alone, morphine, oxycodone, fentanyl, or buprenorphine are still the preferred evidence-based choices for add-on opioid therapy for elderly or frail patients.

Depression‐like Symptoms are Associated with Dysbalance in Vascular Norepinephrine Uptake. This is Worsening by Antidepressants and Increases the Risk for Hypertension.

Antidepressants affecting norepinephrine (NE) reuptake are known to increase the risk for hypertension. Anhedonia ‐ a decreased ability to experience pleasures ‐ is a central symptom in depression and can be evoked in preclinical models exploring the role of the stressful environment in mediating affective signs and autonomic function.Some rats exposed to Chronic Mild Stress (CMS) developed depression‐like symptoms (i.e. anhedonia, measured by sucrose intake) while others were resilient to 8 wks of CMS. Normal blood pressure and decreased cardiac function suggested increased peripheral resistance in rats with depression‐like symptoms. Chronic treatment with escitalopram (SSRI) did not affect blood pressure but normalized behavior in ~50% of treated rats, e.g. responders.Resistance (small mesenteric and femoral) arteries from CMS and non‐stressed rats responded similarly to NE in vitro. Inhibition of neuronal reuptake with cocaine increased NE sensitivity more in rats with depression‐like symptoms than in resilient and non‐stressed groups. Corticosterone‐sensitive extra‐neuronal catecholamine uptake was diminished in rats exposed to CMS. These changes were associated with upregulation of the neuronal NE transporter and reduced expression of the extra‐neuronal transporter (OCT‐2) in arteries from 'depressed' rats. Escitalopram further upregulated neuronal NE reuptake in all groups.Our results indicate that depression‐like symptoms are associated with changes in NE uptake in the vascular wall and could explain pro‐hypertensive action of some antidepressants.

Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy

Tapentadol is an analgesic agent for treatment of acute and chronic pain that activates the µ-opioid receptor combined with inhibition of neuronal norepinephrine reuptake. Both mechanisms are implicated in activation of descending inhibitory pain pathways. In this study, we investigated the influence of tapentadol on conditioned pain modulation (CPM, an experimental measure of endogenous pain inhibition that gates incoming pain signals as a consequence of a preceding tonic painful stimulus) and offset analgesia (OA, a test in which a disproportionally large amount of analgesia becomes apparent upon a slight decrease in noxious heat stimulation). Twenty-four patients with diabetic polyneuropathy (DPN) were randomized to receive daily treatment with tapentadol sustained-release (SR) [average daily dose 433 (31) mg] or placebo for 4 weeks. CPM and OA were measured before and on the last day of treatment. Before treatment, none of the patients had significant CPM or OA responses. At week 4 of treatment, CPM was significantly activated by tapentadol SR and coincided with significant analgesic responses. CPM increased from 9.1 (5.4)% (baseline) to 14.3 (7.2)% (placebo) and 24.2 (7.7)% (tapentadol SR, P<0.001 vs placebo); relief of DPN pain was also greater in patients treated with tapentadol than placebo (P=0.028). Neither placebo nor tapentadol SR treatment had an effect on the magnitude of the OA responses (P=0.78). Tapentadol's analgesic effect in chronic pain patients with DPN is dependent on activation of descending inhibitory pain pathways as observed by CPM responses. The study was registered at trialregister.nl under number NTR2716.

Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit

A multi-mechanistic approach offers potential enhancement of analgesic efficacy, but therapeutic gain could be offset by an increase in adverse events. The centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and neuronal noradrenaline reuptake inhibition (NRI), both of which contribute to its analgesic effects. Previously, isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated pronounced synergistic interaction between the two mechanisms of action of tapentadol in two models of antinociception (low-intensity tail-flick and spinal nerve ligation). The present study investigated the nature of interaction of the two mechanisms on a surrogate measure for gastrointestinal adverse effect (inhibition of gastrointestinal transit). Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid receptor antagonist, naloxone, or the α2 -adrenoceptor antagonist, yohimbine, to reveal the effect of tapentadol based upon MOR agonism, NRI, and combined mechanisms. The dose-effect curve of tapentadol was shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Analysis revealed a simple additive interaction between the two mechanisms on this endpoint, in contrast to the synergistic interaction previously demonstrated for antinociception. We believe this is the first published evaluation of mechanistic interaction for a surrogate measure of adverse effect of a single compound with two mechanisms of action, and the results suggest that there is a greater separation between the analgesic and gastrointestinal effects of tapentadol than expected based upon its analgesic efficacy.

A review of the adverse effects and safety of noradrenergic antidepressants

There are a variety of noradrenergic antidepressants available, most of which act by inhibiting neuronal noradrenaline re-uptake, although few drugs are specific for this action. Where drugs have numerous actions the adverse effects of noradrenaline reuptake may be difficult to isolate, although in this respect the adverse effects of reboxetine, a specific noradrenaline re-uptake inhibitor, are illuminating. Noradrenergic antidepressants typically cause minor changes in blood and heart rate, sweating and insomnia. Other pharmacological actions shown by non-specific antidepressants may act to worsen or mitigate these adverse effects. Noradrenergic drugs are less likely than selective serotonin reuptake inhibitors (SSRIs) to cause sexual dysfunction but more likely to cause urinary hesitancy. Doubts remain over the relative propensity for antidepressants with different modes of action to cause diabetes and hyponatraemia. Noradrenergic actions do not seem to confer a risk of death in overdose.

Removal of half the sympathetic innervation does not reduce vasoconstrictor responses in rat tail artery

Following reinnervation of denervated rat tail arteries, nerve-evoked contractions are at least as large as those evoked in normally innervated arteries despite a much lower nerve terminal density. Here nerve-evoked contractions have been investigated after transection of half the sympathetic innervation of normal tail arteries. After 1 week, the noradrenergic plexus 50-70 mm along the tail was about half as dense as control. Excitatory junction potentials recorded in smooth muscle cells of arterial segments isolated in vitro were half their normal amplitude. Surprisingly, nerve-evoked contractions of isometrically mounted segments were not reduced in amplitude, as was also the case after only 3 days. After 1 week, enhancement of nerve-evoked contractions by blocking either neuronal re-uptake of noradrenaline with desmethylimipramine or prejunctional α2-adrenoceptors with idazoxan was similar to control, suggesting that these mechanisms are matched to the number of innervating axons. The relative contribution of postjunctional α2-adrenoceptors to contractions evoked by long trains of stimuli was enhanced but that of α1-adrenoceptors was unchanged. Transiently, sensitivity to the α1-adrenoceptor agonist phenylephrine was slightly increased. After 7 weeks, amplitudes of nerve-evoked contractions remained similar to control, and sensitivity to phenylephrine had recovered but that to the α2-adrenoceptor agonist clonidine was slightly raised. The normal amplitude of nerve-evoked contractions after partial denervation is only partly explained by the greater contribution of α2-adrenoceptors. While the post-receptor mechanisms activated by nerve-released transmitter may be modified to amplify the contractions after partial denervation, our findings suggest that these mechanisms are normally saturated, at least in this artery.

Cardiac autonomic function in adolescents operated by arterial switch surgery

Children with transposition of the great arteries, in whom an arterial switch operation (ASO) is performed, have been shown to have an increased incidence of sudden death, which may be due to cardiac autonomic imbalance and repolarisation instability. We hypothesised that i) cardiac norepinephrine (NE) kinetics and ii) arterial baroreflex sensitivity (BRS), reflecting sympathetic activity and vagal function respectively, are altered in this group. 17 children (15.8 ± 1.5 years of age) with ASO-surgery in the neonatal period were studied. 17 had cardiac BRS assessed by spontaneous fluctuations of systolic blood pressure and RR-interval, and repolarisation was measured as QT variability index. Matched healthy subjects were controls. Cardiac vagal function and repolarisation pattern were unchanged following ASO-surgery. At cardiac catheterisation, we infused tritiated NE in 8 of these children to examine total body and cardiac sympathetic function at baseline and following 5 min of adenosine infusion to induce reflex sympathetic activation. Blood was sampled simultaneously from the aorta and coronary sinus. Cardiac fractional extraction of ([3H])NE was substantially lower in operated children, being 56 ± 10 vs. 82 ± 9% (p=0.0001). Following i.v. adenosine in the operated group, NE total body spillover doubled vs. baseline (p<0.002) and the coronary venous-arterial concentration gradient of ([3H])dihydroxyphenylglycol increased 4-fold (p=0.04). Arterial switch operation performed neonatally appears to leave cardiac vagal function intact and, although cardiac sympathetic activation in response to adenosine occurs, cardiac neuronal NE reuptake is impaired. This may be pro-arrhythmic by reducing removal capacity of NE from the cardiac synaptic cleft.

Neuroadrenergic Dysfunction Along the Diabetes Continuum

Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m2), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = −0.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = −0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.

393 NEUROADRENERGIC DYSFUNCTION ALONG THE DIABETIC CONTINUUM

Background: Neuroadrenergic function in type 2 diabetic (T2D) patients is poorly characterized, particularly in the early stages of disease, before the onset of peripheral neuropathy. We therefore compared sympathetic nervous system (SNS) activity at rest and during a standard oral glucose tolerance test (OGTT) in obese metabolic syndrome (MetS) subjects classified using WHO criteria as glucose intolerant (IGT) or treatment naïve T2D. Design and methods: Untreated subjects (17 IGT, 17 T2D) matched for age (mean 59 ± 1 yr), gender, body mass index (32.4 ± 0.6 kg/m2) and family history of diabetes were studied. We measured muscle sympathetic nerve activity (MSNA) by microneurography, whole-body noradrenaline kinetics by isotope dilution, neuronal noradrenaline re-uptake as the steady state tritiated 3,4-dihydroxyphenylglycol to tritiated noradrenaline ratio (3H-DHPG: 3H-NA), insulin sensitivity by euglycaemic hyperinsulinemic clamp (M/I) and MetS components. Results: T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats, P = 0.05) and arterial noradrenaline levels (264 ± 33 versus 167 ± 16 pg/ml, P = 0.02), lower plasma noadrenaline clearance (by 17%, P = 0.03) and reduced neuronal re-uptake compared with IGT subjects (by 46%, P = 0.04). Moreover, noradrenaline spillover responses to glucose ingestion were significantly blunted in T2D subjects. The M/I value independently predicted whole-body noadrenaline spillover (r = −0.47, P = 0.008), whilst fasting insulin level related to neuronal noradrenaline re-uptake (r = −0.35, P = 0.047). Conclusions: These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness and altered noradrenaline disposition.

The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments.

Nine analogues of the azasteroid muscle relaxant chandonium have been tested for neuromuscular blocking activity, ganglion blocking activity, inhibitory effects on cardiac muscarinic receptors, and for effects on noradrenergic transmission. Experiments were performed in anaesthetized cats and in isolated preparations. The two bisquaternary compounds HS-626 and HS-627, choline and acetylcholine-like analogues of chandonium respectively, were approximately equipotent with chandonium as neuromuscular blocking agents in the cat, but HS-672 possessed slightly more vagal blocking action. No evidence was obtained for ganglion block. The monoquaternary analogues, HS-408 and HS-465 and two 4-aza-androstanes, (HS-522 and HS-523) were more than 100 times less active than the bisquaternary compounds as neuromuscular blocking agents, and produced vagal blockade and ganglion blockade at sub-neuromuscular blocking doses. pA2 determinations in the chick biventer cervicis muscle, the guinea-pig atria and guinea-pig ileum showed that the bisquaternary compounds chandonium, HS-626 and HS-627 were much more potent in blocking cardiac than intestinal muscarinic receptors and that HS-626 possessed the widest margin between concentrations blocking the nicotinic receptors at the neuromuscular junction and the cardiac muscarinic receptors. Evidence for the three bisquaternary compounds blocking neuronal noradrenaline reuptake was obtained only at very high concentrations. HS-626 possessed a slightly more desirable spectrum of activities than chandonium, but the degree of improvement over the parent compound is insufficient to merit extensive clinical testing.

Review Article: Bupropion for the Treatment of Neuropathic Pain

Neuropathic pain is a common problem in clinical practice, affecting patients physically, emotionally, financially, and socially. Current treatment includes antidepressants, antiepileptics, and opioid analgesics. Bupropion is a specific inhibitor of neuronal noradrenaline reuptake and a weak inhibitor of dopamine reuptake, which shows some promise in the treatment of neuropathic pain.

Antidepressants that inhibit neuronal norepinephrine reuptake are not associated with increased spontaneous reporting of cardiomyopathy

A recent literature review linked norepinephrinergic stimulation to alterations in cyclic adenosine monophosphate (cAMP)-mediated signaling in cardiac myocytes and suggested that this might contribute to the pathological mechanisms that lead to chamber enlargement and hypocontractility, which are seen in dilated cardiomyopathy. This accompanies a large body of literature linking cardiac sympathetic outflow activation in early heart failure with progressive myocyte deterioration. As the mode of action of a number of antidepressants involves the inhibition of neuronal norepinephrine reuptake to varying degrees, this study was conducted to assess whether such agents might be associated with disproportionate reporting of cardiomyopathy. Limited data exist specifically examining the association between the antidepressant use and the cardiomyopathy. Using a data mining algorithm (DMA), we quantitatively investigated the association between antidepressant agents that predominantly exert their effects through inhibiting neuronal norepinephrine reuptake (rather than serotonin) and cardiomyopathy. We retrospectively applied a Bayesian DMA, the Bayesian Confidence Propagation Neural Network, to the cumulative reports in the Food and Drug Administration Adverse Event Reporting System (through the fourth quarter of 2006) and World Health Organization Vigibase (through the second quarter of 2007) databases. A threshold of the posterior interval 95% lower limit > 0 was used to define a signal of disproportionate reporting with individual or groups of antidepressants and cardiomyopathy-related terms. The analysis suggested that there is no direct relationship between antidepressants with greater norepinephrine reuptake inhibitor activity (affinity for norepinephrine reuptake transporter or selectivity for norepinephrine versus serotonin) and reporting of cardiomyopathy. In contrast, an inverse correlation might exist with a higher number of cases identified with tricyclic antidepressants showing lower norepinephrine reuptake inhibition and the serotonin/norepinephrine reuptake inhibitors as well as with serotonin/ norepinephrine/slight dopamine reuptake inhibitor.

Human Sympathetic Nerve Biology

Patients with panic disorder provide a clinical model of stress. On a "good day," free from a panic attack, they show persistent stress-related changes in sympathetic nerve biology, including abnormal sympathetic nerve single-fiber firing ("salvos" of multiple firing within a cardiac cycle) and release of epinephrine as a cotransmitter. The coreleased epinephrine perhaps originates from in situ synthesis by phenylethanolamine N-methyltransferase (PNMT). In searching for biological evidence that essential hypertension is caused by mental stress--a disputed proposition--we note parallels with panic disorder, which provides an explicit clinical model of stress: (1) There is clinical comorbidity; panic disorder prevalence is increased threefold in essential hypertension. (2) For both, epinephrine cotransmission is present in sympathetic nerves. (3) In panic disorder and essential hypertension, but not in health, single-fiber sympathetic nerve firing salvos occur. (4) Tissue nerve growth factor is increased in both conditions (nerve growth factor is a stress reactant). (5) There is induction of PNMT in sympathetic nerves. Essential hypertension exhibits a further manifestation of mental stress: there is activation of noradrenergic brain stem neurons projecting to the hypothalamus and amygdala. These pathophysiological findings strongly support the view that chronic mental stress is important in the pathogenesis of essential hypertension. A hypothesis now under test is whether in both disorders, under prevailing conditions of ongoing stress, PNMT induced in sympathetic nerves acts as a DNA methylase, causing the norepinephrine transporter (NET) gene silencing that is present in both conditions. PNMT can have an intranuclear distribution, binding to DNA. We have demonstrated that the reduced neuronal noradrenaline reuptake present in both disorders does have an epigenetic mechanism, with demonstrable reduction in the abundance of the transporter protein, the NET gene silencing being associated with DNA binding by the methylation-related inhibitory transcription factor MeCP2.

Acute myocardial infarction in a 24 year-old man possibly associated with sibutramine use

Sibutramine is an anti-obesity drug, which acts by inhibiting neuronal re-uptake of noradrenaline and serotonin. Although the most frequently seen effect of sibutramine on cardiovascular system is an increase in blood pressure and pulse rate, rare but severe side effects such as sibutramine-induced ventricular arrhythmias, heart failure and cardiovascular disease-related death are also reported. We describe a 24 year-old man with low atherosclerotic risk profile who had acute myocardial infarction possibly associated with sibutramine use.

Cardiac norepinephrine transporter protein expression is inversely correlated to chamber norepinephrine content

The cardiac neuronal norepinephrine (NE) transporter (NET) in sympathetic neurons is responsible for uptake of released NE from the neuroeffector junction. The purpose of this study was to assess the chamber distribution of cardiac NET protein measured using [(3)H]nisoxetine binding in rat heart membranes and to correlate NE content to NET amount. In whole mounts of atria, NET was colocalized in nerve fibers with tyrosine hydroxylase (TH) immunoreactivity. NE content expressed as micrograms NE per gram tissue was lowest in the ventricles; however, NET binding was significantly higher in the left ventricle than the right ventricle and atria (P < 0.05), resulting in a significant negative correlation (r(2) = 0.922; P < 0.05) of NET to NE content. The neurotoxin 6-hydroxydopamine, an NET substrate, reduced NE content more in the ventricles than the atria, demonstrating functional significance of high ventricular NET binding. In summary, there is a ventricular predominance of NET binding that corresponds to a high NE reuptake capacity in the ventricles, yet negatively correlates to tissue NE content.

Extended-Release Tramadol (ULTRAM®ER): A Pharmacotherapeutic, Pharmacokinetic, and Pharmacodynamic Focus on Effectiveness and Safety in Patients with Chronic/Persistent Pain

Tramadol is a centrally acting synthetic opioid analgesic that has a dual mechanism of action, binding to mu-opioid receptors and weakly inhibiting the neuronal reuptake of norepinephrine and serotonin. Extended-release (ER) tramadol tablets (ULTRAM ER) are indicated for the management of moderate to moderately severe chronic (also referred to as persistent) pain in adults who require around-the-clock treatment of pain for an extended period of time. Because once-daily tramadol ER results in less frequent fluctuations in plasma concentrations than equivalent daily doses of short-acting tramadol, it may benefit patients experiencing pain throughout the dosing interval. On the basis of computer-generated pharmacokinetic models, one can easily transition patients who are receiving short-acting tramadol for chronic/persistent pain to tramadol ER, by calculating the current total daily dose of short-acting tramadol and starting tramadol ER at the nearest lower 100-mg-dose increment. In clinical studies, tramadol ER significantly reduced pain in patients with chronic pain from osteoarthritis and improved pain-related sleep parameters, joint stiffness, and physical function. Tramadol ER has been shown to be safe and well-tolerated and may be a suitable alternative for patients with inadequate analgesic response or contraindications (eg, cardiovascular disease, gastrointestinal ulcer) to use of nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors. The proven efficacy and safety profile--and the low potential for abuse--make tramadol ER a viable therapeutic option for the management of chronic/persistent nonmalignant pain in some patients. This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, dosage, delivery system, administration, analgesic efficacy, and safety and tolerability profile of tramadol ER.

In Vitro Continuous Amperometry with a Diamond Microelectrode Coupled with Video Microscopy for Simultaneously Monitoring Endogenous Norepinephrine and Its Effect on the Contractile Response of a Rat Mesenteric Artery

Continuous amperometry with a diamond microelectrode and video microscopy were used to record (in vitro) endogenous norepinephrine release simultaneously with the evoked contractile response of a mesenteric artery from a healthy Sprague Dawley rat. Norepinephrine (NE) is a vasoconstricting neurotransmitter released from sympathetic nerves that innervate the smooth muscle cell layers surrounding arteries and veins. Using these two techniques along with several drugs, the NE released at sympathetic neuroeffector junctions nearby the microelectrode was measured as an oxidation current. Key to the amperometric measurement was the use of a diamond microelectrode because of the response sensitivity, reproducibility, and stability it provided. NE release was elicited by electrical stimulation at frequencies between 1 and 60 Hz, with a maximum response seen at 20 Hz. Confirmation that the oxidation current was, in fact, associated with endogenous NE came from the results of several drugs. Tetrodotoxin (TTX, 0.3 microM), a voltage-dependent sodium channel antagonist that blocks nerve conduction, abolished both the oxidation current and the arterial constriction. The alpha(2)-adrenergic autoreceptor antagonist, yohimbine (1.0 microM), caused an increase in the oxidation current and the corresponding constriction. The addition of cocaine (10 microM), an antagonist that inhibits neuronal NE reuptake, caused both the oxidation current and the contractile response to increase. These results, combined with the fact that the hydrodynamic voltammetric E(1/2) for endogenous NE was identical to that for a standard solution, confirmed that the oxidation current was due to NE and that this compound caused, at least in part, the contractile response. The results demonstrate that continuous amperometric monitoring of NE with a diamond microelectrode and video imaging of vascular tone allow real time local measurement of the temporal relationship between nerve-stimulated NE release and arterial constriction.