Clonidine and ketamine for stable hemodynamics in off-pump coronary artery bypass.

BACKGROUND: The current era of fast-track extubation and faster recovery after cardiac surgery requires agents that provide perioperative sedation, suppress sympathetic response, reduce opioid requirement, and maintain hemodynamic stability. METHODS: In a prospective randomized double-blind study, 75 off-pump coronary artery bypass patients were divided into 3 groups of 25 each: group A had clonidine 1 µg·kg(-1), group B had clonidine 1 µg·kg(-1) and ketamine 1 mg·kg(-1), and group C had a saline placebo. Perioperative changes in heart rate, systolic and diastolic blood pressure, sedation score, pain score, and requirement of analgesics, beta blockers, fentanyl, propofol, and inotropes were recorded, as well time to extubation, intensive care unit stay, and 30-day mortality. RESULTS: The combination of clonidine and ketamine led to stable hemodynamics and reduced beta-blocker dosage. The sedation score was highest in groups A and B up to 24 h postoperatively. The pain score was lowest in group B in the first 24 h, and the total dose of analgesics was highest in group C. Clonidine and ketamine or clonidine alone reduced extubation time, but intensive care unit stay was unchanged CONCLUSIONS: Combined low-dose clonidine and ketamine produced perioperative sedation and effective suppression of sympathetic response with stable hemodynamics. Intraoperative beta-blocker use was reduced without increasing inotrope requirement. This combination prolonged the analgesic effect of opioids, reducing postoperative pain score and analgesic requirement. Low-dose clonidine alone produced sedation but did not completely block sympathetic response. Intensive care unit stay and patient outcome were not affected by clonidine or ketamine.

Direct Vasodilators and Sympatholytic Agents.

Direct vasodilators and sympatholytic agents were some of the first antihypertensive medications discovered and utilized in the past century. However, side effect profiles and the advent of newer antihypertensive drug classes have reduced the use of these agents in recent decades. Outcome data and large randomized trials supporting the efficacy of these medications are limited; however, in general the blood pressure-lowering effect of these agents has repeatedly been shown to be comparable to other more contemporary drug classes. Nevertheless, a landmark hypertension trial found a negative outcome with a doxazosin-based regimen compared to a chlorthalidone-based regimen, leading to the removal of α-1 adrenergic receptor blockers as first-line monotherapy from the hypertension guidelines. In contemporary practice, direct vasodilators and sympatholytic agents, particularly hydralazine and clonidine, are often utilized in refractory hypertension. Hydralazine and minoxidil may also be useful alternatives for patients with renal dysfunction, and both hydralazine and methyldopa are considered first line for the treatment of hypertension in pregnancy. Hydralazine has also found widespread use for the treatment of systolic heart failure in combination with isosorbide dinitrate (ISDN). The data to support use of this combination in African Americans with heart failure are particularly robust. Hydralazine with ISDN may also serve as an alternative for patients with an intolerance to angiotensin antagonists. Given these niche indications, vasodilators and sympatholytics are still useful in clinical practice; therefore, it is prudent to understand the existing data regarding efficacy and the safe use of these medications.

The role of systematic reviews in pharmacovigilance planning and Clinical Trials Authorisation application: example from the SLEEPS trial.

BACKGROUND: Adequate sedation is crucial to the management of children requiring assisted ventilation on Paediatric Intensive Care Units (PICU). The evidence-base of randomised controlled trials (RCTs) in this area is small and a trial was planned to compare midazolam and clonidine, two sedatives widely used within PICUs neither of which being licensed for that use. The application to obtain a Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) required a dossier summarising the safety profiles of each drug and the pharmacovigilance plan for the trial needed to be determined by this information. A systematic review was undertaken to identify reports relating to the safety of each drug. METHODOLOGY/PRINCIPAL FINDINGS: The Summary of Product Characteristics (SmPC) were obtained for each sedative. The MHRA were requested to provide reports relating to the use of each drug as a sedative in children under the age of 16. Medline was searched to identify RCTs, controlled clinical trials, observational studies, case reports and series. 288 abstracts were identified for midazolam and 16 for clonidine with full texts obtained for 80 and 6 articles respectively. Thirty-three studies provided data for midazolam and two for clonidine. The majority of data has come from observational studies and case reports. The MHRA provided details of 10 and 3 reports of suspected adverse drug reactions. CONCLUSIONS/SIGNIFICANCE: No adverse reactions were identified in addition to those specified within the SmPC for the licensed use of the drugs. Based on this information and the wide spread use of both sedatives in routine practice the pharmacovigilance plan was restricted to adverse reactions. The Clinical Trials Authorisation was granted based on the data presented in the SmPC and the pharmacovigilance plan within the clinical trial protocol restricting collection and reporting to adverse reactions.

[Similarity of cycloprolylglycine to piracetam in antihypoxic and neuroprotective effects].

The antihypoxic activity of the endogenous cyclic dipeptide cycloprolylglycine (CPG) has been studied on a model of normobaric hypoxia with hypercapnia and its neuroprotective activity has been studied on a model of human neuroblastoma SH-SY5Y cell damage by 6-hydroxydopamine. It is established that CPG exhibits the antihypoxic activity at doses of 0.5 and 1.0 mg/kg (i.p.) on outbred and BALB/c mice, but not on C57B1/6 mice. The neuroprotective activity of CPG was detected in 10(-5) - 10(-8) M concentration range only when the treatment was carried out 24h before toxin introduction. The obtained data confirm the hypothesis that piracetam is a mimetic of the endogenous CPG neuropeptide.

Systemic therapy for primary hyperhidrosis: a retrospective study of 59 patients treated with glycopyrrolate or clonidine.

BACKGROUND: Data regarding systemic medications in the management of hyperhidrosis (HH) are limited. OBJECTIVE: The goal of this study was to provide evidence for the safety and efficacy of systemic medications for primary HH. METHODS: A retrospective chart review was conducted of patients seen at an academic dermatology department prescribed systemic medications for primary HH. RESULTS: A total of 71 patients were prescribed systemic agents. Twelve patients (17%) were lost to follow-up and were excluded from further analysis. A total of 59 patients with at least 2 months of follow-up data (mean age 28.9 ± 12.0 years; 37 women, 22 men; mean follow-up 19.5 months) were included in the analysis. Palmoplantar and/or axillary HH was most common (42/59; 71%); followed by generalized (9/59; 15%) and craniofacial (8/59; 14%) HH. Glycopyrrolate (generally 1-2 mg once or twice daily) was prescribed to 45 patients, with response rate of 67% (30/45). Fifteen treatment failures included 6 nonresponders and 9 with adverse effects, including xerostomia and gastrointestinal disturbance. Clonidine (0.1 mg twice daily) was prescribed to 13 patients, with a response rate of 46% (6/13). Seven treatment failures included 3 nonresponders and 4 with adverse effects, all relating to decreased blood pressure. One patient responded to oxybutynin at 5 mg twice daily. There were no significant differences in efficacy (P = .21; odds ratios 0.43, 95% confidence interval 0.12-1.5) or adverse effects (P = .46; odds ratios 1.78, 95% confidence interval 0.44-7.1) in comparing glycopyrrolate versus clonidine. LIMITATIONS: This was a retrospective study from a single, university-based population. CONCLUSION: Systemic therapy with glycopyrrolate or clonidine can be effective for HH. Nearly two-thirds responded to therapy, and less than a quarter had treatment-limiting adverse effects, all of which were self-limited and nonserious.

Pharmacological properties of the central antihypertensive agent, moxonidine.

The sympathetic nervous system plays a central role in the pathophysiology not only of hypertension and other cardiovascular diseases but also metabolic disorders including disturbances of glucose and lipid homeostasis. A centrally acting sympathetic agent is therefore attractive not only for lowering blood pressure, but also intervening with multiple disease processes. Older agents such as clonidine and guanabenz have numerous side effects, including sedation and dry mouth that limit their acceptability to patients. Moxonidine and the related agent rilmenidine have greatly reduced side effects, because they have reduced activity at the α(2) -adrenergic receptors that mediate these undesirable actions. Instead, moxonidine and rilmenidine act primarily through a novel cellular site, termed the I(1) -imidazoline receptor. The molecular biology of the I(1) -imidazoline receptor protein has recently been described, and the cell signaling pathways linked to this protein have been characterized. Moxonidine has unique effects on a number of cell types through this unusual cellular site of action. There are multiple therapeutic implications of these cellular actions, especially for metabolic syndrome and its associated derangements in glucose and lipid metabolism. Finally, the clinical trials that seemed to identify an unfavorable outcome in severe heart failure are dissected and critiqued. We conclude that moxonidine and future successors to this agent could be of great value in treating multiple chronic diseases.

Intranasally applied L-DOPA alleviates parkinsonian symptoms in rats with unilateral nigro-striatal 6-OHDA lesions.

l-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective drug for therapy of Parkinson's disease. However, the current clinical route of L-DOPA administration is variable and unreliable because of problems with drug absorption and first-pass metabolism. Administration of drugs via the nasal passage has been proven an effective alternate route for a number of medicinal substances. Here we examined the acute behavioral and neurochemical effects of intranasally (IN) applied L-DOPA in rats bearing unilateral lesions of the medial forebrain bundle, with severe depletion (97%) of striatal dopamine. Turning behavior in an open field, footslips on a horizontal grid and postural motor asymmetry in a cylinder were assessed following IN L-DOPA or vehicle administration with, or without, benserazide pre-treatment. IN L-DOPA without benserazide pre-treatment mildly decreased ipsilateral turnings and increased contralateral turnings 10-20 min after the treatment. IN L-DOPA with saline pre-treatment reduced contralateral forelimb-slips on the grid while no effects were evident in the cylinder test. These results support the hypothesis that L-DOPA can bypass the blood-brain barrier by the IN route and alleviate behavioral impairments in the hemiparkinsonian animal model.

Central sympatholytic drugs.

KEY POINTS: • Central sympatholytic drugs reduce blood pressure mainly by stimulating central α(2) -adrenergic receptors in the brainstem centers, thereby reducing sympathetic nerve activity and neuronal release of norepinephrine to the heart and peripheral circulation. • This class of drugs, however, is currently used mainly as fourth-line (or beyond) drug therapy for hypertension because of side effects of drowsiness, fatigue, and dry mouth. • Rebound hypertension is also another major concern in certain drugs with a short half-life, particularly in patients who are nonadherent to the regimen. Therefore, their use on a "PRN" basis for treatment of blood pressure surge in the absence of symptoms or acute target complications should also be avoided.

Symptoms and signs of tear film dysfunction in glaucomatous patients.

PURPOSE: The purposes of this study were to evaluate the presence of symptoms of tear film dysfunction by using the Ocular Surface Disease Index (OSDI) questionnaire in glaucomatous patients and to examine whether they have ocular surface signs. METHODS: Fifty patients with ocular hypertension or open-angle glaucoma were sequentially examined. All patients used preserved antiglaucomatous drops once, twice, 3 times, or 4 times a day. Each patient filled out an OSDI questionnaire. Fluorescein corneal staining, lissamine green conjunctival staining, break-up time, and Schirmer I test were performed in patients with positive OSDI. RESULTS: Using the OSDI, 26 of 50 patients (52%) showed at least mild symptoms of tear film dysfunction (score >12); of them, 17 (34%) had severe OSDI (Score >32). Decrease in tear production was seen in only 8 glaucomatous patients. The break-up time was <7 s in 18 patients. Lissamine green conjunctival staining was positive in at least one eye of all the 26 patients, whereas fluorescein corneal staining was positive in at least one eye of 22 patients. A statistically significant (P<0.05) difference was found for lissamine green conjunctival staining between 16 patients using ipotensive drops once or twice a day and 10 patients using drops 3 or 4 times a day. In the group of patients using only ß-blocker agents, we found a positive correlation between symptoms and vital staining of the ocular surface. CONCLUSION: Fifty-two percent of patients in therapy with preserved antiglaucomatous drops showed symptoms of tear film dysfunction. Signs of ocular surface diseases seemed to be greater in patients under >2 medications. Symptoms correlated to signs only in patients in monotherapy with ß-blockers drops.

A single 4 mg dose of nicotine decreases heart rate variability in healthy nonsmokers: implications for smoking cessation programs.

INTRODUCTION: The vast majority of work on the physiological effects of nicotine in humans has been done in smokers or smokers trying to quit. Such studies can be confounded by tolerance, desensitization of receptors, or withdrawal. Because of these difficulties, there is still some dispute as to whether nicotine is proparasympathetic or prosympathetic in humans. To circumvent these difficulties, we assessed the effect of nicotine on autonomic function by measuring changes in heart rate variability (HRV) in nicotine-naive healthy subjects. METHODS: Twenty males and 20 females aged between 18 and 25 years received 4 mg oral nicotine lozenge or placebo. HRV was assessed in 15-min periods before, during, and after ingestion. RESULTS: There were no significant changes in any measure after placebo administration. During and after nicotine ingestion, heart rate increased to 78 ± 2 beats per minute (bpm) from a baseline level of 75 ± 2 bpm (p < .01). Nicotine significantly increased low frequency (LF; normalized units) from 66 ± 2 at baseline to 70 ± 2 at 15-30 min postingestion (p < .01) and decreased high frequency (HF; normalized units) from 28 ± 2 to 24 ± 1 (p < .01). LF/HF ratio was therefore substantially increased from 2.9 ± 0.3 to 3.7 ± 0.3 (p < .01). CONCLUSIONS: A single dose of 4 mg oral nicotine produces a significant reduction in HRV (i.e., a proportional decrease in high-frequency variability) in healthy young nonsmokers consistent with a reduced vagal activity. This has implications for nicotine replacement treatments aimed at cessation of smoking.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects neurons and repairs the Parkinson disease-like symptoms in a rat 6-hydroxydopamine model. We show a three-dimensional solution structure of human MANF that differs drastically from other neurotrophic factors. Remarkably, the C-terminal domain of MANF (C-MANF) is homologous to the SAP domain of Ku70, a well known inhibitor of proapoptotic Bax (Bcl-2-associated X protein). Cellular studies confirm that MANF and C-MANF protect neurons intracellularly as efficiently as Ku70.

Teratogenic potential of pholedrine: a sympathomimetic vasoconstrictive drug - a population-based case-control study.

Pholedrine was a frequently used drug for the treatment of severe hypotension in some countries, including Hungary. The possible teratogenic effect of pholedrine was not checked; therefore; the birth outcomes, particularly congenital abnormalities (CAs), of infants born to women treated with pholedrine during pregnancy, and pregnancy complications were evaluated in the population-based large dataset of the Hungarian Case-Control Surveillance System of Congenital Abnormalities. Cases with CA and their matched controls without CA born to mothers with pholedrine use during pregnancy were compared. Of 22 843 cases and 38 151 controls, 768 (3.4%) and 1509 (4.0%) were born to mothers with pholedrine treatment, respectively (adjusted odds ratios [OR] with 95% CI: 0.9, 0.8-1.0). There was no higher risk for any CA group in the offspring of mothers who used pholedrine during the second and/or third month of pregnancy (i.e. the critical period of most major CA). The mean gestational week at delivery and birthweight was similar in newborns of women with or without pholedrine treatment during pregnancy. The pattern of pregnancy complications was characteristic (lower incidence of preeclampsia/eclampsia, while higher incidence of severe nausea/vomiting and anemia), explained mainly by the underlying maternal hypotension. In conclusion, pholedrine treatment in pregnant women was not associated with a higher risk for CA or other adverse birth outcomes, such as preterm birth or low birthweight. The knowledge of the teratogenic potential of pholedrine may contribute to the evaluation of other sympathomimetic drugs.

The sympathetic nervous system modulates CD4(+)FoxP3(+) regulatory T cells via a TGF-beta-dependent mechanism.

CD4(+)FoxP3(+) Tregs are essential mediators of the peripheral immune response to self-antigens. Accordingly, the homeostatic regulation of Treg activity and number would impact on the immune response to both self- and non-self antigens. Because the sympathetic nervous system (SNS) interacts chemically and physically with the central and peripheral immune system and exerts a direct influence on antigen-presenting cells and effector lymphocytes, we have investigated the effect of chemical ablation of the SNS on the number and function of peripheral Treg. Removal of murine peripheral sympathetic innervation by 6-hydroxydopamine induced an increase in splenic and lymph node CD4(+)FoxP3(+) Tregs by a TGF-beta-dependent mechanism. Further, this increase in Tregs coincides with an inhibition of the induction of experimental autoimmune encephalomyelitis. Our results demonstrate that the SNS is an important contributor to the maintenance of peripheral Treg and TGF-beta acts as a bridge between the immune system and the nervous system. Neurological events mediated by the SNS, such as a stress response, may affect the number of T cells that regulate an immune response. Additionally, targeting Tregs via the SNS may be a novel approach to the prevention or treatment of autoimmune diseases.

Intoxicación por brimonidina en pediatría. Presentación como síndrome de hipertensión intracraneal / Brimonidine intoxication in paediatrics. A presentation as intracranial hypertension syndrome

Antecedentes: La brimonidina es un fármaco muy lipofílico absorbido muy bien por vía transcorneal, que atraviesa la barrera hematoencefálica, con el potencial efecto tóxico para el sistema nervioso central que esto supone. Objetivos: Dar a conocer los efectos secundarios de la brimonidina tópica y remarcar la necesidad de precaución con fármacos tópicos en pediatría. Conclusiones: La brimonidina se desaconseja en niños pequeños y lactantes. Sus efectos secundarios sistémicos pueden ser graves o incluso letales. Debemos sospecharlo en pacientes tratados con síntomas compatibles en los que se descarta patología orgánica. Debemos actuar suspendiendo el fármaco y adoptando las medidas de soporte necesarias

Background: Brimonidine is an extremely lipophilic drug which is absorbed very well through the cornea and thus crosses the blood-brain barrier. This is very important for any potential toxic effects on the CNS. Objectives: To show the adverse effects of brimonidine and advise the need for caution in its use in the paediatric population. Conclusions: Brimonidine is prohibited from use in toddlers and infants. Its adverse effects can be severe or lethal. It should be suspected in treated patients with compatible symptoms in whom organic disease has been ruled out. We must stop the use of brimonidine and adopt support measures

Randomized clinical trial of moxonidine in patients undergoing major vascular surgery.

BACKGROUND: Myocardial ischaemia is the leading cause of perioperative morbidity and mortality after surgery in patients with coronary artery disease. The aim of this study was to evaluate the effects of moxonidine, a centrally acting sympatholytic agent, on perioperative myocardial ischaemia and 1-year mortality in patients undergoing major vascular surgery. METHODS: In this double-blind, placebo-controlled two-centre trial, 141 patients were randomly assigned to receive moxonidine or placebo on the morning before surgery and on the following 4 days. Levels of cardiac troponin I (cTnI) were analysed before surgery and on days 1, 2, 3 and 7 thereafter. Holter electrocardiograms were recorded for 48 h starting before the administration of the study drug. Patients were followed daily during admission and by telephone interview 12 months after surgery. RESULTS: The incidence of raised perioperative cTnI levels or alteration in the ST segment in the Holter electrocardiogram or both was 40 per cent in the moxonidine group and 37 per cent in the placebo group (P = 0.694). All-cause mortality rates within 12 months were 10 per cent in the moxonidine group and 11 per cent in the placebo group (P = 0.870). CONCLUSION: Small oral doses of moxonidine did not reduce the incidence of perioperative myocardial ischaemia and had no effect on mortality in patients undergoing vascular surgery. REGISTRATION NUMBER: NCT00244504 (http://www.clinicaltrials.gov).

Requirement of intact sympathetic transmission for the ocular hypotensive effects of melatonin and 5-MCA-NAT.

Melatonin and its analogue, 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), potently reduce intraocular pressure, and may be good candidates for the treatment of ocular hypertension and glaucoma. After chemical sympathectomy by reserpine or 6-hydroxydopamine, the hypotensive effects of melatonin and 5-MCA-NAT are severely inhibited. This indicates that the sympathetic nervous system is involved in the production and drainage of aqueous humour by the ciliary body and trabecular meshwork, and that it mediates the effects of melatonin and its analogue, 5-MCA-NAT.

Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin.

This article reviews the neurobiologic rationale for and presents clinical guidance concerning the use of medications that reduce central nervous system noradrenergic activity in the treatment of intrusive symptoms of posttraumatic stress disorder. The authors reviewed neurobiological studies, nonclinical studies using animal models, clinical case reports, open-label drug studies, and blinded, placebo-controlled drug studies. This review of the basic science and clinical literature, and the authors' clinical experience with culturally and demographically diverse populations, indicate that clonidine and prazosin can play a useful role in treating sleep disturbance and hyperarousal in posttraumatic stress disorder, with minimal adverse effects and low financial cost.