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Impulsivity refers to a wide spectrum of actions characterized by quick and nonplanned reactions to external and internal stimuli, without taking into account the possible negative consequences for the individual or others, and decision-making is one of the biologically dissociated impulsive behaviors. Changes in impulsivity may be associated with norepinephrine. Various populations of drug addicts all performed impulsive decision making, which is a key risk factor in drug dependence and relapse. The present study investigated the effects of clonidine, which decreased norepinephrine release through presynaptic alpha-2 receptor activation, on the impaired decision-making performance in abstinent heroin addicts. Decision-making performance was assessed using the original version of Iowa Gambling Task (IGT). Both heroin addicts and normal controls were randomly assigned to three groups receiving clonidine, 0, 75 µg or 150 µg orally under double blind conditions. Psychiatric symptoms, including anxiety, depression and impulsivity, were rated on standardized scales. Heroin addicts reported higher scores on the Barratt Impulsiveness Scale and exhibited impaired decision-making on the IGT. A single high-dose of clonidine improved the decision-making performance in heroin addicts. Our results suggest clonidine may have a potential therapeutic role in heroin addicts by improving the impaired impulsive decision-making. The current findings have important implications for behavioral and pharmacological interventions targeting decision-making in heroin addiction.

To examine the effect of bolus vs. continuous infusion adjustment on severity and duration of alcohol withdrawal syndrome (AWS), the medication requirements for AWS treatment, and the effect on ICU stay in surgical intensive care unit (ICU) patients. Prospective randomized, double-blind controlled trial in a surgical ICU. 44 patients who developed AWS after admission to the ICU. Patients were randomized to either (a). a continuous infusion course of intravenous flunitrazepam (agitation), intravenous clonidine (sympathetic hyperactivity), and intravenous haloperidol (productive psychotic symptoms) if needed (infusion-titrated group), or (b). the same medication (flunitrazepam, clonidine, or haloperidol) bolus adjusted in response to the development of the signs and symptoms of AWS (bolus-titrated group). The administration of \"as-needed\" medication was determined using a validated measure of the severity of AWS (Clinical Institute of Withdrawal Assessment). Although the severity of AWS did not differ between groups initially, it significantly worsened over time in the infusion-titrated group. This required a higher amount of flunitrazepam, clonidine, and haloperidol. ICU treatment was significantly shorter in the bolus-titrated group (median difference 6 days) due to a lower incidence of pneumonia (26% vs. 43%). We conclude that symptom-orientated bolus-titrated therapy decreases the severity and duration of AWS and of medication requirements, with clinically relevant benefits such as fewer days of ventilation, lower incidence of pneumonia, and shorter ICU stay.

Purpose Calcium channel blockers (CCBs) are recommended second-line antihypertensives for renin-angiotensin system (RAS) inhibitor-treated patients with chronic kidney disease (CKD), but they do not always ameliorate the progression of CKD. However, small clinical studies suggest that sympatholytic CCBs may protect against kidney injury. Therefore, a clinical trial was designed to test whether the sympatholytic CCB azelnidipine decreases the urinary albumin levels of CKD patients treated with the angiotensin receptor blocker olmesartan more potently than the widely-used non-sympatholytic CCB amlodipine. Methods A multi-center, open-labeled, randomized clinical intervention trial was designed to compare the antialbuminuric effect of azelnidipine (8–16 mg/day) and amlodipine (2.5–5 mg/day) in olmesartan-treated hypertensive (blood pressure 130–180/80–110 mmHg) patients with type 2 diabetes (fasting blood sugar ≥126 mg/dL or treatment with antidiabetic agents) and albuminuria (urinary albumin/creatinine ratio ≥30 mg/g). The primary study endpoint is the change in the urinary albumin/creatinine ratio after 12 months of treatment. Conclusions The present trial is expected to clarify whether the sympatholytic CCB azelnidipine is a beneficial second-line choice for RAS inhibitor-treated hypertensive patients with CKD, such as diabetic nephropathy.

Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering N G -nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.

Accumulating evidence in humans demonstrated that visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson disease (PD). These deficits have been generally attributed to cortical dopamine degeneration. However, more recent evidence suggests that dopamine loss in the striatum is responsible for the visuo-spatial abnormalities in PD. Studies based on animal models of PD did not specifically address this question. Thus, the first goal of this study was to analyze the role of dopamine within the dorsal striatum in spatial memory. We tested bilateral 6-OHDA striatal lesioned CD1 mice in an object-place association spatial task. Furthermore, to see whether the effects were selective for spatial information, we measured how the 6-OHDA-lesioned animals responded to a non-spatial change and learned in the one-trial inhibitory avoidance task. The results demonstrated that bilateral (approximately 75%) dopamine depletion of the striatum impaired spatial change discrimination. On the contrary, no effect of the lesion was observed on non-spatial novelty detection or on passive avoidance learning. These results confirm that dopamine depletion is accompanied by cognitive deficits and demonstrate that striatal dopamine dysfunction is sufficient to induce spatial information processing deficits.

Enhanced sympathetic nervous system activity is associated with increased mortality in many cardiac conditions including heart failure and coronary artery disease (CAD). To ensure adequate image quality of coronary CT angiography (CCTA), pre-scan β-adrenergic blockers (BB) are routinely administered. It is currently unknown whether sensitivity to sympathicolytic compounds is associated with severity of CAD. A total of 2633 consecutive patients (1733 [65.8%] men and 900 [34.2%] women, mean age 56.7 ± 11.5 years) undergoing CCTA for exclusion of significant CAD at our department between 06/2013 and 12/2016 were evaluated. Acute heart rate (HR) responses to BB administration were recorded in all patients. Coronary plaque burden as indicated by segment severity score (SSS), segment involvement score (SIS), and significant CAD (i.e. > 50% luminal narrowing) was higher in weak responders to BB as compared to strong responders to BB (p = 0.001 for SSS and SIS, and p = 0.021 for significant CAD). Accordingly, in a multiple linear regression model adjusted for known risk factors of CAD such as smoking, hypertension, diabetes and dyslipidaemia, as well as age, sex, body mass index (BMI), glomerular filtration rate, and HR during CCTA scan, a strong response to BB was selected as a significant independent negative predictor of coronary plaque burden (beta coefficient − 0.08, p = 0.001). We demonstrate that individuals with a weak acute response to BB administration encounter an increased risk of severe CAD. Taking into account sensitivity to sympatho-inhibition may add complementary information in patients undergoing CCTA for evaluation of CAD.

Background/Aims: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test. Methods: In 40 children referred for an oral clonidine test, blood samples were drawn for clonidine and GH. Vital statistics and sedation scores were recorded until 210 min post-dose. We explored the relationship between clonidine concentrations and effects such as GH peak and blood pressure. Results: Of 40 participants, 5 children were GH deficient. Peak clonidine concentrations of 0.846 ± 0.288 ng/ml were reached after 1 h. Serum levels declined slowly, with concentrations of 0.701 ± 0.189 ng/ml 210 min post-dose. A large interindividual variation of serum levels was observed. During the procedure, systolic blood pressure dropped by 12.8%, diastolic blood pressure by 19.7% and heart rate by 8.4%. Moderate sedation levels were observed. Concentration-effect modeling showed that the amount of GH available for secretion as determined by previous bursts was an important factor influencing GH response. Conclusion: Clonidine concentrations during the test were higher than necessary according to model-based predictions. A lower clonidine dose may be sufficient and may produce fewer side effects.

Centrally acting (moxonidine) and peripherally acting (metoprolol) sympatholytic agents might have different actions upon penile circulation in hypertensive men with erectile dysfunction. A total of 11 nonsmoking, hypertensive but otherwise healthy men with erectile dysfunction were studied after 8 weeks on moxonidine monotherapy (0.4 mg per day, increased to 0.6 mg if needed) and then after 8 weeks of metoprolol monotherapy (100 mg per day, increased to 200 mg if needed) in a crossover design. At the end of each treatment phase, the subjects were asked about their subjective erectile capacity (nocturnal and coital erections), and resting and stimulated (after intracavernosal injection of a mixture of alprostadil and phentolamine) penile deep artery diameters and systolic peak velocities were measured by color Doppler ultrasonography. There were no significant differences in blood pressure after either therapy. The change from earlier antihypertensive therapy, moxonidine produced significant subjective amelioration of sexual dysfunction in 9/11 of the men ( P <0.001), whereas 9/11 returned to impaired dysfunction after crossover to metoprolol treatment. Resting and stimulated deep penile diameters and peak systolic velocities were higher after moxonidine treatment compared with metoprolol (diameters: P <0.004, P <0.0001; velocities: P <0.008, P <0.038). The centrally acting sympatholytic agent moxonidine seems to improve erectile function both subjectively and objectively and has a better effect on penile circulation compared with the peripherally acting sympatholytic agent metoprolol.

We aimed to document our experience with oral clonidine when used as a sedative in combination with intravenous morphine and lorazepam in a group of mechanically ventilated children with single-organ, respiratory failure. In particular, our objectives were to establish the relationship between oral dose, plasma concentration, and sedative effect, and second, to document the side-effect profile. Prospective, cohort study over a 72-h period. Regional paediatric intensive care unit. Twenty-four children were enrolled (median age 3 months) of whom ten were excluded (six due to extubation before 72 h, three sedation failures, one protocol violation). Plasma clonidine was measured using gas chromatography mass spectrometry, and sedation assessed using the COMFORT score. Using a dose of 3-5 microg/kg every 8 h, plasma concentrations appeared to plateau at approximately 41 h giving a mean value of 1.38 ng/ml (95% confidence interval 1.0-1.8). Adequate sedation was achieved during 82% (837/1022 h) of the study period; however, this decreased to 70.3% when analysed on an intention-to-treat basis. There was a concomitant overall decrease in the average hourly requirements for both morphine ( P = 0.02) and lorazepam ( P = 0.003). There were no documented episodes of bradycardia, hypotension or hyperglycaemia. Oral clonidine may be a safe and effective sedative in combination with morphine and lorazepam for young children with single-organ, respiratory failure. This agent may also exhibit opioid and benzodiazepine sparing effects in this patient group. A full pharmacokinetic study is warranted.

Background While primary hyperhidrosis can be seen in men, accompanying hot flushes is rarely seen in men. Primary hyperhidrosis is thought to be related to overactivity of the sympathetic nervous system while hot flushes are believed to be related to altered peripheral vascular reactivity and a narrowed thermoregulatory zone. Case presentation I report the case of a 29-year-old man of Arab origin who presented to a dermatology clinic with a complaint of generalized sweating, with heavier involvement of his inguinal region, axilla, and lower back. His complaint was associated with a transient hot sensation and erythema over the affected areas. He did not respond to topical antiperspirants containing aluminum chloride, topical aluminum chloride, or to botulinum toxin A injected in both inguinal areas. He was then referred to an endocrinology clinic to rule out secondary causes of hyperhidrosis and hot flushes; a primary diagnosis was confirmed. He did not respond to oral glycopyrrolate and additionally was complaining of its anticholinergic side effects. The glycopyrrolate was then replaced with oral clonidine 0.15 mg twice a day. Clonidine was well tolerated without remarkable side effects and he quickly started to feel marked improvement which was maintained for 2 years. Conclusions I report an atypical presentation of primary hyperhidrosis and hot flushes that was effectively controlled by clonidine without remarkable side effects. Further research on a large number of patients may be required before recommending clonidine in similar conditions.