Inhalation of nitric oxide in the treatment of SARS in Beijing

BACKGROUND: Patients with severe acute respiratory syndrome (SARS) frequently suffer from hypoxemia despite supplemental oxygen and mechanical ventilator support. Inhalation of nitric oxide (INO) could improve oxygenation in intubated ARDS patients. However, whether INO has similar effect in the patients with severe acute respiratory syndrome (SARS), and whether INO could be administrated in adults with non-invasive ventilator support is not known yet. METHOD: Fourteen patients with severe SARS (in two ICU units) were studied. Six patients received INO (30 ppm, 3-7 d), and eight patients served as controls. Oxygen saturation, hemodynamic index, inspired oxygen fraction, and chest x-ray were studied. A 4-week follow up was made. RESULTS: In the INO group, oxygen index (.P_(aO_2)/F_(iO_2)) increased from 94 till 250 mmHg. CPAP/BiPAP could be discontinued in all four patients and PEEP lowered in the intubated patient with no decrease of arterial oxygenation. The effects were remained after INO was discontin     

Importance of the Locus coeruleus and involvement of α-adrenergic receptors in the post-decapitation reflex in the rat

The latency, duration, hindlimb kick frequency, and total activity components of the post-decapitation reflex (PDR) were measured in the rat using a movement-sensitive transducer. Reduction of brain and spinal cord norepinephrine (NE) caused by neonatal administration of 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine, which also reduced brain serotonin, decreased all components of the PDR. Depletion of serotonin or dopamine alone reduced the vigor of the reflex, suggesting that these pathways can influence the PDR but are not essential for the response. Lesions of neurons in the Locus coeruleus, made electrolytically or with 6-OHDA, decreased the intensity of the PDR, with the 6-OHDA-induced lesion being more effective. Depletion of forebrain NE terminals with 6-OHDA did not alter the PDR, consistent with a critical involvement of spinal noradrenergic fibers. The PDR was also decreased by phentolamine and prazosin, but not by propanolol, suggesting an involvement of -adrenergic receptors in the response. This hypothesis was further supported by the finding that the efficacy of a variety of drugs (such as tricyclic antidepressants, phenothiazines, and antihypertensive compounds) for blocking the reflex was apparently related to their affinity for -adrenergic receptors. Thus, the PDR is dependent on noradrenergic fibers in the spinal cord and may provide a simple screen for drugs with suspected -adrenergic blocking properties or for agents that disrupt the function of central noradrenergic fibers.Bruce A. Pappas was a visiting Professor on sabbatical leave from the Department of Psychology, Carleton University, Ottawa, Canada K1S 5B6     

Possible involvement of the opioid receptor gene expression in the mechanisms of the analgesic action of melatonin

In the present study, we attempt to analyse the potential involvement of the opioid receptor gene expression in the mechanisms of the analgesic action of melatonin. A trauma-pain model was established in Wistar rats by combining right - hind limb amputation with 50℃ tail - flick test. Antinociception was determined by tail-flick latency to hot waster at 50℃. Melatonin produced the antinociceptive effect in dose-dependent manner after i. p or i. c.v. administration Injected i. c. v. to rats, naloxone（10μg） obviously antagonized the antinociceptive effect induced by i.p. melatonin.     

A review of the fate of inhaled α-quartz in the lungs of rats

The distribution of dust particles within the lungs and their excretion are highly associated with their pulmonary toxicity. Literature was reviewed to discern pulmonary translocation pathways for inhaled α-quartz compared to those for inhaled TiO₂. Accordingly, it was hypothesized α-quartz particles in the alveoli were phagocytized by alveolar macrophages but silica-containing macrophages remained in the alveoli for longer time in contrast to the rapid elimination from the alveoli seen for TiO₂-containing macrophages. In addition, it was presumed that free silica particles are translocated in the interstitium, possibly through the cytoplasm of Type I epithelial cells, as observed with TiO₂. Free silica particles are presumed to be phagocytized by interstitial macrophages soon after the particles penetrate the interstitium; these dust cells are then translocated to the ciliated airway regions in the lumen through bronchus-associated lymphoid tissue (BALT). The pulmonary retention half-time of dust particles in rats exposed to α-quartz is several times longer than that of rats exposed to TiO₂, as long as the lung dust burden is ≈ 3?mg. The reduced pulmonary particle clearance ability in rats exposed to α-quartz aerosol is presumably attributed to the long-term retention of dust cells both in the alveoli and in the interstitium; this retention may be caused by the reduced chemotactic abilities of α-quartz-containing dust cells. However, the accumulation of α-quartz-containing dust cells in the lungs is not associated with the occurrence of pulmonary inflammation.     

On the role of α-methyldopamine in the antihypertensive effect of α-methyldopa

Summary In renal hypertensive rats the cerebral concentration of -methyldopa, -methyldopamine, -methylnoradrenaline, dopamine and noradrenaline as well as the blood-pressure were determined simultaneously. The antihypertensive effect followed a time course identical to that of the increase in the cerebral concentration of -methyldopamine and of the decrease in the concentration of dopamine, whereas lowering of blood pressure on the one hand, and changes in the levels of -methylnoradrenaline and noradrenaline, on the other, were not related to each other. Dose-response relationships showed the same correlations and lack of correlations, respectively.These results suggest that non--hydroxylated catecholamines play a major role in mediating the antihypertensive effect of -methyldopa or, alternatively, that only the newly biosynthesized -methyl-noradrenaline is effective in lowering blood pressure.A preliminary communication has been presented at the Spring Meeting 1973 of the German Pharmacological Society at Mainz (Waldmeier et al., 1973).     

Bias in the Wagner–Nelson Estimate of the Fraction of Drug Absorbed

Purpose. To examine and quantify bias in the Wagner-Nelson estimate of the fraction of drug absorbed resulting from the estimation error of the elimination rate constant (k), measurement error of the drug concentration, and the truncation error in the area under the curve. Methods. Bias in the Wagner-Nelson estimate was derived as a function of post-dosing time (t), k, ratio of absorption rate constant to k (r), and the coefficient of variation for estimates of k (CV _k), or CV _c for the observed concentration, by assuming a one-compartment model and using an independent estimate of k. The derived functions were used for evaluating the bias with r= 0.5, 3, or 6; k= 0.1 or 0.2; CV _c = 0.2 or 0.4; and CV _k =0.2 or 0.4; for t= 0 to 30 or 60. Results. Estimation error of k resulted in an upward bias in the Wagner-Nelson estimate that could lead to the estimate of the fraction absorbed being greater than unity. The bias resulting from the estimation error of k inflates the fraction of absorption vs. time profiles mainly in the early post-dosing period. The magnitude of the bias in the Wagner-Nelson estimate resulting from estimation error of k was mainly determined by CV _k. The bias in the Wagner-Nelson estimate resulting from to estimation error in k can be dramatically reduced by use of the mean of several independent estimates of k, as in studies for development of an in vivo-in vitro correlation. The truncation error in the area under the curve can introduce a negative bias in the Wagner-Nelson estimate. This can partially offset the bias resulting from estimation error of k in the early post-dosing period. Measurement error of concentration does not introduce bias in the Wagner-Nelson estimate. Conclusions. Estimation error of k results in an upward bias in the Wagner-Nelson estimate, mainly in the early drug absorption phase. The truncation error in AUC can result in a downward bias, which may partially offset the upward bias due to estimation error of k in the early absorption phase. Measurement error of concentration does not introduce bias. The joint effect of estimation error of k and truncation error in AUC can result in a non-monotonic fraction-of-drug-absorbed-vs-time profile. However, only estimation error of k can lead to the Wagner-Nelson estimate of fraction of drug absorbed greater than unity.     

Analgesic efficacy of buprenorphine in the presence of high levels of SDF-1α/CXCL12 in the brain

Although morphine is often the best option for treating acute and chronic severe pain, its analgesic activity can be blocked in situations in which there are elevated levels of chemokines. Indeed, recently we have shown that elevated brain levels of the chemokine stromal cell-derived growth factor-1alpha (SDF-1α/CXCL12, the ligand of the HIV co-receptor CXCR4) diminish the antinociceptive effect of morphine. The purpose of the present study was to investigate whether such an effect is restricted to morphine or extends to other opioid medications such as buprenorphine. A sterilized stainless-steel C313G guide cannula was implanted into the periaqueductal grey (PAG), a brain region critical to the processing of pain signals, and a primary site of action of many analgesic compounds. The cold-water (-3°C) tail-flick test (CWT) was used to measure antinociception. Rats were pretreated with SDF-1α/CXCL12 administered into the PAG, and the antinociceptive actions of buprenorphine were measured. Direct infusion of SDF-1α/CXCL12 into the PAG failed to alter the antinociceptive action of buprenorphine. The presence of SDF-1α/CXCL12 in the PAG differentially alters the antinociceptive function of opioid medications. While it was able to diminish the antinociception induced by morphine (Adler et al., 2006), SDF-1α/CXCL12 did not affect the buprenorphine-induced antinociception. Buprenorphine appears to be more effective in the presence of high levels of SDF-1α/CXCL12 in the brain (which frequently occurs during neuroinflammatory conditions).     

Noradrenergic mechanism in the regulation of seizures in GEPR.

Genetically epilepsy prone rat (GEPR) is a model of generalized tonic/clonic epilepsy and a useful tool in the understanding of basic mechanisms of human epilepsy. GEPR is susceptible to audiogenic seizure, hyperthermia induced seizure,and has lower threshold for electrical and chemical stimuli. Several strains of GEPR, from GEPR-3 to GEPR-9, are available depending on the degree of the intensity of audiogenic seizure.     

Stimulation of α2-adrenergic receptors in the central nucleus of the amygdala attenuates stress-induced reinstatement of nicotine seeking in rats

Tobacco addiction is a chronic disorder that is characterized by craving for tobacco products, withdrawal upon smoking cessation, and relapse after periods of abstinence. Previous studies demonstrated that systemic administration of α2-adrenergic receptor agonists attenuates stress-induced reinstatement of drug seeking in rats. The aim of the present experiments was to investigate the role of noradrenergic transmission in the central nucleus of amygdala (CeA) in stress-induced reinstatement of nicotine seeking. Rats self-administered nicotine for 14–16 days and then nicotine seeking was extinguished by substituting saline for nicotine. The effect of the intra-CeA infusion of the α2-adrenergic receptor agonists clonidine and dexmedetomidine, the nonselective β1/β2-adrenergic receptor antagonist propranolol, and the α1-adrenergic receptor antagonist prazosin on stress-induced reinstatement of nicotine seeking was investigated. In all the experiments, exposure to footshocks reinstated extinguished nicotine seeking. The administration of clonidine or dexmedetomidine into the CeA attenuated stress-induced reinstatement of nicotine seeking. The administration of propranolol or prazosin into the CeA did not affect stress-induced reinstatement of nicotine seeking. Furthermore, intra-CeA administration of clonidine or dexmedetomidine did not affect operant responding for food pellets. This suggests that the effects of clonidine and dexmedetomidine on stress-induced reinstatement of nicotine seeking were not mediated by motor impairments or sedation. Taken together, these findings indicate that stimulation of α2-adrenergic receptors, but not blockade of α1 or β-adrenergic receptors, in the CeA attenuates stress-induced reinstatement of nicotine seeking. These findings suggest that α2-adrenergic receptor agonists may at least partly attenuate stress-induced reinstatement of nicotine seeking by stimulating α2-adrenergic receptors in the CeA.     

Evaluation of the cost-effectiveness of rifaximin-α for the management of patients with hepatic encephalopathy in the United Kingdom

Objective: Rifaximin-α 550?mg twice daily plus lactulose has demonstrated efficacy in reducing recurrence of episodes of overt hepatic encephalopathy (OHE) and the risk of hepatic encephalopathy (HE)-related hospitalizations compared with lactulose alone. This analysis estimated the cost effectiveness of rifaximin-α 550?mg twice daily plus lactulose versus lactulose alone in United Kingdom (UK) cirrhotic patients with OHE.

Method: A Markov model was built to estimate the incremental cost-effectiveness ratio (ICER). The perspective was that of the UK National Health Service (NHS). Clinical data was sourced from a randomized controlled trial (RCT) and an open-label maintenance study in cirrhotic patients in remission from recurrent episodes of OHE. Health-related utility was estimated indirectly from disease-specific quality of life RCT data. Resource use data describing the impact of rifaximin-α on hospital admissions and length of stay for cirrhotic patients with OHE was from four single-center UK audits. Costs (2012) were derived from published sources; costs and benefits were discounted at 3.5%. The base-case time horizon was 5 years.

Results: The average cost per patient was £22,971 in the rifaximin-α plus lactulose arm and £23,545 in the lactulose arm, a saving of £573. The corresponding values for benefit were 2.35 quality adjusted life years (QALYs) and 1.83 QALYs per person, a difference of 0.52 QALYs. This translated into a dominant base-case ICER. Key parameters that impacted the ICER included number of hospital admissions and length of stay.

Conclusion: Rifaximin-α 550?mg twice daily in patients with recurrent episodes of OHE was estimated to generate cost savings and improved clinical outcomes compared to standard care over 5 years.     

Is histamine the final neurotransmitter in the entrainment of circadian rhythms in mammals?

Adaptation of circadian rhythms to the environmental light-dark cycle is necessary for the survival of organisms. This synchronization or entrainment is only caused by light (photic input) during the dark period, according to the internal biological clock of an organism. During the light period, internal factors (non-photic input), rather than light, are able to entrain circadian rhythms. In this article, the data that implicate the neurotransmitter system for histamine in circadian entrainment are reviewed. Furthermore, we speculate that histamine receptors are the final gate at which both photic and non-photic entrainment mechanisms converge before sending a resetting signal to the intracellular biological clock.     

Effects of β-adrenoceptor antagonists on the firing rate of noradrenergic neurones in the locus coeruleus of the rat

Summary Acute i.v. administration of the non-selective -adrenoceptor antagonist dl-propranolol given in incremental doses (<40 mg/kg) did not affect the firing rate of locus coeruleus (LC) neurones in the rat, as revealed by single cell recording techniques. Furthermore, no effect was seen 4 h after a single i.p. dose of this -blocker (10 mg/kg). However, repeated treatment with dl-propranolol (1, 5, 10 or 20 mg/kg i.p., twice daily for 4 days) produced a significant, dose-dependent decrease of the average LC neuronal firing rate in comparison to controls. The dextro isomer of propranolol, which has negligible -blocking activity but the same local anaesthetic potency as the racemate, had no corresponding effect. The non-selective -adrenoceptor antagonist sotalol, which is one of the most hydrophilic -blockers, had much less inhibitory effect on LC neurones than dl-propranolol. The ₁-selective antagonist metoprolol did not change the firing of noradrenergic neurones in the LC after similar treatment for 4 days. However, when the rats were subjected to oral treatment for 28 days, metoprolol was found to produce a slight inhibitory effect although much less than dl-propranolol.In view of these findings we propose a stimulatory and mainly ₂-adrenoceptor-mediated control mechanism for the noradrencrgic neurones in the LC. This mechanism seems to be characterized by a delayed responsiveness.     

From the first drug to crack: the sequence of drugs taken in a group of users in the city of São Paulo

To identify a progression in drug use and influencing factors among crack users, a qualitative methodology was used for a more in-depth investigation, taking into consideration the view that the interviewee has of the problem. A long duration and a semi-structured interview was used; a purposeful sampling was outlined and a criterion sampling was achieved. Thirty-one crack users or ex-users were interviewed in order to reach theoretical saturation. Two distinct phases of drug use were detected. The first, with licit drugs, where alcohol and tobacco were the most frequent, the relatives and friends were the ones who encouraged use, and the need for self-assurance was the reason most often reported. The early start and the "heavy use" of one or both drugs were determinant for the beginning of a progression towards illicit drugs. Marijuana was the first drug of the second phase. A stronger attitude for the search of a drug as a source of pleasure replaced the reason previously stated. The study reveals that the progression in drug use seems to be associated more with external decisions (e.g., peer pressure, dealing influence, etc.) than to the preference of the user. Two different progressions were identified: among the younger (<30): tobacco and/or alcohol, marijuana, snorted cocaine, and crack, and among the older (>30): tobacco and/or alcohol, marijuana, intravenous medication, snorted cocaine, intravenous cocaine, and crack. This pilot study's findings are limited in generalizability to its sample. Further research is needed.     

Exploring the pharmacology of the pro-convulsant effects of α2-adrenoceptor antagonists in mice

The effects of selective and specific ₂-adrenoceptor antagonists on electroshock seizure threshold in mice were investigated. Idazoxan, at low doses, efaroxan, RX811059 and RX821002 significantly lowered seizure threshold. The ₁-agonist St 587 and the -agonist isoprenaline were also pro-convulsant. On the other hand the ₂-agonists clonidine and UK 14,304 produced small increases in seizure threshold. Anticonvulsant effects were also produced by low doses of the noradrenaline uptake inhibitor desipramine. This compound increases levels of noradrenaline in the synaptic cleft which could subsequently act at post-synaptic ₂-adrenoceptors. The pro-convulsant action of ₂-adrenoceptor antagonists could be explained in terms of two mechanisms: a) blockade of endogenous noradrenaline which may normally exert a tonic anti-convulsant influence on seizure threshold, through post-synaptic ₂-receptors and/or b) increased activation of ₁- and -adrenoceptors by elevated synaptic noradrenaline levels following blockade of pre-synaptic ₂-adrenoceptors. Of the ₂-antagonists tested, idazoxan was unusual in that high doses were not pro-convulsant; this difference may be explained by ₁-adrenoceptor mediated actions or be related to its recently described affinity at a non-adrenoceptor site — a function for which is currently unknown.