Neuromonitoring

The monitoring of critically ill brain injured patients has become increasingly complex. Several techniques are now available for global and regional brain monitoring that provide assessment of cerebral perfusion, oxygenation and metabolic status, and early warning of impending brain hypoxia/ischaemia. Developments in multimodality monitoring have enabled a move away from rigid physiological target setting to an individually tailored, patient-specific approach to the management of acute brain injury. Multimodal monitoring generates large and complex datasets, and systems that analyse and present information in a user-friendly format at the bedside are essential to maximize its clinical relevance. This review describes current neuromonitoring techniques used during the intensive care management of acute brain injury.     

Monitoring vigabatrin in head injury patients by cerebral microdialysis: obtaining pharmacokinetic measurements in a neurocritical care setting

AimsThe aims were to determine blood–brain barrier penetration and brain extracellular pharmacokinetics for the anticonvulsant vigabatrin (VGB; γ-vinyl-γ-aminobutyric acid) in brain extracellular fluid and plasma from severe traumatic brain injury (TBI) patients, and to measure the response of γ-aminobutyric acid (GABA) concentration in brain extracellular fluid.MethodsSevere TBI patients (n = 10) received VGB (0.5 g enterally, every 12 h). Each patient had a cerebral microdialysis catheter; two patients had a second catheter in a different region of the brain. Plasma samples were collected 0.5 h before and 2, 4 and 11.5 h after the first VGB dose. Cerebral microdialysis commenced before the first VGB dose and continued through at least three doses of VGB. Controls were seven severe TBI patients with microdialysis, without VGB.ResultsAfter the first VGB dose, the maximum concentration of VGB (C_max) was 31.7 (26.9–42.6) μmol l⁻¹ (median and interquartile range for eight patients) in plasma and 2.41 (2.03–5.94) μmol l⁻¹ in brain microdialysates (nine patients, 11 catheters), without significant plasma–brain correlation. After three doses, median C_max in microdialysates increased to 5.22 (4.24–7.14) μmol l⁻¹ (eight patients, 10 catheters). Microdialysate VGB concentrations were higher close to focal lesions than in distant sites. Microdialysate GABA concentrations increased modestly in some of the patients after VGB administration.ConclusionsVigabatrin, given enterally to severe TBI patients, crosses the blood–brain barrier into the brain extracellular fluid, where it accumulates with multiple dosing. Pharmacokinetics suggest delayed uptake from the blood.     

Selective Effects of D- and L-Govadine in Preclinical Tests of Positive,Negative, and Cognitive Symptoms of Schizophrenia

There is a critical need to develop novel pharmacotherapeutics capable of addressing the positive, negative, and cognitive symptoms of schizophrenia. Building on recent studies with a racemic mixture of the synthetic tetrahydroprotoberberine, D,L-Govadine, we isolated the D- and L-stereoisomers and employed a battery of behavioral, neurochemical, and electrophysiological procedures to assess their individual therapeutic potential. Rodent models predictive of antipsychotic efficacy and those that model positive symptoms were employed and we found that L-Govadine, but not D-Govadine, improved these measures. Pretreatment with either stereoisomer during CS pre-exposure prevented the disruption of latent inhibition by amphetamine. Moreover, pretreatment with either stereoisomer also improved deficits in social interaction in the neonatal ventral hippocampal lesioned rat. Improved cognitive performance in two different prefrontal cortex-dependent tasks was observed with D-, but not L-Govadine, which strongly suggests that the D-steroisomer may be an effective cognitive enhancer. Alterations in dopamine efflux were also assessed and L-Govadine increased dopamine efflux in both the prefrontal cortex and nucleus accumbens. However, D-Govadine only increased dopamine efflux in the prefrontal cortex and not in the nucleus accumbens. Electrophysiological studies confirmed that L-Govadine is a DA-D2 antagonist, whereas D-Govadine shows no appreciable physiological effects at this receptor. Collectively these data show that L-Govadine performs well on measures predictive of antipsychotic efficacy and rodent models of positive symptoms through antagonism of DA-D2 receptors, whereas D-Govadine improves impairments in compromised memory function in delayed response tasks possibly through selective increases in DA efflux in the frontal cortex.     

Mediastinal microdialysis in the diagnosis of early anastomotic leakage after resection for cancer of the esophagus and gastroesophageal junction

Background

Anastomotic leakage (AL) after gastroesophageal resection for cancer is a serious complication. The aim was to evaluate mediastinal microdialysis in the detection of AL before clinical symptoms.

Methods

Sixty patients were included. Samples were collected every 4 hours in the 1st 8 postoperative days and analyzed for several metabolites.

Results

Forty-four patients had an uncomplicated postoperative recovery, 7 developed anastomotic-related complications, and 5 developed major nonanastomotic-related complications. Six patients were excluded (early catheter malfunction and reoperation). Logistic regression model on several metabolites demonstrated a 100% sensitivity, specificity, and positive and negative predictive values regarding the diagnosis of anastomotic complications within postoperative day 7. However, as independent markers, none of the measured metabolites were able to predict AL.

Conclusion

The diagnosis of anastomotic-related complications before clinical symptoms seemed possible by mediastinal microdialysis, but the diagnosis should be based on an interpretation of several metabolic events.     

基于内标微透析技术同步分析尼古丁透皮贴剂在血液与皮肤的药动学

目的：利用内标微透析采样技术,同步研究尼古丁透皮贴剂的血液和皮肤局部药动学特征,获得其较全面的体内药动学规律。方法：以健康SD大鼠为实验动物,将尼古丁透皮贴剂经皮给药,磷酸可待因作为微透析采样的内标物,采集不同时间点血液和皮肤微透析样品,用高效液相色谱法（HPLC）进行测定,利用DAS 2.1药动学软件计算相关药动学参数。结果：尼古丁在血液和皮肤的平均滞留时间（MRT_0-∞）分别为（16 986.00±486.00）min和（1 597.00±851.00）min,药时曲线下面积（AUC_0-∞）分别为（19 235.42±1 801.92）mg·mL^-1·min和（56 328.82±24 900.42）mg·mL^-1·min,达峰浓度（C_max）分别为（2.00±0.50）mg·L^-1和（32.00±5.00）mg·L^-1,达峰时间（t_max）分别为（325±200）min和（570±106）min。尼古丁在血液与皮肤的药动学参数相比,AUC_0-∞、C_max、t_max在皮肤中较大,MRT_0-∞在血液中较大。结论：尼古丁透皮贴剂经皮给药后,在血液与皮肤的药动学规律存在明显的差异与联系,药动学参数证明尼古丁通过透皮渗透在皮肤中以相对较高的浓度蓄积,能达到快速、有效的吸收,进入血液后血药浓度相对较低且维持稳定,发挥显著长效作用。     

Estrogen potentiates the behavioral and nucleus accumbens dopamine response to continuous haloperidol treatment in female rats

Estrogen has been shown to enhance the effects of antipsychotics in humans. To investigate the mechanisms of how this may occur, the current study examined estradiol's effects on dopaminergic transmission and behavior in amphetamine‐sensitized and non‐sensitized female rats. Sixty‐four ovariectomized female Sprague–Dawley rats were used for this study. Half of the rats were sensitized to four once‐daily injections of 1 mg/kg amphetamine and the other half served as controls. Rats received chronic administration of either low‐dose haloperidol (0.25 mg/kg/day) or saline vehicle via osmotic minipumps implanted subcutaneously. The groups were further subdivided with respect to estradiol treatment: low chronic estrogen (subcutaneous estradiol implant, 0.36 mg/pellet: 90‐day release, plus an additional oil vehicle injection every second day) and high pulsatile estrogen (subcutaneous estradiol implant plus an additional 10 μg/kg estradiol injection every second day). Motor activity was assessed at day 2 and day 12 during haloperidol treatment, while nucleus accumbens dopamine availability was assessed via microdialysis 10 days into antipsychotic treatment. Haloperidol treatment along with high, but not low, estradiol replacement was effective in reducing amphetamine‐induced locomotor activity in sensitized rats. High estradiol treatment also augmented the effects of chronic haloperidol in reducing dopaminergic release in sensitized rats. These data suggest that estradiol levels affect both the behavioral and the dopamine responses to chronic antipsychotic treatment.     

Dynamic detection of non‐protein‐bound strychnine and brucine in rabbit muscle and synovial fluid after topical application of total Strychnos alkaloid patches

Semen Strychni, a known toxic drug in Chinese pharmacopoeia, is notable for its therapeutic effects on local muscle and joint pain. However, oral administration can be risky. Topically administered drugs accumulate in the topical muscles and knee joints without any major increase in plasma levels; only non‐protein‐bound drugs in the biological fluids of target tissues are effective for therapeutic effects. A sensitive and rapid ultra performance liquid chromatography ‐ mass spectrometry (UPLC‐MS) method coupled with a microdialysis technique was developed to determine the non‐protein‐bound strychnine (Str) and brucine (Bru) in rabbit muscle and synovial fluid microdialysate. The UPLC separation was carried out using a 1.7μm BEH C18 column (50 mm × 2.1 mm) with a mobile phase consisting of methanol: water (29.5:70.5, v/v) with 0.1% formic acid and 20 mM ammonium acetate in water. The method was validated at concentrations ranging from 0.58 ng/ml to 467.20 ng/ml for Str and from 0.42 ng/ml to 422.40 ng/ml for Bru. Intra‐day and inter‐day accuracy ranged from 99.1% to 103.2% for Str and from 95.8% to 108.8% for Bru with intra‐day and inter‐day precision within 9.7%. The proposed method was successfully applied to determine non‐protein‐bound Str and Bru, and the analysates concentration remained stable in rabbit muscle and synovial fluid after topical application of total Strychnos alkaloid patches, which indicated that total Strychnos alkaloid patches could substitute for the traditional oral administration of Semen Strychni. Copyright © 2013 John Wiley & Sons, Ltd.     

Regulation of serotonin-facilitated dopamine release in vivo: The role of protein kinase A activating transduction mechanisms

Recent neuroanatomical, biochemical, and electrophysiological studies suggest that serotonin (5HT) can modulate dopaminergic function at the level of the cell body and the nerve terminal. The receptor subtypes, regulatory processes, and intracellular transduction mechanisms mediating these interactions remain to be characterized. The potential involvement of cAMP in mediating 5HT-facilitated increases in extracellular levels of striatal dopamine (DA) was assessed using in vivo microdialysis. Local infusion of 0.4 nmol 5HT delivered via probes located in the anterior striata of chloral hydrate-anesthetized male rats significantly increased extracellular DA levels to approximately 700% of basal control levels. Local, intrastriatal infusion of either 2 nmol forskolin, 2 nmol rolipram, 100 nmol isobutylmethylxanthine, or 200 nmol dibutyryl cAMP significantly increased basal DA levels to 28 ± 3%, 143 ± 5%, 56 ± 7%, and 52 ± 3% above control levels, respectively. Additionally, coperfusion of any of these agents with 5HT significantly decreased the 5HT-facilitory effect on DA release to approximately 50% of observed 5HT controls. The current results suggest a role for the cAMP second-messenger systems in modulating 5HT-facilitated DA release. © 1996 Wiley-Liss, Inc.     

The psychotomimetic drugs D-amphetamine and phencyclidine release calcitonin gene-related peptide in the limbic forebrain of the rat

Calcitonin gene-related peptide (CGRP) is the major product of the calcitonin gene in brain and exerts a number of actions in the central nervous system (CNS). In particular the finding that CGRP affects dopamine (DA) release and metabolism has raised the possibility that it may play a role in several neuropsychiatric disorders. Consequently, we have here studied the effects of two psychotomimetic drugs, namely, d-amphetamine (AMPH) and phencyclidine (PCP), on CGRP concentrations in brain microdialysates from freely moving rats. The animals were stereotaxically implanted with vertical concentric probes in the medial prefrontal cortex (mPFC), the ventral striatum (vSTR), or the hippocampus; and the experiments were performed 48 hr after surgery. The dialysis probes were perfused with a modified Ringer's solution at the rate of 5 μl/min. AMPH 1.5 mg/kg, PCP 2.5 mg/kg, or NaCl 0.9% were injected s.c.; and the perfusates were collected at 60 min intervals before and after the injections and used for CGRP-like immunoreactivity (-LI) determination by radioimmunoassay (RIA). In separate experiments, KCl (100 mM), veratridine (50 μM), or tetrodotoxin (2 μM), were added to the perfusate and infused in the vSTR. Baseline levels of CGRP-LI were detected in dialysates from all three regions. Both AMPH and PCP caused a significant and sustained increase (maximum about 300%) in CGRP-LI concentrations, in particular from the mPFC and vSTR, while saline had no effect. KCl and veratridine also increased CGRP-LI in dialysates during the first posttreatment period, while tetrodotoxin induced a significant but delayed decrease in CGRP-LI levels. Finally, cervical dislocation also elevated CGRP-LI in dialysates from the mPFC and the vSTR. Our findings demonstrate that 1) CGRP-LI can be measured in vivo in microdialysates from mPFC, vSTR, and hippocampus; 2) the release in vSTR is action potential-dependent; and 3) systemic administration of AMPH or PCP results in a long-lasting release of CGRP-LI in the mPFC and vSTR, thus demonstrating a novel action of these drugs in the brain. Since other studies have shown that major antipsychotic drugs appear to reduce CGRP release in brain, our study provides, in principle, support for a role of CGRP in psychotic disorders. © 1996 Wiley-Liss, Inc.     

A novel Na+‐Independent alanine‐serine‐cysteine transporter 1 inhibitor inhibits both influx and efflux of D‐Serine

NMDA receptor dysfunctions are hypothesized to underlie the pathophysiology of schizophrenia, and treatment with D‐serine (D‐Ser), an NMDA receptor coagonist, may improve the clinical symptoms of schizophrenia. Thus, upregulating the synaptic D‐Ser level is a novel strategy for schizophrenia treatment. Na⁺‐independent alanine‐serine‐cysteine transporter 1 (asc‐1) is a transporter responsible for regulating the extracellular D‐Ser levels in the brain. In this study, we discovered a novel asc‐1 inhibitor, (+)‐amino(1‐(3,5‐dichlorophenyl)‐3,5‐dimethyl‐1H‐pyrazol‐4‐yl)acetic acid (ACPP), and assessed its pharmacological profile. ACPP inhibited the D‐[³H]Ser uptake in human asc‐1‐expressing CHO cells and rat primary neurons with IC₅₀ values of 0.72 ± 0.13 and 0.89 ± 0.30 μM, respectively. In accordance with the lower asc‐1 expression levels in astrocytes, ACPP did not inhibit D‐Ser uptake in rat primary astrocytes. In a microdialysis study, ACPP dose dependently decreased the extracellular D‐Ser levels in the rat hippocampus under the same conditions in which the asc‐1 inhibitor S‐methyl‐L‐cysteine (SMLC) increased it. To obtain insights into this difference, we conducted a D‐[³H]Ser efflux assay using asc‐1‐expressing CHO cells. ACPP inhibited D‐[³H]Ser efflux, whereas SMLC increased it. These results suggest that ACPP is a novel inhibitor of asc‐1. © 2016 Wiley Periodicals, Inc.