Pharmacokinetic behavior in plasma, cerebrospinal fluid and cerebral cortex after intranasal administration of hydrochloride meptazinol

The aim of this paper is to investigate the pharmacokinetic behavior of hydrochloride meptazinol (MEP) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal administration (8 mg/kg) in male Sprague-Dawley rats. The pharmacokinetic study of intravenous administration (8 mg/kg) was also performed in rats. CSF and cerebral cortex samples were collected by serial CSF sampling and intracerebral microdialysis, respectively. The concentration of MEP in the biological samples was measured by high performance liquid chromatography (HPLC). It was determined that the absorption of MEP from the nasal cavity to systemic circulation was rapid and complete. The concentration-time profile showed a prolonged duration of MEP concentration in CSF and cortex following intranasal administration. The ratios of AUC values of intranasal to intravenous administrations were 0.96, 1.07 and 1.81 in plasma, CSF and cortex dialysate, respectively. In conclusion, intranasal administration of MEP is a promising alternative to traditional administration modes. Olfactory mucosa did not present intranasal MEP another pathway, in addition to systemic absorption, for transport to the brain.     

Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the nucleus raphe magnus to participate in pain modulation

Hypothalamic paraventricular nucleus (PVN) is one of the main sources of arginine vasopressin (AVP) synthesis and secretion. AVP is the most important bioactive substance in PVN regulating pain process. Our pervious study has pointed that pain stimulation induced AVP increase in the nucleus raphe magnus (NRM), which plays a role in pain modulation. The present study was designed to investigate the source of AVP in the rat NRM during pain process using the methods of nucleus push–pull perfusion and radioimmunoassay. The results showed that pain stimulation increased the AVP concentration in the NRM perfusion liquid, PVN cauterization inhibited the role that pain stimulation induced the increase of AVP concentration in the NRM perfusion liquid, and PVN microinjection of l-glutamate sodium, which excited the PVN neurons, could increase the AVP concentration in the NRM perfusion liquid. The data suggested that AVP in the PVN might be transferred to the NRM to participate in pain modulation.     

Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the caudate nucleus to participate in pain modulation

Arginine vasopressin (AVP), which is synthesized and secreted in the hypothalamic paraventricular nucleus (PVN), is the most important bioactive substance in the pain modulation. Our pervious study had shown that AVP plays an important role in pain modulation in caudate nucleus (CdN). The experiment was designed to investigate the source of AVP in CdN by the nucleus push-pull perfusion and radioimmunoassay. The results showed that: (1) pain stimulation increased the AVP concentration in the CdN perfusion liquid, (2) PVN decreased the effect of pain stimulation which was stronger in both sides than in one side of PVN cauterization; and (3) L-glutamate sodium would excited the PVN neurons by the PVN microinjection that could increase the AVP concentration in the CdN perfusion liquid. The data suggested that AVP in the CdN might come from the PVN in the pain process, i.e., AVP in the PVN might be transferred to the CdN to participate in the pain modulation.     

家兔发热时脑脊液和血浆中精氨酸加压素含量的变化及禁水的抗热作用

本实验观察了发热家兔脑脊液(CSF)和血浆中精氨酸加压素(AVP)含量的变化及禁水对家兔内毒素(ET)发热效应的影响。实验结果表明:1.隔区注射AVP可明显抑制家兔ET性发热效应;2.发热组家兔CSF和血浆中AVP含量较正常组明显降低;3.禁水可明显对抗家兔ET性发热效应,其抗热作用与CSF和血浆中AVP含量升高有关;4.禁水也可使正常家兔体温水平下移。上述实验结果提示,AVP可能是家兔体内一种内源性退热物质,同时在正常体温调节中也可能发挥一定的作用。     

Saturable Retention of Vasopressin by Hippocampus Vessels In Vivo, Associated with Inhibition of Blood-Brain Transfer of Large Neutral Amino Acids

Vasopressin receptors have been reported in the endothelium of brain capillaries. The function of these receptors is not known. To test the prediction that vasopressin receptors in brain capillary endothelium affect amino acid transport across the blood-brain barrier and to assess the role of vasopressin transport across the cerebral vascular endothelium, we measured (a) the endothelial permeability to the large neutral amino acid leucine in the absence and presence of arginine vasopressin (AVP) and (b) the permeability of the blood-brain barrier to AVP relative to manitol. In brain regions protected by the blood-brain barrier, after circulation for 20 s, coinjection of leucine and AVP intravenously led to a decrease of leucine transport unrelated to changes of blood flow. The decrease was most pronounced in hippocampus (42%) and least pronounced in olfactory bulb and colliculi (17 and 19%, respectively). In the latter regions, the endothelial permeability to AVP did not significantly exceed that of mannitol. In hippocampus and in regions with no blood-brain barrier (pituitary and pineal glands), AVP retention in excess of mannitol retention was blocked by unlabeled AVP. The findings do not contradict the hypothesis of a role for AVP in the regulation of large neutral amino acid transfer into brain tissue.     

CSF and Blood Oxytocin Concentration Changes following Intranasal Delivery in Macaque

Oxytocin (OT) in the central nervous system (CNS) influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline) to 15 primates (Macaca mulatta), using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF) and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels.     

Metoclopramide increases plasma but not cerebrospinal fluid vasopressin levels in man: study in hydrocephalic patients.

Arginine vasopressin (AVP) concentrations were determined in plasma and in cerebrospinal fluid (CSF) in 8 adult male patients suffering from hydrocephalus of various etiologies, before and after intravenous administration of 10 mg metoclopramide. Metoclopramide was able to increase the plasma (2.6 +/- 0.2 ng/l in basal conditions and 6.1 +/- 0.6 ng/l at 30 min) but not the CSF AVP levels. The results suggest that the neurons which secrete AVP into the CSF may be functionally different from those secreting into the peripheral circulation.     

Diurnal pattern of plasma and cerebrospinal-fluid vasopressin levels in hydrocephalic patients: absence of a circadian rhythm and of a correlation between plasma and cerebrospinal-fluid variations

The arginine vasopressin (AVP) concentrations were determined in plasma and in cerebrospinal fluid (CSF) during a 24-hour period in 7 male patients suffering from hydrocephalus of differing etiologies. Blood and ventricular CSF samples were simultaneously collected every 2 h during the day (08.00-22.00) and every hour during the night (24.00-07.00). In both plasma and CSF, the AVP levels did not show significant time-related circadian variations. No significant correlation was found between the plasma and CSF AVP values during the 24-hour period. The data obtained indicate the absence of the plasma and CSF AVP circadian rhythm in hydrocephalic patients and suggest that in these patients, and possibly in healthy humans, physiological stimuli which are able to induce variations in the plasma AVP concentration during daily life do not alter the CSF AVP content.     

Effects of treadmill running and swimming on plasma and brain vasopressin levels in rats

The influence of treadmill or swimming exercise on resting values of plasma and brain arginine vasopressin (AVP), and plasma sodium, potassium, osmolality and proteins was studied after 5 weeks of training using female Wistar rats. The duration of daily training sessions was progressively increased to reach 6 h/day for swim training (S) and 3 h/day for treadmill running (T). Compared to their untrained controls, treadmill and swim training were respectively associated with: a significant lower body weight; a decreased plasma AVP (36.4% for T and 47.4% for S) and hypothalamic AVP (20% for T and 16% for S); a higher hypophyseal AVP (145% for T and 36.3 for S); a decreased plasma osmolality (6.7% for T and 6.1% for S), sodium (1.2% for both) and potassium (15% for T and 22.4% for S); and no change in protein concentration. For T, rectal temperature increased (38.5 +/- 0.20 to 39.7 +/- 0.5) and for S rectal temperature decreased from 38.6 +/- 0.12 to 37.74 +/- 0.10). The differences observed in AVP contents of the pineal and Harderian glands (enhanced only in the treadmill groups) could be explained by the supposed role of these glands in thermoregulation. Two conclusions could be drawn from this study: there are no parallel changes in the hypothalamo-hypophyseal system (where AVP plays its endocrine role) and the brain (where AVP is a neurotransmitter); plasma changes could be explained by an extracellular fluid expansion with Na and K loss leading to a decrease in AVP secretion.     

Vasopressin levels in peripheral blood and in cerebrospinal fluid during passive and active avoidance behavior in rats.

Vasopressin (AVP) levels were measured in plasma and cerebrospinal fluid (CSF) of rats during acquisition and retention of a passive avoidance response. Only 5 min after the onset of the retention session a significantly higher level of AVP was found in plasma of animals which displayed a long latency, as compared with the levels of animals which showed a weak passive avoidance response (short latencies), or no passive avoidance behavior at all (controls). Moreover no changes in plasma AVP levels were found in plasma of rats submitted to acquisition or extinction of an active avoidance response. It is suggested that, although an elevated plasma AVP level is associated with strong retention of a passive avoidance response the peripheral circulation as well as the CSF are of minor importance for the transport of this neuropeptide to its site of behavioral action.     

THE CONCENTRATIONS OF FREE AMINO ACIDS AND OTHER ELECTROLYTES IN CEREBROSPINAL FLUID,IN VIVO DIALYSATE OF BRAIN,AND BLOOD PLASMA OF THE DOG*

The concentrations of free amino acids in plasma, CSF and in vivo dialysates of peripheral blood (neck sac fluid) and central nervous tissue (brain sac fluid) from each of five dogs (neck sac fluid from four of five dogs) were determined by ion-exchange chromatography. Dialysates were obtained by implanting small dialysis sacs filled with a dextran-saline solution into the subcutaneous tissue of the neck or the parenchyma of the brain at least 10 weeks before sample collection. The mean plasma concentration of most amino acids was within the range of values reported in the literature for human or dog plasma. The concentrations of most amino acids were higher in the neck sac fluid than in plasma; this discrepancy, however, was, for the most part, small and could most likely be accounted for by falling plasma free amino acid levels prior to sample taking. Previous conclusions that the CSF concentrations of most amino acids are lower than plasma concentrations are confirmed, although the present work indicates that there may be considerable individual variation in the CSF/plasma distribution ratio with respect to most amino acids. In the brain sac fluid the concentration of nearly every amino acid was consistently higher than that in CSF and lower than that in the neck sac fluid. The potassium concentration in the brain sac fluid was significantly higher than, and the total osmolality significantly lower than, those in the neck sac fluid. On the assumption that the brain sac fluid represents a dialysate of the brain extracellular fluid, these results contradict recent findings (Bito and Davson , 1965; 1966) indicating that the potassium concentration of the cortex extracellular fluid is lower than that of ventricular or cisterna magna CSF and certainly lower than that of plasma. Because of this and on the basis of consideration of the reaction of the brain to a foreign body, the possibility that the implanted brain sac lay on the‘blood side’of the bloodbrain barrier was suggested. Some implications of this possibility are discussed.     

Effects of acute exercise and prolonged exercise training on blood pressure, vasopressin and plasma renin activity in spontaneously hypertensive rats

The purpose of this study was to investigate the effect of swimming training on systolic blood pressure (BPs), plasma and brain vasopressin (AVP), and plasma renin activity (PRA) in spontaneously hypertensive rats (SHR) during rest and after exercise. Resting and postexercise heart rate, as well as blood parameters such as packed cell volume (PCV), haemoglobin concentration (Hb), plasma sodium and potassium concentrations ([Na+], [K+]) osmolality and proteins were also studied. Hypophyseal AVP had reduced significantly after exercise in the SHR, whereas PRA had increased significantly in the Wistar-Kyoto (WKY) strain used as normotensive controls. Plasma AVP concentration increased in both strains. By the end of the experiment, training had reduced body mass and BPs by only 10% and 6%, respectively. Maximal oxygen uptake was increased 10% and plasma osmolality 2% by training. The postexercise elevation of heart rate was not significantly attenuated by training. A statistically significant reduction in postexercise plasma osmolality (10%) and [Na+] (4%) was observed. These results suggested that swimming training reduced BPs. Plasma and brain AVP played a small role in the hypertensive process of SHR in basal conditions because changes in AVP contents did not correlate with those of BPs. Moreover, there were no differences between SHR and WKY in plasma, hypophyseal and hypothalamic AVP content in these basal conditions. Finally, during moderate exercise a haemodilution probably occurred with an increase of plasma protein content. This was confirmed by the exercise-induced increase of plasma AVP and the reduction of hypophyseal AVP content, suggesting a release of this hormone, which probably contributed to the water retention and haemodilution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxytocin, but not arginine vasopressin is involving in the antinociceptive role of hypothalamic supraoptic nucleus

Our pervious study has demonstrated that the hypothalamic supraoptic nucleus (SON) plays a role in pain modulation. Oxytocin (OXT) and arginine vasopressin (AVP) are the important hormones synthesized and secreted by the SON. The experiment was designed to investigate which hormone was relating with the antinociceptive role of the SON in the rat. The results showed that (1) microinjection of l-glutamate sodium into the SON increased OXT and AVP concentrations in the SON perfusion liquid, (2) pain stimulation induces OXT, but not AVP release in the SON, and (3) intraventricular injection (pre-treatment) with OXT antiserum could inhibit the pain threshold increase induced by SON injection of l-glutamate sodium, but administration of AVP antiserum did not influence the antinociceptive role of SON stimulation. The data suggested that the antinociceptive role of the SON relates to OXT rather than AVP.     

Intranasal Delivery of Human β-Amyloid Peptide in Rats: Effective Brain Targeting

(1) Intranasal administration is a non-invasive and effective way for the delivery of drugs to brain that circumvents the blood–brain barrier. The aims of the study were to test a nasal delivery system for human β-amyloid (Aβ) peptides, to measure the delivery of the peptides to brain regions, and to test their biological activity in rats. (2) Aβ_1-42, in the form of a mixture of oligomers, protofibrils, and fibrils was dissolved in a nasal formulation containing hydrophobic, hydrophylic, and mucoadhesive components. The peptide solution was administered intranasally to rats as a single dose or in repeated doses. (3) Nasally injected Aβ labeled with the blue fluorescent dye amino-methyl coumarinyl acetic acid (AMCA) could be detected by fluorescent microscopy in the olfactory bulb and frontal cortex. The concentration of the peptide was quantified by fluorescent spectroscopy, and a significant amount of AMCA-Aβ peptide could be detected in the olfactory bulb. Unlabeled Aβ also reached the olfactory bulb and frontal cortex of rats as evidenced by intense immunostaining. (4) In behavioral experiments, nasal Aβ treatment did not affect anxiety levels (open-field test) and short-term memory (Y-maze test), but significantly impaired long-term spatial memory in the Morris water maze. The treatments did not result in Aβ immunization. (5) The tested intranasal delivery system could successfully target a bioactive peptide into the central nervous system and provides a basis for developing a non-invasive and cost effective, new model to study amyloid-induced dysfunctions in the brain.     

基于专家问卷反馈的头痛活血化瘀药物功效强度及用药情况初探

目的:以专家临床经验为积淀,对治疗头痛活血化瘀药物功效强度的量化及用药规律进行初步的探讨。方法:基于专家咨询及中医传承辅助平台软件,将筛选出的活血化瘀中药的专家意见集中程度、协调程度、药物功效强度及常用度,采用Kmeans聚类分析法进行统计分析。结果:对于治疗头痛中活血化瘀功效较强的药物,专家意见在川芎、红花、莪术等,川芎、赤芍、桃仁等协调程度较高,川芎、当归、赤芍等活血化瘀功效较强且临床治疗血瘀头痛中较常使用。结论:对于活血化瘀药物在治疗头痛中的应用,应以辨证论治为先,活血化瘀药物可选择川芎、当归、赤芍等,结合疼痛不同部位选用引经药。此外,虫类药物在治疗血瘀头痛中起不可替代的作用。     

Galanin influences vasopressin and oxytocin release from the hypothalamo-neurohypophysial system of salt loaded rats.

Galanin is a peptide present in the nervous system and peripheral tissues which exerts a broad range of physiological functions. The influence of centrally administered galanin (Gal; 100 pM i.c.v.) on arginine vasopressin (AVP) and oxytocin (OT) content in the hypothalamus and neurohypophysis as well as on their blood plasma concentration was estimated in male Wistar rats drinking ad libitum 2% solution of natrium chloride per 48 hours. In euhydrated rats and subsequently applied i.c.v. with Gal a significant fall in the hypothalamic and neurohypophysial content of OT but not AVP was observed, however, without simultaneous changes in these neurohormones blood plasma concentration. On the contrary, i.c.v. injection of Gal to salt-loaded rats caused a marked raise in AVP and OT level in the hypothalamus and neurohypophysis with subsequent diminution of both neurohormones concentration in blood plasma. These results suggest that in euhydrated rats Gal has an inhibitory influence on the biosynthesis as well as axonal transport of OT, but not AVP. On the contrary, in salt-loaded rats galanin restricts secretion of both neurohormones into the systemic circulation.     

Atrial natriuretic factor: radioimmunoassay and effects on adrenal and pituitary glands

A simple and sensitive radioimmunoassay was developed for measurement of immunoreactive atrial natriuretic factor (IR-ANF) in rat and human plasma and in rat atria. The two atria contain about 20 micrograms ANF per rat. The right atrium contained 2.5 times more ANF than did the left. Ether anesthesia and morphine markedly increased IR-ANF in rat plasma. The concentration of IR-ANF in plasma of clinically normal human subjects was 65.3 +/- 2.5 pg/ml. Paroxysmal tachycardia and rapid atrial pacing significantly increased IR-ANF in human plasma. Two- to seven-fold higher concentrations were found in coronary sinus blood than in the peripheral circulation. In the plasma of rats and humans, circulating ANF is probably a small-molecular-weight peptide. ANF acts on the adrenal and the pituitary. ANF inhibits aldosterone secretion from rat zona glomerulosa and steroid secretion by bovine adrenal zona glomerulosa and fasciculata. ANF stimulated the basal secretion of arginine vasopressin (AVP) in vitro and inhibited KCl-stimulated release of AVP.     

Cellular Specificity of the Blood–CSF Barrier for Albumin Transfer across the Choroid Plexus Epithelium

To maintain the precise internal milieu of the mammalian central nervous system, well-controlled transfer of molecules from periphery into brain is required. Recently the soluble and cell-surface albumin-binding glycoprotein SPARC (secreted protein acidic and rich in cysteine) has been implicated in albumin transport into developing brain, however the exact mechanism remains unknown. We postulate that SPARC is a docking site for albumin, mediating its uptake and transfer by choroid plexus epithelial cells from blood into cerebrospinal fluid (CSF). We used in vivo physiological measurements of transfer of endogenous (mouse) and exogenous (human) albumins, in situ Proximity Ligation Assay (in situ PLA), and qRT-PCR experiments to examine the cellular mechanism mediating protein transfer across the blood–CSF interface. We report that at all developmental stages mouse albumin and SPARC gave positive signals with in situ PLAs in plasma, CSF and within individual plexus cells suggesting a possible molecular interaction. In contrast, in situ PLA experiments in brain sections from mice injected with human albumin showed positive signals for human albumin in the vascular compartment that were only rarely identifiable within choroid plexus cells and only at older ages. Concentrations of both endogenous mouse albumin and exogenous (intraperitoneally injected) human albumin were estimated in plasma and CSF and expressed as CSF/plasma concentration ratios. Human albumin was not transferred through the mouse blood–CSF barrier to the same extent as endogenous mouse albumin, confirming results from in situ PLA. During postnatal development Sparc gene expression was higher in early postnatal ages than in the adult and changed in response to altered levels of albumin in blood plasma in a differential and developmentally regulated manner. Here we propose a possible cellular route and mechanism by which albumin is transferred from blood into CSF across a sub-population of specialised choroid plexus epithelial cells.     

Arginine vasopressin improves the memory deficits in Han Chinese patients with first-episode schizophrenia

The memory impairment is a core deficit in the first-episode schizophrenia patients. Arginine vasopressin (AVP) in the brain can improve learning and memory. We performed multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial to study the cognitive functioning in Han Chinese first-episode schizophrenic patients in a 12-week treatment regime with the intranasal administration of AVP (128 cases) or placebo (131 cases) in addition to the conventional treatment. The methods of positive and negative syndrome scale (PANSS), Wechsler memory scale-4th edition (WMS-IV) and event-related potential (ERP) were used to study the effects of AVP on the cognitive function. The results showed that (1) AVP concentration decreased in cerebrospinal fluid (CSF) of the right-handed Han Chinese first-episode schizophrenic patients comparing with that of the health volunteers (7.1 ± 1.5 pg/ml vs 13.3 ± 1.9 pg/ml, p < 0.01), and did not change in plasma; (2) AVP significantly improved PANSS scores including total scores, positive symptoms, negative symptoms and general psychopathology comparing with those of the placebo group; (3) AVP elevated WMS-IV scores including the long-term memory (accumulation), short-term memory (recognition, comprehension), immediate memory (number recitation) and memory quotient 4, 8 and 12 weeks after treatment; and (4) AVP did not influence the latency and wave amplitude of target stimulus of P₃₀₀ of right-handed Han Chinese first-episode schizophrenic patients. The data suggested that AVP might improve cognitive process, such as memorizing and extraction of the information although there were many changes of cognitive functions in the right-handed Han Chinese first-episode schizophrenic patients.     

Only through the brain nuclei, arginine vasopressin regulates antinociception in the rat

The effect of arginine vasopressin (AVP) on rat antinociception was investigated. Intraventricular injection of 50 or 100 ng AVP dose-dependently increased the pain threshold; in contrast, intraventricular injection of 10 μl anti-AVP serum decreased the pain threshold; both intrathecal injection of 200 ng AVP or 10 μl anti-AVP serum and intravenous injection of 5 μg AVP or 200 μl anti-AVP serum did not influence the pain threshold. Pain stimulation reduced AVP concentration in hypothalamic paraventricular nucleus (PVN), and elevated AVP concentration in hypothalamic supraoptical nucleus (SON) and periaqueductal gray (PAG), but no change in AVP concentration was detected in pituitary, spinal cord and serum. The results indicated that AVP regulation of antinociception was limited to the brain nuclei.