利培酮治疗与细胞色素P4502D6/C188T酶基因多态性的关联分析

目的　研究利培酮临床效应的个体差异与其代谢酶细胞色素P4 5 0 2D6 (cytochromeP4 5 02D6 ,CYP2D6 )酶基因多态性的相关性。方法　对 88例符合CCMD 3精神分裂症诊断标准的患者和 96例健康对照者作病例 -对照分析。精神分裂症患者给予利培酮治疗 8周 ,用阳性和阴性症状量表 (posi tiveandnegativesymptomscale ,PANSS)评分评价利培酮疗效。采用聚合酶链反应扩增及限制性片段长度多态性 (PCR RFLP)技术对CYP2D6exonⅠ的C188T位点突变进行检测 ,分析利培酮临床效应与其主要代谢酶CYP2D6 /C188T酶基因多态性的相关性。结果　中国上海地区人群的CYP2D6 /C188T突变率(弱代谢型 )为 36 .3% ,病例组和正常对照组间基因型频率总体分布比较无显著差异 (χ2 =1.15 ,df=2 ,P >0 .0 5 ) ,两组间的等位基因频率之间比较也无显著性差异 (χ2 =0 .78,df=1,P >0 .0 5 )。进行性别及有否家族史分组后分析 ,亦无差异存在 ,且CYP2D6 /C188T突变与利培酮临床效应之间并无相关性 (χ2 =1.12 ,df=2 ;χ2 =0 .0 3,df=1,P >0 .0 5 )。结论　未发现中国人CYP2D6 /C188T多态性与利培酮临床效应的个体差异有相关性。     

Pharmacological characterization of the receptor mediating the adrenergic inhibition of responses to substance P in the cingulate cortex

The excitatory responses of neurones in the anterior cingulate cortex of the rat to iontophoretically applied substance P (SP) are reduced by noradrenaline (NA) applied iontophoretically or released from noradrenergic pathways. In order to determine the receptor involved in this inhibitory effect we have studied the effects of a number of receptor-specific adrenergic agonists and antagonists on responses of cingulate neurones to SP in rats anaesthetized with chloral hydrate. Low iontophoretic currents (0-15 nA) of NA, adrenaline and the beta-agonist, clenbuterol, all strongly reduced responses to SP. Isoprenaline was also effective but less consistently so, although problems were experienced with its iontophoretic release from micropipettes. The alpha 1-agonists, phenylephrine and methoxamine were also able to reduce responses to SP. However, this reduction required higher iontophoretic currents (15-60 nA) and was associated with depressant effects on baseline firing rate. The alpha 2-agonist clonidine was only weakly active at high currents and this too was associated with depression of baseline firing. Similar weak effects were noted with dopamine. The inhibitory effects of NA on SP responses were convincingly blocked or reversed by the beta-antagonist, practolol, but not by the alpha 1-antagonist, prazosin. The reduction of SP responses by phenylephrine was also blocked by practolol but unaffected by prazosin. Finally, reduction of SP excitations by activation of the coeruleocortical pathway was also blocked by practolol applied iontophoretically to the cortical cells. These results are consistent with the hypothesis that the effect of NA on SP responsiveness in the cingulate cortex is mediated by beta-adrenoreceptors.     

Substance P and human nasal mucociliary activity

Summary Substance P (SP), a potent inflammatory agent, has been found in sensory nerve fibres in the nasal mucosa in several experimental animals as well as in man. It may participate in the inflammatory response as part of the mucosal defence against foreign materials. In experimental animals SP has been found to increase mucociliary in airway mucosa. The present study was performed in order to find out the relationship between topically applied SP and nasal mucociliary function in humans. Thirteen healthy volunteers were challenged with 65 µg SP or placebo in a randomized cross over fashion and mucociliary transport time was determined each time using the saccharine dye test. The dose of SP was chosen after an open dose-response study. No statistically significant change in the mucociliary transport time was found after challenge with SP as compared to placebo. The possible reasons for this are discussed.     

Interactions between serotonin and substance P in the spinal regulation of nociception

Interactions between 5-hydroxytryptamine (5-HT) and substance P (SP) in the mouse spinal cord were investigated using the tail-flick test and the behavioral response evoked by intrathecal (i.th.) SP or i.th. 5-HT. I.th. injection of 5-HT (20 μg) or the 5-HT₁ receptor agonists(+)-8-hydroxy-2-(di-n-propylamino)tetralin ((+)-8-OH-DPAT) (20 μg) or 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (RU 24969) (20 μg) markedly inhibited the tail-flick reflex. The effect of these compounds was reduced when SP (5 μg) was given i.th. 55 min, or 55 and 45 min before the agonists. The tail-flick latencies recorded 5 min before injection of a 5-HT agonist were similar in animals treated with SP or vehicle. The changes in the tail-flick test were not due to changes in tail skin temperature since only minimal differences in the skin temperature were recorded between the groups injected with SP or vehicle. I.th. injection of SP (10 ng) or 5-HT (2 μg) produced a similar behavioral response consisting of biting, licking and scratching of the caudal part of the body, indicative of nociceptive stimulation. The responses both to i.th. SP and 5-HT were reduced after i.th. application of SP receptor antagonist [d-Arg¹,d-Trp^7,9,Leu¹¹]-SP (Spantide) (5 μg), as well as 5 min after i.th. injection of the 5-HT receptor antagonist metergoline (4 μg). The data may indicate functional interactions between SP and 5-HT in the mouse spinal cord, which may take place in neurons involved in the processing of nociception.     

Substance P-like immunoreactivity in human cerebrospinal fluid

In a study to elucidate molecular mechanisms in pain, substance P-like immunoreactivity (SP-LI) was measured in lumbar CSF from 75 patients with lower back pain. Two samples – one before and one after lidocaine treatment – were obtained from each patient, and total SP-LI was measured in unfractionated (no HPLC) samples. SP-LI data were separated into three categories: placebo responders, pharmacological responders, and pharmacological non-responders. A significant difference was observed between the total SP-LI measurement of first and second samples of pharmacological non-responders. Distribution of SP-LI immunoreactive molecular species in two CSF patient samples (no ODS) was analyzed with a combination of reversed phase (RP) HPLC and RIA. Immunoreactivity in collected HPLC fractions was measured at calibrated retention times of synthetic SP-sulfoxide (SP-O), SP, and SP_5–11. Qualitative and quantitative differences in those HPLC-RIA metabolic profiles were observed within and between those two patients' samples. These data indicate that the type and amount of SP metabolism and SP precursor-processing differs in CSF between these two representative patients and within the short amount of time elapsed between acquiring these two samples.     

Axonal transport and tissue contents of substance P in rats with long-term streptozotocin-diabetes. Effects of the aldose reductase inhibitor ‘statil’

This study examined the axonal transport of substance P-like immunoreactivity (SPLI) and its content in dorsal root ganglion, trigeminal ganglion, stomach and ileum of non-diabetic rats and two groups of rats with streptozotocin-induced diabetes of 9 months duration. One diabetic group received the aldose reductase inhibitor ‘Statil’ throughout the period of study. To reduce morbidity all diabetic animals were given twice-weekly injections of a long-acting insulin which restricted weight loss but did not prevent regular and severe hyperglycaemia. Axonal transport of SPLI was studied by measurement of accumulation at 12 h ligatures on the left sciatic nerve. There were no differences between the 3 groups either in the calculated anterograde and retrograde mean rates of accumulation (ranges 6.0 to 7.6 and 0.38 to 0.72 mm/h respectively) or mobile fractions of SPLI (means from 0.54 to 0.58). There were, however, marked reductions in anterograde and retrograde accumulations of SPLI in the constricted nerves of the ‘untreated’ diabetics (respectively 57 and 33% of controls;P < 0.01 for both). In the ‘Statil’-treated rats these deficits were attenuated (80 and 75% of controls). Diabetes also reduced the SPLI content of unligated sciatic nerve and trigeminal ganglion (65 and 75% of controls). ‘Statil’ prevented the deficit in the ganglion, but not in the nerve. ‘Statil’ treatment prevented themyo-inositol depletion and attenuated the sorbitol and fructose accumulation seen in the sciatic nerves of the untreated diabetic animals suggesting effective inhibition of aldose reductase in this tissue. The total SPLI content of the stomach and 1-cm segments of ileum were unaltered in the diabetic animals but due to the increased weights of these tissues the SPLI content per unit weight was reduced. These changes were unaffected by ‘Statil’.     

荧光定量PCR与ELISA法检测HBV-DNA结果分析

目的 :应用荧光定量PCR方法精确检测HBV -DNA的拷贝数 ,为临床判断病毒复制程度提供指标 ;对比分析荧光定量PCR方法和ELISA方法检测HBV -DNA的结果。方法 :用荧光定量PCR法检测 10 14例用ELISA法诊断为乙型肝炎病人的血清HBV -DNA拷贝数。结果 :10 14例病人中 ,病毒拷贝数≥ 1× 10 5的 4 99例 ,阳性率4 9.2 % ;HBeAg阳性患者的HBV -DNA拷贝数≥ 1× 10 5的阳性率显著高于HBeAg阴性患者。结论 :荧光定量PCR检测HBV病毒复制情况结果准确 ,对临床工作指导意义更大 ;HBeAg是一项重要指标。     

Synthesis and biological activity of Substance P C-terminal hexapeptide and heptapeptide analogues

The analogues [Glu(OBzl)¹¹]SP_6–11 and [Glu(OBzl)¹¹]SP_5–11 of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the SCH₃ group of Met¹¹ is replaced by the COOCH₂C₆H₅ group. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD), and rat portal vein (RPV). The selectivity for the different receptors has been studied by utilizing atropine-treated guinea pig ileum (GPI + At). The results showed that both analogues are mainly active on GPI through the NK-1 receptor and that both analogues are equipotent to Substance P.     

Effect of Short-Term Ethanol Feeding on Rat Testes as Assessed by 31P NMR Spectroscopy, 1H NMR Imaging, and Biochemical Methods

31P Nuclear magnetic resonance (NMR) spectroscopy and 1H NMR imaging were used to examine the effect of short-term ethanol feeding on the rat testis. Weanling rats were pair-fed for 10 weeks either on ethanol containing liquid diet (36% ethanol of total calories) or a diet in which dextrimaltose was isocalorically substituted for the ethanol of the alcohol-containing diet. In vivo 31P NMR of the testes was used to determine the intratesticular pH and the relative concentrations of various phosphorus-containing metabolites. The integrity of the blood-testes barrier was evaluated using 1H NMR imaging following a gadolinium diethylene tetramine pentaacetic acid derivative (Gd-DTPA) administration as a vascular contrast agent. After the completion of NMR studies, the testis and the liver were freeze-clamped to allow for the assay of their adenosine-5'-triphosphate (ATP) contents. Serum was assayed for its content of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alcohol and testosterone. Ethanol feeding resulted in the following: (a) a reduction in the body weight (p less than 0.05), (b) a reduction in the testicular phosphodiesters (PDE) PDE/ATP ratio (p less than 0.05), (c) an increased change in the testis image intensity difference between pre- and post-iv Gd-DTPA images, (c) a reduction in the testicular and hepatic content of ATP, and (d) increased serum levels of AST and ALT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inflammation-induced increase in the density of neuropeptide-immunoreactive nerve endings in rat skeletal muscle

The density of substance P (SP)-, calcitonin gene-related peptide (CGRP)- and vasoactive intestinal polypeptide (VIP)-immunoreactive (ir) nerve endings was quantitatively evaluated in intact and inflamed gastrocnemius-soleus muscle of the rat. In persistently inflamed muscle (12 days after a single injection of Freund’s adjuvant into the muscle), the density of SP-ir fibres was significantly increased. CGRP- and VIP-ir fibres displayed an insignificant increase in density. The density of fibres ir for nerve growth factor (NGF) and for growth-associated protein 43 (GAP-43/B-50), a marker for axonal sprouting, regeneration and synaptic reorganisation, increased significantly in persistently inflamed muscle. The data are consistent with the established contribution of NGF on the expression of SP and GAP-43 in afferent neurones under the influence of a persistent inflammation. Received: 8 September 1997 / Accepted: 12 February 1998