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1.
The site of antipyretic action of AD-1590 in the sequential process involved in the development of fever caused by bacterial pyrogen (LPS) was investigated in rabbits. AD-1590 (1g/ml) did not inactivate both LPS and leucocytic pyrogen (LP) and did not affect the generation of LP in thein vitro test. AD-1590 (0.1 mg/kg i.v.) prevented the fever caused by LP as well as LPS, but did not prevent the fever by PGE2 (100 ng/rabbit) injected into the preoptic anterior hypothalamic (PO/AH) regions. A significant antipyretic effect of AD-1590 on LPS-fever was found when AD-1590 (4 g/rabbit) was injected into the PO/AH regions. AD-1590 (0.4 mg/kg i.v.) did not produce antipyretic activity against 2,4-dinitrophenol-hyperthermia; the monoamine levels in the brain were not affected with AD-1590 (10 mg/kg p.o.). These results suggest that AD-1590, like acidic non-steroidal anti-inflammatory drugs, produces its antipyretic action through the central mechanisms.  相似文献   

2.
Research into the complex humoral and neurophysiological events of pyrogen-induced fever has proceeded rapidly to establish the thermal and non-thermal components of the fever syndrome. The major breakthroughs derive from the elucidation of the identity of the endogenous pyrogen interleukin 1 with the humoral factors responsible for the acute phase reaction and for the activation of lymphocytic, cellular, and immunological defence as host responses to infections. As a consequence, fever research is no longer concerned primarily with the changes in temperature regulation responsible for the febrile alteration of temperature regulation, but aims at the elucidation of the contributions that are made by both the thermal and non-thermal components of the fever syndrome to the defence of the host against the microbial intruder responsible for this syndrome. In order to account for this development in these introductory remarks to the current issues of fever research, this review has tried to pay particular attention to the following points: 1) The role of humoral factors in the generation of febrile hyperthermia, including endogenous pyrogens as well as mediators acting on the thermoregulatory center. 2) The "fever syndrome" with special consideration of its regulation and of the significance of its components from the viewpoint of fever as a host-defence reaction. 3) The assessment of the role of PG's in the generation of the fever syndrome, both as putative central mediators and as systemically released agents, with special consideration of the inhibitory action of the established antipyretic drugs on PG synthesis.  相似文献   

3.
给大鼠腹腔注射大肠杆菌内毒素(endotoxin, ET)复制发热模型,观察大鼠ET性发热时不同脑区组织cAMP含量和腺苷酸环化酶(adenylate cyclase, AC)活性的变化。结果发现:大鼠在发热高峰时与对照组比较,丘脑下部cAMP含量明显增加(P<0.01),并与体温变化呈正相关关系(r=0.827);丘脑下部AC活性也显著增强(P<0.001),也与体温变化呈正相关关系(r=0.774)。脑干AC活性显著增强(P<0.05),但与体温变化无正相关关系(r=0.203),cAMP含量也无明显变化。脑皮质cAMP含量和AC活性均无明显变化。以上结果显示:ET可能是通过共同信息物质——内生致热原(EP),以一定方式作用于丘脑下部视前区神经元的细胞膜内AC,使其活化作用于ATP,使ATP分解生成cAMP,从而使局部cAMP含量增加,再通过某种方式使体温调定点上移,导致体温升高。  相似文献   

4.
It is a requirement that parenteral medicines be tested for pyrogens (fever causing agents) using one of two animal-based tests: the rabbit pyrogen test and the bacterial endotoxin test. Understanding the human fever reaction has led to novel non-animal alternative tests based on in vitro activation of human monocytoid cells in response to pyrogens. Using 13 prototypic drugs, clean or contaminated with pyrogens, we have validated blindly six novel pyrogen tests in ten laboratories. Compared with the rabbit test, the new tests have a lower limit of detection and are more accurate as well as cost and time efficient. In contrast to the bacterial endotoxin test, all tests are able to detect Gram-positive pyrogens. The validation process showed that at least four of the tests meet quality criteria for pyrogen detection. These validated in vitro pyrogen tests overcome several shortcomings of animal-based pyrogen tests. Our data suggest that animal testing could be completely replaced by these evidence-based pyrogen tests and highlight their potential to further improve drug safety.  相似文献   

5.
Addition of cholinergic agonists, namely carbamylcholine (carbachol), acetylcholine, eserine, eserine plus acetylcholine and eserine plus choline chloride, and dibutyryl cyclic guanosine moue-phosphate inhibited the norepinephrine-induced accumulation of cyclic adenosine monophosphate in incubated slices of rat cerebral cortex. Methacholine was ineffective and atropine did not overcome the action of carbachol on the stimulation of cyclic adenosine monophosphate synthesis by norepinephrine. Carbachol stimulated the production of cyclic guanosine monophosphate in the tissue slices white norepinephrine did not influence cyclic guanosine monophosphate levels to a significant degree.The data are in keeping with the ‘Yin-Yang’ hypothesis in which under particular situations the intracellular levels of cyclic guanosine monophosphate may modulate cyclic adenosine monophosphate concentrations.  相似文献   

6.
Effects of intravenously injected endogenous pyrogen on the unit activity of temperature-responsive neurones (TR neurones) of medulla oblongata were investigated in urethanized rabbits with an intact or lesioned preoptic/anterior hypothalamic area (PO/AH). TR neurones of the medulla responded to pyrogen in the same manner as did those of the PO/AH; the firing rate in the warm-responsive neurones were depressed and the cold-responsive neurones augmented. However, one-fourth of the medullary TR neurones did not respond to pyrogen in the PO/AH intact group (the control group). Following lesion of the PO/AH, the relative frequencies of TR neurones affected by pyrogen decreased as compared with those in control, and such was suggested to be more apparent in TR neurones discharging at rates of 10 imp./sec or more. Effects of the PO/AH-lesion were also seen in that the magnitude of the facilitatory or inhibitory effect of pyrogen was reduced in the PO/AH-lesioned group as compared with the control group. In some TR neurones an antipyretic agent (Sulpyrine, 48--151 mg/kg) was found to abolish responses to pyrogen.  相似文献   

7.
In cat hypoglossal motoneurons after axotomy the synaptic efficacy of inhibitory synapses made by the lingual nerve afferent fibers was studied. The amplitude of the short- and the long-lasting inhibitory postsynaptic potential produced in tongue protruder motoneurons 24 days after axotomy by stimulation of the lingual nerve was significantly reduced in size as compared with the control on the unoperated side. In most protruder motoneurons 40 days after axotomy a large excitatory postsynaptic potential and a spike was produced by stimulation of either the ipsilateral or the contralateral lingual nerve. We have demonstrated that the decline of synaptic efficacy of inhibitory synapses for the short-lasting inhibitory postsynaptic potential was more prominent than that for the long-lasting inhibitory potential in the motoneuron 24 days after axotomy. After the cut axons of protruder motoneurons were re-united to tongue muscles, we have demonstrated that the decline of synaptic efficacy of inhibitory synapses for the short-lasting inhibitory postsynaptic potential was less prominent than that in axotomized protruder motoneurons.  相似文献   

8.
Inhibitors of cytochrome P-450 augment fever in rats and mice, indicating that the metabolite of the enzyme is candidate of endogenous antipyretic. Cytochrome P-450 of arachidonic acid cascade leads to the formation of regioisomeric 5,6-, 8,9- 11,12- and 14,15-epoxyeicosatrienoic acid (EET). Various isomers of EET were administrated into the preoptic area and anterior hypothalamus (PO/AH) to test their influence on fever induced by interleukin-1β (IL-1β) administrated into the PO/AH in conscious rats. The IL-β-induced fever was attenuated in the 11,12-EET-pretreated rats, although 5,6-, 8,9- and 14,15-EET did not affect the fever. Intra-PO/AH injection of 11,12-EET did not alter normal body temperature. The results suggest that 11,12-EET acts in the hypothalamus as an endogenous antipyretic.  相似文献   

9.
J. Folbergrová 《Neuroscience》1981,6(7):1405-1411
Cyclic AMP levels and phosphorylase a activity were investigated in the cerebral cortex of mice during seizures induced by homocysteine thiolactone, following pretreatment with various doses of propranolol and, also, after administration of subthreshold doses of homocysteine.The accumulation of cyclic AMP accompanying homocysteine-induced seizures was not influenced by theophylline, so that adenosine is not likely to be the mediator involved. Since it has been suggested that there exists a receptor for certain acidic amino acids which participates in cyclic AMP accumulation in brain cortex slices in vitro, it seemed of interest to ascertain whether homocysteine, or possibly its metabolic product, could not have a direct effect on the cyclic AMP-generating system. However, subthreshold doses of homocysteine thiolactone (which did not evoke seizures) did not influence the levels of cyclic AMP in the cerebral cortex for a period of up to 1 h. The accumulation of cyclic AMP was markedly reduced or completely prevented by pretreatment with DL-propranolol ; phentolamine exerted no effect. This suggests that, during homocysteine-induced seizures, catecholamines might interact with the cyclic AMP-generating system, possibly through β-adrenergic receptors.The increased activity of phosphorylase accompanied not only homocysteine-induced seizures, but was also present after pretreatment with subthreshold doses of homocysteine or propranolol. The pretreatment with subthreshold doses of homocysteine or 20 mg/kg propranolol enhances phosphorylase activity while cyclic AMP levels remain unchanged. This suggests that in the brain, as in some other tissues, phosphorylase activation may be independent of cyclic AMP in some situations.  相似文献   

10.
11.
清开灵对家兔内毒素性发热的作用及机制研究   总被引:7,自引:0,他引:7       下载免费PDF全文
目的:探讨清开灵(QKL)注射液对家兔内毒素性发热的解热作用和机制。方法:复制家兔内毒素(ET)性发热模型, 用数字温度计测量家兔的直肠温度, 用放免法测定下丘脑的IL-1β和cAMP、脑脊液中的cAMP、腹中隔区的AVP含量。结果:QKL+ET组的△T(0.24±0.10)℃、TRI1(1.02±0.81)、下丘脑IL-1β(3.02±0.58)ng/g、下丘脑cAMP(1.37±0.23)nmol/g、CSF中cAMP(14.13±3.80)nmol/L、腹中隔区AVP(25.24±2.61)ng/g, 分别低于ET组的△T(0.40±0.11)℃、TRI1(1.78±0.79)、下丘脑IL-1β(6.08±0.79)ng/g、下丘脑cAMP(2.90±0.40)nmol/g、CSF中cAMP(32.10±4.51)nmol/L、腹中隔区AVP(47.32±3.77)ng/g, 两者相比差异显著(P<0.01)。结论:QKL抑制下丘脑内生致热原和中枢发热介质的生成, 促进解热物质的释放, 可能是QKL对内毒素性发热的重要解热机制。  相似文献   

12.
1. A suspension of the killed cell bodies of either E. coli, S. dysenteriae or S. typhosa was micro-injected through cannulae implanted chronically at specific sites within the diencephalon and mid-brain of the unanaesthetized monkey. A biphasic, monophasic or an undifferentiated fever could be induced by each type of micro-organism, but the type of response depended solely upon the locus of injection.2. Although little difference in the potency of the three pyrogens was found, the rise in body temperature was in each instance dependent upon the concentration of the endotoxin. A more intense fever was accompanied by shivering, vasoconstriction of the ear vessels, piloerection and huddling behaviour. Tolerance to the pyrexic effect of repeated injections of endotoxin did not develop.3. The febrile response having the shortest latency, greatest maximum rise in temperature and largest 10-hr fever index was evoked by micro-injections into the anterior hypothalamic, preoptic area. The incidence of biphasic fevers was also greater after endotoxin was injected into this same region. Endotoxin given similarly in the posterior hypothalamus or in the mesencephalon had either no effect or produced a smaller elevation in temperature after a longer latency. The distance of an injection site from the coronal plane formed by the optic chiasm and anterior commissure correlated significantly with the latency and magnitude of the temperature change as well as the fever index.4. When given intravenously, endotoxin in a quantity at least 100 times greater was required to evoke a fever similar to that produced when the pyrogen was micro-injected into the anterior hypothalamic, preoptic region. However, a biphasic fever was evoked with a latency of from 3 to 15 min when a larger amount of endotoxin was injected intravenously. Tolerance developed rapidly to the febrile effect of endotoxin administered by this route although toxic reactions were not observed.5. After the fever evoked by the hypothalamic injection of endotoxin had reached a plateau, 300-1200 mg sodium salicylate administered intragastrically produced a dose-dependent fall in temperature, but had no effect on the body temperature of an afebrile monkey.6. It is concluded that in the rhesus monkey, a bacterial pyrogen can evoke a fever which is mediated entirely by an action on the central nervous system, the principal site being the anterior hypothalamic, preoptic area. The first phase of a biphasic fever caused by bacteria acting either by the central or peripheral route seems to be due either to a direct action of the pyrogen on the cells of the anterior hypothalamus, or to the secondary release within this region of an intermediary thermogenic substance such as 5-hydroxytryptamine or prostaglandin. The finding that sodium salicylate counteracts a centrally evoked fever is not compatible with the hypothesis that an antipyretic exerts its action by preventing a pyrogen that is circulating in the blood stream from entering the central nervous system.  相似文献   

13.
1. Samples of cisternal cerebrospinal fluid (c.s.f.) were collected from unanaesthetized cats while rectal temperature was continuously recorded. From the same cat, samples were collected during normal body temperature, during pyrogen fever and when the fever was brought down by an I.P. injection of an antipyretic. Fever was produced by injection of the bacterial pyrogen of Shigella dysenteriae either into the third ventricle, cisterna magna or I.V. The samples of c.s.f. were assayed for PGE(1)-like activity on the rat stomach fundus strip preparation rendered insensitive to 5-HT.2. In samples of c.s.f. collected during normal body temperature, usually either no PGE(1)-like activity was detected, or its activity was low. Higher values were obtained in only a few cats.3. In each experiment the PGE(1)-like activity increased, often many-fold, in samples collected during the pyrogen fever, irrespective, of the route of administration of the pyrogen. However, on I.V. injection, about 1000 times larger doses of the pyrogen were required than on injection into the liquor space to produce fever and the increase in PGE(1)-like activity of cisternal c.s.f.4. The antipyretic drugs indomethacin, paracetamol and aspirin, injected I.P. during the pyrogen fever, brought down temperature, and the PGE(1)-like activity of the cisternal c.s.f. again became low.5. When samples of cisternal c.s.f. were subjected to thin layer chromatography the prostaglandin-like activity was solely or mainly found in the zone corresponding to the prostaglandins of the E series.6. These findings support the theory that pyrogens produce fever by increasing synthesis and release of prostaglandin in the preoptic anterior hypothalamic area, and that antipyretics of the aspirin type bring down this fever because they inhibit this synthesis.7. It is concluded that pyrogen increases prostaglandin synthesis not only in the preoptic anterior hypothalamic area. When injected into the liquor space increased synthesis of prostaglandin probably occurs in many regions near the surface of the brain stem, and when injected I.V. may occur in other parts of the C.N.S. as well. But to produce fever the prostaglandin has to act on the preoptic anterior hypothalamic area.  相似文献   

14.
Leukocytic pyrogen and sodium acetylsalicyclate (NaASA) were microinjected into the preoptic/anterior hypothalamic (PO/AH) area of cats to examine the direct effects of these agents on identified thermoregulatory neurons. The pyrogen and NaASA were administered under thermoneutral conditions to preparations that displayed peripheral or peripheral and central thermoreceptor input. The majority of neurons studied with proximate injection of pyrogen responded in a manner consistent with the set-point hypothesis; i.e., units responding to heating with increased activity were depressed and those showing a decreased discharge with the heat test were excited by the pyretic agent. Injection of NaASA without pyrogen pretreatment caused no significant modification of thermoregulatory neuron discharge in most cases. However, when NaASA was administered after pyrogen, it uniformly antagonized the pyretic effect causing a return of the discharge to the control rate. It may be concluded that pyrogen and NaASA act directly in the PO/AH area to produce fever and antipyresis, respectively, by appropriately offsetting the activity of thermoregulatory neurons.  相似文献   

15.
The purpose of this study was to investigate the effect of dopamine on the function of synapses formed by cholinergic neurons derived from the rat retina. We used an experimental culture system in which rat striated muscle cells served as postsynaptic targets for cholinergic neurons of the retina. This culture system permitted the physiological monitoring of acetylcholine release at synapses formed by retinal neurons. We found that dopamine could facilitate evoked transmission at retina-muscle synapses. This facilitation by dopamine was reversible and could be blocked by haloperidol, a dopamine receptor antagonist. The adenosine 3':5'-phosphate analogue, 8-bromoadenosine 3':5'-phosphate, mimicked the facilitating effect of dopamine. In addition, dopamine elevated markedly the levels of adenosine 3':5'-phosphate in cultures of rat retinal cells. The results suggest that dopamine can regulate transmission through retinal neurons. Our findings support the hypothesis that a dopamine-induced facilitation of stimulus-evoked transmission involves the activation of dopamine receptors and the intracellular accumulation of adenosine 3':5'-phosphate.  相似文献   

16.
Three exogenous pyrogens (Escherichia coli lipopolysaccharide, synthetic double-stranded ribonucleic acid. Newcastle disease virus) were compared with respect to their mechanisms of fever induction in rabbits. All inducers stimulated the production of an endogenous pyrogen demonstrated in the blood as well as prostaglandins of the E group, and of cyclic adenosine 3',5'-monophosphate in the cerebrospinal fluid. The concentrations of these compounds were elevated approximately twofold as compared to the controls. Independently of the mode of induction, the fever reaction could be prevented by pretreatment with 5 mg of cycloheximide per kg, although the three fever mediators were induced as in febrile animals. Consequently, at least one additional fever mediator that is sensitive to a 30 to 50% inhibition of protein synthesis by cycloheximide has to be postulated. The comparable reactions of the rabbits after administration of different pyrogens argues for a similar fever mechanism. In contrast to fever induction there was no stimulation of endogenous pyrogen, prostaglandins of the E group, and cyclic adenosine 3',5'-monophosphate in hyperthermia as a consequence of exposure of the animals to exogenous overheating. Furthermore, hyperthermia could not be prevented by cycloheximide.  相似文献   

17.
The progressive increase of cyclic nucleotide values from normal breast tissue to benign disease to cancer suggests a natural progression of breast diseases. A promotional role for caffeine and other methylxanthines on fibrocystic breast disease in predisposed women, which has been established, coupled with epidemiological studies which showed a lower incidence of breast cancer in populations abstaining from caffeine support the hypothesized progression.  相似文献   

18.
The role of brain catecholamines in the regulation of growth hormone secretion was investigated in pentobarbital-anesthetized dogs by using drugs which modify the function of adrenergic neurons and receptors. Intravenous administration of L-dopa produced a prompt, statistically significant increase in plasma growth hormone concentration. This response was not significantly reduced by blockade of peripheral dopa decarboxylase activity with carbidopa. Clonidine, an alpha-agonist which penetrates the brain, increased plasma growth hormone secretion. Norepinephrine, epinephrine, dopamine and isoproterenol, catecholamines which do not penetrate the blood-brain barrier, failed to affect plasma growth hormone concentration when administered intravenously. Apomorphine did not produce a statistically significant increase in plasma growth hormone concentration when administered directly into the the third ventricle, and pimozide failed to abolish the increase in plasma growth hormone produced by L-dopa. The increase in plasma growth hormone concentration produced by intravenous L-dopa and clonidine was prevented by administration of phentolamine or phenoxybenzamine directly into the third ventricle. The response to L-dopa was also abolished by intraventricular procaine. In dogs in which central beta-adrenergic blockade was produced by intraventricular L-propranolol, the growth hormone response to L-dopa was greater than it was in control dogs treated with intraventricular D-propranolol. The data indicate that in pentobarbital anesthetized dogs, the increase in growth hormone secretion produced by L-dopa is mediated by norepinephrine, rather than dopamine, that the site of action of the norepinephrine is central, above the median eminence and inside the 'blood-brain barrier', and that the norepinephrine acts via alpha-adrenergic receptors.  相似文献   

19.
Presence of pyrogens on implants, medical devices, drugs and biological materials compromise on the biosafety and poses a major health hazard in therapeutics. Detection of pyrogenic contamination has so far been done with either in vivo rabbit pyrogen assay or Limulus Amoebocyte Lysate (LAL) methods, each of which having their distinct advantages and disadvantages. An indigenously developed ELISA method quantifying the pro-inflammatory response triggered by pyrogens on human whole blood is demonstrated for its versatility to detect the pyrogenic response to gram-negative, gram-positive bacteria, chemical and biological pyrogens. The method was used to test and quantitate the pyrogen levels in polymeric biomaterials. Unlike the existing pyrogen test procedures, this assay is adapted to detect all pyrogens, besides yielding faster, sensitive and quantifiable data, thereby reduce/replace animal experimentation. The method also provided insight into the possible correlation between variable blood profile among individuals and their role in determining inflammatory response to different pyrogenic stimuli.  相似文献   

20.
The antipyretic action of aminopyrine and sodium salicylate when administered by different methods to rabbits with fever were studied. After systemic administration of these antipyretics in equal doses, aminopyrine was more effective at reducing fever, but when injected into the brain, on the contrary, aminopyrine had a weaker action. Comparison of the action of pyrogens and antipyretics when injected into different parts of the cerebrospinal fluid system shows that the points of application of pyrogenic and antipyretic stimuli for their central action do not coincide exactly.  相似文献   

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