Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three major lines of evidence support a role of eicosanoids and PAF in shock. Formation of each of the cyclooxygenase metabolites of arachidonate is enhanced at some point during the shock; these metabolites include PGE2, PGF2 alpha, PGI2, and TXA2. Enhanced formation of 5-HETE and the cysteinyl-LTs provides evidence for activation of the 5-lipoxygenase pathway of arachidonate metabolism, and preliminary biochemical evidence suggests that formation of PAF in anaphylactic and endotoxic shock is also enhanced. Second, TXA2, cysteinyl-leukotrienes, and, to an even greater extent, PAF are able to produce shock and death in intact animals. Third, pharmacological studies show that selective antagonists or synthesis inhibitors modify the course of the shock. While any of these lines of evidence may not by itself provide proof for a cause-effect relationship, the data taken together strongly suggest that vasoactive lipids might be involved in fundamental processes in the pathophysiology of shock. However, the role of vasoactive lipids might vary in different shock paradigms, change at various time points during the evolution of the shock, and depend on the species studied. Moreover, while the majority of the reports tend to focus on a specific substance, the metabolism of all of the eicosanoids mentioned, as well as PAF and probably other arachidonate metabolites (e.g. 15-lipoxygenase products such as lipoxins), changes during shock states. This fact probably causes most of the discrepancies in studies using specific antagonists or synthesis inhibitors to modify the state of shock. Thus, while blockade of one mediator might provide some protection, it might not be sufficient to halt or reverse the main course of the pathophysiological process. For example, the increase in vascular permeability, a fundamental phenomenon in trauma, anaphylaxis, or endotoxemia, might be mediated by PAF, LTs, PGs, peptides (e.g. kinins, substance P, CGRP) and amines (e.g. histamine in some species). Attempting to reverse such a complex phenomenon by blocking one specific factor might not be productive unless the specific substance played a key role in generation of the other factors. It seems, however, that while interactions between PGs, LTs, and PAF do occur (31, 32, 70), none of the shock states are crucially dependent on one class of the vasoactive lipids. Therefore, the therapeutic strategy should be based on multiple sites of action, either by drug combinations or multiple actions of a specific drug.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prostaglandins, leukotrienes, and platelet-activating factor in shock. 303 39

Substance P (SP), a putative peptide neurotransmitter, was measured in human lumbar cerebrospinal fluid (CSF) by radioimmunoassay. Substance P-like immunoreactivity (SPLI) was present in the CSF of 18 neurologically normal adults in concentrations ranging from 2.9 to 11.1 fmol per milliliter, with a mean of 7.0 /+- 0.6 fmol per milliliter (mean /+- SE). Slightly more than half of the CSF-SPLI cochromatographed with synthetic SP on Sephadex G-25. There was no apparent gradient in CSF-SPLI concentration over the first 30 ml of CSF removed by lumbar puncture. Mean concentrations CSF-SPLI in patients with Huntington disease, parkinsonism, miscellaneous dyskinesias, progressive supranuclear palsy, myopathy, and amyotrophic lateral sclerosis did not differ significantly from normal. Patients with neuropathy or multiple-system atrophy (Shy-Drager syndrome) had significantly reduced mean CSF-SPLI concentrations. These observations suggest that lumbar CSF-SPLI arises largely from spinal cord, nerve roots, or dorsal root ganglia, and that pathologic processes affecting these structures may be reflected by reduced levels of CSF-SPLI.
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PMID:Substance P in human cerebrospinal fluid: reductions in peripheral neuropathy and autonomic dysfunction. 616 19

The beta 2-adrenergic agonist formoterol has been shown to inhibit plasma extravasation in the respiratory mucosa associated with neurogenic inflammation as well as that caused by histamine or bradykinin. It is unknown whether these effects of formoterol are mediated through an action of sensory nerves or through a direct effect on the leaky blood vessels. In the present study we sought to determine whether capsaicin-sensitive sensory nerves are essential for the anti-edema effect of formoterol in the rat trachea. Substance P (5 micrograms/kg), PAF (hexadecyl-PAF, 5 micrograms/kg), or bradykinin (10 mg/kg) was injected intravenously to increase vascular permeability. The amount of plasma extravasation was measured with two tracers, Evans blue dye and Monastral blue pigment. The effectiveness of formoterol's anti-edema action was assessed in two groups of rats. One was pretreated with capsaicin to eliminate tachykinin-containing sensory nerves and another, the control group, was not pretreated. We found that in control rats formoterol inhibited to a similar extent the extravasation of Evans blue and Monastral blue caused by all three mediators. The highest intravenous dose of formoterol (10 micrograms/kg) reduced substance P-induced extravasation of Monastral blue by 59%, reduced PAF-induced extravasation by 74%, and reduced bradykinin-induced extravasation by 58%. Pretreatment of rats with a dose of capsaicin that eliminated at least 94% of the substance P-immunoreactive nerve fibers did not significantly reduce the effectiveness of formoterol against any of the mediators.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anti-edema action of formoterol in rat trachea does not depend on capsaicin-sensitive sensory nerves. 750 46

Airway responsiveness is increased in a variety of airway diseases. To understand the mechanism of enhanced airway responsiveness, in particular as it pertains to asthma, animal models have been developed and extensively explored. The guinea pig and Basenji-greyhound dog are the best characterized animals showing airways hyperresponsiveness and appear to bear substantial resemblances to asthmatic human subjects. Challenge with bronchoconstrictive agonist results in bronchoconstriction and transient vascular leak. Both phenomena contribute to the degree of airway narrowing. Adenosine challenge tests not only the responsiveness of the airways, but also that of the airway effector cells such as the mastocyte. Bradykinin and tachykinin cause indirect airway narrowing, probably by liberation of leukotrienes. Responsiveness can be enhanced by immune and non-immune challenges. Ozone, Sephadex, various contractile agonists (leukotriene D-4, bradykinin, platelet-activating factor), as well as certain cytokines (IL-1, IL-2, TNF-alpha) can enhance airway responsiveness. Cyclooxygenase and lipooxygenase products appear to be involved. Allergen-induced hyperresponsiveness is associated with airway inflammation and appears to involve bradykinin and PAF acutely and growth of airway smooth muscle chronically.
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PMID:[Animal models of bronchial hyperreactivity]. 751 8

Pursuing our researches on quinolizidinyl derivatives of phenothiazine and on the ground of antidepressive, diuretic, antianginal and antiarrhythmic activities of several 10-(3-dialkylamino) propionylphenothiazines (as chloracizine, moricizine, etc.), six 10-homolupinanoyl-2-R-phenothiazines were prepared and subjected to a broad pharmacological screening with in vivo and in vitro assays. Most of these compounds exerted strong antiarrhythmic activity (compounds 1, 3 and 5 were comparable or superior to lidocaine and quinidine in three tests), calcium antagonism on guinea pig ileum and left atria, antagonism to smooth muscle contractile responses induced by several agents and inhibition of rabbit platelet aggregation induced by PAF and ADP. A few other activities were characteristic of single compounds, as antagonism to central and peripheral effects of oxotremorine 1, moderate antihypertensive activity 5, local anesthetic activity and antagonism to substance P 2, antiinflammatory activity with low or absent gastric irritation 2, 3, powerful saluretic action 6, inhibition of arachidonate induced platelet aggregation 1 and antagonism to PAF induced mortality 1, 4. The last activity is very unusual and deserves further investigation. The capacity of compound 1 to displace specific ligands from several receptors was also investigated. Significant binding for M1 (IC50 = 0.03 microM), M3 (IC50 = 10 microM), sigma receptors and Na+ channels (IC50 = 1 microM) were evidentiated.
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PMID:Preparation and pharmacological activities of 10-homolupinanoyl-2-R-phenothiazines. 791 Apr 63

The (quinolizidin-1 alpha-yl)methanthiol (thiolupinine) was prepared and, utilizing the thiol group reactivity, several S-substituted derivatives were obtained among which was a group of 3-[(lupinylthio)methyl]indoles. Eight of the prepared compounds were subjected to a broad pharmacological screening that evidentiated for many of them good level of the following activities in vivo and in vitro: antiarrhythmic, local anesthetic, negative chronotropic on isolated atria, calcium antagonism on ileum and atria, inhibition of spontaneous contraction of isolated trachea, inhibition of guinea pig ileum contractions induced by angiotensin I and II, bradykinin and cholecystokinin, inhibition of platelet aggregation induced by PAF and ADP. Single compounds were remarkable for additional antagonistic activities: 4 against P1-purine receptor, 8 against substance P, 12 against methacholine and 13 strongly inhibited arachidonate induced platelet aggregation. Very peculiar was the ability of compound 6 to protect mice from PAF induced mortality.
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PMID:Thiolupinine and some derivatives of pharmacological interest. 821 67

From current information, a brief review was made on the basic properties of a possible process of eosinophil activation and degranulation. The "activated" eosinophils show the following characteristics: diminished cell density, morphologic alterations, increased surface receptors, heightened parasite killing, increased metabolic activity and prolonged survival. Immune complexes (secretory IgA, IgG, IgE) are known as potent triggering stimuli of eosinophil degranulation as well as complement fragments (C3b, C3bi). Cytokines (IL-5, GM-CSF), PAF and peptides (substance P) act both as weak degranulation inducer and degranulation enhancer. Synergism between the two pathways, Ca2+ and protein kinase C, is now recognized as a common feature of control of secretion in eosinophils.
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PMID:[Eosinophil granule proteins (MBP, ECP, EPX/EDN, EPO)--a possible process of eosinophil activation and degranulation]. 849 33

We report an immunohistochemical investigation of the striatal efferents in the striatum, globus pallidus, and substantia nigra of five patients with multiple system atrophy (MSA): olivopontocerebellar atrophy (2), striatonigral degeneration (2), and Shy-Drager syndrome (1). All patients manifested parkinsonism during the clinical course of their illness. The administration of levodopa improved the symptoms of two patients, but not of the other three. Brain tissues from five age-matched neurologically normal subjects served as controls. Immunohistochemical assays were carried with antibodies against met-enkephalin, substance P, and calbindin-D28k. Irrespective of the clinical form of multiple system atrophy, the immunoreactivity with the antibodies was reduced at the dorsolateral portion of the striatum and the ventrolateral portions of the globus pallidus and of the substantia nigra. The woolly fiber arrangement of reaction product deposits seen in both segments of the globus pallidus of normal individuals was totally absent in the ventrolateral portions of the three patients who did not have a response to levodopa. By contrast, there were positively stained woolly fibers in globus pallidum segments of the two levodopa-responsive patients, even though their number and size were decreased in comparison with controls. These results indicate that the three clinical forms of multiple system atrophy share common topographic alterations of the striatal efferent system and that the severity of the involvement correlates with the clinically observed effect of levodopa on the parkinsonism.
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PMID:Striatal efferent involvement and its correlation to levodopa efficacy in patients with multiple system atrophy. 890 45

Inflammatory mediators play a key role in acute pancreatitis and the resultant multiple organ dysfunction syndrome, which is the primary cause of death in this condition. Recent studies have confirmed the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, PAF, IL-10, C5a, ICAM-1, and substance P. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicaemia, severe burns, and trauma. The delay between the onset of inflammation in the pancreas and the development of the systemic response makes acute pancreatitis an ideal experimental and clinical model with which to study the role of inflammatory mediators and to test novel therapies. Elucidation of the key mediators involved in the pathogenesis of acute pancreatitis will facilitate the development of clinically effective anti-inflammatory therapy.
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PMID:Inflammatory mediators in acute pancreatitis. 1065 8

According to the "Guideline for Diagnosis and Treatment of Asthma" established by the Japanese Society of Allergy in 1998, inhaled adrenergic beta 2 agonists and inhaled corticosteroids are recommended for treatment of asthma. Thereafter, the development of new drugs for the treatment of asthma has begun changing. The concepts upon which the development of investigational drugs for asthma are based include improvements of drug delivery systems (ease of use, long-acting preparations, fewer side-effects), device design and appropriate auxiliary instrumentation. Moreover, chronic asthma has come to be recognized as an inflammatory disease of airway mucosa. At present, various antiallergic compounds such as tachykinin, leucotrien, PAF antagonists and others are under investigation thanks to the identification of new chemical mediators of airway inflammation and studies have progressed to the synthesis and manufacturing of new pharmaceuticals with antagonistic action. Thus, this review classified and introduced various new investigational anti-asthma and further describes the structure-activity relationships of beta 2 agonists and inhaled corticosteroids.
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PMID:[The 1999 domestic state of development of anti-asthma]. 1118 7


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