UMLS:C0030193 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iloprost is an analogue of epoprostenol (prostacyclin; PGI2; a potent but short-lived prostanoid mainly produced in the vascular endothelium) and mimics the pharmacodynamic properties of this compound, namely: inhibition of platelet aggregation, vasodilatation and, as yet ill-defined, cytoprotection. Improved metabolic and, in particular, chemical stability enhance the clinical utility of iloprost. When administered as an intermittent intravenous infusion at less than or equal to 2 ng/kg/min for 2 to 4 weeks, iloprost reduced rest pain and improved ulcer healing in 40 to 60% of patients with critical leg ischaemia, including diabetic patients, and delayed amputation in the majority of responding individuals. Similar benefits have been seen in thromboangiitis obliterans and, in patients with severe Raynaud's phenomenon, shorter courses of therapy reduced the frequency, intensity and duration of ischaemic episodes for at least 6 weeks. The very few comparative trials reported to date (i.e. vs nifedipine in Raynaud's phenomenon; vs low-dose aspirin in thromboangiitis obliterans) have favoured iloprost, but comparisons with more established agents are needed to assess this drug's value in less severe forms of peripheral ischaemia, such as intermittent claudication. At present, iloprost is administered intravenously and this is a limitation to treatment. The potent, rapidly reversible antiplatelet activity of iloprost suits it for use in extracorporeal circulation and for the intraoperative management of heparin-induced platelet activation. Although results in animal models of ischaemic myocardial injury are encouraging, preliminary clinical experience in patients with myocardial ischaemia or infarction has been disappointing. Most patients tolerate iloprost infusion rates of up to 2 ng/kg/min. Headache and flushing are extremely common and are the suggested end-point of dose titration, as higher doses are associated with a significant incidence of gastrointestinal distress and, ultimately, hypotension. Thus, iloprost provides a pharmacotherapeutic option for patients with severe peripheral vascular disease, a condition for which few alternative drug therapies exist. Its potent but short-lived effects make it well-suited to certain therapeutic niches such as the management of intraoperative platelet activation. Prostanoid analogues have far-reaching therapeutic potential and further experience with iloprost will no doubt help to define its clinical applications.
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PMID:Iloprost. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peripheral vascular disease, myocardial ischaemia and extracorporeal circulation procedures. 137 60

Changes in platelet function have been observed for sickle cell disease (SCD). Levels of the arachidonic acid metabolites, thromboxane A2 (released by stimulated platelets) and prostacyclin (released from vascular endothelium), which stimulate and inhibit platelets, respectively, have been implicated in overall regulation of platelet function. Circulating basal levels of thromboxane and prostacyclin were determined in 1) a group of SCD volunteers (n = 21; at half-yearly steady state intervals and also at 24 hr, 72 hr, and 7 days after start of pain crisis) and 2) an age-, sex-, and race-matched control group (n = 18; single determinations). Circulating levels of beta-thromboglobulin (beta-TG), as well as thrombin (clotting)-stimulated platelet release of thromboxane, were also determined. Statistically significant decreases were found for prostacyclin, basal thromboxane, and thrombin-induced (maximal) thromboxane (alone or per platelet), for steady state SCD vs. normal controls. In addition, significant increases in maximal thromboxane were identified in crises (24, 72 hr) compared with steady state. Crisis beta-TG (24 hr) was significantly elevated compared with controls or steady state SCD. The ratio of basal thromboxane to prostacyclin was increased in crisis, but not significantly. Crisis frequency may correlate in part with changes in platelet function: steady state maximal thromboxane and released thromboxane per platelet were significantly lower in SCD volunteers who had crises during the study vs. those who did not (equivalent study time). The data support altered platelet function in SCD, possibly refractoriness (desensitization), manifest as decreased thromboxane release, to thrombin and/or other stimuli: alternate explanations are discussed.
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PMID:Platelet regulatory prostanoids and platelet release products in sickle cell disease. 153 87

We have conducted a series of studies using discontinuous arabinogalactan density gradient ultracentrifugation of erythrocytes from the peripheral blood of: patients with sickle cell anemia (SCA), in and out of pain crisis; hydrated SCA, hemoglobin SC, and normal individuals all of whom were pain-free; and patients with SCA given short courses of oral vasodilator compounds. Our results indicate that in pain crisis patients develop an echinocytic change that is most prominent in the denser layers (specific gravity greater than 1.128 g/ml) of the discontinuous gradient and effects both irreversibly sickled cells (ISC) and non-ISC. This echinocytic change, we have previously shown, correlates with a decrease in erythrocyte reduced glutathione, a major intraerythrocyte anti-oxidant compound. We could find no consistent change in the percentage of dense cells in pain crisis versus out of crisis. However, out of crisis, hydration led to a marked increase in the percentage of dense erythrocytes in sickle cell anemia and in a HbSC patient, compared to the same individual out of crisis and on ad lib fluids. There was no consistent change in echinocytic forms. Because hydration may be expected to have produced an increase in intravascular volume and vasodilation, we determined whether short courses of three different vasodilators would increase the dense fraction in patients with SCA who were pain-free. There was no change in percentage of dense erythrocytes or in the percentage of echinocytes. We concluded that painful crisis occurs in association with an echinocytic change that may be induced by oxidant injury and that in the pain-free state, hydration, but not short courses of vasodilator drugs, increased the percentage of dense erythrocytes but not the degree of echinocytosis they displayed. The differential effect of hydration, with respect to painful crisis, may indicate that these dense cells are bound to vascular endothelium or trapped in blood vessels at the time of crisis but mobilized by hydration in the out-of-crisis state.
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PMID:Painful crisis and dense echinocytes: effects of hydration and vasodilators. 361 3

The non-ionic X-ray contrast media metrizamide, iopamidol, iohexol, and iopromide do not bind calcium and are less hyperosmolar than the conventional ionic contrast media, for instance amidotrizoate (diatrizoate), iothalamate, or ioglicate. Hence the use of non-ionic contrast media is associated with less undesirable side-effects that are attributable to hypertonicity such as an increase in circulating plasma volume, decreased deformability of red blood cells, damage of vascular endothelium with consequent activation of blood coagulation, the complement system and fibrinolysis, increased release of bradykinin and histamine, cardiac arrhythmias, diuresis, vasodilation and decreased blood pressure, pain and heat sensation. Because of less dilution the quality of imaging is also better. According to the intravenous LD50 in experimental animals the acute toxicity of non-ionic contrast media is lower than that of ionic media. With respect to contrast quality and the rate of side-effects the various non-ionic contrast media appear to be equivalent. Despite their higher price and higher viscosity it is probable that the non-ionic contrast media will replace the classical ionic media, especially in angio- and myelography.
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PMID:[Pharmacology of nonionic roentgen contrast media]. 372 93

Pain block in obstetric epidural anesthesia is usually accompanied by relatively persistent retention of motor power; however, the reason for this is not entirely clear. The differential effect has been ascribed to a relatively high resistance of large fibers to conduction block. However, recent results from individual axons are incompatible with that explanation and have prompted the suggestion that greater vascularity in ventral than in dorsal roots might account for the phenomenon. To test this hypothesis, transverse sections of five sets of human dorsal and ventral C-8, T-7, and L-5 roots were examined by an immunohistochemical method that is specific for factor VIII and stains the vascular endothelium. A naive tally of the stained vessels failed to reveal any excess vascularity of the ventral roots, and the hypothesis was therefore rejected. However, it was noted at autopsy that the thin dural sleeve surrounding the roots, where epidural anesthetic is most likely to penetrate to the nerve fibers, may measure less than 5 mm from the dural sac to the intervertebral foramen, a distance probably too short to contain three internodes of motor fibers, the minimum length of fiber necessary for block by local anesthetic. This anatomy might help explain the clinical differential.
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PMID:Mechanism of differential epidural block. 395 7

All current intravascular radiological contrast media are salts and produce solutions of very high osmolality--five to eight times that or tissue cells, plasma or tissue fluid (all of which have an osmolality of 300 mosmols per kg water). Erythrocytes and vascular endothelium are adversely affected by the high osmolality of intravascular contrast media, resulting in tissue anoxia and increased capillary permeability, the latter causing damage to the blood-brain barrier. Vasodilatation, systemic hypotension and osmotic hypervolaemia are generalized manifestations of the high osmolality of contrast media. New low osmolality contrast media have been synthesized, utilizing a non-ionizing radical (such as amide or amine) instead of the carboxyl group of a tri-iodinated substituted benzoic acid. Such examples are metrizamide (Amipaque) and Iopamidol (both non-ionic amides) and Hexabrix (salts of a mono-acid dimer). Early clinical evaluation suggests that these low osmolality solutions have major advantages in reducing pain, heat sensation and adverse reactions of angiography.
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PMID:Osmolality of intravascular radiological contrast media. 743 83

Vaso-occlusive pain episodes in sickle cell anemia are hypothesized to be precipitated by adherence of sickle erythrocytes to vascular endothelium in the microcirculation. Febrile episodes, thought to be viral in etiology, are frequently associated with vaso-occlusion; however, a direct link between viral infection and vascular occlusion has not yet been established. Many pathogenic viruses contain double-stranded RNA or replicate through double-stranded RNA intermediates. Double-stranded RNA has been shown to induce vascular cell adhesion molecule-1 (VCAM-1) protein expression on endothelial cells. Recently, a new adhesion pathway has been described between VCAM-1 expressed on cytokine stimulated endothelium and the alpha 4 beta 1 integrin complex expressed on sickle reticulocytes. Based on these observations, the hypothesis was developed that viral infection, through double-stranded RNA intermediates, increases endothelial VCAM-1 expression leading to sickle erythrocyte adhesion to endothelium via an alpha 4 beta 1-VCAM-1--dependent mechanism. In support of this hypothesis, endothelial cells exposed to the synthetic double-stranded RNA poly(I:C) or the RNA virus parainfluenza 1 (Sendai virus) express increased levels of VCAM-1 and support increased sickle erythrocyte adherence under continuous flow at 1.0 dyne/cm2 shear stress as compared with unstimulated endothelium. Blocking antibodies directed against either VCAM-1 on the endothelium or alpha 4 beta 1 on sickle erythrocytes inhibit nearly all of the increased sickle cell adherence caused by poly(I:C) or Sendai virus. These results support the hypothesis that viruses, through double-stranded RNA elements, can induce sickle erythrocyte adherence to endothelium through alpha 4 beta 1-VCAM-1--mediated adhesion and provide a potential link between viral infection and microvascular occlusion precipitating sickle cell pain episodes.
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PMID:Double-stranded RNA induces sickle erythrocyte adherence to endothelium: a potential role for viral infection in vaso-occlusive pain episodes in sickle cell anemia. 753 85

Adherence of erythrocytes to vascular endothelium likely contributes to the pathophysiology of episodic vascular occlusion in patients with sickle cell disease (SCD). In addition, coagulation activation has been reported in sickle patients during complications such as pain episodes. To test the hypothesis that platelet activation contributes to sickle erythrocyte binding, we investigated whether factors released from activated sickle platelets promote adherence of sickle erythrocytes to human microvascular endothelial cells (MEC) under flow conditions. Activated sickle platelet supernatant (ASPS) promoted high levels of sickle erythrocyte adherence to MEC (55.4 +/- 3.9 erythrocytes/mm2) but only moderate adherence of normal erythrocytes to MEC (14.1 +/- 0.7 erythrocytes/mm2). When MEC were incubated with an antibody (OKM5) against CD36 (a thrombospondin [TSP] receptor), platelet supernatant mediated sickle erythrocyte adherence was inhibited 86%, suggesting that TSP participated in the adherence. To further define the role of TSP in adherence, additional studies using purified TSP were performed. At a concentration of 0.2 micrograms/mL TSP in serum-free media (SFM), sickle erythrocyte adherence to MEC was 33.9 +/- 2.7 erythrocytes/mm2 and sixfold greater than either sickle erythrocyte adherence in the absence of TSP or normal erythrocyte adherence in the presence of TSP. Doubling the concentration of TSP to 0.4 micrograms/mL proportionally increased adherence of sickle erythrocytes. Incubation of MEC with OKM5 or anti-alpha v monoclonal antibodies inhibited TSP-mediated sickle erythrocyte adherence more than 95%. These data suggest that activated platelet release factors, including alpha-granule TSP, which promote receptor-mediated sickle erythrocyte adherence to microvascular endothelium. Such factors released during in vivo platelet activation could contribute to vaso-occlusive complications by promoting erythrocyte adherence and microvascular occlusion.
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PMID:Thrombospondin from activated platelets promotes sickle erythrocyte adherence to human microvascular endothelium under physiologic flow: a potential role for platelet activation in sickle cell vaso-occlusion. 847 71

Previous studies show that oral antihistamines affect the weal and flare response to intradermal injections of the inflammatory mediators platelet-activating factor (PAF) and bradykinin (BK). The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on weal and flare responses to PAF and BK in healthy non-atopic human volunteers. The effects of doxepin on PAF responses were investigated, as there is evidence that doxepin may have direct anti-PAF effects in addition to its known antihistaminic actions. Terfenadine significantly reduced weal and flare responses to PAF (mean reduction 53 and 73%, respectively) and flare responses to BK (mean reduction 78%) but had no effect on weal responses to BK. Doxepin significantly reduced both weal and flare responses to PAF (mean reduction 43 and 68%, respectively, at higher doses of PAF). Cimetidine had no effect on weal or flare responses to PAF or BK. These findings suggest that the flare response to intradermal BK is mediated via histamine release while the weal response is not. The effects of the various antagonists of PAF-induced responses suggest that its effects too may be mediated via histamine, the similarity of the effects of terfenadine and doxepin on these responses indicating that the effects of doxepin may be due to its known antihistamine activity rather than to any specific PAF-antagonistic properties. Platelet-activating factor (PAF) is a phospholipid which is released from a wide range of cell types and also from vascular endothelium. PAF is formed by the conversion of ether-linked phospholipids initially to the biologically inactive lyso-PAF and then by acetylation to PAF. Intradermal injection of PAF in human skin causes vasodilatation and increased vascular permeability, producing a weal and flare response with accompanying pruritus. Bradykinin (BK) is a vasoactive polypeptide formed by the action of enzymes known as kallikreins on inactive precursors called kininogens. Its effects include an increase in blood flow and vascular permeability and stimulation of the release of prostaglandins and histamine. On intradermal injection in human skin it causes a weal and flare response with associated pain rather than pruritus. Previous studies have suggested that the weal and flare response to PAF may be mediated in part by histamine release. Given that BK is known to cause histamine release it appears possible that the responses to both compounds may be modified by conventional antihistamines. Experiments based on this premise have found that antihistamines have a pronounced effect on the flare response to PAF but a less marked effect on weal responses. The weal response to BK was unaffected by systemic antihistamines but studies have produced conflicting results with regard to effects on the flare response. The aim of this study was to compare the effects of terfenadine (an H1-antagonist) and cimetidine (an H2-antagonist) on PAF- and BK-induced weal and flare responses in healthy, non-atopic human volunteers. Based on the treatment of cold urticaria it has been suggested that doxepin, which has known H1- and H2-antagonistic effects, may in addition show specific anti-PAF activity. We compared the effects of doxepin on PAF-induced intradermal responses with those of terfenadine and cimetidine in this study.
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PMID:Effects of H1- and H2-antihistamines on platelet-activating factor and bradykinin-induced inflammatory responses in human skin. 868 66

Adherence of sickle erythrocytes to vascular endothelium likely initiates or participates in microvascular occlusion, leading to ischemic tissue and organ damage characteristic of sickle-cell pain episodes. In vitro, sickle-cell adherence to endothelium involves adhesive plasma proteins and integrin and nonintegrin receptors on sickle cells and endothelial cells. The involvement of arginine-glycine-aspartic acid (RGD) sequences in adhesive plasma proteins and integrin receptors suggests that RGD-containing peptides may inhibit sickle-cell/endothelial-cell adherence. In the present study, inhibition of plasma-mediated sickle-erythrocyte adherence to endothelium using conformationally constrained RGD-containing peptides was quantified in vitro under continuous flow at a shear stress of 1.0 dyn/cm2. Two conformationally constrained RGD peptides were investigated: 6Z (which has high affinity for alpha5beta1, alpha(V)beta3, and alpha(IIIb)beta3 integrin receptors), and TP9201 (which preferentially binds to alpha(IIb)beta3). Peptide 6Z at 50 microM inhibited plasma-mediated sickle-cell adherence to microvascular endothelium 70% when incubated with sickle red cells, and 63% when incubated with endothelium. Under similar conditions, peptide TP9201 inhibited plasma-mediated sickle-cell adherence up to 85% at concentrations from 250 to 500 microM TP9201. The inhibition of plasma-mediated adherence by conformationally constrained RGD peptides, but not by linear or circular constructs, suggests that the tertiary structure of the peptide containing the binding sequence is important. Inhibition of plasma-mediated sickle-cell adhesion with these peptides in vitro suggests that such conformationally constrained RGD peptides could provide therapeutic interventions in the course of the disease by inhibiting receptor-ligand interactions.
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PMID:Inhibition of plasma-mediated adherence of sickle erythrocytes to microvascular endothelium by conformationally constrained RGD-containing peptides. 889 33

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