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)

Topically administered ketorolac (Acular), a cyclooxygenase inhibitor, has recently been reported as clinically beneficial for treating allergic conjunctivitis. The ability of ketorolac to relieve the itching associated with allergic conjunctivitis is intriguing because cyclooxygenase inhibitors are not regarded as useful in treating allergic dermatoses and prostaglandins (PG) do not elicit an itch response in human skin. To gain further insight into the mechanisms involved in the antipruritic activity of ketorolac, we used a method of reproducibly assessing ocular surface itch responses in the guinea pig. The measurement of conjunctival pruritus involved a recently developed behavioral model whereby hind limb scratching episodes directed toward the afflicted area were quantified. Itch-scratch episodes have previously been delineated from foreign body and pain sensations, which do not evoke such a behavioral response. Ketorolac significantly inhibited the itching associated with experimental allergic conjunctivitis. The basis of this antipruritic activity may be ascribed to preventing the biosynthesis of itch-producing PGs because ketorolac inhibited arachidonic acid-induced pruritus. In contrast to skin studies, PGE2 and PGI2 were found to be potent pruritogens at the guinea pig ocular surface. PGD2 was a weak pruritogen, and PGF2 alpha and the thromboxane-mimetic U-46619 produced no meaningful response. Further studies involving selective agonists and antagonists suggested that EP1 receptors, IP receptors and PGD2-sensitive receptors may mediate prostanoid-induced conjunctival itching. No evidence for the involvement of other prostanoid receptor subtypes was obtained. Although the EP1 receptor antagonist AH 6809 and the DP receptor antagonist BW A868C inhibited PGE2- and PGD2-induced itching, respectively, neither antagonist alone significantly affected the itching associated with experimental allergic conjunctivitis. A combination of AH 6809 and BW A868C, however, did exhibit antipruritic activity. It appears that for effective relief of itching in allergic conjunctivitis, it is not sufficient to block the effects of a single pruritogenic PG. It is preferable to reduce the participation of all pruritogenic PGs by either using combined receptor antagonists or by using a cyclooxygenase inhibitor such as ketorolac to block their biosynthesis.
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PMID:Characterization of receptor subtypes involved in prostanoid-induced conjunctival pruritus and their role in mediating allergic conjunctival itching. 885 86

In two female patients with an ischaemic peripheral disease, 49 and 32 years old, thromboangiitis obliterans (Buerger's disease) was diagnosed. One suffered from ulceration of her left second toe, the other from pain of both hands followed by ulceration of two fingers. Both were smokers. Surgical treatment (amputation) was required, and they also had a prostacyclin infusion. They recovered and stopped smoking. Thromboangiitis obliterans is a non-arteriosclerotic, segmental occlusive disease of medium-sized and small arteries and veins, occurring predominantly in young male habitual smokers. In the nineteen-seventy less than 2% were women, but recent publications mention 23%, an increase which may be attributed to increased smoking in women. Recognition of Buerger's disease in women with peripheral occlusive arterial disease is important; the prognosis is good if they stop smoking.
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PMID:[Thromboangiitis obliterans (Buerger's disease) in 2 women]. 892 30

Sympathetic post-ganglionic neurons may be involved in the generation of pain, hyperalgesia and inflammation under pathophysiological conditions. Two categories of influence of the sympathetic neuron on afferent neurons can be distinguished and this distinction seems to be related to whether the coupling between afferent and sympathetic neuron develops after nerve lesion or after tissue trauma with inflammation (Fig. 15): A. Peripheral nerve lesion generates plastic changes of the afferent and sympathetic postganglionic neurons, depending on the type of nerve lesion (e.g. complete, partial). Both afferent and post-ganglionic neurons exhibit degenerative and regenerative changes and unlesioned neurons may show collateral sprouting in the periphery as well as in the dorsal root ganglion. This reorganization of the peripheral neurons may lead to chemical coupling between sympathetic and afferent neurons. The coupling is responsible for sensitization and/or activation of primary afferent neurons by the sympathetic neurons. The mediator probably is norepinephrine, but other substances cannot be excluded. The afferent neuron expresses or upregulates functional adrenoceptors. The type of adrenoceptor involved is probably alpha 2. The coupling may occur at different sites of the primary afferent neuron, e.g. at the lesion site, remote from the lesion site in the dorsal root ganglion or between nonlesioned sympathetic and afferent neurons which show collateral sprouting. The biochemical signals which trigger these changes probably are neurotrophic substances, their receptors which are synthesized by the peripheral neurons, Schwann cells and other cells in response to the peripheral lesions. B. Sympathetic nerve terminals in peripheral tissues may serve as mediator elements in hyperalgesia and inflammation following tissue trauma without nerve lesion. Experiments show that these functions are largely independent of activity in the sympathetic neurons and independent of vesicular release of transmitter substances (such as norepinephrine). Sensitization of nociceptive afferents for mechanical stimuli and venular plasma extravasation in the synovium which are induced by the inflammatory mediator bradykinin are, at least in part, dependent on the sympathetic terminal. The signal to venules and afferent receptors is synthesized and released from the sympathetic terminal or in association with it. It is a prostaglandin (probably PGE2). Sympathetically mediated (neurogenic) inflammation and neurogenic inflammation mediated by afferents may interact reciprocally and enhance the inflammatory process as well as the sensitization of nociceptive afferents. Norepinephrine may also lead to sensitization of nociceptive afferents under inflammatory conditions. This sensitization is presumably mediated by alpha 2-adrenoceptors in the sympathetic varicosities and by a prostaglandin (probably PGI2) which is synthesized and released by or in association with the sympathetic varicosities.
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PMID:Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma. 900 34

Prostanoids are a group of bioactive lipids working as local mediators and include D, E, F and I types of prostaglandins (PGs) and thromboxanes. Prostacyclin (PGI2) acts on platelets and blood vessels to inhibit platelet aggregation and to cause vasodilatation, and is thought to be important for vascular homeostasis. Aspirin-like drugs, including indomethacin, which inhibit prostanoid biosynthesis, suppress fever, inflammatory swelling and pain, and interfere with female reproduction, suggesting that prostanoids are involved in these processes, although it is not clear which prostanoid is the endogenous mediator of a particular process. Prostanoids act on seven-transmembrane-domain receptors which are selective for each type. Here we disrupt the gene for the prostacyclin receptor in mice by using homologous recombination. The receptor-deficient mice are viable, reproductive and normotensive. However, their susceptibility to thrombosis is increased, and their inflammatory and pain responses are reduced to the levels observed in indomethacin-treated wild-type mice. Our results establish that prostacyclin is an antithrombotic agent in vivo and provide evidence for its role as a mediator of inflammation and pain.
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PMID:Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. 926 2

The prognosis of cholesterol embolism is often poor, and no treatment is presently available. We report the use of a stable prostacyclin analogue in treating cholesterol embolism in a diabetic patient with arteriopathy. As a sole therapy, it improved cutaneous manifestations and pain, in parallel with an increased transcutaneous oxymetry. We think that prostacyclin analogues are novel candidates for the treatment of cholesterol embolism.
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PMID:Use of a prostacyclin analogue in cholesterol crystal embolism. 954 30

The most serious threat to a claudicant is not the possible future need for a major amputation, but rather that the medium-term mortality is two to three times that of the general age-matched population. In patients with more severe disease in the legs, approximately 45% will have had a major amputation or be dead within a year of developing rest pain, ulcers or gangrene. These are the challenges for pharmacotherapy in peripheral arterial occlusive disease. In the short and medium term, pharmacotherapy can only have a significant effect by modifying the microcirculatory response to the low perfusion pressure caused by the arterial disease. The microcirculatory changes in the leg in severe leg ischaemia are ill understood, but theoretically a number of pharmacological effects could be beneficial. In practice, the only type of drugs widely tested clinically in severe leg ischaemia are prostacyclin and its analogues. In the last 12 years the results of properly controlled randomized trials involving patients with chronic limb ischaemia have been carried out in approximately 2000 patients in Europe. The largest number were entered into trials using the prostacyclin analogue iloprost. Some of these trials have shown a significant benefit compared to placebo in terms of major amputation or death during the 6 months following a 2-4 week course of intravenous iloprost. The possible future indications for this type of therapy, as well as the use for prostaglandins in claudicants, is discussed.
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PMID:Prostanoid drug therapy for peripheral arterial occlusive disease--the European experience. 954 31

Prostanoid receptor-mediated sensitization of sensory nerve fibres is a key contributor to the generation of hyperalgesia. It is generally thought that prostaglandin (PG) E2 is the principal pro-inflammatory prostanoid. Consequently, prostanoid EP receptors on sensory neurones have been identified as potential therapeutic targets. However, IP prostanoid receptors are also present on sensory neurones, and recent data from transgenic mice lacking the IP receptor demonstrate its importance in the induction of oedema and pain behaviour. PGI2, the primary endogenous agonist for the IP receptor, is rapidly produced following tissue injury or inflammation; thus, it may be of equal, or greater, importance than PGE2 during episodes of inflammatory pain. In this review, Keith Bley, John Hunter, Richard Eglen and Jacqueline Smith compare the roles of EP and IP receptors in nociception and suggest that the IP receptor constitutes a novel target for anti-nociceptive agents.
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PMID:The role of IP prostanoid receptors in inflammatory pain. 961 89

Prostaglandins are generated through two isoforms of the enzyme cyclooxygenase, the constitutively expressed cyclooxygenase (Cox)-1 and Cox-2, which is induced at sites of inflammation. Selective inhibition of Cox-2 is desirable as this may avoid the gastropathy and platelet inhibition seen with nonselective agents. Moreover, these agents will allow us to examine the relative contribution of the two isoforms to prostaglandin formation in man. We examined the activity of nimesulide, a Cox-2 selective nonsteroidal antiinflammatory drug, in vitro against purified enzymes and in vivo in man. Nimesulide 100 mg twice daily or aspirin 300 mg three times daily were administered randomly for 14 days to 20 subjects complaining of musculoskeletal pain. Serum thromboxane B2 was determined as an index of Cox-1 activity and endotoxin-induced prostaglandin E2 formation in whole blood as an index of Cox-2 activity. Urinary excretion of prostaglandin metabolites was determined by GC/MS. Nimesulide was highly selective against ovine Cox-2, so that at concentrations attained in vivo, it had no effect on Cox-1 but completely suppressed Cox-2. Aspirin markedly inhibited serum thromboxane B2 (181.92 +/- 19.77 to 2.83 +/- 0.96 ng/ml, P <. 002), whereas nimesulide had very little effect (207.53 +/- 47.30 to 181.15 +/- 54.59 ng/ml). In contrast, nimesulide suppresses endotoxin-induced prostaglandin E2 formation (35.03 +/- 8.73 to 2.62 +/- 0.95 ng/ml, P =.002). As expected, aspirin reduced TX metabolite excretion, whereas nimesulide had no significant effect. In contrast, both compounds suppressed PGI2 formation to the same extent. The findings suggest that TX is largely Cox-1 derived. Moreover, Cox-2 is expressed in man and generates prostaglandin I2.
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PMID:Selective cyclooxygenase-2 inhibition by nimesulide in man. 980 83

Cyclooxygenase (COX)-2 is the predominant COX isoform present at sites of inflammation, and produces prostaglandins (PG) that cause swelling and pain. However, in situations where the release of protective PGs by COX-1 has been lost, the induction of COX-2 may compensate and reduce inflammatory responses. This is particularly likely in large blood vessels, where, under physiological conditions, the release of prostacyclin by COX-1, present in the endothelium, is an important component of cardiovascular homeostasis. We, and others, have recently shown that COX-2 can be induced by proinflammatory cytokines in human blood vessels, and also in human airway cells. Moreover, recent data from our group have suggested that in these structures, COX-2 is anti-inflammatory at the level of cellular proliferation, adhesion receptor expression, and cytokine release.
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PMID:Cyclooxygenase-2 as a therapeutic target. 983 29

The authors, after examination of pharmacologic profile of Iloprost, prostacyclin synthetic analogue, report their clinical experience from January 1992 to June 1997 on 105 patients with severe ischaemia of inferior limbs. They utilize two protocols: 0.5-2 ng/kg/min x 6 hs once a day x 28 days and 1-1.5 ng/kg/min x 6 hs twice a day x 12 days. The first protocol were practise along the first 2 years; the second on following period as long as today. The results, evaluated on clinical criteria, are referred entity and time of pain remission and decrease of analgesic use, performance status improvement, increase of gear autonomy and, if present, wound healing. The incidence of amputation was 4.76% (5 pts). The authors issue that Iloprost is a conservative treatment, often alternative with amputation, giving sometimes to patients a longtime functional "restitutio ad integrum".
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PMID:[Our experience in using a synthetic prostacyclin analog in the treatment of critical ischemia of the extremities]. 983 85


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