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)

In a randomized open controlled study the clinical effects and tolerability of prostaglandin E1 (PGE1) and the stable prostacyclin (PGI2) analogue, iloprost in the management of diabetic and non-diabetic patients with advanced peripheral arterial occlusive disease (PAOD Fontaine stage IV) were compared. 267 patients were enrolled in this multicentre study and treated for 21-28 days, either by daily infusions of 6 h with iloprost or 2 x 2 h with PGE1. At the end of treatment patients were assessed for evidence of improvement of trophic lesions, relief of rest pain and change of global clinical status. 228 patients were considered as evaluable for efficacy analysis, which revealed 52.7% responders in the iloprost group and 43.1% for PGE1 (p = 0.148). Whereas iloprost showed similar effects in diabetics and non-diabetics (53.3% and 51.4% response rates, respectively), the diabetics treated with PGE1 had a considerably poorer outcome (36.6% versus 53.3%). At 6 months follow-up 62.2% of patients in both groups were alive with a viable limb. Slightly more iloprost patients underwent major amputation (32.1% versus 27.2%), but the number of deaths was reduced by 50% in the iloprost group compared to the PGE1 group (7.5% versus 14.6%, p = 0.10). Side-effects such as headache, flushing and gastrointestinal symptoms were significantly more common in the iloprost group (73.9%) than in the PGE1 group (31.0%), particularly during the first 3 days of dose titration. No specific toxic or unexpected reactions were reported in either group.
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PMID:Treatment of patients with peripheral arterial occlusive disease Fontaine stage IV with intravenous iloprost and PGE1: a randomized open controlled study. 769 55

Excessive release of kinin (BK) in the synovial fluid can produce oedema, pain and loss of functions due to activation of B1 and B2 kinin receptors. Activation of the kinin forming system could be mediated via injury, trauma, coagulation pathways (Hageman factor and thrombin) and immune complexes. The activated B1 and B2 receptors might cause release of other powerful non-cytokine and cytokine mediators of inflammation, e.g., PGE2, PGI2, LTs, histamine, PAF, IL-1 and TNF, derived mainly from polymorphonuclear leukocytes, macrophages, endothelial cells and synovial tissue. These mediators are capable of inducing bone and cartilage damage, hypertrophic synovitis, vessel proliferation, inflammatory cell migration and, possibly, angiogenesis in pannus formation. These pathological changes, however, are not yet defined in the human model of chronic inflammation. The role of kinins and their interacting inflammatory mediators would soon start to clarify the detailed questions they revealed in clinical and experimental models of chronic inflammatory diseases. Several B1 and B2 receptor antagonists are being synthesized in an attempt to study the molecular functions of kinins in inflammatory processes, such as rheumatoid arthritis, periodontitis, inflammatory diseases of the gut and osteomyelitis. Future development of specific potent and stable B1 and B2 receptor antagonists or combined B1 and B2 antagonists with y-IFN might serve as a pharmacological basis for more effective treatment of joint inflammatory and related diseases.
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PMID:Pathogenic responses of bradykinin system in chronic inflammatory rheumatoid disease. 770 72

1. Intrathecal (i.t.) administration of prostaglandin E2 (PGE2) to conscious mice induced allodynia, a state of discomfort and pain evoked by innocuous tactile stimuli, and hyperalgesia as assessed by the hot plate test. We characterized prostaglandin E receptor subtypes (EP1-3) involved in these sensory disorders by use of 7 synthetic prostanoid analogues. 2. Sulprostone (EP1 < EP3) induced allodynia over a wide range of dosages from 50 pg to 5 micrograms kg-1. The maximal allodynic effect was observed at 5 min after i.t. injection, and the response gradually decreased over the experimental period of 50 min. This sulprostone-induced allodynia showed a time course similar to that induced by PGE2. 3. 17-Phenyl-omega-trinor PGE2 (EP1 > EP3) and 16,16-dimethyl PGE2 (EP1 = EP2 = EP3) were as potent as PGE2 in inducing allodynia, and more potent than sulprostone. Butaprost (EP2), 11-deoxy PGE1 (EP2 = EP3), MB 28767 (EP3), and cicaprost (prostaglandin I2 (IP-) receptor) induced allodynia, but with much lower scores. 13,14-Dihydro-15-keto PGE2, a metabolite of PGE2, did not induce allodynia. 4. 16,16-Dimethyl PGE2 as well as PGE2 induced hyperalgesia over a wide range of dosages (16,16-dimethyl PGE2: 5 pg-0.5 micrograms kg-1 PGE2: 50 pg-0.5 micrograms kg-1) with two apparent peaks at 0.5 ng kg-1 and 0.5 micrograms kg-1. Sulprostone (EP1 < EP3) and 17-phenyl-omega-trinor PGE2 (EP1 > EP3) showed a bell-shaped hyperalgesia at lower doses of 5 pg-5 ng kg-1 and 50 pg-50 ng kg-1, respectively. MB28767 (EP3)showed a monophasic hyperalgesic action over a wide range of dosages at 50 pg-S5 Microg kg-1. Butaprost(EP2) induced hyperalgesia at doses higher than 50 ng kg-1.5. These results demonstrate that PGE2 may exert allodynia through the EP1-receptor and hyperalgesia through EP2- and EP3-receptors in the mouse spinal cord.
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PMID:Characterization of EP-receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice. 792 97

The clinical usefulness of prostaglandin derivatives was reviewed for the treatment of peripheral vascular diseases such as arteriosclerosis obliterans, Buerger's disease, Raynaud's disease, and collagen disease etc. PGE1 was initially used for this purpose, however, it had to be infused intra-arterially or intravenously for hours. PGE1 incorporated in lipid microsphere (Lipo PGE1) was made for one-shot use and the targeting drug delivery because the lipid microsphere is easily taken up by some inflammatory cells. Lipo PGE1 was revealed to be effective to improvement of considerably large ischemic ulcer and pain. Beraprost sodium (PGI2 derivative) was produced for oral use, and has been widely used. The effectiveness was similar to Lipo PGE1, but the complications such as hypotension, headache, and numbness were more common in PGI2.
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PMID:[Treatment of the peripheral vascular diseases with prostaglandin]. 793 9

The aim of this trial was to compare the efficacy of combination antithrombotic therapy with a prostacyclin-sparing aspirin plus anticoagulation versus conventional aspirin plus anticoagulation, when added to antianginal therapy, in patients with unstable angina or non-Q wave myocardial infarction already being treated with aspirin. In a double-blind (for the aspirin) study, 144 prior aspirin users were randomized; 72 patients received controlled-release, prostacyclin-sparing aspirin 75 mg daily plus anticoagulation (intravenous heparin followed by warfarin to maintain the international normalized ratio at 2-3), and 72 patients received conventional aspirin 75 mg daily plus the same anticoagulation. Controlled-release aspirin was formulated to preserve endothelial cell prostacyclin synthesis. Trial therapy was begun by 13.2 +/- 12.3 h of qualifying pain, and continued for 12 weeks. The frequency of recurrent angina with electrocardiographic changes, myocardial infarction, or death, was analysed by intention to treat. At 12 weeks, events were: [table: see text] Twenty-six of the 42 (62%) recurrent ischaemic events occurred within 7 days of presentation. Four of the 144 patients (3%) experienced a major bleeding complication. It is concluded that in spite of maximal antithrombotic therapy, there is a significant failure rate of medical therapy in aspirin users presenting with unstable angina or non-Q wave myocardial infarction while at rest. Prostacyclin-sparing aspirin offers no clinical benefit over conventional aspirin.
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PMID:Prospective evaluation of a prostacyclin-sparing aspirin formulation and heparin/warfarin in aspirin users with unstable angina or non-Q wave myocardial infarction at rest. The Antithrombotic Therapy in Acute Coronary Syndromes Research Group. 798 19

PEM-420, the active isomer of pemedolac, inhibited the writhing responses induced by phenylbenzoquinone (PBQ), acetic acid, and acetylcholine in mice with ED50's of 0.80, 0.92, and 0.075 mg/kg p.o., respectively. In the rat acetic acid writhing assay, PEM-420 exhibited an ED50 value of 8.4 mg/kg p.o. In the Randall-Selitto test, PEM-420 raised the pain threshold of the yeast-injected paw (ED50 = 0.55 mg/kg p.o.). Like other NSAIDs, PEM-420 inhibited the PBQ-induced production of PGI2 and PGE2 in the mouse peritoneal cavity, with ED50 values of 0.5 and 1.2 mg/kg p.o., respectively. It had weak ulcerogenic liability in rats (acute UD50 = 99 mg/kg p.o. in fasted rats; subacute UD50 = 74 mg/kg/day for 4 days in fed rats). The data indicate that PEM-420 is a potent and safe peripheral analgesic.
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PMID:Analgesic activities of PEM-420, the active eutomer of pemedolac. 827 76

Aspirin is one of the oldest and most commonly used nonprescription drugs in the world. Although commonly it is used for relief from common headache and muscular pain, its use in the prevention and treatment of platelet related complications in cardiovascular diseases (CVD) and cerebrovascular disease (CBVD) is quite controversial. A brief review of the major aspirin trials indicated that a full strength aspirin taken daily had no significant beneficial effect in reducing mortality of patients with CVD/CBVD. However, two major trials (ISIS-2, PHS) in which either low dose aspirin (160 mg) or one aspirin administered every other day, have demonstrated significant reduction in fatal and nonfatal cardiovascular events. Even a dose as low as 1 mg aspirin per day significantly lowers platelet thromboxane synthesis. As a result of these studies, low dose aspirin should be the choice of prophylactic therapy aimed at the inhibition of platelet cyclooxygenase activity. Controlled-release low dose aspirin may favorably reduce platelet thromboxane production and spare vascular prostacyclin synthesis. At least 100 mgs of aspirin per day are essential to completely inhibit steady state thromboxane formation. Low dose aspirin (160 mgs) has been shown to be as effective as the full strength aspirin (325 mgs) in reducing clinical complications related to platelet activation. The antithrombotic effect of aspirin is well established and improved formulations, well thought out therapeutic protocols, customized dosage, appropriate timing of delivery, a better understanding of platelet function and pathophysiology of CUD/CBUD will facilitate maximization of the beneficial effects of aspirin.
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PMID:Aspirin in ischemic heart disease--an overview. 836 57

The effects of beta-phorbol 12,13-dibutyrate (PDBu) on the discharge properties of slowly conducting knee joint afferents (group III and group IV fibers) were studied to determine the role of protein kinase C in nociception. Extracellular single unit recordings were made from small filaments dissected from the medial articular nerve in cats anesthetized with alpha-chloralose. PDBu was applied intra-arterially close to the joint in concentrations of 10(-6) up to 10(-4) M. The afferents were classified as low-threshold and high-threshold units with regard to their sensitivity to passive noxious and innocuous movements of the knee joint. Following PDBu application, an excitation occurred in 28% of the group III and in 40% of the group IV fibers. An enhancement of responses to passive movements of the joint (sensitization) occurred in 37% of group III and 19% of group IV afferents. In summary, 37.5% of the low-threshold and 50% of the high-threshold fibers proved to be sensitive to PDBu. Most of the PDBu-positive units responded also to bradykinin, whereas only a few PDBu-positive units were sensitive to prostaglandin I2 and E2. We conclude from these results that, in a distinct population of slowly conducting joint afferents, protein kinase C is likely to be involved in the process of transduction. Thus, pain and hyperalgesia may be mediated at least partly by intracellular mechanisms that are linked to protein kinase C.
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PMID:The effects of phorbol ester on slowly conducting afferents of the cat's knee joint. 838 19

In 12 patients with severe Raynaud's phenomenon (RP: ischemic ulcers or intractable pain despite use of narcotic analgetics), we studied the acute and long-term hemodynamic effects of epoprostenol on systemic and finger skin circulation. Epoprostenol was infused intravenously (i.v., initial infusion rate of 2 ng/kg/min, with a subsequent increase of 2 ng/kg/min every 30 min to the individually tolerated maximal dose of 8 ng/kg/min) in a triple, 5-h, double-blind, placebo-controlled cross-over study. During epoprostenol infusion, systolic blood pressure (SBP) remained stable, while diastolic BP (DBP) decreased (-8 mm Hg, p < 0.02), with a simultaneous increase in heart rate (HR + 14 beats/min, p < 0.001). Forearm blood flow (FBF) increased and forearm vascular resistance (FVR) decreased during epoprostenol as compared with placebo infusion (p < 0.01). Epoprostenol caused a significant increase in fingertip skin temperature (p < 0.01) as well as in laser Doppler flux (p < 0.02) before and after a standardized cooling test of the hand as compared with placebo. The increase in transcutaneous oxygen tension reached significant difference only during recovery (p < 0.02). No long-term improvement was noted during two additional cooling tests performed 1 and 6 weeks after the completed epoprostenol or placebo triple-infusion cycle. Repeated long-lasting epoprostenol infusion immediately improves the microcirculation, but these effects are not sustained after 1 week.
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PMID:Double-blind, placebo-controlled study of intravenous prostacyclin on hemodynamics in severe Raynaud's phenomenon: the acute vasodilatory effect is not sustained. 858 79

In an open study the clinical efficacy and tolerability of the stable prostacyclin (PGI2) analogue iloprost in the treatment of 900 patients with advanced peripheral arterial occlusive disease (Fontaine stage III and IV), enrolled by 169 centres, were investigated. Of these patients, treated with infusions over 6 h daily up to 42 days, 853 could be evaluated: four were excluded because of wrong diagnosis. The responder rates, defined as pain relief, no or reduced use of analgesics (stage III and IV), improvement of trophic lesions, i.e. complete or > or = 50% healing of ulcers, demarcation of necroses (stage IV), and global improvement, were 75.0% and 66.0% in stage III and 46.3% and 41.8% in stage IV patients in the valid case and intention-to-treat group, respectively. A complete healing of ulcers was observed in 12.3% of those patients (n = 375) presenting with ulcerations at the beginning of treatment. Diabetic and non-diabetic patients were comparable with regard to efficacy of iloprost. 71.4% and 66.2% (stage III and IV) of initial responders at 6 months follow-up were still free from rest pain and showing complete or partial healing of trophic lesions. 7.9% of stage III and 16.9% of stage IV patients underwent major amputation during the whole study period with a reduced amputation rate in responders compared to non-responders in stage IV. 7.9% stage III and 13.2% stage IV patients died. 83.2% and 86.0% of stage III and IV patients presented with adverse events at any time of treatment, mainly headache, nausea and flush as well as gastrointestinal symptoms, occurring mostly during the titration phase. The investigators' judgement, however, revealed a very good and good tolerability in 74.8% of stage III and in 73.7% of stage IV patients.
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PMID:Treatment of patients with peripheral arterial occlusive disease Fontaine stage III and IV with intravenous iloprost: an open study in 900 patients. 883 61


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