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)

The molecular mechanisms that underlie the primary headaches-migraine, cluster headache and tension-type headache-have not yet been clarified. On the basis of studies in headache induced by intravenous infusions of glyceryl trinitrate (an exogenous nitric oxide donor) and histamine (which liberates nitric oxide from vascular endothelium), it has been suggested that nitric oxide is a likely candidate responsible molecule. The present review deals with the biology of this small messenger molecule, and the updated scientific evidence that suggests a key role for this molecule in primary headaches. This evidence suggests that the release of nitric oxide from blood vessels, perivascular nerve endings or from brain tissue is an important molecular trigger mechanism in spontaneous headache pain. Pilot trials have shown efficacy of a nitric oxide synthase inhibitor in both migraine attacks and chronic tension-type headache. These observations suggest new approaches to the pharmacological treatment of headache.
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PMID:Nitric oxide in primary headaches. 1137 54

Pain can be effectively controlled by endogenous mechanisms based on neuroimmune interactions. In inflamed tissue immune cell-derived opioid peptides activate opioid receptors on peripheral sensory nerves leading to potent analgesia. This is brought about by a release of opioids from inflammatory cells after stimulation by stress or corticotropin-releasing hormone (CRH). Immunocytes migrate from the circulation to inflamed tissue in multiple steps, including their rolling, adhesion, and transmigration through the vessel wall. This is orchestrated by adhesion molecules on leukocytes and vascular endothelium. Intercellular adhesion molecule-1 [ICAM-1 (or CD54)] is expressed by endothelium and mediates adhesion and extravasation of leukocytes. The goal of this study was to show that ICAM-1 regulates the homing of opioid-producing cells and the subsequent generation of analgesia within sites of painful inflammation. This was accomplished using immunofluorescence, flow cytometry, and behavioral (paw pressure) testing. We found that ICAM-1 is upregulated on the vascular endothelium, simultaneously with an enhanced immigration of opioid-containing immune cells into inflamed paw tissue. The intravenous administration of a monoclonal antibody against ICAM-1 markedly decreased the migration of opioid-containing leukocytes and of granulocytes, monocytes-macrophages, and T cells to the inflamed tissue. At the same time, circulating immunocytes increased in numbers, and macroscopic inflammation (hyperalgesia, paw volume, and paw temperature) remained primarily unchanged. Most importantly, peripheral opioid analgesia elicited either by cold water swim stress or by intraplantar administration of CRH was dramatically reduced. Together, these findings indicate that ICAM-1 expressed on vascular endothelium recruits immunocytes containing opioids to promote the local control of inflammatory pain.
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PMID:Opioid control of inflammatory pain regulated by intercellular adhesion molecule-1. 1209 10

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are distinct but related aspects of the same dynamic disease process known as venous thromboembolism (VTE). An estimated 200,000 new cases occur in the United States every year, including 94,000 with PE, resulting in an incidence of 23 per 100,000 patients per year-cases. Without treatment, pulmonary embolism is associated with a mortality rate of approximately 30%, causing nearly 50,000 deaths per year. Moreover, based on post-mortem studies, two-thirds of the patients with pulmonary emboli remain undiagnosed. Clinically, PE may present as (1) isolated dyspnea, (2) pleuritic pain and/or hemoptysis, and (3) circulatory collapse. However, clinical history and examination can be notoriously misleading in reaching a diagnosis. A number of acquired etiologic risk factors (predispositions) are associated with a tendency to develop VTE. These include increasing age, immobilization, surgery, trauma, hospital or nursing home confinement, malignancy, neurologic disease with extremity paresis, as well as certain types of oral contraception and hormone replacement therapy. In addition, a variety of genetic risk factors, such as factor V Leiden, protein S or C deficiency have also been identified. However, in at least half of the instances, no predisposing factors can be identified (idiopathic PE). In the majority of cases thromboemboli originate in the deep veins of the calf or pelvis. The pathogenic conditions for VTE comprise a triad of factors and include (1) venous stasis, (2) hypercoagulable states, and (3) vascular endothelium injury. Occlusion of pulmonary arteries has variable and transient clinical and pathophysiologic consequences, involving both mechanical and reflex effects of vascular occlusion with a consecutive perfusion defect as well as the release of vasoactive and other inflammatory mediators. The objectives of this article are to present an overview of the etiologic and pathogenic factors promoting VTE as well as the pathophysiologic and inflammatory processes following PE.
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PMID:Principle mechanisms underlying venous thromboembolism: epidemiology, risk factors, pathophysiology and pathogenesis. 1258 87

Most hypersensitivity reactions to drugs occur within several weeks of administration; signs and symptoms are often consistent with known immune-mediated reactions, including anaphylaxis, rashes, fever, cytopenias and vasculitis. The culprit immune mechanisms range from immunoglobulin E antibody to T cells inducing apoptosis of keratinocytes, in the case of bullous exfoliative rashes. Many drugs induce reactions via altered hepatic metabolism, with production of reactive intermediates which induce a common syndrome of rash and fever plus variable types of other signs. Examples of this reactive metabolite syndrome include the rash and fever in HIV-positive patients given sulfamethoxazole and reactions to the aromatic anticonvulsants. With the notable exception of anaphylaxis and severe bullous exfoliative rashes, most immune reactions to drugs are not life-threatening and generally resolve once the drug is discontinued. The key is prevention. Specific immune testing is standardized only for penicillin. If test results are negative, however, the patient can tolerate all beta-lactam antibiotics. Of those patients with a positive penicillin skin test, only 2% develop reactions when given cephalosporins. Sulfa and quinolone antibiotics, and muscle relaxants, also frequently induce reactions. If there is a history of bullous rash, the patient should never again receive sulfa or quinolone, or related drugs. In other cases, a cautious graded challenge or desensitization can be done. Vancomycin, protamine, and radiocontrast media induce non-immune reactions secondary to their irritant effects on vascular endothelium. Narcotic pain medications cause histamine release by binding to a specific receptor on mast cells in sensitive patients. In contrast to true immune reactions, most patients can receive these medications again, if they are pretreated and the drugs are given slowly. Angiotensin-converting enzymes, aspirin, and non-steroidal anti-inflammatory drugs induce adverse reactions by their effect on enzymes. Readministration usually results in repeat symptoms. It is possible to desensitize patients to aspirin. Some patients appear to develop similar adverse symptoms with multiple unrelated drugs. Although these cases present management problems, most patients can complete a therapeutic course of a vital drug, after careful review of the history, immune testing when possible, and graded challenge or desensitization.
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PMID:Hypersensitivity reactions to drugs: evaluation and management. 1263 3

An adhesion of the subacromial bursa in the shoulder causes pain during joint motion and restricts the range of motion of the glenohumeral joint. To understand the biologic features of an adhesion, the gene expressions in adhesive subacromial bursa were analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction. The gene expressions in adhesive subacromial bursae were approximately threefold to fourfold greater than those in nonadhesive bursae for the genes for Type I and Type III procollagens, CD34 antigen in vascular endothelium, hyaluronan synthase-3, and interferon-gamma. The gene expression of interleukin-8 was predominant in adhesive bursa. The gene expressions of hyaluronan synthase-1, hyaluronan synthase-2, and interleukin-10 which is an antiadhesive cytokine were predominant in nonadhesive bursae. Chromatography analysis revealed that a hyaluronan, of which molecular weight was more than 100 kDa, was present in the cavity of nonadhesive subacromial bursae. It is suggested that pathologic fibrosis and vascularization are maintained by the presence of interferon-gamma and interleukin-8 in adhesive subacromial bursae and that high molecular weight hyaluronan or interleukin-10 plays a role for antiadhesion.
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PMID:Pathologic gene expression in adhesive subacromial bursae of human shoulder. 1283 53

The vaso-occlusive process in patients with sickle cell disease is complex and is likely to involve interactions between hemoglobin S red blood cells (SS RBCs) and vascular endothelium, as well as between SS RBCs and leukocytes. Vaso-occlusive events lead to recurrent pain and a wide spectrum of end-organ damage, including pulmonary hypertension and renal failure. However, the triggers inducing adhesion and vaso-occlusion are only now being elucidated. Investigators have characterized the ability of a number of RBC surface structures to adhere to both endothelial cells and components of the subendothelial extracellular matrix. In addition, evidence is accumulating to suggest that SS RBC adhesion receptors undergo activation under physiologic conditions. An understanding of these mechanisms at the molecular level should ultimately allow development of new preventive and treatment strategies to abrogate vaso-occlusive events.
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PMID:Erythrocyte adhesion in sickle cell disease. 1290 Nov 40

Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6% of patients had taken rofecoxib 50 mg/day for longer than recommended. Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.
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PMID:Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? 1581 52

The present study sought to compare the vascular status of human primary teeth with that of human permanent teeth, and to determine whether caries or painful pulpitis was associated with changes in vascularity. Coronal pulps were removed from 62 primary and 62 permanent mandibular molars with a known pain history. Teeth were categorized as intact, moderately carious or grossly carious. Pulp sections were labelled with Ulex europaeus I lectin (UEIL), which is a marker of human vascular endothelium. Image analysis was then used to quantify the percentage area of UEIL-labelled tissue (vascularity) and the number of blood vessels present within three regions: the pulp horn, the subodontoblastic region, and the mid-coronal pulp. Only the mid-coronal region of the primary tooth pulp was found to be significantly more vascular than the corresponding area of the permanent tooth pulp. Both dentitions showed a significant increase in vascularity within the pulp horn region with caries progression, but this was not accompanied by an increase in vessel number. There was no correlation between vascularity and pain symptoms. These findings suggest that the primary tooth pulp is more vascular than its successor within the mid-coronal region. However, the functional and clinical significance of this finding remains speculative.
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PMID:Vascular status in human primary and permanent teeth in health and disease. 1581 18

Fabry Disease (alpha-galactosidase A deficiency) is an X-linked hereditary disorder leading to the pathological accumulation of globotriaosylceramide (GL-3) in lysosomes, particularly in the vascular endothelium of the kidney, heart and brain. We report the results of an open-label phase 2 study that was undertaken to evaluate whether ethnic differences exist that would affect agalsidase beta (Fabrazyme) treatment of Fabry patients in the Japanese population, relative to safety and efficacy. The study design mirrored the design of the completed phase 3 clinical trial that led to approval of the product agalsidase beta. The 13 Japanese, male Fabry patients enrolled in the study received the enzyme replacement therapy over a period of 20 weeks as biweekly infusions. All selected efficacy end points showed improvements that were comparable with findings from the phase 3 study. These improvements included reductions of GL-3 accumulation in both kidney and skin capillary endothelial cells to (near) normal levels (92% of patients). Kidney and plasma GL-3 levels decreased by 51.9% and 100%, respectively, by ELISA. Renal function remained normal. Fabry-associated pain, and quality of life, showed improvement over baseline in multiple categories. Related adverse events were mild or moderate in intensity and mostly infusion-associated (fever and rigors). As expected, IgG antibody formation was observed in 85% of the patients, but had no effect on treatment response. These results suggest that treatment with agalsidase beta is safe and effective in Japanese patients with Fabry disease. With regard to safety and efficacy, no differences were observed as compared to the caucasian population.
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PMID:Enzyme replacement therapy in Japanese Fabry disease patients: the results of a phase 2 bridging study. 1590 61

Selective inhibitors of cyclooxygenase-2 (COX-2, 'coxibs') are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non-steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myo cardial infarction and atherothrombotic events. This has led to the withdrawal of rofecoxib from global markets, and warnings have been issued by drug authorities about similar events during the use of celecoxib or valdecoxib/parecoxib, bringing about questions of an inherent atherothrombotic risk of all coxibs and consequences that should be drawn by health care professionals. These questions need to be addressed in light of the known effects of selective inhibition of COX-2 on the cardiovascular system. Although COX-2, in contrast to the cyclooxygenase-1 (COX-1) isoform, is regarded as an inducible enzyme that only has a role in pathophysiological processes like pain and inflammation, experimental and clinical studies have shown that COX-2 is constitutively expressed in tissues like the kidney or vascular endothelium, where it executes important physiological functions. COX-2-dependent formation of prostanoids not only results in the mediation of pain or inflammatory signals but also in the maintenance of vascular integrity. Especially prostacyclin (PGI(2)), which exerts vasodilatory and antiplatelet properties, is formed to a significant extent by COX-2, and its levels are reduced to less than half of normal when COX-2 is inhibited. This review outlines the rationale for the development of selective COX-2 inhibitors and the pathophysiological consequences of selective inhibition of COX-2 with special regard to vasoactive prostaglandins. It describes coxibs that are current ly available, evaluates the current knowledge on the risk of atherothrombotic events associated with their intake and critically discusses the consequences that should be drawn from these insights.
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PMID:Selective COX-2 inhibitors and risk of myocardial infarction. 1597 6


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