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 hypothalamic-pituitary-adrenal (HPA) system has been a model for neuroendocrine control of responses of organisms to stressors since the turn of the century. Despite this, the pathways by which infectious insults interact with the HPA system remained poorly defined. Recently, evidence has been presented suggesting that humoral mediators released by inflammatory cells (cytokines) may participate in two-way communication between the site of inflammation and the central nervous system. In this review, we detail the current understanding of the responses of the HPA system to the classic physiologic stimuli of hypovolemia and pain, with an emphasis on the cellular mechanisms and mediators discovered in recent years. We also examine the data substantiating a role of interleukin 1, interleukin 6, and tumor necrosis factor in the direct humoral activation of the HPA system and consider the evidence favoring a physiologic negative feedback relationship between the HPA and the immune systems. Such as interaction is an exciting concept with broad clinical implications. However, we believe that the temporal and quantitative aspects of experiments designed to evaluate this interaction must be carefully evaluated to assure that true physiologic stimuli are studied and that the responses observed are not due to pharmacologic effects of inflammatory mediators acting through "classic" neuroendocrine pathways.
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PMID:The hypothalamic-pituitary-adrenal-immune axis. A critical assessment. 136 94

The antineoplastic properties of suramin, a polyanionic agent with demonstrated antigrowth factor activity, are under evaluation in vitro, in vivo, and in clinical trials. Suramin has been shown to have antitumor activity in patients with advanced, hormone refractory prostate cancer. During these trials, significant resolution of osseous pain was observed in nearly three quarters of the patients treated with suramin. To evaluate the effect of suramin on bone cells, we studied the effect of suramin on bone resorption in a neonatal mouse calvarial assay. Suramin inhibited bone-resorbing activity in a dose-related fashion and had an additive effect with calcitonin. Calvaria pretreated with suramin had less bone-resorbing activity, fewer attached osteoblasts, and less medium alkaline phosphatase activity than control calvaria. Suramin also inhibited osteoclastic release of tritiated proline from labeled bone in a dose-dependent fashion. The effect of metastatic prostate carcinoma on bone is incompletely understood, but may be moderated by tumor-produced factors and/or cytokines. The effects of several such agents, therefore, were examined in combination with suramin. Bone resorption induced by PTH, epidermal growth factor, tumor necrosis factor, and a tumor-produced factor, PTH related-protein, was blocked by suramin. The ability of suramin to inhibit the bone-resorbing effects of several cytokines suggests that its mechanism may involve direct action on bone metabolism. Autoradiography performed on calvaria treated with labeled suramin demonstrated heavy deposition of suramin on the outer surface of the matrix, adjacent to osteoblasts and osteoclasts lining the outer table, suggesting that bone cells may be subject to high local concentrations of the drug, in keeping with this hypothesis.
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PMID:Suramin inhibits bone resorption and reduces osteoblast number in a neonatal mouse calvarial bone resorption assay. 142 26

Interleukin-2 (IL-2) is frequently incorporated in antineoplastic therapy: While the effect of interferon on the thyroid has been extensively studied the impact of other cytokines on thyroid function is less well understood. We monitored the thyroid function in six patients who received IL-2 in combination with tumor necrosis factor-alpha (TNF) or alpha-Interferon (alpha IFN). Hyperthyroxinemia with suppressed TSH developed within the first four weeks of IL-2 administration; during this phase, there was no technetium or iodine uptake by the thyroid gland. During the following few weeks, serum thyroxine decreased and serum TSH rose, consistent with the development of primary hypothyroidism; during this phase, thyroidal isotope incorporation was normal. All hypothyroid patients received thyroxine replacement therapy upon documentation of hypothyroidism; in several cases thyroxine was successfully discontinued after 2-3 months. None of the patients had detectable antithyroidal antibodies and none experienced thyroid-related pain, although two patients developed thyroid enlargement. We conclude that IL-2 administration is associated with the development of transient, subacute, painless thyroiditis. The frequency and severity of this complication requires further elucidation through systematic, prospective study.
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PMID:Acute thyroid dysfunction (thyroiditis) after therapy with interleukin-2. 142 15

Recent findings suggest that the protective role that misoprostol exerts in the gastrointestinal tract against nonsteroidal anti-inflammatory drug (NSAID) damage may be extended to a variety of other tissues and other noxious stimuli including those mediated by molecules such as interleukin 1 (IL-1), tumor necrosis factor (TNF), and endotoxin. The protective effects of misoprostol outside the gastrointestinal tract may involve prevention of triggering activities that would otherwise initiate a sequence of tissue damaging events. If this capacity of misoprostol to maintain homeostasis in a variety of settings is recognized, a cohesive pattern of action emerges. Numerous studies have shown that misoprostol is likely to act as a regulator within various cascades of immunological regulatory events. The in vitro and in vivo experimental data described in this paper suggest that the events which trigger episodes of pain and inflammation may be controllable by the administration of misoprostol. Mitigation of adverse effects of certain NSAIDs on renal function and cartilage metabolism has also been observed. Demonstration of this latter phenomenon in the clinical setting will greatly benefit the patient if it is shown to modify the arthritis disease process. The therapeutic applications of misoprostol beyond the gastrointestinal tract appear to be among the most interesting of therapeutic advances offered by any class of compound in the next decade. Because of the inflammatory and pain processes associated with arthritis disease progression, particular emphasis and confirmation through further clinical study should be placed on the potential effect of misoprostol on chondroprotection and synergy with NSAIDs.
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PMID:Misoprostol: new frontiers; benefits beyond the gastrointestinal tract. 157 87

The National Cancer Institute (NCI) Canada Clinical Trials Group conducted a phase II study of recombinant tumor necrosis factor (rTNF) given intravenously daily for 5 days every other week, in measurable metastatic renal cell carcinoma. Two of 26 patients responded with responses lasting greater than 200 days. Toxicity was severe including rigors, fever, headache, fatigue, hypotension, and localized pain. We conclude that rTNF, given as described, has only modest antitumor activity in renal cell carcinoma and produces considerable toxicity. We plan no further studies of rTNF in this disease.
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PMID:A phase II study of recombinant tumor necrosis factor in renal cell carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group. 173 50

Interleukin-1 alpha and tumor necrosis factor-alpha induce an increase in pain thresholds in the rat. We now show that also the corticotropin releasing hormone induces an analgesic effect that, similarly to what is observed with the two cytokines, is not reversible by naloxone. Moreover, we also show that after the administration of interleukin-1 alpha, tumor necrosis factor-alpha, and corticotropin releasing hormone, naloxone becomes analgesic itself. A similar observation was also made in the human and the experimental animal after exposure to stressful conditions. The results obtained suggest that the two cytokines share with corticotropin releasing hormone some characteristics of stress mediators.
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PMID:Corticotropin releasing hormone, interleukin-1 alpha, and tumor necrosis factor-alpha share characteristics of stress mediators. 185 44

Sixteen previously treated (with only one prior regimen) patients with histologically proven metastatic or locally recurrent colorectal carcinoma were treated with recombinant tumor necrosis factor (rTNF) administered by 30-minute i.v. infusions twice daily for 5 consecutive days every other week for 8 weeks. Patients received 100 micrograms/m2 twice daily on day 1 of cycle 1 with escalation to 150 micrograms/m2 twice daily thereafter. Patients were concomitantly treated with indomethacin 25 mg every 6 hours and acetaminophen 650 mg every 4 hours to obviate fever and chills. Toxicities included: nausea/vomiting (69%), headache (25%), chills (69%), pain at tumor sites (63%), hypotension (31%), and hypertension (38%). Hematologic toxicity included leukopenia less than 2000 cells/mm3 (38%) and thrombocytopenia less than 100,000 cells/mm3 (13%). Liver function abnormalities occurred independently of the site or extent of metastatic disease and inconsistently in each treatment cycle. Four patients developed bilirubinemia greater than 2.5 x baseline values (range, 2.5 to 10.3 U/L); five patients had greater than 2.5 x elevations in alkaline phosphatase (range, 624 to 1663 U/L). Two patients developed retinal vein thrombosis in the absence of hemostatic abnormalities. In both instances, this complication occurred several weeks after completion of therapy. No objective responses were noted in 14 evaluable patients (95% confidence interval: 0 to 0.23). Three patients had stable disease for a median duration of 4.5 months. In conclusion, i.v. rTNF at this dose and schedule has no demonstrable antitumor efficacy. Twice-daily i.v. administration of this agent is associated with more hepatotoxicity than previously reported in trials using subcutaneous or once daily i.v. administration. Retinal vein thrombosis may be a late complication of i.v. rTNF at this dose and schedule.
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PMID:A phase II trial of recombinant tumor necrosis factor in patients with advanced colorectal carcinoma. 238 95

This short review updates information on the release mechanisms of the systemic response to surgical injury and the modifying effect of pain relief. Initiation of the response is primarily due to afferent nerve impulses combined with release of humoral substances (such as prostaglandins, kinins, leukotrienes, interleukin-1, and tumor necrosis factor), while amplification factors include semi-starvation, infection, and hemorrhage. The relative role of the various signals in producing the complex injury response has not been finally determined, but the neural pathway is probably most important in releasing the classical endocrine catabolic response, while humoral factors are important for the hyperthermic response, changes in coagulation and fibrinolysis immunofunction, and capillary permeability. The modifying effect of pain relief on the surgical stress response is dependent upon the technique of analgesia. However, the effect on humoral-mediated responses is small, regardless of the technique used. Afferent neural blockade with local anesthetics is the most effective technique for reducing the endocrine-metabolic response, but only in operations in the lower part of the abdomen, probably because of insufficient afferent blockade during thoracic epidural analgesia. Systemic opiate administration, as well as non-steroidal antiinflammatory drugs, exert only a small modifying effect on the response. Low-dose combined analgesic regimens may provide total pain relief, but exert no important effect on the stress response. In summary, pain alleviation itself may not necessarily lead to an important modification of the stress response, and a combined approach with inhibition of the neural and humoral release mechanisms is necessary for a pronounced inhibition or prevention of the response to surgical injury.
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PMID:The stress response to surgery: release mechanisms and the modifying effect of pain relief. 265 70

The effect of interleukin-1 together with lipopolysaccharide, tumor necrosis factor and interferon on a pain-like response was investigated with the phenylquinone-induced writhing test in mice. Recombinant human interleukin-1 alpha (rHu-IL-1 alpha) inhibited writhing dose relatedly at doses of 0.25-5 micrograms/kg i.v., and its potency was about 1000 times that of morphine on a molar basis. Potent anti-writhing activity was also seen after an i.v. dose of recombinant human tumor necrosis factor (rHu-TNF) and mouse alpha-interferon (mIFN alpha). Lipopolysaccharide, unlike rHu-IL-1 alpha, needed a lag time of about 1 h to develop its anti-writhing action. The relative potency ratios of intracisternal to i.v. and i.p. to i.v. administration of rHu-IL-1 alpha were about 38 and 0.1, respectively. The activity of rHu-IL-1 alpha and rHu-TNF, unlike mIFN alpha, was not naloxone-reversible. rHu-IL-1 alpha did not produce an increase in writhes counts even if injected directly into the peritoneal cavity. These results suggest that rHu-IL-1 alpha, as well as lipopolysaccharide, rHu-TNF and mIFN alpha, had potent anti-writhing activity when given i.v. and its action is due to a central mechanism but is not naloxone-reversible, and that rHu-IL-1 alpha is not algesic under the experimental conditions used.
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PMID:Interleukin-1 induces analgesia in mice by a central action. 326 Aug 69

Cytokines are best known as mediators of host defense responses to infection and other environmental stresses. However, some of these proteins (interleukin-1 and tumor necrosis factor) may modulate clearance and repair processes in skeletal muscle following injury, and others (fibroblast growth factor and platelet-derived growth factor) may be involved with the sustained viability of muscle cells. Muscle repair and vitality also require neuronal contact (influenced by nerve growth factor and ciliary neurotrophic factor) as well as angiogenesis and connective tissue matrix formation (influenced by transforming growth factor beta). Successful muscle aging will depend in part on how well a muscle repairs itself after damage. This includes not only overt injury, but also the daily "wear and tear" that may not be perceived via pain or alterations in function. Age-related loss of muscle mass or function may be the cumulative result of repeated episodes of incomplete repair. Abnormal production or sensitivity to cytokines by aged cells may contribute to these changes in muscle mass and function.
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PMID:Cytokines in aging and muscle homeostasis. 749 4


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