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)

This study was undertaken to evaluate the effect of ketorolac (Toradol), a potent cyclooxygenase inhibitor used for postoperative pain, on microvascular thrombosis in an established thrombosis model. Bilateral 3-mm arterial inversion grafts (n = 66) were constructed in the femoral arteries of New Zealand White rabbits. ALZET (ALZA Corporation, Palo Alto, Calif.) osmotic pumps were implanted in the external jugular veins for drug delivery. The blinded protocol called for the experimental animals to receive intravenous doses of ketorolac of 1.72 mg/kg per day (group 1) or 3.44 mg/kg per day (group 2), while control animals received equivalent volumes of saline. Patency was assessed at 7 days. Whereas 52 percent (13 of 25) of control vessels remained patent, 70 percent (14 of 20) and 86 percent (18 of 21) of group 1 and group 2 vessels, respectively, were patent at 1 week. This decrease in microvascular thrombosis with delivery of ketorolac was statistically significant (p = 0.0094). Ketorolac, at experimental doses approximating 9 and 18 mg IV q6h in a 70-kg man, demonstrated a statistically significant reduction in microvascular thrombosis. This study supports its use in clinical microvascular surgery.
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PMID:The effect of ketorolac on microvascular thrombosis in an experimental rabbit model. 925 40

Nerve growth factor (NGF) is known to produce hyperalgesia as well as to stimulate synthesis of neuropeptides in dorsal root ganglia (DRG). In the present study, we wanted to determine the effects of local NGF administration and assess to which extent mast cell-dependent factors are mediating NGF responses. Rats received 1 daily unilateral intraplantar injection for 3 days. Local edema (days 1-3), changes in thermal nociceptive threshold (days 1-4), and the content of calcitonin gene-related peptide (CGRP) and substance P (SP) in the sciatic nerve (day 4), were determined. NGF injection caused edema which was absent in rats pretreated with compound 48/80 as well as in rats treated neonatally with capsaicin ('capsaicin denervation'). NGF-induced edema was not reduced by the neurokinin-1 receptor antagonist SR140333, but attenuated by the CGRP receptor antagonist CGRP[8-37]. On each day, NGF injection caused a decrease in thermal nociceptive threshold which lasted for less than 3 h. Capsaicin denervation, but not treatment with indomethacin, abolished NGF-induced thermal hyperalgesia. Treatment with compound 48/80 attenuated hyperalgesia produced by the first, but not by subsequent, NGF injections. On day 4, 24 h after the last of 3 NGF injections, thermal nociceptive threshold was not different from control values, but at that time, CGRP and SP were elevated in the sciatic nerve. We suggest therefore that NGF-induced local edema was caused by mast cell-derived vasoactive compounds which act together with afferent neuron-derived CGRP to increase vascular permeability. NGF-induced thermal hyperalgesia most likely was caused by an increased sensitivity of peripheral endings of capsaicin sensitive afferents. This effect of NGF was not mediated by products of the cyclooxygenase pathway, and was also observed in mast cell-depleted rats.
Pain 1996 Feb
PMID:Intraplantar injection of nerve growth factor into the rat hind paw: local edema and effects on thermal nociceptive threshold. 874 Jun 10

Lipopolysaccharide (LPS), an endotoxin, produces pain behavior, inflammation, and changes in immune function. Many of these effects are secondary to the production of cytokines. In the present study, we investigated the effect of LPS on the releasing function of afferent terminals as measured by calcitonin gene-related peptide (CGRP) release in ex vivo perfused rat trachea, and examined the possible role of the cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) as intermediaries in this effect. Systemic injection of LPS (0.75 mg/kg, i.p.) in adult rats induced an increase in body temperature followed by hypothermia, indicating ongoing infection. We observed that capsaicin-induced (0.1 microM) tracheal CGRP release was significantly enhanced in the LPS-treated animals after 5 hr. This enhancement of the peptide release by LPS was blocked by IL-1beta tripeptide antagonist Lys-D-Pro-Thr (10 microM) and mimicked by IL-1beta and TNF-alpha (10-100 pg/ml), suggesting that the potentiating effect of LPS on CGRP release is mediated by generation of IL-1beta and TNF-alpha. IL-1beta-induced augmentation of CGRP release was blocked by Lys-D-Pro-Thr. Additionally, the cyclooxygenase inhibitor ketorolac (10 microM) significantly attenuated the facilitatory effects of LPS and IL-1b, indicating involvement of prostanoids. These findings suggest that endotoxin treatment generated cytokines such as IL-1b and TNF-alpha that regulated the peripheral releasing function of primary sensory afferents by sensitizing the terminals and facilitating peptide release. This effect is prostanoid dependent.
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PMID:Involvement of cytokines in lipopolysaccharide-induced facilitation of CGRP release from capsaicin-sensitive nerves in the trachea: studies with interleukin-1beta and tumor necrosis factor-alpha. 876 61

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) continues to be an important therapeutic intervention throughout the world for patients with pain and inflammation. The six major classes of NSAIDs (including the salicylates) bear the common property of inhibiting cyclooxygenase, the enzyme that catalyzes the synthesis of cyclic endoperoxides from arachidonic acid to yield prostaglandins. Anecdotal evidence has accumulated that the nonacetylated salicylates are as efficacious as the other NSAIDs, but there have been few controlled trials demonstrating that they are reasonable anti-inflammatory agents. This paper discusses the newest of the available clinical observations that nonacetylated salicylates are as efficacious as one of the newer NSAIDs in patients with rheumatoid arthritis. Because the nonacetylated salicylates are weak prostaglandin inhibitors, several other non-prostaglandin mediated mechanisms of action for the NSAIDs have been postulated and are described in this paper. In addition to papers describing NSAID effects on cartilage, this year several interesting papers described further effects of tenidap, a novel NSAID presently in development. Other papers reviewed attempts to develop NSAIDs with less severe gastrointestinal effects. Some reports discuss the use of topical NSAIDs, which are not clearly better than oral preparations. Data are also reviewed demonstrating that misoprostol effectively decreased significant poor gastrointestinal outcomes in patients who were treated with this NSAID for 6 months. New treatment regimens for decreasing misoprostol-induced toxicity are also reviewed. Finally, the effects of NSAID prophylaxis in preventing heterotopic bone formation in patients with osteoarthritis who undergo hip replacement surgery are noted.
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PMID:Actions and toxicity of nonsteroidal anti-inflammatory drugs. 879 74

This 12-week, open-label, multicenter study assessed the safety, tolerability, and efficacy of the tablet formulation of meloxicam 15 mg, a new, nonsteroidal antiinflammatory drug (NSAID), in patients with confirmed osteoarthritis (OA) of the hip or knee. Meloxicam differs from established NSAIDs in its preferential activity against cyclooxygenase type 2 compared with cyclooxygenase type 1. One hundred thirty-nine patients were given meloxicam tablets 15 mg once daily. Data were analyzed using an intent-to-treat analysis. Assessments of global tolerability at the end of the study showed meloxicam tablets to be well or very well tolerated by 83% of patients, with only 4% rating the tablets poorly. This finding was supported by the low incidence of adverse events. Only 11% of patients discontinued therapy due to gastrointestinal adverse events, and no serious gastrointestinal adverse events related to meloxicam 15-mg tablets occurred during treatment. Efficacy results showed significant improvement from baseline, with 41% of patients experiencing mild or no pain by the end of the study. In conclusion, the tablet formulation of meloxicam 15 mg is well tolerated and effective in patients with moderate-to-severe, clinical confirmed OA of the hip or knee.
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PMID:Evaluation of the safety, tolerability, and efficacy of meloxicam tablets in patients with osteoarthritis. 882 18

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

Rhein, the active metabolite of diacerein, inhibits interleukin-1 activity. Consequently, collagenase production in articular cartilage is reduced. Rhein dose-dependently inhibits superoxide anion production, chemotaxis and phagocytic activity of neutrophils, and macrophage migration and phagocytosis. Articular cartilage damage is reduced by diacerein in animal models of osteoarthritis. Diacerein does not alter renal or platelet cyclooxygenase activity and may therefore be tolerated by patients with prostaglandin-dependent renal function. In clinical trials of < or = 6 months' duration, oral diacerein 50mg twice daily was associated with improvement in 57 to 85% of patients with osteoarthritis. Pain scores and measures of joint function were generally reduced compared with baseline and placebo. Diacerein had similar efficacy to NSAIDs, but a slower onset of action, in comparative trials of < or = 2 months' duration conducted in patients with osteoarthritis. The predominant adverse effects of diacerein are diarrhoea and related disorders.
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PMID:Diacerein. 901 Jun 51

Whilst treating a patient with traumatic direct carotico-cavernous fistula, pain relief was difficult to achieve. Adequate doses of ibuprofen and codeine were ineffective, but single doses of ketoprofen alleviated pain in a reproducible manner. Although similar in analgesic efficacy to codeine, and a potent inhibitor of cyclooxygenase like ibuprofen, ketoprofen has other actions which may account for the differential response seen. This observation may help elucidate the nature of local mediators involved in the pathogenesis of vascular headache pain.
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PMID:Ketoprofen and carotico-cavernous fistula. 905 35

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the signs and symptoms of inflammation. They originated from man's early use of willow bark in the treatment of rheumatism. Although these drugs have been developed because of their effects on arthritis, their substantial analgesic and antipyretic actions have led to their widespread application. The NSAIDs are classified on the basis of their chemical structure under the category of acidic and nonacidic agents. The anti-inflammatory, analgesic and antipyretic effects of NSAIDs are attributable to their suppression of prostaglandin synthesis activity through cyclooxygenase inhibition. Regarding the analgesic effects of NSAIDs, initially, the peripheral mechanism was proposed. It has been assumed that the effects result from inhibition of the synthesis of prostaglandins in the peripheral inflamed tissue because prostaglandin may sensitize the peripheral nociceptors to the effects of other mediators released from the inflamed tissue. However, the central mechanism, acting within supraspinal or spinal level, was also suggested recently. Their exact sites and modes of action within the spinal cord are poorly defined, and even controversial. There are two main hypotheses to elucidate this issue. One is that the spinal analgesic actions are associated with prostaglandins synthesis, because of the excitatory effect of prostaglandins in the spinal cord and the other is dissociated from prostaglandins synthesis, and their effect may be related to their ability to affect the spinal nociceptive, processing cellularly or intracellularly. However, both mechanisms are probably linked. In conclusion, although the real mechanisms of the spinal analgesic actions of NSAIDs remain unclear, further basic and clinical studies should be made. In this way, we may hopefully provide more opportunities for effective pain management.
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PMID:Spinal actions of nonsteroidal anti-inflammatory drugs. 908 22

Chronic inflammatory conditions produce a state of hyperalgesia which is evident from a few hours to days after administration of an inflammatory stimulus. The molecular mechanisms involved in the initiation of hyperalgesia are not well understood and in this study we have investigated the role of prostaglandins in this process in the rat. Unilateral intraplantar injection of Freund's complete adjuvant produces an immediate localized swelling (oedema) with the development of altered pain responses in the ipsilateral paw such as a reduced threshold to noxious stimuli (hyperalgesia) and lowered thresholds such that normally innocuous stimuli produce a pain response (allodynia). We have monitored levels of cyclooxygenase messenger RNA and prostaglandins in lumbar spinal cord in parallel with these behavioural responses (oedema, hyperalgesia and allodynia) and identified a marked increase in cyclooxygenase-2 messenger RNA (3-fold), maximal at 2-4 h after Freund's complete adjuvant, followed by a significant increase in 6-keto prostaglandin F1alpha and prostaglandin E2 which is maximal by 8 h. Pretreatment of animals with the unselective cyclooxygenase inhibitor indomethacin attenuated oedema (approximately 40%) and allodynia (80-100%), but had no effect on the development of mechanical hyperalgesia. Pretreatment with the cyclooxygenase-2 selective inhibitors DuP 697, flosulide and SC58125 also attenuated allodynia (by 80-100%) but had no effect on the development of oedema or mechanical hyperalgesia. The marked increase in cyclooxygenase-2 messenger RNA in the lumbar spinal cord following intraplantar Freund's complete adjuvant suggests that the cyclooxygenase enzyme and its product may have a role in the adaptive response that occurs in the lumbar spinal cord during a peripheral inflammatory reaction. Pharmacological analysis reveals that prostaglandins are directly involved in the development of allodynia. However, these studies show that the development of mechanical hyperalgesia does not require the production of prostaglandins indicating that more than one pathway mediates the altered pain responses associated with a peripheral inflammatory lesion.
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PMID:The potential role of spinal cord cyclooxygenase-2 in the development of Freund's complete adjuvant-induced changes in hyperalgesia and allodynia. 915 62


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