Effects Of Non-steroidal Anti-inflammatory Agents Research Articles

Effects of non-steroidal anti-inflammatory agents on systemic hemostasis during the most acute period of cold injury in rats

Non-steroidal anti-inflammatory drugs (NSAIDs) have recently been considered promising agents for the prevention and treatment of cold injuries. The results of previous studies demonstrate a distinct frigoprotective effect of diclofenac sodium and etoricoxib.
 The aim of the study: to assess the impact of diclofenac sodium and etoricoxib, as the most effective frigoprotectors among NSAIDs, on coagulation indicators during the most acute phase of cold injuries using an acute model of general cooling in rats.
 Materials and Methods: The experiment was carried out using 41 outbreed male rats weighing 310±10 g. Cold injury was induced by acute general cooling (exposure to –18 °C for 2 hours). Diclofenac sodium (7 mg/kg) and etoricoxib (5 mg/kg) were administered intragastrically 30 minutes before the onset of cold exposure. Rectal temperature was measured before and after cold exposure. Immediately after exposure, plasma was used to determine prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen levels, and in blood serum – the residual amount of prothrombin, thrombin, fibrinogen, as well as D-dimer using species-specific immunoenzymatic analysis kits.
 Results: Etoricoxib and especially diclofenac sodium significantly reduced the degree of hypothermia (rectal temperature decreased by 1.3 % and 1.9 %, respectively, compared to a 5.4 % decrease in the control group, p < 0.05). In the acute phase of cold injury in the untreated control group, there was a significant increase in D-dimer (by 2.7 times) and fibrinogen content (by 1.9 times) in blood serum, alongside a 21.7 % increase in thrombin time, indicating a heightened risk of thrombus formation and DIC syndrome development. The other coagulation indicators did not show significant changes. Both diclofenac sodium and etoricoxib significantly reduced elevated D-dimer and serum fibrinogen, normalizing thrombin time and indicating an antithrombotic effect. There was no significant difference in the effect of both NSAIDs on blood coagulation status.
 Conclusions: The acute phase of cold injury demonstrates a dangerous shift in blood coagulation towards thrombus formation and DIC syndrome development. Prophylactic use of diclofenac sodium and, to a lesser extent, etoricoxib displays an anti-hypothermic effect, reducing the risk of thrombosis and DIC syndrome. This proves the expediency of using these NSAIDs for acute cold injury

Effect of Nonsteroidal Anti-inflammatory Agents on Small Intestinal Injuries as Evaluated by Capsule Endoscopy.

Currently, because the population is aging, use of medications has been increasing, including use of nonsteroidal anti-inflammatory drugs (NSAIDs) and antithrombotic agents. This study aims to investigate whether NSAIDs can cause damage to the small bowel (SB) mucosa. Endoscopic videos of subjects who had undergone capsule endoscopy (CE) were evaluated by three experts in order to identify SB injury. All medications taken within 2weeks from the time of CE were investigated. Cases with a final diagnosis of intestinal tuberculosis, inflammatory bowel disease, Behcet's disease, Peutz-Jeghers syndrome, small bowel lymphoma, or Henoch-Schönlein purpura were excluded from the analysis. Among the 273 subjects, 125 (45.8%) had SB erosions or ulcers (erosion group) and the remaining 148 (54.2%) did not (no erosion group). SB erosions or ulcers were more common in females, patients aged > 60years, and subjects taking NSAIDs (p = 0.048, 0.032, and < 0.001, respectively). No statistically significant differences were found between the two groups in the following variables: history of cancer and GI surgery, reasons for the test, comorbidities, and use of anticoagulants and antiplatelet agents. Multivariate analysis showed that use of NSAIDs [OR 4.191 (95% CI 1.858-9.458), p < 0.001] was an independent risk factor for SB erosions or ulcers. Use of NSAIDs is the only independent risk factor for SB injury identified in this study. Antithrombotic agents do not cause or exacerbate damage to the SB, according to our results. KCT0004795.

Abstract 5065: Pharmacological modulation of inflammation and p53 signaling synergize to prevents muscle invasive bladder cancer in-vivo

Abstract Bladder cancer (BC) is the second most common genitourinary cancer and a leading cause of death globally. Muscle invasive BC (MIBC) has high mortality (&amp;gt;85% patients) leading to death within 2 years of diagnosis, if untreated. Although new treatment options were approved recently, it is still very challenging and most expensive to manage. Preventing BC is highly desirable to reduce recurrence, mortality and improve quality of life. Inactivation of p53 signaling and chronic inflammation are frequent hallmarks of MIBC. In spite of the promising chemopreventive effects of non-steroidal anti-inflammatory agents (NSAIDs), their clinical translation is hampered due to side-effects associated with their chronic intake and higher doses. Here we investigated a combinatorial approach to modulate inflammation with NSAIDs (licofelone or NO-Naproxen) and p53 signaling pathways using CP-31398 (CP) for preventing MIBC bladder in-vivo. Transgenic UPII-SV40T mice developing spontaneous MIBC were generated and fed control or experimental diets containing the licofelone (150ppm), NO-naproxen (300 ppm), CP (150ppm) alone or in combination starting at early tumor stage (6 weeks age). After 34 weeks of agent administration, mice were euthanized and urinary bladders were evaluated. Control diet fed transgenic mice developed high grade, muscle invasive, urothelial transitional cell carcinoma (TCC) leading to 3-5 fold increase in bladder weights (140.2±9.8 mg Vs 27.3±0.8 mg; p&amp;lt;0.0001) and (34.2±0.8 mg vs 14.8±0.53 mg; p&amp;lt;0.0001) in males and females compared with wild type mice. These tumors had dysregulated cell cycle and inflammation markers similar to human tumors. Treatment with licofelone, NO-Naproxen or CP alone led to significant suppression of bladder tumor. While NSAIDs had significant inhibitory effect in males (65% - 78%; p&amp;lt;0.0001) and females (31% - 34%; p&amp;lt;0.01-p&amp;lt;0.0001) compared to control group, CP had strongest tumor growth suppressive effect (80%; p&amp;lt;0.0001 and 36%; p&amp;lt;0.0001) in both genders. CP had no effect on invasion in male mice while in females ~50% inhibition was observed, while moderate effect of licofelone (12% - 42% inhibition; p&amp;lt;0.005) and NO-Naproxen (38% - 42% inhibition; p&amp;lt;0.001) was observed. Importantly, the combination of two agents led to a synergistic effect leading to significant inhibition of both tumor growth (~80% in males; p&amp;lt;0.0001 and 55% females; p&amp;lt;0.0001) and invasion ~62% inhibition (p&amp;lt;0.0001) in both genders. Molecular analysis of urothelial tumors showed inhibitory effect on proliferation and inflammatory markers (PCNA, Cyclins, p53, p21, COX2, and IL1β). Our results suggest that safer dose combination of targeted agents may yield better chemopreventive effects than higher dose of individual agents. Specifically, NSAID plus CP may be a promising combination for preventing MIBC. (Supported in part by NCI-PREVENT program - NCI-CN-53300) Citation Format: Venkateshwar Madka, Yuting Zhang, Nandini Kumar, Gopal Pathuri, Nicole Stratton, Stanley Lightfoot, Adam S. Asch, Vernon E. Steele, Altaf Mohammed, Chinthalapally V. Rao. Pharmacological modulation of inflammation and p53 signaling synergize to prevents muscle invasive bladder cancer in-vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5065.

抗炎症剤,6-Chloro-5-cyclohexyl-1-indancarboxylic acid(TAI-284)のCF#1マウス胎児の発生・分化に及ぼす影響について

抗炎症剤,6-Chloro-5-cyclohexyl-1-indancarboxylic acid(TAI-284)のCF#1マウス胎児の発生・分化に及ぼす影響について

The inhibitory effect of non-steroidal anti-inflammatory agents on aggregation of red cells in vitro.

Abstract Aggregation of red cells of rat in saline suspension was induced by gelatin, high molecular weight dextran and fibrinogen. Except chloroquine, non-steroidal anti-inflammatory agents (NAIA) inhibited macromolecule-induced red cell aggregation in vitro. Glucocorticoids failed to inhibit red cell aggregation even in large concentrations. Of many drugs examined, only the NAIA and certain antihistamines, having experimental anti-inflammatory effects proved to be effective inhibitors of gelatin-induced red cell aggregation, in vitro.

Current Evidence of the Management of Undifferentiated Spondyloarthritis: A Systematic Literature Review

To examine the efficacy of available drugs in undifferentiated spondyloarthritis (u-SpA). Systematic review of studies retrieved from Medline (1961-July 2009), Embase (1961-July 2009), and Cochrane Library (up to July 2009). A complementary hand search was also performed. The selection criteria were as follows: (population) u-SpA patients; (intervention) nonsteroidal anti-inflammatory agents, disease-modifying antirheumatic drugs, anti-tumor necrosis factor α, anakinra, abatacept, biphosphonates, or thalidomide; (outcome) pain, function, structural damage and quality of life; (study design) randomized controlled trials (RCT), cohort studies, and case reports; (level of evidence) according to The Oxford Centre for Evidence-based Medicine (update 2009). An additional narrative review was performed to analyze the effects of drug therapies in patients with spondyloarthritis according new Assessment of Spondyloarthritis International Society criteria. The following 7 studies were included: 2 RCT, 1 cohort study, and 4 case reports, which included 117 patients with u-SpA (mostly young men). No evidence related to the effect of nonsteroidal anti-inflammatory agents or disease-modifying antirheumatic drugs on u-SpA patients was found. Infliximab and etanercept showed some benefit regarding clinical outcomes, function, and quality of life. Two RCT reported important benefit of infliximab and adalimumab also in patients with predominantly axial spondyloarthritis. Rifampicin plus doxycycline improved some clinical outcomes but ciprofloxacin had no benefit. Anecdotal positive evidence was reported with pamidronate. No serious adverse events were reported in the retrieved studies. Low-quality evidence suggests a benefit of tumor necrosis factor α blockers in u-SpA and good-quality evidence in predominantly axial spondyloarthritis. The use of antibiotics remains controversial. High-quality trials are needed to definitively assess the effect of available drugs in these patients.

Toxic effects of non-steroidal anti-inflammatory agents in rats

The toxicosis of some non-steroidal anti-inflammatory drugs, piroxicam,indomethacin, phenylbutazone, and aspirin, which occasionally arelocally used in Nigeria as rodenticides have been evaluated in rats usingchanges in the serum biochemical and haematological parameters asindices of toxicity. In the study, no clinical symptoms were observed in allthe treatment groups except in the group of animals exposed toindomethacin which showed decreased feed intake, sluggishness,diarrhoea and some mortality were also recorded in the group. On theserum biochemical parameters, indomethacin and piroxicam causedincreases in the level of total bilirubin and decreases blood urea nitrogen.Aspirin, indomethacin, and phenylbutazone produced increases in serumaspartate aminotransferase and this increase is significant (P

The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: Implications for a role of COX-1

Systemic inflammation gives rise to metabolic and behavioural changes, largely mediated by pro-inflammatory cytokines and prostaglandin production (PGE2) at the blood–brain barrier. Despite numerous studies, the exact biological pathways that give rise to these changes remains elusive. This study investigated the mechanisms underlying immune-to-brain communication following systemic inflammation using various anti-inflammatory agents.Mice were pre-treated with selective cyclo-oxygenase (COX) inhibitors, thromboxane synthase inhibitors or dexamethasone, followed by intra-peritoneal injection of lipopolysaccharide (LPS). Changes in body temperature, open-field activity, and burrowing were assessed and mRNA and/or protein levels of inflammatory mediators measured in serum and brain.LPS-induced systemic inflammation resulted in behavioural changes and increased production of IL-6, IL-1β and TNF-α, as well as PGE2 in serum and brain. Indomethacin and ibuprofen reversed the effect of LPS on behaviour without changing peripheral or central IL-6, IL-1β and TNF-α mRNA levels. In contrast, dexamethasone did not alter LPS-induced behavioural changes, despite complete inhibition of cytokine production. A selective COX-1 inhibitor, piroxicam, but not the selective COX-2 inhibitor, nimesulide, reversed the LPS-induced behavioural changes without affecting IL-6, IL-1β and TNF-α protein expression levels in the periphery or mRNA levels in the hippocampus.Our results suggest that the acute LPS-induced changes in burrowing and open-field activity depend on COX-1. We further show that COX-1 is not responsible for the induction of brain IL-6, IL-1β and TNF-α synthesis or LPS-induced hypothermia. Our results may have implications for novel therapeutic strategies to treat or prevent neurological diseases with an inflammatory component.

Dysmenorrhoea

Dysmenorrhoea is commonly divided into primary dysmenorrhoea, where pelvic anatomy and ovarian function are normal and there is no co-existent pathology, and secondary dysmenorrhoea where there is an identifiable pathological condition. The true incidence is difficult to establish due to an inconsistency in the definition used and the population studied, but dysmenorrhoea probably affects between 40% and 70% of women of reproductive age, and compromises daily activities in up to 10% of women. It is associated with significant psychological distress, including both anxiety and depression, which may be co-existent, and requires considered, empathetic management by healthcare practitioners. Although the exact pathophysiological mechanisms that underlie the disease are incompletely understood, the pain most likely reflects increased myometrial activity induced by an excessive production of prostaglandin. This is supported by the clearly beneficial effect of non-steroidal anti-inflammatory agents, although optimal management of dysmenorrhoea depends on an understanding of the underlying cause with treatment specifically directed at this. Patients with primary dysmenorrhoea may simply need reassurance and simple analgesics, whereas those with secondary dysmenorrhoea require investigation and treatment of the underlying organic problem. Treatment is generally supportive, however, with adequate symptomatic relief provided for the majority of patients through the single or combined use of non-steroidal anti-inflammatory agents and the combined oral contraceptive pill. Lack of response to these agents increases the likelihood of a secondary cause for dysmenorrhoea prompting further investigations and specifically directed treatment upon diagnosis.

NS-398, a Cyclooxygenase-2-Specific Inhibitor, Delays Skeletal Muscle Healing by Decreasing Regeneration and Promoting Fibrosis

Nonsteroidal anti-inflammatory drugs are often prescribed after muscle injury. However, the effect of nonsteroidal anti-inflammatory drugs on muscle healing remains primarily controversial. To further examine the validity of using these drugs after muscle injury, we investigated the working mechanism of NS-398, a cyclooxygenase-2-specific inhibitor. In vitro experiments showed that NS-398 inhibited the proliferation and maturation of differentiated myogenic precursor cells, suggesting a detrimental effect on skeletal muscle healing. Using a mouse laceration model, we analyzed the in vivo effect of NS-398 on skeletal muscle healing at time points up to 4 weeks after injury. The in vivo results revealed delayed muscle regeneration at early time points after injury in the NS-398-treated mice. Compared to controls, lacerated muscles treated with NS-398 expressed higher levels of transforming growth factor-beta1, which corresponded with increased fibrosis. In addition, transforming growth factor-beta1 co-localized with myostatin, a negative regulator of skeletal muscle growth. We also found reduced neutrophil and macrophage infiltration in treated muscles, indicating that the delayed skeletal muscle healing observed after NS-398 treatment could be influenced by the anti-inflammatory effect of NS-398. Our findings suggest that the use of cyclooxygenase-2-specific inhibitors to treat skeletal muscle injuries warrants caution because they may interfere with muscle healing.

The Effect of Nonsteroidal Anti-Inflammatory Agents on Spinal Fusion

A large body of information suggests NSAIDS have a negative impact on the healing of bone. Although each clinical healing scenario presents a slightly different level of challenge, the healing of a posterolateral spinal fusion is one of the most difficult challenges in bony healing. Clinically, this results in a relatively high rate of nonunions using traditional fusion techniques. Spinal fusion models have confirmed NSAIDS have a definite inhibitory effect on healing of the fusion. Although data are limited, it appears this effect is most severe when NSAIDS are administered in the early postoperative period. Moreover, the effect may be worse with certain types initial inflammatory, subsequent reparative, and final remodeling phases. Because of the anti-inflammatory activity of NSAIDS, one might assume their effects would be worse when administered in the inflammatory phase. Indeed, the study by Riew et al suggests the inhibitory effects are more significant when NSAIDS are administered earlier following fusion. Other studies conducted with non-spinal models also suggest early administration of NSAIDS results in greater inhibition of bone formation (Goodman et al). Unfortunately, the length of the inflammatory phase in humans is not well known. This leaves the clinician unsure about the safe time to allow resumption of NSAID usage clinically. It appears likely NSAID use following a spinal fusion procedure will increase the rate of pseudarthrosis. The literature suggests that avoidance of NSAIDS in the postoperative period may avoid nonunion. Additionally, we propose that chronic NSAID usage should be addressed in a similar manner to cigarette smoking. While neither are absolute contraindications to elective spinal fusion, patients should be counseled to discontinue the use of NSAIDS in the peri- and postoperative period to maximize their chance for a successful fusion.

In this issue

In this issue

Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention.

Malignant mesothelioma (MM) remains the most lethal pleural, peritoneal and pericardial cancer. Here, we characterize the effects of nonsteroidal anti-inflammatory agents (NSAIDs) on in vitro and in vivo experimental MM models. Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced the in vitro proliferation of several MM cells derived from previously untreated MM patients. Moreover, celecoxib significantly inhibited MM cell colony formation in soft agarose (63-78% at 5 x 10(-5) M; p < or = 0.05) and it elicited remarkable antitumor activity, leading to long-term survival in >37% of nude mice bearing intraperitoneal MM. Celecoxib was more efficient in inhibiting MM cell growth than acetylsalicylic acid (10(-6) M-10(-2) M), indometacin (10(-6) M-10(-2) M) and the COX-2 inhibitor NS-398 (10(-6) M-10(-4) M). Efficacy of these different compounds was not related to the amount of COX-2 protein levels present on MM cells. Celecoxib, in a dose- and time-dependent manner, induced MM cell apoptosis, which involved decreased Akt phosphorylation, loss of Bcl-2 and Survivin protein expression and caspase-3 activation. Furthermore, vascular endothelial growth factor (VEGF), an MM autocrine growth factor and Akt inducer, rescued celecoxib-induced apoptosis and Akt dephosphorylation. When the VEGF receptor (KDR/Flk-1) inhibitor, SU-1498, was used in combination with celecoxib, IC50 of celecoxib in vitro was reduced up to 65%. These data demonstrate that celecoxib may have antitumor properties in MM and provide a rationale for the therapeutic use of celecoxib in combination with a selective VEGF inhibitor.

Influence of acetylsalicylic acid and ketoprofen on canine thyroid function tests

Many factors including drugs can influence thyroid function in humans, rats and dogs. Studies in humans report significant effects of non-steroidal anti-inflammatory agents (NSAIDs) on thyroid function tests, which can lead to misinterpretation of the results and inappropriate therapeutic decisions. As NSAIDs are used more and more frequently in dogs, it is important to know to what extent they can influence results. Eighteen spayed female beagle dogs were randomly assigned to three treatment sequences in a 3×3 crossover study design with treatments consisting of acetylsalicylic acid (ASA) (25 mg/kg BW q 12 h), ketoprofen (Keto) (1 mg/kg BW q 24 h) or placebo administered for a 1-week period with a 3-week washout period between treatment periods. Blood samples for determination of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), thyrotropin (TSH), reverse triiodothyronine (rT3), Keto and ASA concentrations were taken during each treatment period on days 0, 1, 3 and 7. During the washout period samples were taken weekly. A significant decrease in TT4 was observed as soon as 24 h after ASA administration, whereas the decrease in TT3 was less pronounced and differed significantly from the placebo only after 1 week of administration. No significant effects were found for free T4 and TSH with ASA administration. No significant effects on thyroid results were found following Keto administration. The results indicate that TT4 can be markedly decreased by ASA therapy and until the results of further studies are available, thyroid function test results should be interpreted cautiously in dogs on NSAIDs therapy.

Effect of Nonsteroidal Anti-Inflammatory Agents and Finasteride on Prostate Cancer Risk

Effect of Nonsteroidal Anti-Inflammatory Agents and Finasteride on Prostate Cancer Risk

Effect of Nonsteroidal Anti-Inflammatory Agents and Finasteride on Prostate Cancer Risk

We examine the relationship of nonsteroidal anti-inflammatory drugs and finasteride on the risk of prostate cancer. Participants in this case control study using a prospective collection of data were drawn from consecutive patients who underwent prostate biopsy at 12 different departments of urology from January 1999 to June 2000. Medication use was assessed by self-questionnaire as well as questions about dietary and lifestyle factors that might be relevant for prostate cancer risk. The study included 639 patients with prostate cancer and 659 cancer-free controls. Univariate analysis showed no significant impact of aspirin and finasteride on prostate cancer risk while the nonaspirin nonsteroidal anti-inflammatory drug users had a lower risk (OR 0.80, 95% CI 0.64-0.99). After adjusting for potential confounders, the protective effect of nonaspirin nonsteroidal anti-inflammatory drugs was no longer significant (OR, 0.84, 95% CI 0.66-1.07), while finasteride showed a significant protective effect (OR 0.58, 95% CI 0.37-0.92). The results suggest that finasteride could have a chemopreventive role in prostate cancer. While aspirin did not show any impact on prostate cancer risk, the role of nonaspirin nonsteroidal anti-inflammatory drugs warrants further studies.

INHIBITION OF CYCLOOXYGENASE-2 SUPPRESSES ANGIOGENESIS AND THE GROWTH OF PROSTATE CANCER IN VIVO

INHIBITION OF CYCLOOXYGENASE-2 SUPPRESSES ANGIOGENESIS AND THE GROWTH OF PROSTATE CANCER IN VIVO

In vitro effects of nonsteroidal anti-inflammatory agents and prostaglandins I2, E2, and F2α on contractility of taenia of the large colon of horses

Abstract Objectives To determine the in vitro effect of various prostaglandins (PG) and nonsteroidal anti-inflammatory drugs (NSAID) on contractile activity of the large-colon taenia of horses. Animals 14 healthy horses. Procedure The taenia was collected from the ventral colon, cut into strips (2 × 10 mm), and mounted in a tissue bath system (20-ml capacity) that contained oxygenated Krebs buffer solution warmed to 37.5 ± 0.5 C. After equilibration, incremental doses of PGE2, PGF2α, PGI2, flunixin meglumine, carprofen, ketoprofen, and phenylbutazone were added to the baths, and contractile activity was recorded. Magnitude of the response was calculated by comparing contractile activity before and after administration of the PG or NSAID to the tissue baths. Results PGE2 and PGF2α caused a significant increase in contractile activity, whereas PGL2 induced an inhibitory response. Activity of NSAID on contraction was predominantly inhibitory. At low concentrations, ketoprofen induced an excitatory effect, which then became inhibitory at high concentrations. Compared with the other NSAID, carprofen significantly reduced contractile activity at lower concentrations. Conclusions PGE2 and PGF2α appear to enhance contractility of large-colon taenia of horses, whereas PGL2 was inhibitory in the in vitro model. Administration of NSAID also inhibited contractility, with carprofen having the most potent effect. Clinical Relevance Administration of NSAID in combination with liberation of endogenous PG may predispose horses to development of intestinal stasis and subsequent impaction. (Am J Vet Res 1999;60:1004-1009)

Chapter 2. Cutaneous polymodal receptors: characteristics and plasticity

The cutaneous sensory units labeled C-fiber polymodal nociceptors have a broadly coherent set of responsive characteristics. These include; (a) elevated thresholds to mechanical stimulation and to heat; (b) excitation by irritant and algesic chemicals; and (c) sensitization by injury or algesic substances. These characteristics and the match between the signals produced by C-polymodal nociceptors to pain-causing stimuli and human reports of pain indicate a probable causal connection. Nevertheless, there are indications that this population of sensory units may contain functionally-distinct subtypes. Some human C-polymodal nociceptors have been reported to be excited by histamine at low concentrations, whereas much of the population lacks such responsiveness. Further, in vitro studies of the effects of non-steroidal anti-inflammatory agents and low pH on sensitization suggest distinctions in the responsiveness of different elements whose general characteristics place them into the C-polymodal category. The enhanced responsiveness of C-polymodal nociceptors after heat stimulation or exposure to acidity has a probable relationship to the primary hyperalgesia produced after injury to hairy skin or in the presence of inflammation. Furthermore, the alterations of C-polymodal nociceptor characteristics after partial nerve injury and sympathectomy imply a change in phenotype of neurons spared by denervation and are suggestive of a possible relationship to sympathetically related pain and post-sympathetic neuralgias. These evidences of plasticity in responsiveness of a set of sense organs putatively associated with cutaneous pain represent lessons in the adaptability of biological mechanisms, and clues to the pathophysiology of pain.

5-lipoxygenase: properties, pharmacology, and the quinolinyl(bridged)aryl class of inhibitors.

In conclusion, an effective modulator of the AA cascade for the treatment of asthma and other inflammatory diseases may require 5-LO inhibitory activity as well as LTD4 antagonism in order to limit the effects of LTB4, LTD4, and 5-HPETE. The unknown role of LTC4 with respect to bronchoconstriction and mucus production could mask the efficacy of a pure LTD4 antagonist in man, whereas the chemotactic property of LTB4 for eosinophils can contribute to lung inflammation. Indeed, it is observed that the blood of patients with bronchial asthma has increased numbers of hypodense eosinophils. In addition, the formation of lipid-derived peroxide radicals, such as 5-HPETE, are believed to be responsible for various types of cellular injuries associated with the inflammatory disease process. Because inhibition of the CO pathway is thought to explain the therapeutic effects of nonsteroidal antiinflammatory agents in rheumatic diseases, a 5-LO inhibitor with CO inhibitory activity may also be desirable profile for an antiasthma agent. The validation of the LT hypothesis of disease had to wait for the demonstration of a clinical effect by either a LTD4 receptor antagonist or a LT synthesis inhibitor (5-LO inhibitor). Only very recently has this evidence become available and it is now apparent that compounds that antagonize LTD4 receptors or inhibit LT synthesis have shown clinical efficacy in a wide range of diseases. Due to the breakthrough nature of this approach, certain of these compounds are being considered for expedited development. The absence of side effects seen in the clinical trials of selective 5-LO inhibitors is gratifying and argues that LTs are not important in homeostasis. Only time will tell whether 5-LO inhibitors will take their place in the therapeutic armamentarium; however, the recent demonstration of clinical efficacy by a number of these compounds is a significant step in this direction.