New non-steroidal anti-inflammatory drugs: Selective inhibitors of the inducible cyclooxygenase

Stichtenoth, Dirk O.; Zeidler, Henning; Frölich, Jürgen C.

doi:10.1007/bf03042637

Cited by 15 publications

(13 citation statements)

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“…Nonsteroidal anti-inflammatory drugs exert their major therapeutic effects by inhibition of prostanoid synthesis [51]. Diclofenac, one of the NSAIDs used in this study, has a potent inhibitory effect on cyclo-oxygenase and reduces the production of leukotrienes by cells participating in the inflammatory process due to decreased availability of intracellular arachidonic acid [23].…”

Section: Discussionmentioning

confidence: 99%

Nucleus pulposus-induced nerve root injury: effects of diclofenac and ketoprofen

et al. 2001

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IntroductionSpinal nerve root injury can be induced by chronic compression and/or the presence of nucleus pulposus [1, 3, 4, 5,20,21,22,26,31,32,33,34,35,36,37,38,39,46,52]. It has been demonstrated experimentally that epidurally applied autologous nucleus pulposus, without any compression, can induce significant changes in nerve root morphology and function in animal models [4, 5,21,22,31,34,35]. Nucleus pulposus has been demonstrated to have inflammatogenic properties [33] and abundant macrophages and interleukin-1β immunoreactive cells have been demonstrated in human disc hernias, suggesting an active inflammation [11, 13]. Inflammatory mechanisms have been suggested to be of pathogenetic significance in sciatAbstract Main problem. Nucleus pulposus and/or chronic compression can induce spinal nerve root injury. Inflammation has been proposed as having major importance in the pathophysiologic mechanisms involved in the induction of such injuries. Corticosteroids, potent anti-inflammatory drugs, have been demonstrated to reduce nucleus pulposusinduced spinal nerve root injury. The aim of the present study was to assess the effects of two potent nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac and ketoprofen, in experimental nucleus pulposus-induced spinal nerve root injury in a pig model. Methods. Eighteen pigs were included in the study. Autologous nucleus pulposus was harvested from a lumbar disc and applied locally around the first sacral nerve root after a partial laminectomy of the first and second sacral vertebrae. Six pigs were treated with daily intramuscular injections of diclofenac, 3 mg/kg body weight, for 7 days. Six other pigs were treated with daily intramuscular injections of ketoprofen, 4 mg/kg body weight, for 7 days. As controls, six pigs received injections with physiologic saline. After 7 days, the pigs were reanesthetized and the nerve conduction velocity over the exposed nerve root area was determined. Results. The nerve conduction velocity was significantly higher in pigs treated with diclofenac than in the salinetreated controls, (57±6 m/s vs 38± 18 m/s, P<0.05, Student's t-test). The velocity in pigs treated with ketoprofen, 42±24 m/s, did not differ significantly from that of controls. Conclusions. This study of two potent NSAIDs indicates that nucleus pulposus-induced nerve root dysfunction may be reduced by diclofenac but not by ketoprofen. The reason for this difference is not known, but it might be related to the fact that ketoprofen and diclofenac belong to different NSAID subgroups and have a different selectivity for the two cyclo-oxygenases COX-1 and COX-2.

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Section: Discussionmentioning

confidence: 99%

Nucleus pulposus-induced nerve root injury: effects of diclofenac and ketoprofen

et al. 2001

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“…It follows, glucocorticoids exert impressive antiinflammatory actions but they are devoid of the NSAID-typical side effects [7,95]. In our context, the absence of unwanted renal effects of glucocorticoids show, that prostanoids derived from an induced COX-2 are of no importance for renal physiology, otherwise glucocorticoids should have detrimental effects on renal function.…”

Section: Human In Vivo Data -Experiences With Selective Cox-2 Inhibitionmentioning

confidence: 95%

“…As far as the gastrointestinal tract and platelets are concerned, there is a large body of evidences that selective COX-2 inhibition hold this promise [for review see [4][5][6][7]50,51]. Furthermore, it turned out that knowledge of COX-isoenzyme selectivity allows a prediction of major therapeutic and side effects of NSAIDs [52,53].…”

Section: Avoidance Of Nsaid Side Effects -Selective Inhibitors Of Cox-2mentioning

confidence: 99%

“…The discovery of two different forms of COX, a constitutive COX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prostanoid production, ushered in a new generation of NSAIDs with the promise of fewer side effects. The COX-2 strategy suggests that a drug with selectivity for COX-2 would inhibit proinflammatory prostanoid synthesis while sparing physiologic prostanoid synthesis, thus this drug should be anti-inflammatory with less or none of the class-typical adverse effects of NSAIDs on gastrointestinal tract, kidneys, platelets and lungs [for review see [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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COX-2 and the Kidneys

Stichtenoth

Jc²

2000

CPD

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The kidney is the second most frequent target of serious adverse effects of non-steroidal antiinflammatory drugs (NSAIDs). The renal side effects of NSAIDs related to inhibition of cyclooxygenase (COX) comprise reduction in renal blood flow (RBF) and glomerular filtration rate (GFR), sodium/water retention, water intoxication and hyperkalemia. The discovery of two COX-isoenzymes, a constitutive COX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prosta noid production, led to the development of new NSAIDs: Preferential and specific COX-2 inhibitors, promising minimal NSAID-typical toxicity with equivalent efficacy. However, we learned that there is no clear distinction in "physiologic" constitutive COX-1 and "inflammatory" inducible COX-2. This is particular true for the kidney of humans and other mammalians, where COX-2 was found constitutively in meaningful amounts. Animal experiments and clinical trials with preferential and specific COX-2 inhibitors revealed that COX-2 is the critical enzyme for sodium excretion, renin release and likely antagonism of antidiuretic hormone. Additionally, a significant role of COX-2 for nephro genesis is suggested. For renal hemodynamics the given evidence point to COX-1 as the predominant enzyme, but further investigations are required. In summary, the gain of renal safety by use of preferential or specific COX-2 inhibitors is small or negligible with respect to sodium retention, hyperkalemia and probably water intoxication. These drugs may be advantageous regarding renal perfusion, but presently the same precautions as for conventional NSAIDs must be used.

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“…Newer NSAID's have a higher COX-2-selectivity [14][15][16][17][18]. Highly selective COX-2-inhibitors like Celecoxib [19] can be of importance in the prophylaxis of atherosclerosis [20] alongside their "classical" indication, the rheumatic diseases, especially where conventional NSAID's are not suited due to their toxicity (gastric ulcus [17,18,21], gastric perforation, gastrointestinal bleeding) [22].…”

Section: Introductionmentioning

confidence: 99%

Investigations on the Significance of Inductable Cyclooxygenase in Atherogenesis in Cholesterol-Fed Rabbits

Wurr¹,

Nölte²,

Stichtenoth³

2012

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Atherosclerosis is the most prevalent disease in middle and later years of human life. Heart attacks and strokes are among the most frequent causes of death. New approaches in therapy are the use of NSAID's (nonsteroidal antiphlogistical drugs) of the new generation (selective inhibitors of COX-2) and DHEA (Dehydroepiandrostenon). The key enzyme of prostaglandin synthesis, the COX-2 isoenzyme, is predominantly found in inflammatory tissue. Out of this results a possible importance of COX-2-inhibitors in prophylaxis of atherosclerosis. Our study intended to examine the significance of COX-2 and the COX-2-formed prostanoids, as well as the significance of COX-2-independent isoprostanes on atherosclerosis. For that purpose we tested the effect of the selective COX-2-inhibitor Celecoxib on rabbits fed with cholesterol and compared this with the effect of the steroid hormone DHEA in 4 groups: healthy control, cholesterol-fed control, DHEA-group and Celecoxib group. In the test prostanoids, nitrate and nitrite were measured by gas chromatograpy/tandem-mass-spectrometry (GC-MS/MS) in 24-hours-collected urine. Additionally we measured cholesterol and triglycerides in plasma. The aortas of the examinated animals were measured optically using a planimetrical method. The measurement of prostanoids, isoprostanes, nitrate and nitrite showed considerable variations and particulary significant differences (p < 0.01) even in the initial values. By the treatment with Celecoxib the rate of atherosclerosis was reduced in a highly significant way in comparison to the cholesterol group and the DHEA-group. Consequently the test demonstrated a significant role of COX-2 in the development of atherogenesis.

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New non-steroidal anti-inflammatory drugs: Selective inhibitors of the inducible cyclooxygenase

Abstract: So far the results suggest, that selective and highly selective COX-2 inhibitors have significantly fewer gastrointestinal and renal adverse effects and do not inhibit platelet aggregation.

Cited by 15 publications

References 97 publications

Nucleus pulposus-induced nerve root injury: effects of diclofenac and ketoprofen

Nucleus pulposus-induced nerve root injury: effects of diclofenac and ketoprofen

COX-2 and the Kidneys

Investigations on the Significance of Inductable Cyclooxygenase in Atherogenesis in Cholesterol-Fed Rabbits

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