"Alf Christophersen" <[email hidden]> wrote in message
news:[email hidden]...
Quoted message said:On Sat, 26 Mar 2005 17:24:29 -0800, "Robert" <[email hidden]>
Quoted message said:We know the effects and in most cases we don't know why.
Just because there is COX inhibition does not anwser all the hows.
Remember that if arachidonic acid is freed and not reacting with COX
anymore, arachidonic acid may undergo many other rearrangements,
almost all them with different physiologic effects.
That is my point and those effects can differ.
Quoted message said:
Like reacting with lipoxygenase 5 giving more leukotrienes, inducing
traumatic shock, SRSA and other spectacular reactions.
Yes. COX reactions are different than other leukotrienes reactions. The COX
can be inhibited with platelet inhibition but the endothelial lipoxygenase
can also be inhibited in higher concentrations of apirin within the
endothelial cells leading to platelet adherance. These are differences of
competing prostacylcin inhibiton in endothelial cells vs COX inhibition in
platelets.
Even within COX1 and COX2 can be contradictory see below.
Quoted message said:
Isoketal formation, isoprostanes, epoxides are even more classes of
signalling compoinds that may be formed in excessive amounts when COX
is inhibited or even inactivated (when inhibited, the time being
inactive is time dependent, while inactivated, the enzyme is killed
and must be replaced by new synthesis. SInce blood platelets do not
contain DNA or RNA, these cells are dead and cannot participate in
blood clotting anymore. Thus breaking the coagulation process and
clots formed can only be of a little size, while taking too much
inactivator, destroys completely the ability of coagulation. That's
why it is a bad idea to take more than a few mg aspirine at a timein
order to prevent heart attacks from clot formed. The dose should only
inactive the COX in about 5-10% of platelets that pass the blood
vessels btw. intestines and liver. Taking 10-50 mg will most often do
so, taking more will kill COX in too many blood platelets.
Platelets are only one part of the equation with regards to COX and I was
referring to endothelial cell levels. There is a normal anti-platelet
anti-stick factor with endothelial cells where the blood circulates
otherwise the platelets and everything else would stick.
That is the prostaglandin levels within the cell.
Curr Opin Pharmacol. 2005 Apr;5(2):204-10. Related Articles, Links
Cardiovascular hazard and non-steroidal anti-inflammatory drugs.
Wong D, [censored] M, Cheng Y, Fitzgerald GA.
Institute for Translational Medicine and Therapeutics and the Department of
Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia,
Pennsylvania, USA.
Selective inhibitors of cyclooxygenase (COX)-2 depress prostacyclin (PGI(2))
without a concomitant inhibition of platelet COX-1-derived thromboxane
(Tx)A(2). Experiments in gene-deleted mice have shown that ablation of the
PGI(2) receptor (the IP) predisposes to an exaggerated response to agonists
which elevate blood pressure, accelerate atherogenesis and induce
thrombosis. Such a class-based effect would be expected to be modulated by
the underlying risk of cardiovascular disease in patients, elements of drug
exposure, such as dose, duration of action and duration of dosing, and
inter-individual variability of drug response. Five placebo-controlled
trials of three structurally distinct selective inhibitors of COX-2 have
revealed an increased hazard of myocardial infarction and stroke consistent
with a mechanism-based class-specific cardiovascular hazard. Sustained
inhibition of platelet TxA(2) by aspirin affords cardiovascular benefit,
despite concomitant inhibition of PGI(2). Although there is no information
from randomized placebo-controlled trials, traditional non-steroidal
anti-inflammatory drugs, such as naproxen, dicofenac and ibuprofen, might
differ in their effects of cardiovascular biology.
PMID: 15780832 [PubMed - in process]
Circulation. 2001 Aug 14;104(7):820-5. Related Articles, Links
Effects of selective cyclooxygenase-2 inhibition on vascular responses and
thrombosis in canine coronary arteries.
Hennan JK, Huang J, Barrett TD, Driscoll EM, Willens DE, Park AM, Crofford
LJ, Lucchesi BR.
University of Michigan Medical School, Department of Pharmacology, Ann Arbor
48109-0632, USA.
BACKGROUND: Prostanoid synthesis via the action of cyclooxygenase-2 (COX-2)
is a component of the inflammatory response. Prostacyclin, a product of
COX-2 in vascular endothelium, has important physiological roles, such as
increasing blood flow to injured tissues, reducing leukocyte adherence, and
inhibiting platelet aggregation. We examined the possibility that selective
COX-2 inhibition could suppress the protective effects of prostacyclin,
resulting in an alteration of the hemostatic balance and vascular tone.
METHODS AND RESULTS: Circumflex coronary artery thrombosis was induced in
dogs by vascular electrolytic injury. Orally administered celecoxib (COX-2
inhibition) or high-dose aspirin (HDA) (COX-1 and COX-2 inhibition) did not
alter time to occlusive thrombus formation compared with controls (celecoxib
77.7+/-7.2 minutes, HDA 72.0+/-18.5 minutes, control 93.0+/-21.8 minutes).
Oral HDA with an endothelial recovery period (HDA-ER) (COX-1 inhibition)
produced a significant increase in time to vessel occlusion (257.0+/-41.6
minutes). The observed increase in time to occlusion was abolished when
celecoxib was administered to animals dosed with HDA-ER (80.7+/-20.6
minutes). The vasomotor effect of endothelium-derived prostacyclin was
examined by monitoring coronary flow during intracoronary administration of
arachidonic acid or acetylcholine. In celecoxib-treated animals,
vasodilation in response to arachidonic acid was reduced significantly
compared with controls. CONCLUSIONS: The results indicate important
physiological roles for COX-2-derived prostacyclin and raise concerns
regarding an increased risk of acute vascular events in patients receiving
COX-2 inhibitors. The risk may be increased in individuals with underlying
inflammatory disorders, including coronary artery disease.
PMID: 11502709 [PubMed - indexed for MEDLINE]
