Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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COX II selective agents not that safe
- Brendon J Smith (12 September 2003)
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Unifying hypothesis for human diseases
- Richard G Fiddian-Green (12 September 2003)
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aspirin, the wonder drug
- dr.manan vasenwala (13 September 2003)
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Can we manage with a weekly dose?
- Robert D. Hoffman (13 September 2003)
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insomia and antidepression
- john h abeles (14 September 2003)
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Consider COX 3 activity also
- Brendon J Smith (14 September 2003)
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If only paracetamol were safer....and properly studied
- Nicholas D Moore (19 September 2003)
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What do we do and WHO should do it?
- Gareth P Morgan (24 September 2003)
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Hyphens
- Robert M. Youngson (4 October 2003)
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High serum Ca-binding capacity of salicylate
- Lars-Fride Olsson (7 October 2003)
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Brendon J Smith, Staff Specialist - Emergency Medicine Bankstown Hospital, Bankstown, 2200, Sydney, Australia
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The summary of the effects of aspirin mentions that COX II selective agents are safer than non selective agents, which is a tenuous conclusion given the available evidence. A major study (1) did not show a reduction in the primary outcome measure of ulcer complications, although less relevant secondary outcomes were reduced to a small extent during 6 months of use (2). The validity of this conclusion is dubious because the data as submitted to the FDA was from the planned 12 month study which showed no benefit. However the published data was for 6 months, presumably because this cut off showed the selective agents in the best light. Recent Australian data demonstrates serious gastrointestinal complications which affect patients even with no risk factors (3). Interestingly, less attention is given to COX II selective agents which are of proven efficacy and safety for analgesia in the group of patients for whom NSAIDs are frequently prescribed. This established drug is better known as paracetamol (acetaminophen), which acts on central COX II receptors. The BMJ POEM series has previously highlighted the risk from COX II selective agents (4), and the POEM from the same issue as the editorial dispels the recycled myth that they are of benefit in Alzeimher's disease (5). It is unfortunate that the myths regarding the safety and unproven benefits of COX II selective agents continue to be perpetuated, even when disproved a few pages on, although industry links of the author are noted. 1. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000;284:1247-1255 2. Lichtenstein, DR , Wolfe, MM. COX-2-Selective NSAIDs. New and Improved? JAMA. 2000;284:1297-1299 3. Australian Adverse Drug Reactions Bulletin Volume 22, Number 3, August 2003. Available at http://www.tga.gov.au/adr/aadrb/aadr0308.htm#3 (accessed September 12, 2003) 4. POEM - Harms outweigh benefits of COX 2 for many patients. BMJ 2003;326 15 March, 2003 5. POEM - Anti-inflammatories don't slow cognitive decline in Alzheimer's. BMJ 2003;327, 13 September, 2003 Competing interests: None declared |
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Richard G Fiddian-Green, None None
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That aspirin is apparently effective in preventing many different clinical conditions is compeling evidence in support of an unifying hypothesis for human diseases (1). 1. Richard G Fiddian-Green A common denominator in cancer and thromboembolism? http://bmj.com/cgi/eletters/326/7379/37#29394, 4 Feb 2003 Competing interests: None declared |
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dr.manan vasenwala, consultant-cardiologist (non-invasive) k.k.heart center, aligarh-202002.india
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the indications of aspirin are still evolving. every passing day brings about new possible indications. of particular concern is that nearly one in three patients of myocardial infarction may be aspirin resistant.the implication of these findings may be to use other drug combinations.although aspirin is well established in both primary and secondary prevention of cardiovascular diseases, it does not seem to work equally well in all patients. aspirin resistance is defined as platelet aggregation of 70% or more with 10 micromolar aspirin together with more than 20% aggregation with 0.5mg/ml of arachidonic acid.researchers have found these patients were older, male, diabetic, with more severe coronary artery disease, more likely to have undergone cabg and other coronary procedures.(1) CRP also appear to be attenuated in patients receiving aspirin which suggest that aspirin conferred protection against ischaemic myocardial injury. these data corroborate the idea that aspirin has both anti- inflammatory effect as well as anti-platelet.(2) the cardioprotective effects of aspirin may be further be due to its growth inhibiting effect on chlamydia pneumoniae which is associated with atherogenesis.more specifically,the micro-organism act by increased cytokine expression by nuclear factor(NF)-kappaB, a transcription factor.aspirin is known to inhibit this very activity.(3) aspirin may also be useful in control of diabetes, albeit in high doses.hypoglycemia is a known complication of poisoning with aspirin. in rodents predisposed to obesity and diabetes giving aspirin reversed their insulin resistance leading to lowering of blood glucose and triglycerides.(4) researchers also report that N0-aspirin being more effective than ordinary aspirin in ihd. also there was minimal or no effect on git system.this aspirin was also significantly more effective against coronary restenosis(5). coronary restenosis is currently the achilles' heel for interventional cardiologists. the drug-eluting stents reccommended for its prevention is terribly expensive. despite these advantages of aspirin some controversies have surfaced. this is the claim by some researchers that aspirin makes treatment with ace- inhibitors ineffective.one study has concluded that there is only a weak evidence of any reduction in the benefit of ace-inhibitors therapy when added to aspirin. however,on the contrary, there is a definite evidence of clinically important benefits with ace-inhibitors irrespective of whether concomitant aspirin is used.(6) another potential use of aspirin , hitherto thought to be a weak agent, is its use in dvt and prevetion of pe.(pep trial) the authors conclude that there is good evidence in considering aspirin use routinely in a wide range of surgical and medical groups at high risk of vte, and for continuing it throughout the period of increased risk.(7) 1.International Society on Thrombosis and Haemostasis XIX Congress 2003; Birmingham, UK: 12-18 July 2.J Am Coll Cardiol 2001; 37: 1266-1270 3.Arteriosclerosis, Thrombosis and Vascular Biology 2002; 22: 1075–1080 4.Science 2001; 293: 1673-1677 5.PNAS 2001; 98: 2860-2864. 6.Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review by Koon K Teo, Salim Yusuf, Marc Pfeffer, Lars Kober, Alistair Hall, Janice Pogue, Roberto Latini, Rory Collins for the ACE Inhibitors Collaborative Group* 7.Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.Correspondence to: Dr Anthony Rodgers, Clinical Trials Research Unit, Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand Competing interests: None declared |
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Robert D. Hoffman, Family Physician Rehovot Israel
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The editorial reviewed the importance of Aspirin and other NSAIDs in preventive medicine. Whereas the US Preventive Services Task Force ( http://www.ahcpr.gov/clinic/uspstfix.htm ) guidelines do not support "blanket" use of Aspirin in adult patients many adults regularly use some form of NSAID. If we consider the long effect Aspirin has on platelet activity, it seems to be that intermittent use would be enough to provide the positive benefits of Aspirin use. In the century of use before the advent of the many NSAID's Aspirin was the primary over the counter pain killer. The previous generation probably had the benefits of Aspirin prophylaxis without being aware of lastng effects. I think it appropriate in the era of cost-conscious preventive medicine to look into the benefits of once weekly Aspirin prophylaxis. Our patients will thank us for it. Robert Hoffman Clinical Teacher - Family Medicine Tel Aviv University Medical School Competing interests: None declared |
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john h abeles, prof clin pharm iuhs, st kitts
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yet another use for aspirin? popular anecdotal evidence for the use of aspirin as a sleep aid is widespread; there is also anecdotal evidence for a mood elevating effect. aspirin is known to displace tryptophan from bound sites and hence elevate serum tryptophan levels leading to increased intracerebral serotonin availability. would selective cox-2 inhibitors do the same? i cannot find reference to similar selective cox-2 inhibitor action to that of aspirin on tryptophan displacement. Competing interests: None declared |
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Brendon J Smith, Senior Staff Specialist - Emergency Department Bankstown Hospital, 2200, Sydney, Australia
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I wondered if I may correct an error that went into my earlier rapid response. I mentioned the action of paracetamol acting on central COX 3 receptors, and that it is effective and safer in many patients for whom NSAIDs are prescribed. The published version changed this to COX 2 selective agents which is not correct. Competing interests: None declared |
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Nicholas D Moore, Professor of clinical pharmacology Université Victor Segalen, 33076 Bordeaux
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Sir, The topic of the initial paper is aspirin, which is a truly remarkable if toxic drug, that is still very far from being completely explored. I am not certain that what is found with aspirin will apply fully to other NSAIDs, especially COX-2 inhibitors. Inhibiting both Cox-1 and Cox2 may have merit, for instance in analgesia; the mechanism of inhibition is different, and aspirin has other effects including central effets, as are evident in overdose, that are not shared by other NSAIDs. So that the extension of aspirin's effect to other NSAIDS is at the present time speculative, until the proper studies have been done. This is especially true for paracetamol, a remarkably poorly studied drug. It is reasonably safe in normal use though not a very effective painkiller, being consistently less effective than low dose ibuprofen, diclofenac, or for that matter any NSAID tested, unless doses reaching 4g/day or more are used, at which point it starts havin anti- inflammatory effects and gastro-toxicity. But paracetamol's main weakness is its danger in overdose. The industry should perhaps look for a tweaked paracetamol that has its same activities, but without the terrible liver toxicity, that makes it now he first cause of liver transplant in the US. More generally speaking, paracetamol is a remarkably little known drug. Most of the knowledge is derived from studies of other drugs where paracetamol is a comparator, and from speculations and hypotheses based on possible physiopathological considerations. The comments above are a typical example of speculative affirmation of effects or benefits. The companies plead that they make no money with this old drug, and will not invest in it. Paracetamol is the most widely used drug in France (www.ameli.fr), with more than 137 Million boxes sold (even though these only contain a maximum of 8 g to limit acute toxiciy), with an additional 48 Million boxes of combined paracetamol and dextropropoxyphene. Despite its low price, it is the third drug in the french market (290 Million euros yearly) for reimbursed drugs, i.e. prescription drugs. If combined paracetamol is included, it climbs to the second rank with more than 400 million euros per year. This puts it just behing omeprazole, and before statins (pravastatin is only 295 million, atorvastatin a measly 260) and COX2 inhibitors (Celecoxib and rofecoxib only make about 100 million euros each). This is in addition to the OTC sales, of course, which should be about the same as the prescription sales (at least that is the case for low-dose ibuprofen). With such a blockbuster drug, couldn't the makers and sellers of paracetamol finance a few good studies, to support allegations of its benefits and further the knowledge of the mechanisms of action and effects? Competing interests: I've been working in the field of low-dose NSAID analgesia for years, and with COX-2 inhibitors, and may therefore have a bias towards my own results and opinions. |
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Gareth P Morgan, Public Health Practitioner National Public Health Service for Wales (Swansea Office), Swansea, UK. SA1 5AQ.
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I welcome the paper by Professor Flower as it should generate further interest on aspirin. I would have liked to have seen more discussion of a policy nature. The disease reduction potential of aspirin is enormous and leadership must be given by the World Health Organisation to realising this at a global level. Competing interests: None declared |
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Robert M. Youngson, Retired Consultant Ophthalmologist Home DT11 7NY
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EDITOR--I trust you are aware that the perverse BMJ house style of systematically refusing to hyphenate complex adjectival forms can lead to ambiguities and errors. 'More-important causes' is not the same as 'More important causes'; 'twenty-odd people' is not the same as 'twenty odd people'; and 'the prostaglandin-forming cyclo-oxygenase' is not the same as 'the prostaglandin forming cyclo-oxygenase' (15 September 2003 p 572). Innocent readers who have not yet realized that this has long been BMJ policy are liable to be misled, as are those whose knowledge of biochemistry is shaky. It's high time this silly and unjustified style was corrected. The BMJ has a duty to avoid ambiguity. Robert M. Youngson Medical author Blandford Forum Dorset DT11 7NY Competing interests: None declared |
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Lars-Fride Olsson, Senior researcher (chemist), PhD Gambro AB, P.O.B. 10101, SE-220 10 Lund, SWEDEN
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It may be of interest to know that according to the chemical literature (see below) salicylate binds very strongly to the Ca ion - "serum ionized Ca". The analogous effect of acetylsalicylic acid is considerably less. This knowledge is related to the lines "The half life of aspirin in plasma is short; esterases remove the acetyl group leaving free salicylate, which may have a secondary pharmacological effect through cyclooxygenase inhibition or other mechanism, adding to the complexity of aspirin's action". "other mechanisms": one hypothetically possible one may be the influence of salicylate on serum Ca distribution. According to Arena et.al. "J. Inorg. Nucl. Chem., 40(1978), 1221" the equilibrium constant for Ca-salicylate complex formation is logK = 4.29 at 37 Centigrade and Ionic strength = 0.15 mol/L. It means that even sub-millimolar salicylate concentrations in blood will alter the Ca-distribution, i.e. lower ionized Ca-concentration as well as influence the albumin-bound fraction. Compared to citrate, salicylate anticoagulative effect should be considerably higher; Ca-citrate has logK = 3.2 or ten times lower than that of salicylate. Aspirin is far less important: its short resident time in blood and its lower Ca-aspirin logK (= 2.95) ensures that the effect is unimportant compared to salicylate. Competing interests: None declared |
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