Posted on 05/22/2006 1:39:51 PM PDT by neverdem
Eighteen months.
Ever since Merck pulled its arthritis painkiller Vioxx off the market in September 2004 on evidence that it could cause strokes or heart attacks, the company and its lawyers have stood by the premise that it was dangerous only to patients who took it for at least 18 months.
So it was news last week when prominent medical experts said that new data from Merck indicated that Vioxx's risks started to emerge after only four months of use. The controversy is the latest illustration of how widely open to interpretation and potential corporate pressure the results of clinical trials can be — even when reported in a leading medical journal.
Critics say it is now clear that the previous data analysis was done in a way that minimized the risks of the drug. Some also say that Merck and its academic collaborators should have known about that four-month threshold and made the earlier risks clearer in a medical journal article in March 2005.
It was the first scientific report of the clinical trial results that had prompted the company to withdraw the drug. That article, in The New England Journal of Medicine, concluded: "The increased relative risk became apparent after 18 months of treatment."
The conclusion "makes the drug look a lot safer than it was," Dr. Steven E. Nissen, the interim chairman of cardiovascular medicine at the Cleveland Clinic, said last week after reviewing the new data. "If you wanted to construct a legal defense that says nothing happens for 18 months, this is how you would cut the data."
Merck said the new data, seeming to show an earlier risk from Vioxx, had not yet been compiled in early 2005. But the company argues that even now that the fuller data were available, the numbers do...
(Excerpt) Read more at nytimes.com ...
This is the worst kind of 20-20 hind-sight analysis.
What is not being shown here is the confidence levels for the data. I would suggest that even the 50% confidence levels overlap considerably, and that a strict statistical hypothesis that the two (rate vs. time) curves are not the same would fail.
If you don't take the statistical confidence levels into account, then if the two rates are exactly the same, half the time the drug curve would be under the undrugged curve, and the other half the time it would be over. That means you would reject a good drug 50% of the time.
There is a technical term for this kind of analysis: guessing.
Nigerian Monkeys Drop Hints on Language Origin
Physical performance linked to future mental ability
FReepmail me if you want on or off my health and science ping list.
I used Vioxx at a time in my life that it was critical to have it, and it worked beautifully for me. I took it for only 6 months, and wished I could have it available as needed for longer. It worked where nothing else did.
Did you try Bextra or Celebrex? How about Lodine, aka etodolac, which is supposed to have one of the best GI profiles of the previous NSAIDs?
1: Clin Exp Immunol. 2005 Apr;140(1):41-5. Related Articles, Links
Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro.
Schroecksnadel K, Winkler C, Wirleitner B, Schennach H, Fuchs D.
Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria.
Acetylsalicylic acid (aspirin) is one of the most widely used drugs worldwide, due mainly to its broad therapeutic spectrum with anti-inflammatory, antipyretic, antithrombotic and analgesic effects. However, the exact mechanisms by which aspirin influences inflammation, pain and immune system activation are only partly understood. Within activation of the cellular immune system, Th1-type cytokine interferon (IFN)-gamma induces enzyme indoleamine-2,3-dioxygenase (IDO) which converts tryptophan to kynurenine. In parallel, IFN-gamma induces enzyme GTP-cyclohydrolase I, which gives rise to neopterin production by activated human macrophages. Similarly, tryptophan degradation and neopterin formation increase during several disease states involving Th1-type immune activation. Using stimulated human peripheral blood mononuclear cells (PBMC), the effect of aspirin on tryptophan degradation and neopterin production was investigated. Stimulation of PBMC with mitogens concanavalin A, phytohaemagglutinin and pokeweed mitogen induced significant tryptophan catabolism as was reflected by a decline in tryptophan levels and a parallel increase in kynurenine concentrations compared with unstimulated cells. In parallel, neopterin production was enhanced. Treatment of stimulated PBMC with increasing doses of 1-5 mM aspirin significantly decreased stimulation-induced tryptophan degradation and neopterin production as well. All the effects of aspirin were dose-dependent. The parallel influence of aspirin on both biochemical pathways implies that there was no direct inhibitory effect of aspirin on IDO; rather, it inhibits production of IFN-gamma in mitogen-treated PBMC. The influence of aspirin on biochemical pathways induced by IFN-gamma may represent an important part of its broad pharmacological effect.
PMID: 15762873 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15762873&query_hl=5&itool=pubmed_docsum
High-Carb Drink Eases SAD Symptoms
http://www.forbes.com/forbeslife/health/feeds/hscout/2006/05/23/hscout532860.html
The regulation of rat liver tryptophan pyrrolase activity by reduced nicotinamide-adenine dinucleotide (phosphate). Experiments with glucose and nicotinamide.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8041&query_hl=7&itool=pubmed_docsum
Thanks for the links.
1: Neuropharmacology. 1988 May;27(5):499-505. Related Articles, Links
Effect of aspirin on serotonin and met-enkephalin in brain: correlation with the antinociceptive activity of the drug.
Groppetti A, Braga PC, Biella G, Parenti M, Rusconi L, Mantegazza P.
Department of Pharmacology Emilio Trabucchi, University of Milan, Italy.
Intravenous administration of acetyl salicylate of lysine, a soluble salt of aspirin, reduced in rats the firing discharge of thalamic neurones, evoked by noxious stimuli. Concomitantly, concentrations of 5-hydroxyindole acetic acid increased, while those of met-enkephalin-like immuno-reactive derivatives were decreased in several areas of the brain. Similar electrophysiological and biochemical responses were obtained by administering tryptophan or 5-hydroxytryptophan plus carbidopa. The effect of aspirin on the evoked firing of the thalamic neurones was counteracted by pretreating the animals with metergoline. On the other hand, naloxone did not antagonize the inhibitory effect of aspirin and 5-hydroxytryptophan on pain-induced neuronal excitation. These data indicate that a serotonin-, but not a naloxone-sensitive opiate mechanism, may be relevant for aspirin-mediated antinociception.
PMID: 2455874 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2455874&query_hl=12&itool=pubmed_docsum
1: Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005454. Related Articles, Links
Antidepressants for neuropathic pain.
Saarto T, Wiffen PJ.
Cancer Center, Helsinki University Central Hospital, Haartmaninkatu 4, P O Box 180, Helsinki, Finland, FIN-00029. tiina.saarto@hus.fi
BACKGROUND: For many years antidepressant drugs have been used to manage neuropathic pain, and are often the first choice treatment. It is not clear, however, which antidepressant is more effective, what role the newer antidepressants can play in treating neuropathic pain, and what adverse effects are experienced by patients. OBJECTIVES: To determine the analgesic effectiveness and safety of antidepressant drugs in neuropathic pain. Migraine and headache studies were not considered. SEARCH STRATEGY: Randomised trials of antidepressants in neuropathic pain were identified in MEDLINE (1966 to Dec 2003); EMBASE (1980 to Dec 2003); the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2004, Issue 1; and the Cochrane Pain, Palliative and Supportive Care Trials Register (May 2002). Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of antidepressant drugs in adult patients, with subjective assessment of pain of neuropathic origin. Studies that included patients with chronic headache and migraine were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers agreed the included studies, extracted data, and assessed methodological quality independently. Fifty trials of 19 antidepressants were considered eligible (2515 patients) for inclusion. Relative Risk (RR) estimates and Number-Needed-to-Treat (NNTs) were calculated from dichotomous data for effectiveness and adverse effects. MAIN RESULTS: Tricyclic antidepressants (TCAs) are effective treatments for the treatment of neuropathic pain.Amitriptyline has an NNT of 2 (95%CI 1.7 to 2.5) RR 4.1(95%CI 2.9-5.9) for the achievement of at least moderate pain relief. There is limited evidence for the effectiveness of the newer selective serotonin reuptake inhibitor antidepressant drugs (SSRIs). There were insufficient data for an assessment of evidence of effectiveness for other antidepressants such as St Johns Wort, venlafaxine and L-tryptophan. For diabetic neuropathy the NNT for effectiveness was 1.3 (95%CI 1.2 to 1.5) RR 12.4(95%CI 5.2-29.2) (five studies); for postherpetic neuralgia 2.2 (95%CI 1.7 to 3.1), RR 4.8(95%CI 2.5-9.5)(three studies). There was evidence that TCAs are not effective in HIV-related neuropathies. The number needed to harm(NNH) for major adverse effects defined as an event leading to withdrawal from a study was 16 (95%CI: 10-45). The NNH for minor adverse effects was 4.6 (95%CI 3.3-6.7) AUTHORS' CONCLUSIONS: Antidepressants are effective for a variety of neuropathic pains. The best evidence available is for amitriptyline. There are only limited data for the effectiveness of SSRIs. It is not possible to identify the most effective antidepressant until more studies of SSRIs are conducted.
Publication Types:
Meta-Analysis
Review
PMID: 16034979 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16034979&query_hl=21&itool=pubmed_docsum
1: Br J Pharmacol. 1982 Sep;77(1):59-67. Related Articles, Links
Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by acute administration of small doses of antidepressants.
Badawy AA, Evans M.
1 Administration to rats of a 0.5 mg/kg dose of any of 19 antidepressants, but not that of many other drugs, causes a significant inhibition of the total enzyme and apoenzyme activities of liver tryptophan pyrrolase (of 24-48% and 37-65% respectively) and elevates brain tryptophan concentration by 13-66%. 2 When liver tryptophan pyrrolase activity is enhanced by pretreatment with cortisol or haematin, subsequent administration of a 0.5 mg/kg dose of some, but not other, antidepressants causes inhibition, which is weak (up to 38%). 3 This weak inhibition of the enhanced pyrrolase activity together with other pharmacological and physiological factors could explain the time lag between the start of antidepressant medication and the occurrence of a therapeutic response. 4 The cortisol-induced and haematin-activated pyrrolases respond differentially to inhibition by imipramine and amitriptyline, and this may explain the differential response to these two drugs of depressed patients in relation to urinary excretion of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol. 5 The results are discussed in relation to the mechanism of action of antidepressants and the possible involvement of disturbed hepatic tryptophan metabolism in depressive illness.
PMID: 7126996 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7126996&query_hl=23&itool=pubmed_docsum
1: Life Sci. 1983;33 Suppl 1:739-42. Related Articles, Links
Does naloxone always act as an opiate antagonist?
Badawy AA, Evans M, Punjani NF, Morgan CJ.
Evidence for the ability of the opiate antagonist naloxone to block a variety of metabolic effects exerted by morphine and non-opiate drugs is reviewed. Naloxone prevents or reverses the following effects in the rat: (a) the chronic morphine-induced increase in liver [NADPH]; (b) the consequent chronic morphine-induced inhibition of liver tryptophan pyrrolase activity; (c) the resultant chronic morphine-induced enhancement of brain 5-hydroxytryptamine synthesis; (d) the similar effects on liver and brain tryptophan metabolism exerted chronically by other drugs of dependence (ethanol, nicotine and phenobarbitone); (e) the acute ethanol-induced increase in the hepatic [NADH]/[NAD] ratio. Naloxone also (f) inhibits basal and stimulated lipolysis in fed and 24hr-starved rats. This leads to prevention of (g) the consequent increase in the availability of circulating free tryptophan, and (h) the resultant tryptophan-mediated decrease in liver 5-aminolaevulinate synthase activity. The question of how many of these effects involve changes in endogenous opiates or at opiate receptors is not clearly understood at present and thus merits investigation. However, because most of the above effects are explained on biochemical grounds, and in view of evidence from behavioural and pharmacological studies [see (1)], the possibility must be considered that many of the actions of naloxone may be unrelated to its opiate-receptor-antagonistic properties.
PMID: 6664250 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=6664250&query_hl=29&itool=pubmed_docsum
1: Biochem J. 1981 Apr 15;196(1):161-70. Related Articles, Links
The role of liver tryptophan pyrrolase in the opposite effects of chronic administration and subsequent withdrawal of drugs of dependence on rat brain tryptophan metabolism.
Badawy AA, Punjani NF, Evans M.
1. Chronic administration of morphine, nicotine or phenobarbitone has previously been shown to inhibit rat liver tryptophan pyrrolase activity by increasing hepatic [NADPH], whereas subsequent withdrawal enhances pyrrolase activity by a hormonal-type mechanism. 2. It is now shown that this enhancement is associated with an increase in the concentration of serum corticosterone. 3. Chronic administration of the above drugs enhances, whereas subsequent withdrawal inhibits, brain 5-hydroxytryptamine synthesis. Under both conditions, tryptophan availability to the brain is altered in the appropriate direction. 4. The chronic drug-induced enhancement of brain tryptophan metabolism is reversed by phenazine methosulphate, whereas the withdrawal-induced inhibition is prevented by nicotinamide. 5. The chronic morphine-induced changes in liver [NADPH], pyrrolase activity, tryptophan availability to the brain and brain 5-hydroxytryptamine synthesis are all reversed by the opiate antagonist naloxone. 6. It is suggested that the opposite effects on brain tryptophan metabolism of chronic administration and subsequent withdrawal of the above drugs of dependence are mediated by the changes in liver tryptophan pyrrolase activity. 6. Similar conclusions based on similar findings have previously been made in relation to chronic administration and subsequent withdrawal of ethanol. These findings with all four drugs are briefly discussed in relation to previous work and the mechanism(s) of drug dependence.
PMID: 7197926 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7197926&query_hl=29&itool=pubmed_docsum
1: Biochem J. 1975 Jun;148(3):425-32. Related Articles, Links
The effects of acute and chronic nicotine hydrogen (+)-tartrate administration and subsequent withdrawal on rat liver tryptophan pyrrolase activity and their comparison with those of morphine, phenobarbitone and ethanol.
Badawy AA, Evans M.
Acute administration of nicotine hydrogen (+)-tartrate enhances the activity of rat liver tryptophan pyrrolase by a hormonal mechanism. Chronic nicotine treatment inhibits, and subsequent withdrawal enhances, the pyrrolase activity. The inhibition during chronic treatment is not due to a defective apoenzyme synthesis nor a decreased cofactor availability. Regeneration of liver NADP+ in vitro and in vivo reverses the inhibition. Chronic nicotine administration increases the liver NADPH concentration. The above effects of nicotine resemble to a remarkable degree those previously shown for morphine, phenobarbitone and ethanol. All effects are compared, and their possible significance in relation to drug dependence is discussed.
PMID: 989 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=989&query_hl=29&itool=pubmed_docsum
Sorry, I got carried away, but will some one explain why all these drugs act in the same way? Am I the only one that sees a pattern here? Drugs = inhibitors = tryptophan = problems.
I'm not downplaying the importance of tryptophan and serotonin, but as far as drugs of abuse go, with the exception of ethanol which doesn't have a specific receptor, IIRC, all the other drugs have been found to have specific receptors and involve dopaminergic pathways.
Here is a little A.A. history lesson that has helped many recover that are fortunate to find it.
I am not the author of the below text nor am I selling anything...lets just say I have a family history of folks that need help and have done some research into alcoholism.
Bill W. suffered from depression AFTER he got sober until he met up with Dr's Hoffer and Osmond and started taking Niacin (B-3). Niacin became Bill's total focus after he started taking it. When asked by a reporter late in life what he wanted to be remembered for he said, "My work with niacin" NOT the founding of AA! That is how strongly he felt about Niacin.
The key is the amino acid Tryptophan which is converted in the body to Niacin, Serotonin and a host of other things.
This is still very controversial in A.A. and has got me kicked out of many "Open" meetings.
To anyone reading this PLEASE, do not run out and take a large dose of Niacin, you will not like the results. Niacin must be taken in a certain way. Consult your Physician.
P.S. When reading this remember the term "Schizophrenia" was used for mental disease of just about any kind...depression most notedly.
Below is a portion of the text,
Best,
Oxcart
Bill W.'s Communications to all A. A. physicians on the importance of nutrients to decrease symptoms in recovery and preventing, craving and relapse.
The entire text of Bill W.'s three communications to A. A. physicians runs over 100 single spaced pages and will not be included in their entirety in this text. Only Bill's summary statements are included. The complete text is available and can be obtained from the author.
As Mrs. Wilson wrote in the letter provided from her and presented here, instructing A. A. physicians concerning nutrition was Bill's main priority in the latter part of his life. When the author contacted A. A. about this matter, it was explained to him by a spokesperson from A. A. World Services that Bill's B-3 papers "are classified" and will not be provided by A. A. They also indicated that no attachment was wanted by the A. A. organization to these papers. A more detailed account of this part of Bill W.'s activities can be found in: 'PASS IT ON', The story of Bill Wilson and how the A. A. message reached the world. 1994 Alcoholics Anonymous World Services, Inc., New York, N.Y.
Over thirty years ago Bill W. strongly promoted B3 (Niacin) as a bio-nutritional treatment. No one knew at that time why Niacin was effective in decreasing alcohol craving and depression. Bill Wilson appears to me from his writings and from interviews with people still alive who worked with him to have been a genius. Bill W. strongly advocated the following actions that he thought A.A. should take:
1) To fund and advocate research on Niacin bio-nutrient as a high priority for A.A. and for the medical community outside A.A.
2) To advocate for all its members Niacin bio-nutrient therapy along with an improved nutritional program of whole foods and the reduced intake of excessive sugars, refined carbohydrates and caffeine.
3) That all physicians in A.A. and all physicians treating Alcoholism should learn and advise to their patients about bio-nutrient therapy B3 and improved nutrition.
Bill W.’s wife Lois wrote after Bill W.’s life that Bill’s top priority in the last years of his life trying to get A.A. to incorporate the above measures. In this he failed because A.A. rejected these recommendations then and continues to reject them.
This rejection continues to cause great damage to A.A. members. We now know that Niacin is a factor for the conversion of the amino acids tryptophane and tyrosine to serotonin and the catecholamines. Niacin also decreases the mortality from DT’s and nicotinic acid oxidizes alcohol to reduce acetaldehyde levels which reduces oxidative stress and the formation of the morphine like tetrahydroisoquinoline (THIQ). We also know now that not only Niacin but all of the essential nutrients, whole food diets and the reduction of the intake of sugar and refined carbohydrates are necessary to achieve the optimum long term recovery rates. See The Biggest High – The Natural High section which we now know must be added as an integral part of all therapeutic treatment. If Bill W.’s recommendations had been adopted thousands of lives and huge amounts of individual and societal suffering could have been averted. It is my hope that this work will contribute to the fulfillment of Bill W.’s insight and vision.
A copy of correspondence from Bill's late wife.
MRS. WILLIAM G. WILSON
Stepping Stones
Bedford Hills, N.Y. 10507
Dear Dave, Ed and Russ:
When the matter of the AA Trustee's ratio was finally settled, Bill felt that he had finished his job and done all he could to help AA to build a lasting structure. Then, as rarely happens in life, he was given a second opportunity to aid the sick alcoholic.
Aldous Huxley, a great admirer of AA, introduced Bill to two psychiatrists who were researching the biochemistry of alcoholism as well as schizophrenia. Bill was convinced of the truth of their findings and realized he could again help his beloved alcoholics by telling them about this probable aid for the physical component of alcoholism. He recognized that this work must be kept separate and distinct from AA and wrote a letter to the AA Board so stating.
As you know, Bill's last years were mainly devoted to the spread of this information among alcoholics and other ill persons. With your help, he wrote and distributed to AA doctors a brochure which has twice been enlarged and brought up to date. Before he passed on, he dictated a letter stating his hopes that you three doctors who were interested in AA and had worked closely with him in the niacin field, would extend your endeavors along the latter lines.
I sincerely believe that you only want what is best for the sick alcoholic who, as yet, has not been able to join AA, and that you will continue to place the principles of AA first and researching second.
Bill's great hope was that continued research would find a means whereby those thousands of alcoholics who want to stop drinking but are too ill to grasp the AA program could be released from their bondage and enabled to join AA.
All good wishes.
Affectionately,
(Mrs. William G. Wilson)
A doc at my school stockpiled it after it was banned because he thought it was such a good drug. Too bad the right to contract doesn't exist and a person who wants to be sold a product, and understands the risks, cannot choose to buy it. The legal system needs to be reformed and the FDA abolished, IMO.
agreed. The US is drowning in tort related costs.
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.