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MSM


COX-2 Inhibitor,
Ibuprofen Side Effects, and
Pain Management Without Side Effects


[What is a COX-2 Inhibitor and Why is Inhibiting COX-2 Important?
[What Causes COX-2 to Get Out of Control?]
[Dietary Influence on COX-2 Production]
[Environmental Influence on COX-2 Production
[Is COX-2 Production Present Only in Disease States?]
[Why NSAIDs (Aspirin, Ibuprofen) Have Major Side Effects]
[Nexrutine - A Natural 2nd Generation COX-2 Inhibitor]
[References]

What is a COX-2 Inhibitor and Why is Inhibiting COX-2 Important?

Cyclooxygenase (COX) is an enzyme naturally present in our body. Scientists discovered there were two forms of this Cyclooxygenase COX enzyme -- COX-1 and COX-2 enzymes.

COX-1 enzymes are produced widely throughout the body and is involved in the regulation of day-to-day cellular and metabolic activities such as maintaining stomach lining integrity, regulating blood flow within the kidneys and balancing platelet function. COX-1 enzymes are present in the body always and should not be inhibited.

COX-2 enzymes are necessary for inducing pain. The COX-2 enzyme is present in our bodies, ideally on a limited basis; however, factors such as diet, stress, and injury can influence COX-2 production. When COX-2 is produced on a continual basis, constant pain ensues. Therefore, inhibiting COX-2 is an option for muscle pain management.

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What Causes COX-2 to Get Out of Control?

The consumption of high amounts of saturated fat and the omega 6 unsaturated fatty acids, and a consumption of low amounts of omega 3 fatty acids can give rise to the production of COX-2 enzymes. In a state of ideal dietary balance, our Omega 6 to Omega 3 ratio would be 1:1, certainly no worse than 2:1. Unfortunately, because of our modern dietary indiscretions and the general unavailability of wholesome food, most Americans have an Omega 6 to Omega 3 ratio in the range of 10:1 to 20:1! 

Simply put, by continually having an unbalanced fatty acid intake we are giving the COX-2 enzyme the raw material to create fire, but not the raw material to put out the fire. It's not that COX-2 enzymes are "bad" enzymes. To the contrary, we need them for life. It's just that our diets and the stresses we live in today create way too much COX-2 enzymes, and we don't use the resources to put out the fires.

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Dietary Influence on COX-2 Production

Environmental Influence on COX-2 Production

Is COX-2 production present only in disease states?

No, as mentioned previously, COX-2 enzyme production occurs due to a myriad of factors and COX-2 production does not indicate that you are in a state of disease. The membranes of all cells in the body contain a fatty acid called arachadonic acid. As old cells die and new cells take their place, arachadonic acid is released into body tissues and blood. COX-1 and COX-2 enzymes act upon arachadonic acid to form molecules called prostaglandins.

Prostaglandins are compounds that are produced via the metabolism of fats in our diets. These compounds are simplistically categorized as either "good" or "bad." The good prostaglandins are beneficial and constructive to the body while the bad ones, if produced on a continual basis, can be destructive.

It is interesting to note that the consumption of high amounts of saturated fat and the omega 6 unsaturated fatty acids can give rise to the production of the bad prostaglandins, resulting in our recommendation to decrease animal fat intake and increase more of the unsaturated fats that come from fish into your diet. From a clinical perspective, one of the enzymes that are involved in the production of the destructive prostaglandins, called cyclooxygenase-2 (COX-2), is the target of nutritional intervention in order to suppress these substances. Hence, the introduction of dietary modifications that inhibit the COX-2 enzyme.

So, even though research is examining the role of excessive COX-2 enzyme production as a factor, healthy individuals can experience COX-2 enzyme production in amounts higher than normal, whether it is from diet, trauma or stress, or foreign invaders.

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Why NSAIDs (aspirin, ibuprofen, etc.) Have Major Side Effects

It is estimated that 25% of patients using NSAIDs, such as aspirin and ibuprofen, experience some kind of side effect and about 5% develop serious health consequences (massive GI bleeding, acute renal failure, etc.). This is because both COX-1 and COX-2 enzymes are inhibited to varying degrees by all currently available (1st generation) NSAIDs. These first generation NSAIDS include aspirin, diclofenac, ibuprofen, indomethacin, naprosyn, piroxicam, and others. Studies published so far support the hypothesis that the undesirable side effects of NSAIDs such as gastric erosion and renal dysfunction are due to the inhibition of COX-1 enzymes, while the anti-inflammatory (therapeutic) effects are due to the inhibition of COX-2 enzymes.

The benefits and the side-effects of NSAIDs vary among the 1st generation NSAIDS. Here is the key: Inhibitory potency and selectivity of the conventional, 1st generation NSAIDs for COX-1 and COX-2 enzymes vary greatly. Some NSAIDs (e.g., ketoprofen) are relatively COX-1 selective, some (ibuprofen and naproxen) are essentially non-selective, while others (e.g., diclofenac) are relatively COX-2 selective.  However, even COX-2 "selective" NSAIDs still had sufficient anti-COX-1 enzyme activity to cause potent inhibition of gastric PGE2. Thus, at therapeutic concentrations, none of the currently marketed NSAIDs spare gastric COX-1 activity.

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Selective COX-2 Inhibitor Drugs Under Development

There are currently at least a dozen highly selective COX-2 inhibitors under development by different pharmaceutical companies. These 2nd generation NSAIDs represent a new class of drugs (truly selective COX-2 inhibitors) and are considered a major advance in the management of pain and inflammatory diseases. Of these drugs, celecoxib (SC-58635 or Celebra by Searle) is the first to pass through the FDA advisory panel and will probably be approved shortly for use in rheumatoid and osteoarthritis. Celecoxib is 375 times more selective for COX-2 relative to COX-1 and, at therapeutic doses, its plasma concentration does not reach the level required for effective COX-1 inhibition. In clinical trials celecoxib showed effective anti-inflammatory activity with virtually no gastrointestinal adverse effects compared to placebo. Other agents under developments, now dubbed "the super aspirins", may have a COX-2 selectivity several fold greater than that of celecoxib with virtually on effect on COX-1 and may therefore afford a much wider margin of safety.

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Nexrutine™ — A Natural 2nd-Generation COX-2 Inhibitor

  • Nexrutine™ was developed from a plant (Phellodendron amurense) used safely for more than 1,500 years in Asia.

  • Nexrutine™ has a unique mechanism of action: It is a selective COX-2 enzyme inhibitor 6. Most herbal COX-2 enzyme inhibitors have not been evaluated for their potential to inhibit COX-1 enzymes. Nexrutine™ has cell culture, animal and human data to support its efficacy and safety as well as data that indicate that it has a characteristic that no other natural COX-2 inhibitor has, which is COX-2 enzyme selectivity.

  • Inhibiting COX-1 enzymes could result in greater gastrointestinal irritation, however, Nexrutine™ does not inhibit COX-1 enzymes and is gentle on the stomach 8. To be most useful, the botanical (Nexrutine) must not have a pronounced inhibitory action on COX-1 enzyme activity. Nexrutine™ selectively inhibits the COX-2 enzyme without affecting the important COX-1 enzyme 6.

  • Not only is the key constituent of Nexrutine™ absorbed, 8,9 but also it has been reported to exhibit a strong moderating effect. 1-3,10-12  Human data indicates that a small dosage of Nexrutine™ is needed for efficacy 7 compared to a rather large dose for other ingredients. This equates to less pills an individual must take daily and should improve individual compliance with Nexrutine™.

Cell Culture Data
COX-2 enzyme inhibitory activity was confirmed in human umbilical endothelial cells. Cells were stimulated with one of two agents to provoke a COX-2 enzyme response and then Nexrutine was added to the cell culture. COX-2 enzyme inhibition was measured and the ability of Nexrutine to inhibit COX-2 enzymes was compared to other selective COX-2 inhibitors. The results were favorable and indicated Nexrutine's COX-2 inhibitory potential. Nexrutine also showed little inhibition of COX-1 enzymes. 6

In Vivo Data
A series of three animal studies were conducted to evaluate the analgesic activity and safety of Nexrutine. 4

Human Open Trial
Preliminary data in humans suggest that Nexrutine™ was well accepted and gentle on the stomach.

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References

  1. Hsu and Associates. Oriental Materia Medica. Keats Publishing, Inc. 1986.

  2. Wang et al. Effects of Oren-gedoku-to and Unsei-in, Chinese traditional medicines on interleukin-8 and superoxide dismutase in rats. J Pharm Pharmacol 1997, 49: 102-104.

  3. Ikuta and Nakamura. Canthin-6 one from the roots of Phellodenderon amurense. Planta Med 1995, 61.

  4. Sufka K. Anti-inflammatory/Analgesic animal model (series of three studies). University of Mississippi. May-Sept 2000 (unpublished).

  5. Patterson D. An acute oral toxicity study in rats with SAC1-0004X. Final Report. Springborn Laboratories, Inc. Ohio Research Center. Oct. 2000. 1-21.

  6. Dupuis P. Study of the effects of NPS0029 (Nextrutine™) on various human cyclooxygenase activities. Cerep Laboratories, France (unpublished).

  7. Dennis and Company Research. Anti-inflammatory Dietary Supplement HUT: Open Human clinical trial evaluating the efficacy and safety of Nexrutine™. Sept 2000 (unpublished).

  8. Bhide MB et al. Absorption, distribution and excretion of berberine. Ind Jour Med Res 1969; 57 (11).

  9. Zeng X. HPLC determination of berberine in plasma of patients with ischemic heart failure. Chormatographia 1998; 48(7/8).

  10. Ckless K et al. Inhibition of in vitro lymphocyte transformation by the isoquinoline alkaloid berberine. J Pharm Pharacol 1995 Dec, 47(12A): 1029-31.

  11. Fukuda K et al. Inhibition of berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells. J Ethnopharmacol 1999 Aug, 66(2): 227-33.

  12. Yasukawa K et al. Relative inhibitory activity of berberine type alkaloids against 12-O-tetradecanoylphorbo-13-acetate induced inflammation in mice. Chem Pharm Bull (Tokyo) 19991 Jun, 39(6): 1462-5.

  13. Vane JR; Bakhle YS; Botting RM Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol, 1998, 38:, 97-120
  14. Cryer B; Feldman M Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med, 1998 May, 104:5, 413-21
  15. Bjorkman DJ The effect of aspirin and nonsteroidal anti-inflammatory drugs on prostaglandins. Am J Med, 1998 Jul 27, 105:1B, 8S-12S
  16. Kawamori T; Rao CV; Seibert K; Reddy BS Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res, 1998 Feb, 58:3, 409-12
  17. Lipsky PE; Isakson PC Outcome of specific COX-2 inhibition in rheumatoid arthritis. J Rheumatol, 1997 Jul, 24 Suppl 49:, 9-14
  18. Wu KK. Biochemical pharmacology of nonsteroidal anti-inflammatory drugs Biochemical Pharmacology. 1998; 55(5):543-7.
  19. Simon LS; Lanza FL; Lipsky PE; Hubbard RC; Talwalker S; Schwartz BD; Isakson PC; Geis GS. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum, 1998 Sep, 41:9, 1591-602.

Reprinted with exclusive permission from Natrol, Inc.  (with the exception of the paragraph: "Why NSAIDs Have Major Side Effects."

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