Lodine

Bob Garrison, MA, RPh and CEO of Next Pharmaceuticals, has pioneered in the world of herbal medicine, and heralded an alternative pain reliever long before the COX-2 controversy. Bob is a pharmacist with over 25 years experience in health communications and product development. He has played a significant public relations role within the dietary supplement industry and introduced standardized herbal extracts to the US mass market while President and Co-founder of Botalia Pharmaceutical, Inc. Bob was CEO and Founder of Health Media of America, Inc., and is co-author of The Nutrition Desk Reference and The Pharmacist's Guide to Over-the-Counter and Natural Remedies.

Kerry Hughes: Can you tell me what got you interested in natural medicines and therapeutic agents with COX-2 activity?

Bob Garrison: Well, first of all, my mentor was the late Dr. Varro Tyler, Dean Emeritus Purdue University and one of the world leaders in pharmacognosy. He pointed me toward botanicals that had been standardized and put into clinical trials. Once I understood the potential of developing natural self-care products that would be worthy of placement into clinical trials, I co-founded Next Pharmaceuticals (Next) to develop safe and effective ingredients for healthy living. Our initial platform was to develop ingredients that affect different inflammatory pathways, and ingredients that fit into the behavioral arena, such as anxiety and sleep. As we started our research, the COX-2 story (the early one with all the promises) was just emerging so it looked like a great entry point.

KH: Recent controversy and regulatory actions on the commonly prescribed COX-2 inhibiting pharmaceuticals for arthritis have caused many health practitioners and patients to search for alternatives, products that will not increase the risk for cardiovascular events. At the same time, there has also been increasing concern about the safety of dietary supplements--in large part due to the Ephedra controversy. What kind of advice can you offer doctors in choosing natural COX-2 alternatives for pain and arthritis relief?

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BG: I believe this is an important topic because one out of every three persons in the US is already using--or have used--some form of natural medicine. As doctors are one of the most trusted sources of medical or health information for people, they will need to educate themselves in the wide range of alternatives available for arthritis and pain relief. I like to give three simple guidelines to choosing a natural alternative:

1. What is the mode of action of the alternative, and does it suit the needs of your patient, both from a nutritional and pharmaceutical perspective?

2. Is the supplement clinically studied and/or have a long and compelling traditional use?

3. Do you know the company producing it has strict quality control procedures it uses to produce the supplement?

KH: Can you elaborate on your first guideline--understanding the mode of action of the alternative and its application to your patient?

BG: Yes, first a doctor needs to decide, what are the pharmaceutical choices and what are the dietary supplement alternatives? In assessing this question, the doctor should stay open to the idea of there being a possible natural alternative or complement to therapy. In other words, looking at the desired therapeutic indication, there may be more than one way to meet this goal, and there may also be nutritional approaches that provide some therapeutic activity, as well as satisfying the nutritional needs of the body. Natural alternatives for osteoarthritis are a very good example of how nutritional approaches may have both therapeutic and preventative or restorative activity.

The most conservative approach--from the Western medical perspective--to choosing an alternative is to first look at what other pharmaceutical agents might provide similar therapeutic benefit. In the case of VIOXX, the initial obvious alternative was to switch to other COX-2 inhibitors, such as Pfizer's Bextra or Celebrex. However, as the cardiac risk concerns over the entire group of COX-2 inhibitors surfaced, doctors and patients alike searched for alternatives that did not have their main mode of activity as COX-2 inhibition.

Other conventional pharmaceutical approaches include sulfa drugs, NSAIDs, acetaminophen, or COX-2 "preferential" NSAIDs. Sulfa drugs address arthritis pain, but present a problem for the 3.5% of the population who are allergic or hypersensitive to them. NSAIDs, of course, opens people up to the risk of gastrointestinal damage--an effect that many were trying to avoid by taking COX-2 drugs in the first place.

Some people decide to take acetaminophen (Tylenol[R]) for arthritis pain instead of the GI-damaging NSAIDs, however, acetaminophen lacks antiinflammatory properties and has recently been associated with high blood pressure in long-term usage. Another route taken is considering a COX-2 "preferential" NSAID, such as etodolac (Lodine) or meloxicam (Mobic) to try to limit the potential for cardiovascular risk.

However, in any of these approaches, only the pain and inflammation of arthritis is addressed, and not the causative issue of what is causing the joint malfunction.

KH: How would alternatives or dietary supplements address this problem any differently?

BG: There are several dietary supplements that may bring nutrients to the joints, and therefore not only help relieve the pain and inflammation in the process, but also actually repair the damage to the joint. None of the standard pharmaceutical agents can do this.

To give you an example, there is, of course, one that we have all heard about, glucosamine sulfate, or glucosamine hydrochloride. Glucosamine is believed to exert its activity by incorporating into the proteoglycans of the joint cartilage with the joint space, thereby repairing the joint. An increase of glucosamine in the diet may also be able to promote the chondrocytes (cartilage cells) to produce new cartilage matrix (both collagen and proteoglycans). There are numerous clinical studies that show benefit of glucosamine supplementation for arthritis. There are also several which have compared glucosamine's (1500 mg/day) effect against NSAIDS, such as ibuprofen (1200 mg/day), and found fewer side effects with glucosamine, and little difference in perceived efficacy (pain) between the treatment groups over time. Although the many clinical studies on glucosamine have not been long-term, many animal studies have found it to be safe, and few side effects have been reported.

Other dietary supplements that may be able to help in the repair process, as well as affect pain and inflammation are chondroitin sulfate, Methylsulfonylmethane (MSM), and green-lipped mussel. Chrondroitin sulfate has a similar activity of glucosamine, and although it used to be poorly studied, recent clinical studies are showing an equivalent effect as with glucosamine. Although there has been some promising clinical evidence, there is still a lack of clinical studies on green-lipped mussel's role in arthritis treatment.

MSM is believed to work through a different mechanism--providing the body with much needed sulfur that is essential to a number of metabolic pathways in the body involving the skin, hair, nail, tendon and cartilage production. However, even though increases in serum sulfur have shown clinical benefit, there is little clinical support for its efficacy, especially at the lower doses usually found in supplements.

KH: Are there any herbal or botanical dietary supplements for arthritis support?

BG: Yes, two well known botanicals happen to also be spices. However, it is their extracts that have been thought to provide the most efficacy for the inflammation associated with arthritis. These are ginger extract, and a special extract from turmeric called curcumin. Although these two spices clearly have an excellent safety record, they may not provide as much pain relief as other options.

There is one botanical that I have been involved with, along with Next Pharmaceuticals. It is a proprietary extract from the bark of the Phellodendron tree (Phellodendron amurense) that we call Nexrutine[R], and has been a rich source of traditional medicine in Asia for more than 1500 years with good results as an anti-inflammatory, a pain reliever and arthritis supplement. It appears that the primary mechanism of action is by inhibiting the gene expression of the COX-2 enzyme. While this may not seem to be significant, the primary active in Nexrutine[R] is clearly cardio-protective.

In clinical studies, the (Nexrutine[R]) has also been found to be effective as a rapidly acting supplement for pain associated with physical activity or over-exertion. In a placebo controlled study on osteoarthritis, the quality of life of the participants was found to increase significantly while taking Nexrutine[R] extract, including increased scores in the areas of physical, vitality, and mental health. In addition, the primary anti-inflammatory compound in Phellodendron extract was also tested for its effect on platelets and found not to cause aggregation, therefore it does not increase the risk for thrombosis, such as the drug COX-2 inhibitors might. This action has also been shown to significantly lower cholesterol levels. Therefore, Nexrutine[R] may carry the extra benefit of being "cardio-protective," as well as an anti-inflammatory and pain reliever for osteoarthritis and general aches and pains. The added safety with Nexrutine[R] is believed to be partially due to its gene expression inhibition rather than acting directly on the COX-2 enzyme.

KH: You have given many examples of alternatives for arthritis, including pharmaceutical and dietary supplements. How does someone then decide which to go with?

BG: It will depend on whether they are open to alternatives that are dietary supplements. If pharmaceutical options are all they are comfortable with, then there is a risk-benefit decision on which mode of action most suits someone's needs, and what they will best respond to. If they are open to dietary supplements, the combination of well-studied supplements can not only lessen pain and inflammation, but also nutritionally support the joint, such as taking glucosamine sulfate alone, or along with Nexrutine[R] to help lessen pain.

KH: Can you elaborate on your second guideline--about choosing an alternative with compelling clinical and/or traditional use?

BG: Yes, it is important to determine, when choosing an alternative to a pharmaceutical drug, whether or not that herbal or dietary supplement has been tested in well-designed clinical trials, or whether there is enough convincing traditional use for a particular herb, or some combination of the two.

In discerning good clinical evidence for herbal medicines there are some factors that should be considered beyond what is normal for testing pharmaceuticals. Over the course of the past ten years as herbal medicines have become popular, and have also faced controversy, many poorly designed clinical studies have been heralded as the latest news and last word on whether herbs work or not. However, several of these studies have been poorly designed, sometimes with the wrong dosage levels (as in the case of garlic), sometimes drawing conclusions when other confounding variables exist (as in the case with kava kava), and sometimes even lacking evidence that the correct herb was tested (as in the case with Echinacea)!

However, it is important to remember that the use of herbal medicine originally does not come from clinical evidence. Typically, herbal medicine is something that exists as a part of a greater whole--that of a traditional medicine system. Therefore, typically, these herbs have been in use by humans over long periods of time--sometimes thousands of years. One aspect that does not get enough attention in the scientific arena is the role of traditional use in proving the efficacy of herbal supplements. Many consider traditionally used herbs to be untested just because they have not been proven in a clinical trial. However, thousands of years of use in a human population should be as valid as most clinical trials, if not more so. The trick, however, is to be sure that the traditional use was in a similar form and dosage (and for the similar intended use) as that which a company may be promoting.

KH: Can you elaborate on your third guideline--about quality control for herbal medicines?

BG: Yes, most dietary supplements that are not herbs--like glucosamine sulfate or MSM--are relatively easy to test and confirm identity and quality in routine QA/QC procedures. This is because the non-botanical dietary supplements are generally single chemical identities. However, when it comes to herbal medicines, this task becomes more complicated. An herb is a combination of sometimes hundreds of chemical compounds that together make up the structure and substance of the herb. As herbs also rarely work by one main active component alone, it is difficult to quantify and demonstrate what is a good quality herb. The best companies producing herbs will have strict QA/QC standards, and also follow an herb straight from the source to the bottle so that they know exactly where that herb has been. And if the herb is going to be standardized for use in clinical trials, such as the case with Nexrutine[R], there needs to be sufficient research to support the choice of the marker compound that is controlled at a particular level during manufacturing, for assuring consistency in each and every dose.

New GMP standards are now being put in place by dietary supplement companies due to new regulatory government action. To find dietary supplements that are of high quality, companies are required to follow these GMP guidelines, although not all companies have adapted them yet. Additionally, there are other quality procedures, such as Good Agricultural Procedures (GAPs), that may be developed and followed by high quality dietary supplement companies, although not mandatory by the current regulatory environment in the United States.

KH: As more people will be looking for alternatives to VIOXX, Celebrex and Bextra, your suggestions seem like good practical guidelines. I thank you for your time.

BG: Thank you, it is my pleasure.

Correspondence:

Bob Garrision, PharmD

President & Chief Executive Officer

Next Pharmaceuticals, Inc.

Six Venture, Suite 265

Irvine, California 92618 USA

949-450-0203 ext. 12

Fax: 949-450-0163

garrison@nextpharmaceuticals.com

http://www.nextpharmaceuticals.com

by Kerry Hughes, MSc

COPYRIGHT 2005 The Townsend Letter Group
COPYRIGHT 2006 Gale Group