December 2nd, 2014

Why Are Drug Companies Sponsoring Studies on Natural Products? Taking a Closer Look at a Recent Evaluation on Glucosamine/Chondroitin in Osteoarthritis

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Introduction:

In the late 1990s, St. John’s wort (SJW) extract rocketed to tremendous success in the United States and Europe as a natural anti-depressant, but a dubious 2002 study funded by the drug company giant Pfizer, led to a crushing 97% drop in its popularity that year and it has never recovered. Pfizer’s drug, Zoloft, was the number one selling antidepressant at the time. Many experts felt that the researchers stacked the deck against SJW especially since several double-blind studies afterwards showed that SJW is more effective and have fewer side effects than Zoloft and other antidepressant drugs. In fact, a 2008 Cochrane Database Review concluded based on the results from over 30 double-blind studies with SJW extract that it is: “ a) is superior to placebo in patients with major depression; b) is similarly effective as standard antidepressants; c) and has fewer side effects than standard antidepressants.”

Two of the most popular and clinically proven natural products are glucosamine sulfate and chondroitin sulfate, used alone or in combination in the prevention and treatment of osteoarthritis. Products containing glucosamine or chondroitin sulfate represent about $800 million in annual sales in the United States, while over-the-counter drugs like aspirin, ibuprofen and related non-steroidal anti-inflammatory drugs (NSAIDs) including prescription forms like Celebrex, produce approximately $8 billion in annual sales.

It seems like the drug companies are taking the “St. John’s wort approach” to try to curb sales of glucosamine and chondroitin products based upon a recent study that was funded in part by drug companies like Pfizer; Novartis; Merck; and GlaxoSmithKline. Why else would these drug companies invest in studying the effects of a natural product that is a direct competitor to their highly profitable drugs?

Background Data:

Glucosamine and chondroitin are naturally produced in the body, but as some people age they may lose the ability to manufacture sufficient levels of these critical components of cartilage leading to osteoarthritis (OA). Extensive preclinical and clinical research, including long-term double-blind studies, support a rationale and role for glucosamine, as well as chondroitin sulfate, as an effective treatment of OA.

In fact, numerous head-to-head double-blind studies have shown glucosamine sulfate (GS) to produce much better results compared with NSAIDs or acetaminophen in relieving the pain and inflammation of OA. While some of the studies comparing GS to NSAIDs or acetaminophen show similar reduction in pain and symptom scores, only GS improves measures of joint function or markers showing improvement of cartilage structure. Typically the advantages of GS over these other treatments is seen after 4-6 weeks of use, but there is some evidence that the longer GS is used, the greater the therapeutic benefit.

The two longest placebo-controlled trials with GS are of three years in duration. The results from these studies show quite convincingly that GS slows down the progression of osteoarthritis, and in many cases, produces regression of the disease, as noted by x-ray improvements, and significantly reduces the need for total joint replacement even after as much as 5 years after GS discontinuation.

GS may also have a role as a preventive measure against the development of OA, especially in athletes subjected to joint strain as shown in recent clinical trials.

While GS has shown significant clinical benefit, unfortunately several large, well-publicized studies utilized the hydrochloride form (glucosamine hydrochloride) and failed to show benefit. It is thought that the sulfur component is critical to the overall effect of GS.

In regards to chondroitin sulfate (CS), while many studies have combined it with glucosamine, it also has shown benefits in the treatment of osteoarthritis on its own and has also shown to promote healthier cartilage.

New Data:

The new data was not from a new study, but rather it involved sifting through the 4-year follow-up data from the Osteoarthritis Initiative study that involved subjects with or at risk of developing OA of the knee. The researchers identified 1,625 subjects who were not using glucosamine or chondroitin products at baseline. During the 4-year period, 18% of these participants began using glucosamine or chondroitin products. Using detailed clinical assessments and then adjusting the data for potential confounders, the researchers stated they found no clinically significant differences between those subjects who used of glucosamine or chondroitin versus those that never-used the products in terms of pain scores, joint function, and structural progression of the disease confirmed by x-ray. But, there appears to be more to the story.

Commentary:

While this analysis has received considerable attention, the media has for some reason ignored the sponsors of the study and failed to ask even the most basic questions if they even bothered to look at the data. Most of the time these sorts of studies hit the newswire or Internet they are not critically analyzed. So, let me offer some insight here.

It is important to distinguish that this study is one that is classified as an uncontrolled observational study. These sorts of studies are generally used to note trends so that properly conducted randomized, controlled double-blind studies can be performed. These are exactly the type of studies that have already been conducted with glucosamine/chondroitin.

Perhaps the first question to be answered is why did some of the subjects start taking glucosamine/chondroitin? You can probably guess the right answer. It is because their joint pain was getting worse. This situation makes it very hard for researchers to compare groups because it may simply be that they are comparing outcomes in people who were getting worse, to people who were not getting worse. The researchers tried to control for this confounding variable, but it is still an issue no matter how much math is involved.

The next question is how were subjects identified as using glucosamine or chondroitin products? They were asked in a questionnaire “During the past 6 months, did you use the following health supplements for joint pain or arthritis?” with separate questions for glucosamine and chondroitin sulfate use. A participant was considered as taking glucosamine or chondroitin if he/she reported using it for at least 4 days per week, and not taking the supplement if they reported not using it or using it for less than 4 days per week.

On the surface, this categorization seems reasonable even though there is no clinical difference between taking glucosamine/chondroitin 3 vs. 4 days a week. But, my feeling is that the biggest shortcoming was not getting a better idea of dosage. In my experience, I have found many consumers do not take the proper dosage of natural products. In the analysis, there was no indication of form or dosage of the products used. This shortcoming alone makes the data meaningless in my opinion.

Nonetheless, let’s take a look at the data. But first, let me ask another question. Does the data support the conclusion that the researchers “found no clinically significant differences between those subjects who used of glucosamine or chondroitin, versus those that never-used the products?” I don’t believe so. Here is why. Their stated conclusion is preceded in the article by the statement acknowledging it was made “after adjustment for potential confounders with marginal structural models.” In other words, they adjusted the data to create their conclusion

The key finding of the analysis that is briefly mentioned in the study that clearly shows there was benefit noted was that there was an absolute reduction in joint space narrowing in the knee in those subjects taking glucosamine/chondroitin products. The narrowing of the joint space is one of the key signs of progression of the disease process of osteoarthritis. Compared to never-users, those who reported previous use of glucosamine/chondroitin for three yearly assessments had on average 0.11mm wider joint space of the knee. To me, that is a clear sign of benefit and reason alone to take glucosamine/chondroitin. However, the researchers concluded that the average of 0.11 mm wider joint space in the users was not clinically significant because it did not reach what they considered the meaningful value of 0.2 mm wider. But, it is important to point out that the range increased with each yearly assessment meaning many of the subjects achieved improvements much greater than 0.2 mm wider. Compared to never-users, those who reported previous use for three, two and one assessments had a range in joint width of -0.21 to 0.44 mm (average 11 mm); -0.07 to 0.35 mm (average 14 mm); and -0.16 to 0.10 mm (average -0.03), respectively. This clearly shows a treatment effect in many of these users. It would have been interesting to see the median as opposed to the average. Again, keep in mind that this study was an observational study and not a clinical trial looking for specific treatment outcomes. In two separate long-term controlled trials (i.e., 3-year double-blind studies) with glucosamine sulfate there was significant clinical evidence on improving joint space width (a sign of healthier cartilage), thereby showing a significant effect on reducing the progression of osteoarthritis. This effect of preventing joint space narrowing led to GS being referred to as possessing a “structure modifying effect” in the treatment of osteoarthritis. Chondroitin sulfate alone and in combination with glucosamine has also shown positive effects on cartilage health and structure as also produces a structure modifying effect.

The bottom line is that while the headlines are claiming no benefit noted, this uncontrolled observational study should not blind anyone to the benefits noted in well-designed, controlled clinical trials. In addition, looking at the objective data instead, it is clear that the reported use of glucosamine/chondroitin products by some of these subjects was associated with a significant effect on modifying the progression of the disease, as the joint space width was considerably greater in some of these users of these supplements compared to non-users.

Keep in mind that although nonsteroidal anti-inflammatory drugs (NSAIDs) provide short-term symptomatic relief, they may actually increase the rate of degeneration of the joint cartilage. Experimental studies have shown that aspirin and other NSAIDs inhibit collagen matrix synthesis and accelerate cartilage destruction. Some retrospective clinical studies have shown that NSAID use is associated with acceleration of osteoarthritis and increased joint destruction.

The paragraph above is important because people that are in pain due to osteoarthritis are both most likely to use NSAIDs and natural products containing glucosamine/chondroitin. My recommendation is to avoid NSAIDs at all costs in osteoarthritis as they are a classic example of a drug suppressing a symptom while at the same time fueling the progression of the disease process. Fortunately, there are safe and effective natural alternatives.

Reference:

Yang S, Eaton CB, McAlindon TE, Lapane KL. Effects of glucosamine and chondroitin on treating knee osteoarthritis: An analysis with marginal structural models. Arthritis Rheumatol. 2014 Nov 4. doi: 10.1002/art.38932. [Epub ahead of print]

Dr. Michael Murray
12/3/2014

November 25th, 2014

Two New Studies Show the Power of Gratitude and Kindness

gratitudeIntroduction

One of Plato’s greatest observations was that “a grateful mind is a great mind which eventually attracts to itself great things. There is a growing large body of recent scientific work showing that people who are more grateful and kind have higher levels of well-being and are happier, less depressed, less stressed and more satisfied with their lives and social relationships.

Recent research also shows exactly what Plato observed as detailed studies have shown that expressing gratitude leads to other kinds of positive emotions, such as enthusiasm and inspiration, because it promotes the savoring of positive experiences. The end result is that gratitude helps people optimize feelings of enjoyment, no matter what their circumstances are in life.

Two new studies from Utrecht University in the Netherlands add to the now overwhelming documentation on the power of positive psychology to improve our lives.

Background Data:

Several studies have now shown that gratitude appears to be the strongest link to health (and happiness) of any character trait. But, perhaps the best evidence that feelings of gratitude promote health are with studies in which gratitude exercises are used as an intervention.

One of the leading experts in the importance of gratitude as a therapy is Martin Seligman, PhD, former president of the American Psychology Association and one of the major thought leaders in the discipline of positive psychology. In a 2005 review article published in the journal American Psychology, Seligman described a study in which participants were randomly assigned to one of six therapeutic interventions designed to improve their overall quality of life. Of these six interventions, it was found that the biggest short-term effects came from a “gratitude visit” in which participants wrote and delivered a letter of appreciation to someone in their life. This simple gesture caused a significant rise in happiness scores and a significant fall in depression scores. This positive effect lasted up to one month after the visit.

In other studies, the act of keeping “gratitude journals,” in which participants wrote down three things they were grateful for every day, had even longer-lasting effects on happiness scores. The greatest benefits usually occurred around six months after journal keeping began. Similar practices have shown comparable benefits.

New Data:

To test the potential of positive psychological interventions to enhance the quality of life in subject, researchers developed a clinical trial to measure the impact on study-related positive emotions and academic engagement among university students.

The interventions focused on “thoughts of gratitude” and “acts of kindness,” respectively, in two separate randomized controlled trials.

In the first study, participants were asked to think of people that they were grateful for and instructed to focus their gratitude each day on a different passage in their lives. For example, on the first day they were instructed to think back on their years in elementary school and remember a person there were close to and of whom they were grateful to in reference to a specific event, e.g., a friend or family member who helped them with an accomplishment or task. They were also asked to write down a short note whom they wanted to express gratitude towards and why?

In the kindness study, participants of the kindness condition were instructed to pay close attention to their behavior toward the people around them at university and perform at least five acts of kindness per day and report on them in the evening, including the responses of others they received. Examples of acts of kindness included holding a door for someone, greeting strangers in the hallway, helping other students in preparing for an exam, etc.

In both studies, subjects in the control group were given random tasks such as recalling their activities of the day.

Using very sophisticated questionnaires, results revealed that the gratitude intervention had a significant positive effect on daily positive emotions and that it may have a cumulative effect on increasing positive emotions. However, results from this study did not show the same impact as previous studies. The difference is that in previous studies there was a much deeper expression of gratitude. For example, in Seligman’s study participants not only had to write a gratitude letter, but actually deliver and read the letter to the person they were grateful of as well. It is likely that by doing so, positive feedback from the recipient was provoked, which might have boosted positive emotions among the participants

The kindness intervention had a positive influence on both positive emotions and academic engagement. Based upon the researchers analysis, the acts of kindness intervention were much stronger than the effects of thoughts of gratitude. One explanation is that the kindness intervention was more intensive than the gratitude intervention (i.e., five acts of kindness per day versus one thought of gratitude per day). Another possibility is that the acts of kindness evoked immediate positive feedback. Positive reactions of people towards the participants were likely to strengthen the effects of the acts of kindness.

The take away message is the stronger the act of appreciation or kindness, the bigger the impact on positive emotions and social engagement

Commentary:

While many may argue that the need to feel loved is the greatest emotional need we have, I believe there is no greater emotional need than appreciation. The funny thing is that the things we really want in life are usually best obtained by giving more. In other words, if you want to feel more appreciation in your life, begin with expressing more appreciation.

As this is Thanksgiving or “Giving Thanks” week, I would like you to challenge you with the following assignment: Create a gratitude visit or call in your life. We all have had people touch our lives in profound ways. Pick a worthy recipient and figure out a way to make a special acknowledgment, and watch the magic unfold. The more special you make it for the recipient, the more special it will be for you.

That is Assignment A, but I want you to also do Assignment B and C. For Assignment B, I want you to be more aware in your daily life of opportunities to acknowledge people and seize chances to say thank you. And lastly, Assignment C is simply putting yourself to sleep by giving thanks in your mind and heart for at least three wonderful things you have in your life.

If you make these three assignments a daily habit, the impact on your life, your relationships and your health can be absolutely incredible. Gratitude is the most powerful magic bullet for a better life that I know. It’s simple, safe, has no side effects and it is still very powerful medicine

Reference:

Ouweneel E, Le Blanc PM, Schaufeli WB. On being grateful and kind: results of two randomized controlled trials on study-related emotions and academic engagement. J Psychol. 2014 Jan-Feb;148(1):37-60.

Dr. Michael Murray
11/28/2014

November 18th, 2014

Maitake Extract Produces Beneficial Effects on the Immune System in Patients with Bone Marrow Failure

grifola_frondosa_cross-sectionIntroduction

For thousands of years mushrooms have been highly respected in Asia for their health promoting properties. One mushroom was regarded as the “King of the Mushrooms” to signify it’s superior medicinal effects over all other mushrooms. Modern research has shown that this mushroom – Maitake (Grifola frondosa) – is the source of powerful immune enhancing compounds with significant anticancer effects.

A new study conducted at the prestigious Memorial Sloan-Kettering Cancer Center in New York has further validated the immune enhancing effects, and once again establishes maitake above all other mushrooms.

Background Data:

Modern research on maitake began in the early late 1970s in Japan under the direction of Dr. Hiroaki Nanba. He was researching the immune enhancing properties of mushrooms when he came to the conclusion that maitake extracts demonstrated more pronounced antitumor activity in animal tests, than other mushroom extracts.

In 1984, Dr. Nanba identified a fraction of maitake that possessed a significant ability to stimulate white blood cells known as macrophages (literal translation “big eaters). Throughout the late 1980s and into the 1990s, Dr. Nanba and other Japanese researchers continued to study maitake, trying to improve upon the antitumor and immune potentiating activity of maitake. The result of their work was the development and patent of MaitakeGold (U.S. Patent #5,854,404).

Maitake exerts profound effects on immune function. In a nutshell, it appears that the beta-glucan components actually bind to receptors on the outer membranes of macrophages and other white blood cells including natural killer (NK) cells and cytotoxic T-cells. These immune cells are very important in protecting against and fighting cancer because they can attack tumor cells directly.

Just like a key in a lock, the binding of the maitake components literally flips white blood cells on and triggers a chain reaction leading to increased immune activity. In addition to increasing the ability of the macrophages to engulf and destroy cancer cells, microbes, and other foreign cells, the binding stimulates the production of important signaling proteins of the immune system such as interleukin-1 interleukin-2, and lymphokines. These immune activators ramp up defenses by activating immune cells.

Maitake also stimulates the production of white blood cells within the bone marrow – the major area for white blood cell production. Reduced bone marrow production means lowered white cell counts and an increased risk of infection and cancer. This beneficial effect of the beta-glucan is put to good use in cancer patients undergoing radiation therapy or chemotherapy.

New Data:

Given the previous research on maitake showing an ability to stimulate bone marrow function, as well as various aspects of immune function, researchers at Memorial Sloan-Kettering Cancer Center conducted a study in patients suffering from Myelodysplastic Syndrome (MDS) – a bone marrow disorder in which the bone marrow does not produce enough healthy blood cells.

MDS is often referred to as a “bone marrow failure disorder”. The bone marrow manufactures three kinds of blood cells: red blood cells, white blood cells, and platelets. Healthy bone marrow produces immature blood cells — called stem cells, progenitor cells, or blasts — that normally develop into mature, fully functional red blood cells, white blood cells, and platelets. In MDS, these stem cells may not mature and may accumulate in the bone marrow or they may have a shortened life span, resulting in fewer than normal mature blood cells in the circulation. MDS is characterized by an increased risk of infection, with infections being a major cause of death in patients with MDS.

MDS patients received oral maitake extract at 3 mg per kg body weight twice daily for 12 weeks. Results indicated that maitake increased the function of neutrophil and monocyte white blood cells. For example, the researchers demonstrated that white blood cell response to the bacteria E. coli is reduced in MDS patients, but could be restored after 12 weeks of Maitake treatment. Furthermore, they also demonstrated that the ability of monocyte and neutrophils to destroy and digest infecting organisms. The proposed mechanism includes the ability of maitake treatment to stimulate the maturation of these immune cells in the bone marrow, leading to the release of more functionally competent cells.

Commentary:

This study is significant for several reasons. First, it is another study coming from a highly prestigious medical center. Next, the results add to the wisdom of using this valued natural product in modern medicine. Based upon this study and others, it seems that maitake is perfectly suited for patients with MDS. It is also an important consideration to prevent bone marrow suppression in cancer patients on chemotherapy as there is evidence from other studies that it also helps to reduce the side effects of conventional chemotherapy (and radiation) such as nausea, weight loss, fatigue, and immune suppression while at the same time enhancing their effectiveness.

Typically, the daily dosage range of maitake extract based upon body weight has been 0.5mg to 1.0 mg for every 2.2 pounds (1 kg) of body weight per day. That translates to a dosage of approximately 35-70 mg per day. This study used a dosage of 3 mg/kg to show an immediate clinical effect. For best results take 20 minutes before meals or on an empty stomach

Reference:

Wesa KM, Cunningham-Rundles S, Klimek VM, et al. Maitake mushroom extract in myelodysplastic syndromes (MDS): a phase II study. Cancer Immunol Immunother. 2014 Oct 29. [Epub ahead of print]

Dr. Michael Murray
11/18/2014