• The President’s Desk  — Welcoming the Year Ahead

• The Many Faces of Serotonin  — Deficiency Linked to GI Disorders, Depression, Asthma and Fibromyalgia

• Beyond Cholesterol Control  — The Heart-Harming Consequences of Lowering Lipids While Neglecting Other Important Factors

• Digestive Tract Detoxification  — GI Health Depends Upon Eliminating Toxic Environmental Compounds and Candida

• Vitamin K2  — Powerful Bone-Building, Heart-Protecting Nutrient

• Pet Corner  — Brain Aging in Dogs

• New Formula Promotes Restful Sleep and Daytime Energy  — 

• Same Great Cream in a New Convenient Pump  — 

• Pregnenolone  — Hormone's Benefits Include Enhanced Mental Function, Decreased Cortisol, and Improved Mood

• Nutrition Review  — The Latest Research on Depression, Skin Health, Blood Pressure and More

• Hearing Loss
• Liver Health and Birth Control
• Fatigue
• Frequent Thirst
• Female Alopecia
• Tightness in Chin Area
• Digestive Issues
• Multiple Sclerosis
• Age Spots
• Vision Concerns
• Visceral Fat

As 2008 draws to a close, we want to thank you for your ongoing support. We take your patronage and trust seriously, and throughout the coming year you can count on us to provide you with the highest quality products, the latest relevant research, and superior customer service.

We realize that all of us are feeling the effects of the economy and that our country is experiencing tough times. Consequently, we went back to every raw material supplier that had raised our prices and are working with each of them to try and keep our prices stable. In certain instances working closely with these suppliers actually allowed us to reduce the price on some products. Only a few vendors could not work with us, and since we’re not willing to compromise quality, we were forced to raise prices on a few products. We will keep working with those vendors, and you can trust that we will not give up.

In 2009, our primary focus will be on productivity. We have many productivity improvements in the works designed to keep our costs down, and we will pass the savings to you. We will always make an effort to search for initiatives that will save you money so that you can pursue your nutritional supplement health care plan as affordably as possible, without compromising the results.

January marks our 30th year of empowering healthy aging and we’ll continue to bring you exciting new advances in nutritional science. Our mission has always been to be your trusted source for accurate information about the science behind supplements, and as always, we will share with you the valuable nuggets of information our research and development team unearth in their search of the medical literature.

Regulatory challenges may surface, but with your help we will tackle those too! Rest assured we will continue to provide you with the highest quality products and attentive customer service.

We wish you and your family happy holidays and a happy and healthy New Year in 2009.

Serotonin is a neurotransmitter often connected to mood. However, while serotonin deficiency is linked to depression, its role in a host of other conditions often goes unrecognized by the general public. Yet, serotonin deficiency is the common denominator in the etiology of a number of other disorders such as irritable bowel syndrome and asthma. Furthermore, serotonin deficiency is linked to sleep disturbances, migraines, fatigue, carbohydrate cravings, and obesity.

Under normal conditions, neurons in the brain release serotonin to carry messages to other neurons: for example, to alter some aspect of mood, appetite, confidence, or sleep. Serotonin is then returned to the parent neuron to be reused for signaling. In people with low serotonin levels, however, the available serotonin is recaptured too quickly, leaving it insufficient time to adequately activate the adjacent neuron and allow the signal to sufficiently continue along the neural network. This can result in a number of disorders.

In this article, I will discuss both serotonin’s role in well-being and the many other ways serotonin affects our health.

Mood Elevator

Targeting serotonin’s vital role in brain chemistry, pharmaceutical companies have developed a class of drugs called selective serotonin reuptake inhibitors (SSRIs). As their name suggests, SSRIs inhibit the reuptake of serotonin, allowing it to remain in the synaptic gaps between neurons for longer so that enough of the hormone builds up to trigger nerve impulses.

The fact that SSRIs were originally prescribed for treating depression but are now widely taken for treating related disorders of serotonin deficit such as insomnia, migraine, fibromyalgia, and IBS confirms serotonin’s wide-reaching role in the body.  However, as popular as the SSRIs have been, they have not been without serious side effects such as nausea, irritability, sexual dysfunction, daytime sedation, insomnia, dry mouth, and tremor, and a heightened risk of suicidal thoughts in children and adolescents.1 (See the article “SSRIs Plus NSAIDs: A Potentially Lethal Combination,” available on the website.)

Far-Reaching Effects of Serotonin

Given serotonin’s diverse actions, a deficiency in this neurotransmitter has a far greater impact beyond depression and is increasingly linked with a wide range of health problems. Manifestation of some of these disorders—specifically, insomnia, weight-control issues, fatigue or loss of energy, and reduced ability to concentrate—is, in fact, used by the American Psychiatric Association for diagnosing major depression.2

Impact on Sleep

Sleep disturbances feature strongly in depression, with insomnia reported by more than 90 percent of depressed patients.3 Altered sleep patterns in depression occur in the phase of sleep associated with memory known as random eye movement (REM) sleep and are considered a marker for major depression. Even in healthy subjects, serotonin deficiency significantly decreases the time spent in both REM sleep and non-REM (deep sleep) and prolongs wakefulness.

In insomnia patients, increasing brain serotonin levels can overcome serotonin depletion’s negative impact on sleep continuity.4 Researchers also believe that complete relief of insomnia may improve the prognosis for depression.3

Emotional Eating

Serotonin also is known to affect appetite, especially for carbohydrates. Low levels of the amino acid tryptophan, a precursor to serotonin in the body, have been linked to binge eating and carbohydrate cravings that lead to unwanted weight gain.5 Tryptophan competes with large neutral amino acids for transport across the blood-brain barrier. Studies have shown that the plasma tryptophan ratio to other amino acids in obese patients is well below normal, suggesting a serotonin deficiency.6

To overcome this deficit, insulin released when carbohydrates are consumed facilitates the removal of competing amino acids from the serum into muscle, thus allowing tryptophan to enter the brain more easily and increase brain serotonin levels.7 As a result, obese people frequently consume carbohydrates over other food types to overcome low tryptophan intake into the brain and achieve “feel good” levels of serotonin. Boosting serotonin levels in the brain therefore creates a feeling of satiety to suppress appetite.

In clinical trials, increasing brain serotonin levels reduces caloric intake in obese or overweight patients8-9 who have been seen to lose weight in these studies despite making no conscious effort to do so.8-9 Overweight diabetic patients also have reduced brain serotonin levels compared with healthy controls.10 Restoring brain serotonin levels in these patients normalizes eating behavior by reducing energy intake from carbohydrates and fats, reducing body weight.10

Headaches

Serotonin is implicated as a key neurotransmitter in migraines. According to epidemiological studies, both migraines and depression are connected11 since the body’s serotonin levels fall during a migraine attack.12 Studies have shown that replenishing brain serotonin levels can relieve migraine as effectively as a standard migraine drug13 and reduce the need for analgesic therapy in patients with chronic tension-type headaches14 due to serotonin’s ability to relax muscles and control the dilation of blood vessels.

Fibromyalgia

Since serotonin is an inhibitory neurotransmitter that calms the nervous system to relieve tension and anxiety, its deficiency is thought to be the reason for the lowering of the pain threshold that occurs in fibromyalgia patients.15

SSRIs are commonly used for treating fibromyalgia, a condition characterized by generalized joint and muscle pain and tenderness in certain parts of the body, but with no manifestation of physical abnormality. Patients with fibromyalgia may also experience stiffness, sleep disturbances, irritable bowel syndrome, temperomandibular joint syndrome, and menstrual disorders. Low serotonin levels in these patients have been inversely correlated with clinical measures of perceived pain.16-17

Researchers have also found that fibromyalgia and migraines commonly occur together18 given their common etiology of low serotonin levels. Furthermore, low serotonin levels are seen in other chronic pain syndromes such as painful diabetic neuropathy and chronic fatigue syndrome.

Irritable Bowel Syndrome

Found abundantly in the digestive system, serotonin is known to influence bowel function. Since most of the serotonin produced in the body is made in the gastrointestinal tract, a serotonin deficiency increases vulnerability to digestive tension, constipation, and irritable bowel syndrome (IBS).

Specialized serotonin-releasing cells in the gastric mucosa are present throughout the digestive system. Serotonin is a powerful smooth muscle stimulant and an important regulator of gut motility.19 In fact, the enteric nervous system (ENS) is often referred to as a second brain since serotonin appears to be the common link in gastrointestinal motility, intestinal secretion, and pain perception between the ENS and the central nervous system.20

Researchers have identified several serotonin (5-HT) receptor subtypes, of which 5-HT3 and 5-HT4 have been found to be the most important for regulating gastrointestinal function.19 Once activated, 5-HT4 receptors modulate peristaltic neurotransmission by facilitating the release of several neurotransmitters, the net result of which is forward movement of contents through the gastrointestinal tract.21

Respiratory Difficulties

In people with asthma, depression and anxiety are strongly associated with decreased pulmonary control, including more visits to the doctor or emergency room, inability to do usual activities, and more days of symptoms compared with those who do not have depression or anxiety.22 Those with asthma are also more than twice as likely than those without the disease to have current depression, a lifetime diagnosis of depression, and anxiety.22

In addition, emotional problems and depression in childhood have been found to increase the vulnerability to developing asthma in early adulthood.23 Improving depression in patients with asthma therefore has a significant impact since greater depressive symptom severity scores are associated with lower asthma-related quality of life.24

Naturally Elevating Serotonin

When investigating natural alternatives to alleviate serotonin deficiency, researchers take into account that serotonin cannot cross the blood-brain barrier and must be synthesized in the brain itself. Fortunately, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is made, can and do cross the blood-brain barrier.

Tryptophan is an essential amino acid found in small amounts in high-protein foods. It is uniquely responsible for serotonin synthesis in the body, using cofactors such as vitamin B6, magnesium, and vitamin C, to facilitate this conversion. Unfortunately, even a normal diet all too frequently does not provide the quantities of tryptophan required since it is the least abundant amino acid found in food. It is believed that the brain receives less than 1 percent of tryptophan from a typical diet as its use is diverted to metabolic functions such as producing various body tissue proteins and vitamin B3 synthesis and it faces tough competition from other amino acids to cross the blood-brain barrier. Modern-day diets, with their emphasis on fast foods and carbohydrates, also make serotonin synthesis more difficult.

Another way to generate higher serotonin levels is to consume its direct precursor 5-HTP, which is made from tryptophan in the body. Unlike tryptophan, 5-HTP absorption is less affected by other amino acids and it cannot be shunted into protein production. Both SSRIs and 5-HTP increase serotonin availability in the brain, but in different ways. SSRIs recycle serotonin, keeping it circulating in the brain for longer, whereas 5-HTP synthesizes new serotonin to replenish depleted levels in the central nervous system.

In a six-week study, 5-HTP was found to be as effective for depression as a common antidepressant drug, but with fewer and less severe side effects than the drug.25 5-HTP also has been shown to relieve anxiety,26 enhance sleep,4 suppress appetite,10 prevent migraines,13 and support the health of fibromyalgia patients.27

Conclusion

Serotonin affects much more than mood. The multifaceted health consequences of serotonin deficiency are based on its complex functions as a neurotransmitter. Adequate brain levels of serotonin are therefore critical for promoting feelings of well-being, satiety, and relaxation.

Ensuring healthy serotonin levels is also important during aging. Excessive tryptophan degradation occurs in aging bodies as a result of increased activity of tryptophan-degrading enzymes, which can cause declining serotonin levels.28 Maintaining optimal serotonin levels can therefore provide important physical and emotional health benefits across all age groups.

References

1. Available at: http://www.fda.gov/bbs/topics/news/2004/new01124.html. Accessed October 29, 2008.

2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: APA, 1994.

3. Thase ME. Antidepressant treatment of the depressed patient with insomnia. J Clin Psychiatry. 1999;60 (Suppl. 17):28-31.

4. Riemann D, Vorderholzer U. Treatment of depression and sleep disorders. Significance of serotonin and L-tryptophan in pathophysiology and therapy. Fortschr Med. 1998 Nov;116(32):40-42.

5. Gendall KA, Joyce PR. Meal-induced changes in tryptophan:LNAA ratio: effects on craving and binge eating. Eat Behav. 2000 Sep;1(1):53-62.

6. Breum L, Rasmussen MH, Hilsted J, Fernstrom JD. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr. 2003 May;77(5):1112-1118.

7. Wurtman RJ, Wurtman JJ. Brain serotonin, carbohydrate-craving, obesity and depression. Obes Res. 1995 Nov;3(Suppl):477S-480S.

8. Ceci F, Cangiano C, Cairella M, et al. The effects of oral 5-hydroxytryptophan administration on feeding behavior in obese adult female subjects. J Neural Transm 1989;76(2):109-117.

9. Cangiano C, Ceci F, Cascino A, et al. Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan. Am J Clin Nutr 1992 Nov;56(5):863-867.

10. Cangiano C, Laviano A, Del Ben M, et al. Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients. Int J Obes Relat Metab Disord. 1998 Jul;22(7):648-654.

11. Breslau N, Davis GC, Schultz LR, Peterson EL. Joint 1994 Wolff Award Presentation. Migraine and major depression: a longitudinal study. Headache. 1994 Jul-Aug;34(7):387-393.

12. Selmaj K. Blood serotonin level in sciatica and the serotonin theory of migraine pathogenesis. Neurol Neurochir Pol. 1979 Mar;13(2):169-172.

13. Titus F, Dávalos A, Alom J, Codina A. 5-Hydroxytryptophan versus methysergide in the prophylaxis of migraine. Randomized clinical trial. Eur Neurol. 1986;25(5):327-329.

14. Ribeiro CA. L-5-Hydroxytryptophan in the prophylaxis of chronic tension-type headache: a double-blind, randomized, placebo-controlled study. For the Portuguese Head Society. Headache. 2000 Jun;40(6):451-456.

15. Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998 Aug;3(4):271-280.

16. Hrycaj P, Stratz T, Muller W. Platelet 3Himipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome. J Rheumatol. 1993;20:1986-1988. [letter]

17. Russell IJ, Michalek JE, Vipraio GA, et al. Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome. J Rheumatol 1992;19:104-109.

18. Nicolodi M, Sicuteri F. Fibromyalgia and migraine, two faces of the same mechanism. Serotonin as the common clue for pathogenesis and therapy. Adv Exp Med Biol. 1996;398:373-379.

19. Fayyaz M, Lackner JM. Serotonin receptor modulators in the treatment of irritable bowel syndrome. Ther Clin Risk Manag. 2008 Feb;4(1):41-48.

20. Gershon MD. The enteric nervous system: a second brain. Hosp Pract (Minneap). 1999 Jul 15;34(7):31-32,35-38,41-42 passim.

21. Grider JR. Desensitization of the peristaltic reflex induced by mucosal stimulation with the selective 5-HT4 agonist tegaserod. Am J Physiol Gastrointest Liver Physiol. 2006 Feb;290(2):G319-G327.

22. Strine TW, Mokdad AH, Balluz LS, Berry JT, Gonzalez O. Impact of depression and anxiety on quality of life, health behaviors, and asthma control among adults in the United States with asthma, 2006. J Asthma. 2008 Mar;45(2):123-133.

23. Goodwin RD, Sourander A, Duarte CS, et al. Do mental health problems in childhood predict chronic physical conditions among males in early adulthood? Evidence from a community-based prospective study. Psychol Med. 2008 May 28:1-11 [Epub ahead of print].

24. Brown ES, Murray M, Carmody TJ, et al. The Quick Inventory of Depressive Symptomatology-Self-report: a psychometric evaluation in patients with asthma and major depressive disorder. Ann Allergy Asthma Immunol. 2008 May;100(5):433-438.

25. Poldinger W, Calanchini B, Schwarz W. A functional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine. Psychopathology. 1991;24:53-81.

26. Kahn RS, Westenberg HG. L-5-hydroxytryptophan in the treatment of anxiety disorders. J Affect Disord. 1985 Mar-Apr;8(2):197-200.

27. Puttini PS, Caruso I. Primary fibromyalgia and 5-hydroxy-L-tryptophan: a 90 day open study. J Int Med Res. 1992;20:182-189.

28. Kepplinger B, Baran H, Kainz A, et al. Age-related increase of kynurenic acid in human cerebrospinal fluid - IgG and beta2-microglobulin changes. Neurosignals. 2005;14(3):126-135.

Awareness of and education regarding heart disease is one of the top public health issues that we as health care providers and members of the public continually hear about. And for good reason, as this collection of illnesses (myocardial infarction, stroke, ischemia, deep venous thrombosis, atherosclerosis, arteriosclerosis, etc.) are the leading cause of death in the United States, killing nearly 700,000 people per year.1 Heart disease is in many cases preventable by addressing several well-known, modifiable risk factors such as alcohol consumption, poor diet, obesity, sedentary lifestyle, and smoking. Other risk factors include diabetes mellitus, high blood pressure, hereditary issues and cholesterol levels.

Of all the risk factors, much of the focus is on cholesterol. Cholesterol receives nothing but “bad press” with the notion that it should be lowered, with no regard to the multiple vital uses of this molecular building block. The advent of the statin class of drugs now allows doctors to manipulate cholesterol levels and has boosted statin drug therapy to first line therapy when it comes to heart disease. Statins lower cholesterol, particularly low-density lipoprotein (LDL) by inhibiting the HMG-CoA reductase enzyme. This leads to a decrease in production of cholesterol, as well as an increase in metabolism of LDL and (very low density lipoprotein) VLDL cholesterol in the liver itself. Statins, while effective in lowering cholesterol levels, are also notorious for side effects such as myalgia, fatigue, and reports of lowering life-sustaining CoQ10.

While the modifiable risk factors do receive some attention, it seems that statin therapy reigns as the preeminent treatment of choice for preventing and treating heart disease from an elevated cholesterol perspective. While elevated cholesterol levels are a cause for concern, there are several other factors that should receive as much, if not more attention. In other words, there is a lot more to heart disease prevention than cholesterol.

In the analysis of two large heart disease studies (Multiple Risk Factor Intervention Trial (MRFIT) and The Framingham Study) it has been statistically shown that half of those people that suffer heart attacks actually have cholesterol levels in the normal and low ranges.2-3 This tells us that we should be concerned about other, less “popular” aspects of prevention, rather than blindly following the standard medical line regarding cholesterol as being the only risk factor. Addressing all aspects of heart disease, especially those mentioned in this article, is imperative to decrease the risk of heart disease in millions of people, especially those without the flashing red light of “elevated cholesterol.”

C-Reactive Protein

C-reactive protein (CRP) provides an indirect measurement of generalized inflammation in the body, and heart disease is a condition that is associated with elevated CRP. Inflammation can be present in the lining of the blood vessels, contributing to heart disease. In fact, highly elevated CRP equates to a threefold risk of myocardial infarction, even in the presence of low LDL cholesterol.4 While elevated CRP is not a direct cause of heart disease, it does signify the level of inflammation that occurs in the body, which in turn contributes to damage in the blood vessels, among other areas.

CRP can be easily measured; a high-sensitivity CRP blood test is available here and can be used as a guideline for monitoring inflammation. One should keep in mind that there are other causes of elevated CRP such as cancer, arthritis or infections.

CRP levels are best reduced by healthy lifestyle choices such as moderate exercises, low-sugar and low-saturated fat diets. Fish oil and vitamin D3 have both been shown to have potent lowering effects on CRP as well.5-6

Fibrinogen

Fibrinogen is a protein that plays several roles in the blood coagulation process; elevated levels of this protein can lead to enhanced creation of blood clots and the atherosclerotic process. Fibrinogen is only recently gaining respect as a major risk factor in heart disease. It can cause cardiovascular problems in a number of ways. Fibrinogen contributes to atherosclerosis plaque formation when it binds to LDL and promotes the growth of smooth muscle in the vascular lining.7 Fibrinogen also contributes to the viscosity of blood and elevated levels can slow blood flow in flow-compromised arteries.8 As a clot precursor, fibrinogen can form abnormal clots inside the coronary arteries,9 and elevated fibrinogen can also cause platelet aggregation inside certain blood vessels leading to occlusive clots.10

Fibrinogen also is easily measured in the blood, and, when combined with CRP testing, evaluation of heart disease risk can be more complete. Fibrinogen can be normalized using several natural substances. The spice turmeric derived from the plant Curcuma longa can lower fibrinogen levels via its antioxidant effects.11-12 Nattokinase is an enzyme derived from Natto, a Japanese soybean-based food.  Nattokinase is a potent fibrinolytic enzyme, and has been shown to lower fibrinogen levels,13 decrease vessel wall thickening after injury in animals,14 and break up clots that form along blood vessel walls.15

Homocysteine

An amino acid commonly found in the blood, Homocysteine is considered a primary risk factor for cardiovascular disease.16 Homocysteine is created in the body by the conversion of another amino acid, methionine. Homocysteine levels are affected by genetic, physiologic, and dietary factors. Homocysteine binds to specific proteins in the vascular wall and disrupts their ability to repair vascular connective tissues, leaving them susceptible to disease processes.17

Homocysteine levels should be monitored and treated appropriately. Most people with elevated homocysteine levels can lower them through nutritional measures. The blood levels of vitamins B6, B12 and folic acid are inversely related to plasma homocysteine levels.  Therapeutic doses of these vitamins are an effective treatment for normalizing homocysteine levels, with no side effects.18-19 Additionally, homocysteine can be lowered by betaine, which is also known as trimethylglycine. It helps to convert homocysteine back to its precursor amino acid methionine.20 Treating homocysteine with these nutritional factors assists in homocysteine undergoing a process known as remethylation; in short homocysteine is converted back into methionine, whereupon it can be used in other less damaging metabolic processes. Remethylation is most efficient if all four factors are utilized.

LDL Oxidation

Elevated low-density lipoprotein (LDL) is an independent risk factor for cardiovascular disease. Yet, despite the conventional medical establishment’s sole focus on the elevation of LDL, what’s actually more important than the LDL level itself is what happens to this form of cholesterol while it’s circulating in the bloodstream. LDL will undergo oxidation as free radicals slowly damage it as it circulates and attaches to the endothelial lining of the vessels. This oxidatively damaged LDL is then targeted by the immune system. Macrophages engulf the LDL on the endothelium and with the assistance of other immunological responses, the resulting product becomes a focal point of degradation.21 This area of degradation allows for the buildup of calcification products, creating a bulge in the arterial wall. As this bulge grows, blood flow dynamics are changed, creating even more localized stress and damage on the arterial lining. After enough time passes, these processes contribute to obstructed arteries and resulting effects such as myocardial infarction, ischemia and stroke, to name only a few.

Free radicals are present everywhere in the body, and the bloodstream is just one area where their damaging effects can drastically affect a person’s health. Knowing that LDL is oxidized, and the resulting damage this causes is enough reason to consider the benefits of antioxidants on this process. Preventing the oxidation of LDL may serve as a primary step in the prevention of heart disease. A key point is that while antioxidants can prevent oxidation of LDL particles, studies of their use in advanced atherosclerotic disease have not shown outstanding results.22 This may be interpreted that antioxidative supplementation should be employed as a preventive therapy rather than reserved until advanced disease has occurred.

Antioxidants are abundant in a variety of forms, and a wide-ranging antioxidant arsenal is an effective way of combating oxidation throughout the body. Vitamins A, C, and E are among some of the most well-researched antioxidants. Botanical compounds or derivatives such as turmeric (derived from Curcuma longa), anthocyanosides derived from bilberry, rosemary, green tea, grape seed and lutein all have potent antioxidative effects.23-28 Perhaps the most effective antioxidant, glutathione, is manufactured in the body from its precursor, N-acetyl cysteine. Glutathione can protect fatty molecules such as LDL from being oxidized.29

Conclusion

Despite the overemphasis that the conventional medical establishment and the consumer media places on cholesterol, there is much more to optimal heart health than simply lowering cholesterol levels. Several other factors are equally important in the prevention of heart disease, yet they garner little attention from the standard medical approach. Highly sensitive C-reactive protein, fibrinogen, homocysteine and LDL oxidation each have direct effects on cardiovascular health paralleling that of elevated cholesterol. Addressing each one of these factors is necessary in order to provide full coverage of the multiple heart disease risks.

References

1. Online Document at: http://cdc.gov/heartdisease/statistics.htm.

2. Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and risk of coronary heart disease. The Framingham Study. Ann Epidemiol. 1992 Jan;2(1-2):23-8.

3. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986 Nov 28;256(20):2823-8.

4. St-Pierre AC, Bergeron J, Pirro M, et al. Effect of plasma C-reactive protein levels in modulating the risk of coronary heart disease associated with small, dense, low-density lipoproteins in men (The Quebec Cardiovascular Study). Am J Cardiol. 2003 Mar 1;91(5):555-8.

5. Ciubotaru I, Lee YS, Wander RC. Dietary fish oil decreases C-reactive protein, interleukin-6, and triacylglycerol to HDL-cholesterol ratio in postmenopausal women on HRT. J Nutr Biochem. 2003 Sep;14(9):513-21.

6. Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002 Dec;95(12):787-96.

7. Brown NJ, Staton CA, Rodgers GR, et al. Fibrinogen E fragment selectively disrupts the vasculature and inhibits the growth of tumours in a syngeneic murine model. Br J Cancer. 2002 Jun 5;86(11):1813-6.

8. Allen JD, Wilson JB, Tulley RT, Lefevre M, Welsch MA. Influence of age and normal plasma fibrinogen levels on flow-mediated dilation in healthy adults. Am J Cardiol. 2000 Sep 15;86(6):703-5.

9. Drouet L, Bal dit SC. Is fibrinogen a predictor or a marker of the risk of cardiovascular events? Therapie. 2005 Mar;60(2):125-36.

10. Bennett JS. Platelet-fibrinogen interactions. Ann N Y Acad Sci. 2001;936:340-54.

11. Miquel J, Bernd A, Sempere JM, Díaz-Alperi J, Ramírez A. The curcuma antioxidants: pharmacological effects and prospects for future clinical use. A review. Arch Gerontol Geriatr. 2002 Feb;34(1):37-46.

12. Ramírez-Boscá A, Soler A, Carrión MA, et al. An hydroalcoholic extract of curcuma longa lowers the apo B/apo A ratio. Implications for atherogenesis prevention. Mech Ageing Dev. 2000 Oct 20;119(1-2):41-7.

13. Chang CT, Fan MH, Kuo FC, Sung HY. Potent fibrinolytic enzyme from a mutant of Bacillus subtilis IMR-NK1. J Agric Food Chem. 2000 Aug;48(8):3210-6.

14. Suzuki Y, Kondo K, Ichise, H, et al. Dietary supplementation with fermented soybeans suppresses intimal thickening. Nutrition 2003;19:261–4.

15. Suzuki Y, Kondo K, Matsumoto Y, et al. Dietary supplementation of fermented soybean, natto, suppresses intimal thickening and modulates the lysis of mural thrombi after endothelial injury in rat femoral artery. Life Sci 2003;73:1289-98.

16. Blum A, Hijazi I, Eizenberg MM, Blum N. Homocysteine (Hcy) follow-up study. Clin Invest Med. 2007;30(1):21-5.

17. Keebler ME, De Souza C, Fonesca V. Diagnosis and treatment of hyperhomocysteinemia. Curr Atheroscler Rep 2001;3:54-63.

18. Krishnaswamy K, Lakshmi AV. Role of nutritional supplementation in reducing the levels of homocysteine. J Assoc Physicians India 2002 May;50 Suppl:36-42.

19. O’Connor JJ, Meurer LN. Should patients with coronary disease and high homocysteine take folic acid? J Fam Pract 2003 Jan;52(1):16-8.

20. Brouwer IA, Verhoef P, Urgert R. Betaine supplementation and plasma homocysteine in healthy volunteers (letter). Arch Intern Med 2000;160:2546-7.

21. Ishigaki Y, Katagiri H, Gao J, et al.  Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis. Circulation. 2008 Jul 1;118(1):75-83.

22. Moats C, Rimm EB. Vitamin intake and risk of coronary disease: observation versus intervention. Curr Atheroscler Rep. 2007 Dec; 9(6):508-14.

23. Chen WF, Deng SL, Zhou B, Yang L, Liu ZL. Curcumin and its analogues as potent inhibitors of low density lipoprotein oxidation: H-atom abstraction from the phenolic groups and possible involvement of the 4-hydroxy-3-methoxyphenyl groups. Free Radic Biol Med. 2006 Feb 1;40(3):526-35.

24. Laplaud PM, Lelubre A, Chapman MJ. Antioxidant action of Vaccinium myrtillus extract on human low density lipoproteins in vitro: initial observations. Fundam Clin Pharmacol. 1997;11:35-40.

25. Ho, C-T., et al. Phytochemicals in tea and rosemary and their cancer-preventive properties. In Ho, C-T., et al., eds., Food Phytochemicals for Cancer Prevention, II: 2-19. Washington, DC: American Chemical Society, 1994.

26. Ouyang P, Peng WL, Lai WY, Xu AL. [Green tea polyphenols inhibit low-density lipoprotein-induced proliferation of rat vascular smooth muscle cells] [Article in Chinese]. Di Yi Jun Yi Da Xue Xue Bao, 2004 Sep;24(9):975-9.

27. Shafiee M, Carbonneau MA, Urban N, Descomps B, Leger CL. Grape and grape seed extract capacities at protecting LDL against oxidation generated by Cu2+, AAPH or SIN-1 and at decreasing superoxide THP-1 cell production. A comparison to other extracts or compounds. Free Radic Res. 2003 May;37(5):573-84.

28. Dwyer JH, Navab M, Dwyer KM, Hassan K, Sun P, Shircore A, Hama-Levy S, Hough G, Wang X, Drake T, Merz CN, Fogelman AM. Oxygenated carotenoid lutein and progression of early atherosclerosis: the Los Angeles atherosclerosis study. Circulation. 2001 Jun 19;103(24):2922-7.

29. Kerksick C, Willoughby D. The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. J Int Soc Sports Nutr. 2005 Dec 9;2:38-44.

The gastrointestinal system is an important organ system involved with detoxification. Many toxins can be absorbed into the circulation through the intestines, as well as numerous toxins are excreted into the intestines for removal from the body. Not only are toxins introduced into the gastrointestinal tract from the diet, there are also toxins produced in the intestines from pathogenic bacteria and yeast, as well as biological by-products from normal physiological functions. Thus, the digestive tract requires a great deal of attention when an individual is wishing to detoxify or decrease their overall toxin burden.

GI Tract Detoxification: Its Crucial Role in Health

It is undeniable that individuals are constantly bombarded with toxins from the environment, including food, air, and water. These chemicals can adversely impact physiological functions and overall well-being. Water supplies are often contaminated with heavy metals, pesticides, pharmaceuticals, and numerous other agricultural and industrial chemicals. In fact, the Environmental Working Group investigation detected 260 contaminants in U.S. public water supplies, and more than half of the chemicals are unregulated without set safety standards.1 Processed foods and non-organic produce also contribute to the overall toxic burden.

In the gastrointestinal tract, toxins can be ingested, excreted from the liver in the bile, released from pathogenic microbes, or created as by-products from normal physiological reactions. For example, ammonia is produced in the intestines as a by-product of bacterial fermentation of protein and other nitrogen-containing substances. Even low levels of ammonia can have adverse effects, such as increased turnover and destruction of the epithelial cells that line the colon.2 The typical Western diet can cause elevated levels of ammonia, which has been associated with increased viral infections, growth of colon cancer cells, cell toxicity, and altered nucleic acid synthesis.3-4

Stomach acid secretion also decreases with age, and low levels of hydrochloric acid can lead to an imbalance of microflora in the digestive tract. Pathogenic microbes can produce toxic amines, carcinogenic substances, and other health-damaging chemicals. In fact, studies with acid-blocking therapies such as cimetidine have shown that low gastric acid secretion significantly increases nitrite and N-nitrosamine concentrations related to the occurrence of nitrate-reducing bacteria.5 These N-nitroso compounds, similar to carcinogenic nitrosamines, are known to contribute to gastric cancer.6 Additional toxin exposure can include mycotoxins such as aflatoxin, which are toxins produced by certain fungi and are a known potent carcinogen. Humans are exposed to aflatoxins by consuming foods contaminated with fungal growth.

Activated Charcoal for Detoxification

Activated charcoal products, such as EnteraKlenz, are one way in which to help detoxify the digestive tract. Activated charcoal is a form of carbon that has been processed to make it extremely porous and thus has a very large surface area available for adsorption or chemical reactions. It is a black, odorless and tasteless powder made from wood or other materials that have been exposed to very high temperatures in an airless environment. It is then treated to increase its ability to adsorb various substances by reheating with oxidizing gas or other chemicals to break it into a very fine powder. The carbon adsorbs a wide range of impurities, contaminants, toxins, and drugs. Preventing absorption of compounds such as carcinogens, toxins and drugs may help prevent many diseases, thus ingestion of high-affinity protein binding substances such as activated charcoal can help establish an absorptive barrier at the gastrointestinal mucosal lining to prevent the uptake of unwanted chemicals.7

Due to its large adsorptive capacity, activated charcoal is used medicinally to bind unwanted substances and toxins in the gut. Activated charcoal has been used for thousands of years to treat digestive complaints and poisoning. In conventional medicine, activated charcoal is used to treat poisoning and overdoses of orally ingested drugs. The charcoal binds to the poison or drug in the gastrointestinal tract preventing the absorption of the substance into the body. Charcoal can also be used medicinally to filter out drugs or other harmful substances from the blood stream of poisoned patients by drawing out toxins from the blood and binding to them in the intestines. Additionally, activated charcoal has been used to manage gastrointestinal disorders such as diarrhea, constipation, bloating, and flatulence.

Several studies have shown the efficacy of activated charcoal for digestive complaints. In a placebo-controlled clinical trial, the effectiveness of activated charcoal in treating intestinal gas following a gas-producing meal was evaluated. Orally administered activated charcoal was shown to be effective in preventing the increase in the number of flatulence events and increased breath hydrogen concentrations that normally occur following a typical gas-producing meal.8 In a double-blind, randomized, multi-center, prospective clinical trial, activated charcoal was given to patients with irritable bowel syndrome for 12 weeks. The results showed that in the activated charcoal group, symptoms were alleviated by approximately 60 percent, and was particularly effective in patients with constipation.9

Other research has shown that activated charcoal adsorbs aflatoxin B1 in an efficient manner in vitro.10 Enterosorbants, such as charcoal, has been shown to have a positive effect on numerous gastrointestinal conditions such as gastro-duodenal ulcers, nonspecific ulcerative colitis, irritable bowel syndrome, chronic enteritis, and colitis, with concurrent intestinal dysbacteriosis by eliminating pathogenic bacteria and improving levels of beneficial bacteria.11 Additional reported benefits of activated charcoal include adsorbing the toxins and enzymes generated by pathogenic bacteria and yeast such as Candida albicans, as well as suppressing the growth of yeast in the intestines. Individuals with candida concerns will find activated charcoal especially helpful on those occasions when sugar or refined carbohydrates are consumed, helping the body detoxify the unhealthy foods. Additionally, activated charcoal is used by practitioners to counteract the Herxheimer reaction, otherwise known as the “die-off reaction,” which is an exacerbation of systemic Candida symptoms caused by the toxins produced as yeast cells die.

In the environment, activated charcoal is commonly used as a water or air purifier removing toxic chemicals and organisms. Activated charcoal has also shown the ability to filter pathogenic organisms such as bacteria and Candida albicans.12 It is also used to bind organic chemicals such as pesticides.13 Other reported uses of activated charcoal include cleaning skin wounds, adsorbing snake venoms, and treating viruses and bacteria. It also has shown anti-aging properties in animal models.

Healthy Cholesterol Levels

Interestingly, charcoal has shown benefit in other common medical disorders. Activated charcoal modulates serum cholesterol levels. It is believed that this activity is due to the ability of charcoal to impact enterohepatic circulation of bile acids. In one study, 20 grams of super-activated charcoal or 8 grams of the pharmaceutical cholestyramine was given twice daily to subjects with elevated cholesterol for 3 weeks. The results showed that super-activated charcoal reduced plasma cholesterol by approximately 21.8 percent, while cholestyramine, a bile acid sequestrant medication, reduced the cholesterol by 16.2 percent.14 In a similar study, activated charcoal was compared to cholestyramine to evaluate the efficacy of charcoal to reduce plasma cholesterol levels. The results indicated that the 2 treatments were similar in efficacy, individually and combined. Serum total cholesterol levels and low-density lipoprotein (LDL) cholesterol were reduced and the ratio of the beneficial high density lipoprotein HDL/LDL-cholesterol was increased by charcoal in a dose dependent manner, demonstrating positive effects for cardiovascular health. Additionally, cholestyramine increased serum triglyceride levels whereas charcoal did not.15

Conclusion

Toxin exposure is unavoidable. To optimize health and well-being, it is critical to limit our exposure and decrease the total toxic burden on the body. EnteraKlenz, a pleasant-tasting, chocolate-mint-flavored activated charcoal product, can significantly decrease toxins from the digestive tract. Activated charcoal has been used medicinally for thousands of years, and is still in use by both conventional and alternative practitioners. In addition to the detoxifying effect of activated charcoal, research has shown it has benefit for numerous other health conditions and that it can play an important role in overall health.

References

1. Environmental Working Group A National Assessment of Tap Water Quality. Dec 2005 Available at: http://www.ewg.org/tapwater/findings.php. Accessed on: 11-2-08.

2. Robinson RR, Feirtag J, Slavin JL. Effects of dietary arabinogalactan on gastrointestinal and blood parameters in healthy human subjects. J Am Coll Nutr. 2001 Aug;20(4):279-285.

3. Visek WJ. Diet and cell growth modulation by ammonia. Am J Clin Nutr. 1978 Oct;31(10 Suppl):S216-S220.

4. Bartram HP, Scheppach W, Schmid H, et al. Proliferation of human colonic mucosa as an intermediate biomarker of carcinogenesis: effects of butyrate, deoxycholate, calcium, ammonia, and pH. Cancer Res. 1993 Jul 15;53(14):3283-3288.

5. Stockbrugger RW, Cotton PB, Eugenides N, et al. Intragastric nitrites, nitrosamines, and bacterial overgrowth during cimetidine treatment. Gut. 1982 Dec;23(12):1048-1054.

6. Calmels S, Béréziat JC, Ohshima H, et al. Bacterial formation of N-nitroso compounds from administered precursors in the rat stomach after omeprazole-induced achlorhydria. Carcinogenesis. 1991 Mar;12(3):435-439.

7. Rasmussen MV, Barker TT, Silbart LK. High affinity binding site-mediated prevention of chemical absorption across the gastrointestinal tract. Toxicol Lett. 2001 Dec 15;125(1-3):51-59.

8. Hall RG Jr, Thompson H, Strother A. Effects of orally administered activated charcoal on intestinal gas. Am J Gastroenterol. 1981 Mar;75(3):192-196.

9. Hübner WD, Moser EH. Charcoal tablets in the treatment of patients with irritable bowel syndrome. Adv Ther. 2002 Sep-Oct;19(5):245-252.

10. Decker WJ, Corby DG. Activated charcoal adsorbs aflatoxin B1. Vet Hum Toxicol. 1980 Dec;22(6):388-389.

11. Krylov AA, Beliakov NA, Sapego AV, et al. Enterosorption in ulcerative lesions of the gastrointestinal tract with concomitant intestinal dysbacteriosis. Ter Arkh. 1996;68(2):24-27.

12. Van Dijck PJ, van de Voorde H. Activated Charcoal and Microflora in Water Treatment. Water Research. 1984;18(11):1361-1364.

13. Yelverton FH, Weber JB, Peedin G, et al. Using Activated Charcoal to Inactivate Agricultural Chemical Spills. Available at: http://www.bae.ncsu.edu/programs/extension/publicat/wqwm/ag442.html. Accessed on: 11-01-08.

14. Park GD, Spector R, Kitt TM. Superactivated charcoal versus cholestyramine for cholesterol lowering: a randomized cross-over trial. J Clin Pharmacol. 1988 May;28(5):416-419.

15. Neuvonen PJ, Kuusisto P, Vapaatalo H, et al. Activated charcoal in the treatment of hypercholesterolaemia: dose-response relationships and comparison with cholestyramine. Eur J Clin Pharmacol. 1989;37(3):225-230.

Vitamin K was first recognized in 1929 for its vital role in the blood-clotting process. Since that time, this multifaceted coenzyme has been shown to be effective in a wide range of conditions, ranging from osteoporosis to heart disease to various forms of cancer. Recent findings have added to our accumulating database of vitamin K’s biological functions and medical applications.

The vitamin occurs naturally in two forms. K1, or phylloquinone, is found in green leafy vegetables. K2, comprised of a group of compounds known as menaquinones, is synthesized by intestinal microflora and also obtained from dietary sources including organ meats, egg yolks, fermented dairy products, and the Japanese fermented soybean dish, natto (the richest food source).

Although vitamin K2 occurs in much smaller amounts in the diet than K1, medical findings suggests that the menaquinone form confers most of the benefits in regards to heart and bone health and the inhibition of cancer. Vitamin K1, meanwhile, has been studied for its beneficial effects in supporting healthy insulin levels.1

Heart Disease and Osteoporosis: The Common Denominator

Although not at first apparent, research has established a connection between two seemingly diverse conditions: osteoporosis and cardiovascular disease. The common link is faulty calcium metabolism caused by a deficiency of vitamin K2.

Vitamin K2 plays a vital role in ensuring that calcium stays in the bones (maintaining adequate bone mineral density) and out of the arteries (avoiding arterial calcium buildup and plaque formation). It is an essential cofactor for a chemical process known as carboxylation, which enables calcium-regulating proteins to perform their functions. One of these proteins, osteocalcin, binds calcium to the bone matrix. However, without sufficient K2, the carboxylation reaction that activates osteocalcin cannot proceed, resulting in the loss of calcium from bone tissue.2-3 Another protein, matrix GLA-protein, is a calcification-inhibitor; that is, it prevents the deposition of calcium in arteries. Similarly, this protein’s precursor must undergo carboxylation, mediated by K2, to convert to its active form. In the absence of vitamin K2, this conversion to matrix GLA-protein is hindered, resulting in vascular calcification.4-5

Adequate levels of calcium-regulating menaquinones are vital, since deficiencies are associated with a greater risk of both fractures3,6,15 and cardiovascular diseases.4,8

Vitamin K2 and Heart Health

In 2004, the results of a ground-breaking seven-year study of 4,800 subjects (known as the Rotterdam Study) linking menaquinone intake with a reduced risk of coronary heart disease (CHD) were published. Participants in the Netherlands were tracked for seven years for dietary intake of vitamins K1 and K2 and development of aortic calcification and CHD. Researchers found that those with the higher levels of vitamin K2 in their diets (at least 32.7 mcg a day) experienced lower death rates from heart disease and less deposition of calcium in the aorta compared with subjects with minimal K2 intake. K1 did not confer this benefit. The researchers concluded, “Our findings suggest a protective effect of menaquinone intake against CHD, which could be mediated by inhibition of arterial calcification. Adequate intake of… menaquinones may contribute to CHD prevention.”4

In the past few years, other studies have confirmed that vitamin K2 decreases the risk of cardiovascular disease by reducing coronary calcification7 and inhibiting arterial calcification.9-10

Healthy Bones

Osteoporosis is the excessive loss of calcium and other minerals from bones, causing them to become porous, brittle, and subject to fracture, a potentially dangerous situation, especially for the elderly.

Much of the research on vitamin K2 has been performed in Japan, where researchers discovered that people who regularly consume the soybean dish, natto, have lower rates of hip fractures11 and postmenopausal bone loss12 compared with less frequent consumers. The active ingredient in natto responsible for these bone-protecting qualities is vitamin K2.

The connection between menaquinone intake and bone health is supported by a slew of other research which confirms that vitamin K2 reduces the occurrence of new bone fractures and maintains bone mineral density (BMD).6,13-15 In addition, it has been shown to augment the positive effects of standard anti-osteoporosis drugs when used in combination treatment.6,15-16 For example, in a 1-year randomized trial, 44 postmenopausal women received either alendronate (a bisphosphonate that inhibits bone resorption), or vitamin K2 (45 mg/day) plus alendronate. The addition of vitamin K2 enhanced osteocalcin carboxylation and led to a greater increase in hip bone mineral density than treatment with the bisphosphonate alone.15

Mutagenic Concerns

MK-4, a vitamin K2 analog, has demonstrated anti-tumor effects on various types of cancer cell lines18-19 and also has been shown to be effective in patients with leukemia, myelodysplastic syndrome, and hepatocellular carcinoma (HCC, liver cancer)18-19 most likely by inducing processes such as apoptosis and cell-cycle arrest.19-20

In a study originally intended to examine the efficacy of MK-4 in treating bone loss in 40 women with liver cirrhosis, researchers observed that subjects receiving the 45 mg dose had a markedly reduced rate of liver cancer development. Two of the 21 women developed HCC in the treated group compared with nine of the 19 subjects in the control group. Researchers concluded that “there is a possible role for vitamin K2 in the prevention of HCC in women with viral cirrhosis.”21

Besides its efficacy in treating HCC, vitamin K2 has also been found to suppress the disease’s recurrence.18,19,22 In one study of 61 patients who had undergone surgical removal of tumors, those receiving 45 mg of MK-4 had significantly lower recurrence rates and higher survival rates than subjects in the control group.22

In the first epidemiologic study linking dietary intake of vitamins K1 and K2 with the development of prostate cancer, over 11,000 men were tracked for over 8.5 years with respect to dietary intake and cancer development. Researchers observed an inverse relationship between the incidence of prostate cancer and total menaquinone intake. (Interestingly, menaquinones from dairy products were associated with lower rates of advanced prostate cancer than those from meat.) K1 intake was unrelated to the incidence of prostate cancer.23

Dosage and Safety

The Food and Nutrition Board of the Institute of Medicine recommendation for vitamin K intake is 120 mcg/day for men and 90 mcg/day for women.24 Although these levels may be sufficient to ensure blood clotting, research indicates that they are not optimal for cardiovascular and bone health.3 Consider that menaquinone intake is 10 percent of total vitamin K intake4; based on the daily recommendation, this translates to 9 and 12 mcg/day of vitamin K2—extremely low values! What is a suitable dose? As we have seen, benefits were obtained over a vast range—as low as 32.7 mcg per day (which provided protection against CHD in the Rotterdam study) to as high as 45 mg a per day (the prescription dose of MK-4 used to treat osteoporosis).

Vitamin K2 appears to have a wide safety margin. According to the Food and Nutrition Board, “No adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals.”24 This is supported by a large body of research, which draws conclusions such as: “the safety, relatively low cost and ease of use of vitamin K2 have led to good compliance with treatment.”19

One caution to keep in mind is that individuals taking Coumadin® (warfarin) should only take vitamin K or K2 under the guidance of a physician.

Conclusion

With its proven record as a safe and effective treatment for heart disease, osteoporosis and cancer, vitamin K2 is a valuable addition to a comprehensive supplement program. However, the menaquinones’ full therapeutic potential is yet to be realized, as research continually reveals new applications for this unique class of compounds.

References

1. Yoshida M, Jacques PF, Meigs JB, Saltzman E, Shea MK, Gundberg C, Dawson-Hughes B, Dallal G, Booth SL. Effect of vitamin K supplementation on insulin resistance in older men and women. Diabetes Care. 2008 Aug 12. Published Online Ahead of Print.

2. Hirao M, Hashimoto J, Ando W, Ono T, Yoshikawa H. Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. J Bone Miner. Metab.2008;26(3):260-4.

3. Bügel S. Vitamin K and bone health in adult humans.Vitam Horm. 2008;78:393-416.

4. Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004 Nov;134(11):3100-5.

5. Schurgers LJ, Teunissen KJ, Knapen MH, et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1629-33.

6. Iwamoto J, Takeda T, Sato Y. Role of vitamin K2 in the treatment of postmenopausal osteoporosis. Curr Drug Saf. 2006 Jan;1(1):87-97.

7. J Tsugawa N, Shiraki M, Suhara Y, et al. Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. Bone Miner Metab. 2008;26(1):79-85.

8. Beulens JW, Bots ML, Atsma F, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2008 Jul 19.

9. Wallin R, Schurgers L, Wajih N. Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification. Thromb Res. 2008;122(3):411-7.

10. Saito E, Wachi H, Sato F, Sugitani H, Seyama Y. Treatment with vitamin k(2) combined with bisphosphonates synergistically inhibits calcification in cultured smooth muscle cells. J Atheroscler Thromb. 2007 Dec;14(6):317-24.

11. Kaneki M, Hodges SJ, Hosoi T, et al. Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk. Nutrition. 2001 Apr;17(4):315-21.

12. Ikeda Y, Iki M, Morita A, et al. Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. J Nutr. 2006 May;136(5):1323-8.

13. Ishida Y. Treatment of osteoporosis and evidence-based medicine. Vitamin k(2). Clin Calcium. 2008 Oct;18(10):1476-82.

14. Tanaka I, Oshima H. Vitamin K2 as a potential therapeutic agent for glucocorticoid-induced osteoporosis. Clin Calcium. 2007 Nov;17(11):1738-44.

15. Hara K, Akiyama Y. Vitamin K and bone quality. Clin Calcium. 2007 Nov;17(11):1678-84.

16. Hirao M, Hashimoto J, Ando W, Ono T, Yoshikawa H. Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. J Bone Miner Metab. 2008;26(3):260-4.

17. Iwamoto J, Takeda T, Sato Y. Menatetrenone (vitamin K2) and bone quality in the treatment of postmenopausal osteoporosis. Nutr Rev. 2006 Dec;64(12):509-17.

18. Mizuta T, Ozaki I. Hepatocellular carcinoma and vitamin K. Vitam Horm. 2008;78:435-42.

19. Tamori A, Habu D, Shiomi S, Kubo S, Nishiguchi S. Potential role of vitamin K(2) as a chemopreventive agent against hepatocellular carcinoma. Hepatol Res. 2007 Sep;37 Suppl 2:S303-7.

20. Okamoto H. Vitamin K and rheumatoid arthritis. IUBMB Life. 2008 Jun;60(6):355-61.

21. Habu D, Shiomi S, Tamori A, et al. Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver. JAMA. 2004 Jul 21;292(3):358-61.

22. Mizuta T, Ozaki I, Eguchi Y, et al. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study. Cancer. 2006 Feb 5;106(4):867-72.

23. Nimptsch K, Rohrmann S, Linseisen. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr. 2008 Apr;87(4):985-92.

24. http://www.iom.edu/Object.File/Master/54/411/DRIs.Vitamins.pdf

Brain aging is a popular subject now especially as my age group is nearing the time to be put out to pasture. Brain aging, which also, of course, occurs in our pets, is a popular catchall term that covers such things as diffuse plaques, amyloid deposition, vascular changes, age-related gliosis and thickening of the meninges with dilation of the ventricles. Brain aging may include one or all of the preceding changes.

Some of the signs that may be associated with changes in the brains of dogs may include such things as changes in reactions to a routine stimuli such as being petted when asleep, changes in the sleep-wake cycle, changes in the responsiveness to commands, changes in social behaviors, and decreases in the response to some stimuli. Furthermore, eliminations may become inappropriate or even incontinence may occur and they may start getting stuck in corners or lost in the house. (Because this also can happen in humans, as someone who has trouble asking for directions, I could be in real trouble.)

There are neurochemical changes in both dogs and humans. Studies have brought about some knowledge of these neurochemistry changes. As an example, the enzyme monoamine oxidase B is elevated and acetycholine is either primarily or secondarily lowered. In canine cognitive dysfunction and Alzheimer’s disease, monoamine oxidase B activity is increased, which goes along with depletion of dopamine and a loss or decreased activity of dopaminergic neurons.

Apoptosis or cell death may relate to an increase in cognitive dysfunction. Free radicals continually banging away on the dopamine producing neurons may induce or augment cell death. Free radicals increase with cell death and that may lead to DNA fragmentation, which will decrease the function of the cells.

A theory that may be included is related to the increased levels of monoamine oxidase, which creates a situation where the dopaminergic neurons are unable to maintain production of dopamine and develop atresia. Either way, or in combination, degeneration of dopaminergic neurons is invariably associated with motor and cognitive defects. Agents that protect against excess monoamine oxidase B or against free radicals may help slow or prevent these changes in dogs.

A program in cognitive assessment from Dr. Bill Milgrams’ lab at the University of Toronto has been working for over a decade evaluating the effects of age, sex, social group and genetic relatedness on performance in dogs. This is measured by a complex, computer driven algorithm for choice experiments that use food rewards. Evaluating canine models for human age-related cognitive decline has brought about acknowledgment that dogs are cognitive individuals.

There are several drugs that may help slow or modify the progression of degeneration in dogs. It may be worth discussing these with your veterinarian. You might also consider the product Neuron Growth Factors (NGF™), available from VRP. NGF is a formula that improves brain function by restoring the outgrowth of neurites on brain cells. Neurites are the branch-like extensions (axons and dendrites) on brain cells where communication takes place. NGF contains acetyl l-carnitine (ALC), which has been shown to increase nerve growth factor activity as much as 100-fold. ALC increases the number of nerve growth factor receptor sites on brain cells, thereby enhancing the rate of neurite outgrowth. A related compound, acetyl carnitine arginate, works synergistically by mimicking the action of nerve growth factor itself. Another ingredient, uridine, has been shown to regrow axons and dendrites during growth and development stages, as well as in older animals. Uridine has also been shown to improve cognitive function. NGF also contains two other cognitive supporting nutrients, ginkgo and gotu kola.

Acetyl-L-carnitine as a single supplement is another option.

Giving your dog these supplements before you notice a decline will result in a better chance of stopping those signs of cognitive dysfunction from occurring.

Herbal Sleep is a newly reformulated blend of traditional botanical ingredients clinically proven to calm the nerves, relieve anxiety and promote restful sleep. This blend includes the most widely used sleep-enhancing herbs and features Seditol®, a patented herbal extract that helps people fall asleep faster and stay asleep longer. In receptor binding assays, the Seditol blend and its principal ingredient were shown to bind to several important receptors that promote relaxation and sleep.1 An open-label trial of nearly 300 subjects showed that Seditol not only promoted sleep, but reduced the fatigue that is typically associated with poor sleep.2

Hops has been valued in Europe for its therapeutic benefits for several centuries. The use of hops for promoting restful sleep is recognized by a number of European expert panels, including Germany’s Commission E, the British Herbal Compendium and the European Scientific Cooperative on Phytotherapy (ESCOP). Like other sedative herbs, hops is frequently used in combination with other herbs such as valerian. Volatile fractions present in the strobile (fruiting body) are thought to be the active principles.3

Passion flower has been recognized for centuries in Europe and the Americas as an effective herb for insomnia, nervousness, anxiety and to help relieve spasm. Active ingredients in passion flower include flavonoids and alkaloid compounds that downregulate nerve excitation via benzodiazepine receptors.4

Documented use of lemon balm dates back to ancient Greek and Roman times, where lemon balm-infused wine was used both internally and topically for its sedative, pain-relieving and antimicrobial properties. Animal studies demonstrate that at relatively low dosage levels, lemon balm effectively induces sleep and shortens the time required to fall asleep.5 Lemon balm has also been shown to reduce the stress response and induce “calmness” while simultaneously improve mood and cognitive performance.6

Valerian may be the single best-recognized herb for helping with sleeplessness and anxiety. Frequently combined with other sedative herbs, valerian has been shown in numerous clinical trials to enhance sleep quality and relieve generalized anxiety. Due to its effectiveness and safety profile, valerian enjoys widespread regulatory approval in the U.S., Canada and Europe. Valerian activity is attributed to compounds called valepotriates that are derived principally from the root. Valepotriates such as valerenic acid have been shown to bind to GABA receptors, inducing calm and reducing the time to sleep onset.7-8 Regular use may enhance valerian effectiveness.

References

1.Koetter U, Barrett M, Lacher S, Abdelrahman A, Dolnick D. Interactions of Magnolia and Ziziphus Extracts with Selected Central Nervous System Receptors. Manuscript Submitted for Publication, October 2008.

2. LaValle J, Pelletier M, LaValle L, Barrett M, Koetter U, Dolnick D. A Proprietary Blend of Magnolia and Ziziphus Extracts Assists with Sleep: An Open-Label Assessment. Manuscript Submitted for Publication, October 2008.

3. Wohlfart R, Hänsel R, Schmidt H. The Sedativ-hypnotic Principle of Hops. Planta Med. 1983 Jun;48(6):120-3.

4. Jellin JM, Gregory PJ, Batz F, Hitchens K, et al. Pharmacist’s Letter/Prescriber’s Letter Natural Medicines Comprehensive Database. 5ht ed. Stockton CA. Therapeutic Research Faculty. 2003. p1014.

5. Soulimani R, et al. Neurotropic action of the hydroalcoholic extract of Melissa officinalis in the mouse. Planta Med. 1991;57:105–109.

6. Kennedy DO, Little W, Scholey AB. Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm). Psychosom Med. 2004 Jul-Aug;66(4):607-13.

7. Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol 1999;51:505-12.

8. Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav 1982;17:65-71.

Nutri-Joint Cream is a fast-absorbing topical cream that delivers two of nature’s most beneficial joint nutrients—glucosamine sulfate and MSM—along with herbal extracts of ginger, rosemary, devil’s claw and yucca, now in a convenient 3 ounce pump.

Glucosamine, the premier joint support nutrient, is a key structural component of cartilage. Numerous clinical trials have confirmed the ability of supplemental glucosamine sulfate to support joint function and improve flexibility.

MSM (methylsulfonylmethane) is a natural source of the essential mineral sulfur, which is vital to the composition of joints, cartilage, skin, hair and nails. Studies indicate that MSM works synergistically with glucosamine to enhance joint function.

Ginger, rosemary, devil’s claw and yucca are plants long recognized for their ability to reduce inflammation and promote joint health. Active compounds derived from these herbs include gingerols, rosemarinic acid, iridoid glycosides, yuccaols and resveratrol. These compounds help downregulate pro-inflammatory enzymes such as COX-2 and 5-lipoxygenase and also help inhibit the synthesis of the inflammatory cytokine TNF-alpha.

Emu Oil demonstrates anti-inflammatory properties, and is reputed to have superior absorption characteristics. Peppermint Oil adds a calming aromatherapy quality to Nutri-Joint Cream, which is paraben free.

Apply Nutri-Joint Cream to affected areas and massage in gently 3 times per day.

Product Code: 1526

Pregnenolone is the precursor (building-block) for all other steroid hormones. It is converted directly into DHEA and/or progesterone. DHEA converts to testosterone and estrogens; progesterone converts to estrogens, cortisol, and aldosterone. It is this succession of conversions that makes human life possible. Without pregnenolone, there can be no human steroid hormone production.

Made from cholesterol, pregnenolone is a natural steroid hormone produced primarily in the adrenal glands, but in smaller amounts by many other organs and tissues of the human body, including liver, brain, skin, gonads, and even the retina of the eye.

Like many health-promoting hormones, levels of pregnenolone drop with age. Although the data are not as abundant or definitive for pregnenolone as they are for DHEA, Dr. Eugene Roberts, a pioneer in hormone research, believes that the age-related drop in pregnenolone is as dramatic as the drop in DHEA. At 75, our bodies typically make 60 percent less pregnenolone than at age 35. This is a point of great concern, considering pregnenolone’s numerous protective, health-promoting properties.

Energizing, Anti-stress Benefits

Some of the earliest investigations of pregnenolone’s many benefits showed it to be an energizing, anti-stress biochemical. During the 1940s, Drs. Pincus and Hoagland gave 50-100 mg/day of pregnenolone to various types of factory workers, as well as pilots and students trained to use a flight simulator. The factory workers noted improved production rates while taking pregnenolone. They felt less fatigued, better able to cope with their jobs and experienced an enhanced sense of happiness and well-being. Interestingly, workers in stressful job environments improved more with pregnenolone than those with less demanding tasks.

The flight simulation machine was designed to test hand-eye coordination, learning, memory and stamina. The subjects were to fly the plane correctly, avoiding obstacles and crashes. Half the subjects were airplane pilots; half were not. Tests conducted over several weeks showed that the ability of all subjects to fly the simulated airplane improved significantly after taking 50 mg pregnenolone before each test run. The improvement was especially noticeable after the subjects had taken pregnenolone for at least two weeks. This suggests pregnenolone’s anti-stress benefits may be cumulative. Also, the professional pilots reported that they performed better in their real flying jobs and that they suffered less fatigue during their pregnenolone-supplementing period.

Pro-memory Effects

Animal studies by Isaacson, Flood, Morely and Roberts have shown that injection of as few as 15 to 145 molecules (!) of pregnenolone directly into the areas of the brain that are thought to mediate memory improved the ability of mice to more quickly remember the way out of a maze that they had run before. Preliminary results of St. Louis School of Medicine researcher R. Sih have shown definite memory enhancement with pregnenolone. Dr. Sih gave 500 mg pregnenolone or a placebo to men and women three hours before they were asked to perform standard memory tests. Pregnenolone resulted in improved memory in both men and women, improved spatial memory and perception in men, and improved verbal recall memory in women.

Mood Elevation

Pregnenolone is known to modulate at least two key nerve receptor systems in the brain: NMDA receptors and GABA receptors. NMDA receptors, which weaken with age, are involved in learning, memory, and alertness. Pregnenolone enhances NMDA receptor function. GABA receptors promote relaxation, mental slowing, sedation and sleep. Benzodiazepine drugs (Valium, Librium, Xanax, etc.) activate GABA receptors, while pregnenolone inhibits GABA receptors. Thus, too little NMDA activity combined with excessive GABA activity would tend to promote mental sluggishness and depression. Since pregnenolone raises NMDA activity and lowers excessive GABA activity, pregnenolone seems to be a natural antidepressant. Indeed a recent study of 27 depressed patients found that their cerebrospinal fluid (which circulates through the brain and spinal cord) was significantly lower in pregnenolone than in 10 non-depressed volunteers. Cerebrospinal fluid levels are generally believed to accurately reflect levels of various biochemicals in the brain.

Anti-arthritis Effects

During the 1940s, pregnenolone was used successfully as a treatment for rheumatoid arthritis. A 1950 review article on pregnenolone reported on a study by Henderson and colleagues which found that 300 mg pregnenolone/day for 40 days resulted in a significant decrease in joint pain, tenderness, and spasticity, with improved strength and range of motion. Another study by Freeman and colleagues, with 64 patients, used 500 mg of pregnenolone daily for periods of 2 to 30 weeks. Twenty-four patients showed striking improvements, and 20 showed minor improvements.

Unfortunately, the advent of the wonder drug cortisone (Cortisol) in the 1950s caused pregnenolone to be passed by for arthritis treatment, since pregnenolone’s results were much slower to manifest. Coincidentally, pregnenolone couldn"t be patented by the drug companies whereas synthetic variants of cortisone could be (and were) patented. By the time the nightmarish side-effects of excessive cortisone were widely known by the medical community in the 1960s (these side effects could include psychotic breakdown, adrenal failure, and even death), pregnenolone had been completely forgotten.

Pregnenolone’s Cortisol-neutralizing Power

Small amounts of cortisol are essential to promote health and even for life itself. Yet under the prodding of chronic stress and aging, our adrenal glands often over-produce cortisol. Indeed, cortisol is the only steroid hormone whose levels tend to increase with age. The level of all other steroids, including pregnenolone, tend to decrease (often radically) with age. Excessive cortisol promotes a host of negative side-effects. High cortisol levels promote depression, as does chronic, unremitting stress in many people (which results in chronically elevated cortisol). Experimental subjects such as factory workers and airplane pilots who were given pregnenolone under stressful conditions actually reported an enhanced sense of well-being and happiness.

Excessive Cortisol

The following are indications of an excessive cortisol level:
(1) accelerated skin aging and deterioration;
(2) damaged structure and function of mid-brain regions involved in memory;
(3) impaired wound healing, poor skin quality and excessive scar tissue;
(4) excess fluid retention and puffy, flabby skin.
(5) poor quality of sleep.

Most of these adverse effects of cortisol are directly counteracted by pregnenolone. For example, Papa and Kligman reported in 1965 that topical application of a pregnenolone-containing skin cream restored youthful properties to aged skin.

Experiments with humans and animals show that pregnenolone enhances the function of the same pro-memory areas of the mid-brain that are damaged by cortisol. A 1994 report by Guth and colleagues found that pregnenolone actually promoted successful healing of otherwise crippling spinal cord injuries in rats. Ray Peat, Ph.D., has reported successful use of pregnenolone to rid the body of cortisol-induced excessive fluid and puffiness, promoting a more lean and taut, youthful appearance to the face. Steiger (1993) used a mere 1 mg of pregnenolone in human volunteers to increase the restorative delta, slow-wave, stage IV sleep. (Larger doses of pregnenolone taken inappropriately at night may, however, also promote insomnia through over-energization). Thus, pregnenolone seems in many ways to be a natural antidote to the dark side of cortisol, which tends to manifest ever more with aging and chronic stress.

Chemo-protective Action

A major determinant of the body’s ability to detoxify poisonous chemicals -- such as pesticides, medical drugs, industrial contaminants and auto exhaust -- is the health and effectiveness of the Cytochrome P450 enzyme system in the liver. This is one of the most broad-spectrum, universal detoxifying enzyme systems possessed by all mammals, including humans. Moderate levels of cortisol (the state-of-siege anti-stress hormone) promote the activity of this detox system. However, larger amounts of cortisol (which is all-too-often over-produced by our adrenal glands due to aging or prolonged stress) degrade the P450 system’s anti-toxin effects. Although pregnenolone does not affect the rate of synthesis of the enzymes in the P450 system, it does stabilize these enzymes against the digestive activity of liver proteolytic enzymes, which would tend to break down the P450 enzymes. Pregnenolone thus increases overall P450 detox enzyme power by promoting conservation of existing P450 enzymes.

Safety

Fortunately, pregnenolone is amazingly safer than other steroids. Pregnenolone researchers working with both human and animal subjects since the 1940s have consistently commented on pregnenolone’s virtual absence of toxicity. For example, the classic review article on pregnenolone by Henderson and colleagues in 1950 states: "It [pregnenolone] has an extremely low order of toxicity; [it] has not shown any adverse effects on endocrine [hormone] physiology ...."

Pregnenolone has been given orally to humans at doses as high as 500 mg/day for as long as 30 weeks without evidence of adverse effects. Mice given 5 grams (1/6 ounce) per kilogram (2.2 pounds) of body weight suffered no ill effects. This would be equivalent to a 154 pound (70 kilogram) human ingesting 350 grams (approximately 3/4 pound) per day! In a long-term study, mice that were given one gram pregnenolone per kilogram of body weight three times weekly for 50 doses suffered no toxic reactions -- including no changes in the size and condition of offspring produced after the 50 doses.

In one human study, eight people received 50 to 150 milligrams per day by intramuscular injection for 75 days, with no reported side effects. Dr. Eugene Roberts gave 20 Alzheimer’s patients 525 mg/day for three months with no toxicity. During rheumatoid arthritis experiments with pregnenolone, Dr. H. Freeman and colleagues gave 500 mg pregnenolone/day for up to 30 weeks, with no toxicity. And Drs. Pincus and Hoagland, two of the pioneer researchers on pregnenolone use by humans in the 1940s, found no toxic reactions with pregnenolone used by hundreds of men and women at dosages of 100 mg/day for four months.

Dosage

The classic studies on pregnenolone and stress in the 1940s by Pincus and Hoagland generally used only 50 mg/day to achieve excellent results, while arthritis studies typically used 200-500 mg daily. Thus, although pregnenolone appears amazingly safe and beneficial, there are still many unanswered questions regarding proper dosage, metabolism, and clinical effects. Keeping these uncertainties in mind, here are some recommendations for dosage.

For those wishing to err on the side of caution, 50 to 100 mg pregnenolone per day would probably be suitable for use without physician monitoring. Perhaps an additional safety margin (for this already amazingly-safe substance) could be achieved through discontinuing use for one week every month. Those wishing to use the higher, anti-arthritis doses (200 - 500 mg/day) should probably do so only under the supervision of their physician, even though many human clinical studies with arthritis at these dosages yielded no problems or toxicities. Morning is the perfect time to take pregnenolone, and a single daily dose is probably best, since pregnenolone is fat-soluble, and probably follows the circadian highs and lows of DHEA and cortisol (highest in the morning, with a drop to baseline by late afternoon). On an anecdotal note, there have been patients taking 100 - 1,000 mg pregnenolone/day intermittently since 1987, with no discernible negative side effects.

Contraindications

While there has been no definite information published as to who should not take pregnenolone, on theoretical grounds, a few cautions can be suggested. Since pregnenolone (especially at high doses) may (in some people) increase estrogen or testosterone levels, men with prostate cancer (which may be worsened by testosterone) and women with breast or ovarian cancer (which may be worsened by estrogen) should probably take pregnenolone only with their doctors consent and supervision. Men with high PSA (prostate specific antigen) blood levels (possible indicator for undiagnosed or future prostate cancer) should also proceed with caution with pregnenolone use. Lastly, because of pregnenolone’s anti-GABA, pro-NMDA action, persons known to suffer from epileptic seizures or who are taking an anti-seizure medication such as Dilantin, Depakote or Tegretol should probably only use pregnenolone with their doctors supervision. Finally, as we age, the body produces ever-less of the enzyme, which converts pregnenolone to DHEA. Thus, while supplementary pregnenolone taken during middle age and beyond will produce at least some normalization back toward more youthful (and healthful) levels of other steroid hormones, pregnenolone will not completely substitute for other steroid hormone supplements in those with medically demonstrated needs for various specific steroids i.e., DHEA, cortisol, estrogen, etc.

References:

Davison, R., et al. Effects of delta 5 pregnenolone in rheumatoid arthritis. Arch Int Med 85: 365-88, 1950.
Flood, J. et al. Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures. Proc Nat Acad Sci USA 92: 10806-10, 1995.
Freeman, H., et al. Therapeutic efficacy of delta 5 pregnenolone in rheumatoid arthritis. JAMA 143: 338-44, 1950.
George, M., et al. CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI Biol Psych 35(10): 775-80, 1994.
Guth, L., et al. Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury. Proc Nat Acad Sci USA. 91(25): 12308-12, 1994.
Henderson, E., et al. Pregnenolone. J Clin Endocrinol 10: 455-74, 1950.
Maione, S., et al. Pregnenolone sulfate increases the convulsant potency of NMDA in mice. Eur J Pharmacol 219 (3): 477-9, 1992.
Majewska, et al. Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons. Neuroscience Letters 90: 279-84, 1990.
Pincus, G. and Hoagland, H. Effects of administered pregnenolone on fatiguing psychomotor performance J Aviation Med 15: 98-115, 1944.
Pincus, G. and Hoagland, H. Effects on industrial production of the administration of delta 5 pregnenolone to factory workers. Psychosom Med 7: 342-46, 1945.
Regelson, W. and Colman, C. Pregnenolone: The Superhormone for Your Brain [material on Dr. R. Sih] in The Superhormone Promise, Simon and Schuster, 1996.
Roberts E. Pregnenolonefrom Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABA-A receptor. Biochem Pharmacol 49: 1-16, 1995.
Steiger, A., et al. Neurosteroid pregnenolone induces sleep EEG changes in man compatible with inverse agonistic GABA-A receptor modulation. Brain Res 615: 267-74, 1993.
Warner, M. and Gustaffson, J. Cytochrome P450 in the brain: neuroendocrine functions. Front Neuroendocrinol 16(3): 224-36, 1995.
Wu, F., et al. Pregnenolone sulfate: a positive allosteric modulator at the NMDA receptor. Mol Pharmacol 40: 333-6, 1991.

St. John’s Wort Effective in Depression

A new review has concluded that St. John’s wort is effective in reducing symptoms of major depression.

Extracts of St. John’s wort (Hypericum perforatum) have already been shown to help in patients with mild to moderate depression. In patients with more severe depression, however, the efficacy has been disputed.

Researchers investigated whether St. John’s wort extracts are more effective than placebo and as effective as standard antidepressants in the treatment of major depression and whether they have fewer adverse effects than standard antidepressant drugs.

The reviewers searched the medical literature for studies on St. John’s wort and included all randomized and double-blind trials of patients with major depression as well as trials that compared extracts of St. John’s wort with placebo or standard antidepressants.

A total of 29 trials (5,489 patients) including 18 comparisons with placebo and 17 comparisons with synthetic standard antidepressants met the inclusion criteria. All the trials used the Hamilton Rating Scale for Depression to determine the severity of depression.

In the nine largest trials of the 18 placebo-controlled studies, St. John’s wort extracts were 28 percent more effective than the placebo. In nine smaller placebo-controlled trials, the response rate was 87 percent higher in the patients receiving the St John’s wort extract compared to the placebo.

When the reviewers looked at trials that compared St. John’s wort to standard antidepressants and selective serotonin reuptake inhibitors (SSRIs), both the herb and drugs were equally effective. However, there was a 76 percent lower drop out rate by patients receiving St John’s wort compared to patients receiving tri- or tetracyclic antidepressants. There was a 47 percent lower drop out rate in subjects taking St. John’s wort compared to patients receiving SSRIs.

According to the reviewers, “The available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants.”

Reference:

Linde K, Berner MM, Kriston L. St John’s wort for major depression. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD000448.

Ginkgo Studied For Strokes

A new study indicates that ginkgo biloba extract may prevent the brain damage that occurs after a stroke.

Ginkgo biloba extracts are used in several countries for their effects on the brain. Past studies have reported that ginkgo can protect neurons against oxidative stress, but the underlying mechanisms are not fully understood.

To develop a clearer understanding of how ginkgo affects the brain, researchers blocked the middle cerebral artery of mice in order to induce cerebral ischemia (strokes) in the animals. One group of mice was pretreated with ginkgo for seven days before the animals’ arteries were occluded. Another group of rodents were treated with ginkgo after blood supply was blocked and then restored to their brains, a process known as reperfusion. The researchers then assessed neurobehavioral scores and infarct volumes. An infarct is an area of tissue that undergoes death following cessation of blood supply. The researchers also investigated whether the antioxidant enzyme heme oxygenase 1 (HO-1) was stimulated by ginkgo and whether this was the means by which ginkgo could protect neurons.

Mice that were pretreated with ginkgo had approximately 50 percent less neurological dysfunction and 48 percent smaller infarct volumes than control mice. In mice bred to lack the HO-1 enzyme, ginkgo did not produce these same results, indicating the botanical was working by increasing the activity of this antioxidant enzyme. In mice that were treated with ginkgo after blood supply was restored to their brains, there also was a significant reduction in infarct size.

The researchers concluded that ginkgo “could be used as a preventive or therapeutic agent in cerebral ischemia.” The scientists also noted that the antioxidant enzyme HO-1 contributes, at least in part, to ginkgo’s neuroprotection.

Reference:

Saleem S, Zhuang H, Biswal S, Christen Y, Doré S. Ginkgo Biloba Extract Neuroprotective Action Is Dependent on Heme Oxygenase 1 in Ischemic Reperfusion Brain Injury. Stroke. 2008 Oct 9. Published Online Ahead of Print.

L-Carnitine May Improve Muscle Function

Supplementation with L-carnitine may improve the function of muscles and reduce the decline of this important amino acid that occurs with age, a new study has found.

During the aging process, muscle fibers atrophy, body fat mass increases, and skeletal muscle oxidative capacities decrease. Compounds that are known to reduce lipid oxidation may be useful in limiting damages that occur in aging muscle. L-carnitine, which has been studied for its potential to improve exercise recovery and to enhance heart health, is a compound known for its ability to reduce lipid oxidation. Therefore, to see whether L-carnitine can help restore the age-related atrophy of muscle, researchers gave the amino acid to old rats for 12 weeks.

The researchers measured the L-carnitine levels in the old animals and found that levels of this amino acid were 34 percent lower compared to in younger rodents. However, L-carnitine supplementation restored levels of L-carnitine in muscle cells of old animals to levels closer to that seen in younger animals. Furthermore, the amino acid induced positive changes in body composition: a decrease in abdominal fat mass and an increase in muscle capabilities without any change in food intake. L-carnitine’s effects were similar to those achieved with moderate physical exercise.

Reference:

Bernard A, Rigault C, Mazue F, Borgne FL, Demarquoy J. L-carnitine supplementation and physical exercise restore age-associated decline in some mitochondrial functions in the rat. J Gerontol A Biol Sci Med Sci. 2008 Oct;63(10):1027-33.

Flax and Borage Oils Reduce Reddening and Roughness of the Skin

Supplementation with flax and borage oils resulted in a number of improvements in the skin, including reduced reddening and roughness and increased hydration in a human study published in the British Journal of Nutrition.

Flaxseed oil consists predominantly of the omega-3 fatty acid alpha-linolenic acid (ALA), with small amounts of omega-6 and monounsaturated oleic acid. Borage oil consists of the omega-6 fatty acids gamma-linolenic acid (GLA) and linoleic acid (LA), as well as oleic acid.

Researchers randomly assigned 45 non-smoking, healthy women between the ages of 18 and 65 to one of three groups. One group received daily supplements of flaxseed oil and another group received daily supplements of borage oil. A third group received a placebo. The scientists then caused skin irritation by applying nicotinate to the subjects’ skin, which induced inflammation and reddening.

After six and 12 weeks of supplementation with flaxseed, there was an increase in blood levels of ALA. Increases in GLA were observed in the group receiving borage oil.

Following administration of flaxseed oil, the researchers noted a significant 45 percent decrease in reddening of the skin. In the borage oil group, there was a 35 percent decrease in reddening. No differences were observed in the placebo group.

Use of the flaxseed or borage oil supplements also was associated with a 10 percent reduction in water loss from the skin after six weeks. At the end of 12 weeks, the flaxseed oil group experienced a 25 percent reduction in water loss from the skin, indicating it was improving the skin’s hydration.

Roughness and scaling of the skin also decreased significantly after 12 weeks of flaxseed and borage oil supplementation. The placebo group did not experience these same improvements.

The study authors theorized that flaxseed and borage oils may exert these beneficial effects because fatty acids are known to play a role in cell membrane health. Another possibility is the role fatty acids from flaxseed and borage oil play in reducing inflammation.

The researchers concluded, “The present data provide evidence that skin properties can be modulated by an intervention with dietary lipids.”

Reference:

De Spirt S, Stahl W, Tronnier H, Sies H, Bejot M, Maurette JM, Heinrich U. Intervention with flaxseed and borage oil supplements modulates skin condition in women. Br J Nutr. 2008 Sep 2:1-6. Published Online Ahead of Print.

Our GLA softgels contain gamma linolenic acid from borage oil. Organic Flaxseed Oil also is available here.

Quercetin and Green Tea Component Support Healthy Blood Vessels

Supplements of the flavonoids quercetin or the green tea component (-)-epicatechin improved endothelial function, a key marker of cardiovascular health, in a new human trial.

Endothelial function refers to the function of the endothelium, the cells lining blood vessels. Numerous studies have shown that consumption of flavonoid-rich foods can enhance endothelial function in subjects with coronary artery disease and healthy volunteers. However, the food components responsible for this effect have not been definitively identified.

In a new, randomized, placebo-controlled, crossover trial, researchers studied whether quercetin, (-)-epicatechin, or another green tea component epigallocatechin gallate could improve endothelial function in 12 healthy men. The subjects were given supplements of 200 mg quercetin, (-)-epicatechin, epigallocatechin gallate or a placebo. To determine whether the flavonoids were having a beneficial effect on endothelial function, the researchers measured levels of nitric oxide, which is used by the endothelium to signal surrounding muscle to relax, thereby dilating the blood vessels. The scientists also measured levels of endothelin-1 (ET-1), which constricts the blood vessels (a substance known as a vasoconstrictor).

Compared to when the subjects were taking a placebo, quercetin and epicatechin resulted in a significant increase in nitric oxide production. Quercetin and (-)-epicatechin resulted in a significant reduction in plasma endothelin-1 concentration and quercetin significantly decreased the urinary endothelin-1 concentration. Epigallocatechin gallate did not affect either of these markers of endothelial function.

The results led the researchers to conclude, “Dietary flavonoids, such as quercetin and (-)-epicatechin, can augment nitric oxide status and reduce endothelin-1 concentrations and may thereby improve endothelial function.”

Reference:

Loke WM, Hodgson JM, Proudfoot JM, McKinley AJ, Puddey IB, Croft KD. Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am J Clin Nutr. 2008 Oct;88(4):1018-25.

Bilberry Protects Against Stress-Induced Damage

Bilberry protects against the damage that occurs when animals are exposed to excessive stress, researchers recently reported.

Previous studies have shown that restraint of an animal promotes lipid peroxidation in liver tissue. This in turn leads to oxidative damage to the liver. Consequently, scientists restrained mice to induce oxidative stress and fed them an anthocyanin-rich bilberry extract for five days.

Serious liver damage was observed in the new study following 18 hours of restraint of the mice. This was associated with increases in blood levels of alanine aminotransferase (ALT), and decreases in the oxidative activity of the blood, measured by the oxygen radical absorbance capacity (ORAC) values in the plasma.

Bilberry extract reduced oxidative stress by changing the oxidative status and improving antioxidant processes in mice subjected to stress. Mice supplemented with the bilberry extract at doses of 50, 100, and 200 milligrams per kilogram per day experienced lower ALT levels than non-supplemented restrained animals. Moreover, levels of malondialdehyde (MDA), a byproduct of lipid peroxidation, were significantly lower in the bilberry-supplemented groups.

The study authors also found that blood levels of vitamin C were significantly lowered following restraint of the animals, with free mice having average vitamin C levels of almost 400 micrograms per gram of tissue, compared to only 173 micrograms per gram in the stressed, unsupplemented animals. Following supplementation with 100 or 200 mg per kg per day of the bilberry extract, vitamin C levels were measured at 347 and 451 micrograms per gram of tissue, respectively.

According to the researchers, “These results suggest that bilberry extract plays an important role in protecting against restraint stress-induced liver damage by both scavenging free radicals activity and lipid peroxidation inhibitory effect. This study showed the beneficial health effects of bilberry extract through its antioxidative action.”

Reference:

Bao L, Yao XS, Yau CC, Tsi D, Chia CS, Nagai H, Kurihara H. Protective effects of bilberry (Vaccinium myrtillus L.) extract on restraint stress-induced liver damage in mice. J Agric Food Chem. 2008 Sep 10;56(17):7803-7.

Green Tea Extract Helps Lower Blood Pressure, Cholesterol and Inflammation

Consuming daily supplements of green tea extract may lower blood pressure, cholesterol levels, oxidative stress and inflammation in as little as three weeks, according to the results of a new human trial.

Researchers conducted a randomized, double-blind, placebo-controlled, parallel study on 111 healthy adult volunteers ages 21 to 70 years old who were given a capsule of green tea compounds twice per day. Before and after three weeks, blood pressure, serum lipids, serum amyloid-alpha (a marker of chronic inflammation), and serum malondialdehyde (a marker of oxidative stress) were measured.

After three weeks, green tea lowered systolic and diastolic blood pressures by 5 and 4 mmHg, respectively. After three months, systolic blood pressure remained significantly lower. Green tea also lowered serum amyloid-alpha by 42 percent and lowered malondialdehyde by 11.9 percent, indicating it was effective at lowering both inflammation and oxidative stress. In men, there were 10- and 9-mg/dL reductions in total and low-density lipoprotein (LDL) cholesterol, respectively. In all subjects with a baseline LDL cholesterol level greater than 99 mg/dL, there was a 9 mg/dL lowering of total and LDL cholesterol.

The study authors concluded that a supplement containing “Camellia sinensis compounds was effective for decreasing, in as quickly as three weeks, blood pressure, LDL cholesterol, oxidative stress, and a marker of chronic inflammation, all independent cardiovascular risk factors.”

Reference:

Nantz MP, Rowe CA, Bukowski JF, Percival SS. Standardized capsule of Camellia sinensis lowers cardiovascular risk factors in a randomized, double-blind, placebo-controlled study. Nutrition. 2008 Oct 8. Published online ahead of print.

The Green Tea Extract capsules available here are very low in caffeine and are high in EGCG, antioxidant compounds thought to be responsible for many of green tea’s significant health benefits.

Gamma-Tocotrienol Works With EGCG or Resveratrol To Reduce Activity of Genes Involved in Cancer, Autoimmunity and Schizophrenia

During a new in vitro study, gamma-tocotrienol, when combined with either the green tea component EGCG or resveratrol, reduced the activity of two genes associated with cancer, autoimmunity and schizophrenia.

Researchers set out to determine whether a multicomponent approach involving lower doses of natural agents may be developed into what they called a “chemopreventive strategy for breast cancer.” Using the estrogen receptor-positive MCF-7 breast cancer cells as a model, they studied whether the combination of epigallocatechin gallate (EGCG) from green tea, resveratrol and gamma-tocotrienol at low doses act synergistically in suppressing cell proliferation, modulating gene expression, and increasing antioxidant activity, as compared to each of the three phytochemicals added alone.

The results showed that when the agents were tested individually, EGCG stopped cancer cell proliferation by 33 percent, resveratrol by 50 percent and gamma-tocotrienol by 58 percent.

The researchers then tested low doses of each of the three substances in pairs against the breast cancer cells as well as all three substances combined. Even though there was no synergistic effect when all three substances were tested simultaneously, when resveratrol was combined with gamma-tocotrienol there was a significant additive effect in suppressing cell proliferation of breast cancer cells. Moreover, when gamma-tocotrienol was combined with either EGCG or resveratrol, the two substances were able to significantly reduce the expression of cyclin D1 and bcl-2, two genes involved in cancer and other diseases.

Mutations, amplification and overexpression of the cyclin D1 gene are frequently observed in a variety of tumors and may contribute to tumor development. The Bcl-2 gene is thought to be involved in a number of cancers including melanoma, breast, prostate and lung as well as in schizophrenia and autoimmunity. Research also indicates Bcl-2 is involved in resistance to conventional cancer treatment.

According to the study authors, “These results suggest that diet-based protection against breast cancer may partly derive from synergy amongst dietary phytochemicals directed against specific molecular targets in responsive breast cancer cells, and provide support for the feasibility of the development of a diet-based combinatorial approach in the prevention and treatment of breast cancer.”

Reference:

Hsieh TC, Wu JM. Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and gamma-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells. Int J Oncol. 2008 Oct;33(4):851-9.

Annatto Tocotrienols are a good source of gamma-tocotrienol and can be taken along with either Green Tea Extract or Extension Resveratrol.